CA2115121A1

CA2115121A1 - Antimicrobial quaternary ammonium group-containing polymers, compositions thereof, and monomers used to produce said polymers

Info

Publication number: CA2115121A1
Application number: CA002115121A
Authority: CA
Inventors: James Richard Robertson
Original assignee: Ciba Geigy AG
Current assignee: Novartis AG
Priority date: 1993-02-09
Filing date: 1994-02-07
Publication date: 1994-08-10
Also published as: ATE153679T1; JPH06256421A; FI940558A; NZ250832A; MX9400946A; AU5491894A; ZA94844B; US5536861A; IL108540A; ES2102795T3; EP0611782B1; GR3024439T3; NO940421L; EP0611782A1; AU676238B2; DE69403358T2; NO940421D0; FI940558A0; DE69403358D1; IL108540A0

Abstract

Antimicrobial quaternary ammonium group-containing polymers, compositions thereof, and monomers used to produce said polymers ABSTRACT OF THE DISCLOSURE

Antimicrobial quaternary ammonium group-containing organosilicon polymers, aqueous disinfectant solutions containing such polymers, and lenses produced from such polymers are provided herein. The polymers are produced by homopolymerizing or copolymerizing, with a suitable comonomer, a quaternary ammonium group-containing organosilicon monomer of formula I as defined herein. A preferred monomer of formula I is the monomer of formula II:

Description

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;; Antimicrobial qllaternar~ ammonium group-containing polymers, compositions thereof, and monomers used to produce said polylmers , A jl This invention relates to quaternary ammODiUm group-containing organosilicon polymers and novel monomers used to produce these polymers. The invention also relates tomethods of producing such polymers and monomers. The polymers may be used in wide applications as antimicrobial agents as, for example, in solutions to disinfect contact lenses and certain of these polymers may be used to produce solid structures, such as i~. contact lenses.

~i Contact lenses are typically made of hydrophilic and partially hydrophilic plastic materials. These materials have a high capacity to absorb water and swell to a soft mass or hydrogel. This hydrogel is characteIized by excellent mechanical properties, complete transparency, good shape retention and high resistance to degradation in boiling water.
Such hydrophilic or partially hydrophilic plastic materials are described in such patents as US-A-2,976,576, US-A-3,499,862 and US-A-3,503,942. These patents disclose, inter alia, ~he production of the so-called soft contact lenses.

One of the problems associated with cleaning soft contact lenses made from the aforementioned hydrophilic materials, is in the disinfecting and cleaning of such lenses.
These lenses have a high capacity to absorb water, i.e. upwards of about 38 weight %
water, based on the total weight of the hydrogel. Therefore, the compounds employed to disinfec~ the contact lenses are often absorbed and possibly even concentrated in the lenses and later released when the soft contact lenses are worn on the eye. This, of course, may `-¦ damage or stain the contact lenses and harm the sensitive tissues of the eye. Such preservative or disinfectant materials typically used to disinfect the contact lenses may be such materials as chlorohexidine or thimerosal, for example.
;., To overcome these problems, materials such as quaternary ammonium group-cont~ining ,l polymers having antimicrobial activity may be used to disinfect the lenses. The advantage of using antimicrobial polymers is that they have a larger molecular size and are less ~ll likely to penetrate or be absorbed into the soft contact lenses, and tend to be less toxic.

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-2- 2~ ~ ~121 ,! Examples of such polmyers are the polymeric quaternary ammonium compounds having recurring vinyl benzene ammonium units. Such polymers are disclosed in U~-A-4,482,680. These polymers have a disadvantage in that they have relatively poor solubility in water.
... .
Another example of polymers employed for disinfecting contact lenses are the organo-silicon quaternary ammonium compounds disclosed in US-A-4,615,8~2. These polymers are produced by reacting an organosilicon quaternary ammonium salt having a hydro-lyzable group with a water soluble high molecular weight organic polymer, such as polyvinyl alcohol, reactive with said hydrolyzable group. The hydrophilic polymers described in US-A-4,615,B82 have silicone and quaternary ammonium components as required in the present invention, however the synthesis of the polymers disclosed in the patent result in the formation of hyd~olytically unstable linkages, e.g. silicon-oxygen-carbon linkages. Such Si-O-C bonds are unstable, break down over time, and the existence of such bonds could lead to toxicity problems.
The present invention relates to quaternary ammonium group-containing organosilicon polymers having antimicrobial activity which do not have the unstable linkages, i.e. the silicon-oxygen-carbon linkages of US-A-4,615,882 and therefore are free of the toxicity problems due to the breakdown of these compounds with time.

The antimicrobial polymers of the present inven~ion are suitable for treating soft contact lenses and are especially suitable for cleaning and disinfecting such lenses to remove proteinaceous depo~its which tend to forrn and build on the lenses du~ing wear and handling.

The polymers of the present invention are of such a molecular size that they do not penetrate the contact lenses polymer matrix as readily as non-polymeric organic molecules, and when they do penetrate, are less toxic than said non-polymeric compounds.
Therefore, they are less apt to darnage the lenses or injure the eye as is typical of non-polmyeric materials which penetrate the lenses and may leach out and damage the soft tissues of the eye during the use thereof.
:, The organosilicon quaternary ammonium compounds of the present invention may '~ typically be dissolved or dispersed in a solution, especially an aqueous solution, used to disinfect the contact lenses and are used in amounts sufficient to disinfect the lenses. The ... .
polymers of the present invention have advantages over the poly(vinylbenzyl quaternary ammonium) halide structure disclosed in the Sheldon patent, US-A-4,482,680, in that they are more water soluble and therefore can be more easily dissolved in aqueous solutions.
The solutions, according to the present invention, are preferably aqueous based solutions, occasionally containing organic solvents, which are nontoxic to the eye, i.e. are ophthalmically safe for use.

Although the quaternary ammonium-containing organosilicon compounds of the present i invention are especially suitable for disinfecting soft lenses, they can also be used for other utilities where the antimicrobial properties are effective, i.e. for hair care and in `0~ other topical pharmaceutical products. Specific uses may be in the therapeutic skin care ~r1 preparations and use as deodorants or antimicrobials for the body, etc. In addition, the products can be formulated with various cleanser components to form disinfectants for ;~j home or hospital use.

The quaternary arnmonium group-containing organosilicon polymers of the present invention can be produced by homo- or copolymerizing a monomer of the following . ' generic structure of formula I
.~ :

~, C=C--~La)z--(R1OLa1)z R4 --(SiO)y--Si--R~N~3 R9 )(~3 (I
~`i R6 R6 R8 wherein Rl, R2 and R3 are independently hydrogen, Cl-C7 alkyl, or -COORI3 with Rl3 being hydr~gen o~ Cl-C4 aLtcyl;
; ~ Zl and Z2 are independently 0 or 1;
`i La is -C(O)O-, -C(O)N(Ra)-, or a bond;
/ La1 is a bond, -C(O)O-, -C(O)N(Ra)-, -O-, -OC(O)O-, -N(Ra)C(O)N(Ra)- or -N(Ra~C(O)O-;
wherein Ra is hydrogen or Cl-C8 aLkyl;
¦, R1o is a bivalent C1-C20 aliphatic, C3-C2s cycloaliphatic or C6-C20 aryl group, each of which may be substituted with up to five halogen atoms, or (CH2CH(Ra)O);, wherein j is 1 an integer from 1 to 50 and Ra is as defined hereinbefore;
', R4 and R7 are independently a bivalent group selected from C2-C10 aliphatic, such as C2-C8 alkylene, C1-C4 alkylene-(oxy-C1-C4 alkylene)g, C1-C4 alkylene-OCH2-(hydroxy :

4 ~ 2 ~
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Cl-C4 alkylene)-CH2, cycloaliphatic up to 25 carbon atoms and aryl up to 25 carbon atoms, wherein g is an integer from 1 to 10;
y is an integer from 1 to 10;
Rs and R6 are independently C1-C8 alkyl, C6-C2s aryl, or C6-C2s cycloaliphatic which may be substituted by one or more halogen, hydroxy, Cl-C4 alkyl, carboxy or Cl-CI2 perhaloalkyl groups, or Rs and R6 may be -Si(C)SiCH3)3;
R8 and R9 are independently Cl-C24 aLIcyl, C3-C24 cycloaliphatic or C6-C2s aryl, which groups may be each substituted with from 1 to 11 groups selected from hydroxy, Cl-C4 alkyl, carboxy, C1-CI2 perhaloalkyl, and halogen, or R8 and Rg may also be (CH2CH20)XH units, where x ;s an integer from 1 to 10, and X is an ophthalmically acceptable counterion.

The ophthalmically acceptable counterion X is preferably a halogen, hydroxy, acetate, so42-, co32-, or PO43~ for example. If not otherwise defined, a bivalent Cl-C20 aliphatic group is preferably Cl-C10 alkylene~ more preferred Cl-C6 alkylene. Likewise, the cycloaliphatic groups are all ple~erably groups having 3 to 25 carbon atoms, more preferred cycloaLkyl groups containing 6 to 1~ carbon atoms, and more preferably 5 to 7 membered cycloaliphatic groups, including e.g. combinations of cycloalkyl and ]ower alkyl. A pre~erred cycloalkyl is cyclohe~syl. Likewise, aryl groups preferably have 6 to 25 carbon atoms, more preferred 6 to 10 carbon atoms. A preferred aryl group is phenyl.
Halogen is e.g. fluoro, chloro or bromo, of which fluoro and chloro are preferred.

Preferred are those monomers of formula I wherein Rl, R2 and R3 are independendyhydrogen or Cl-C4 alkyl;
zl and Z2 are independently O or l;
La is -C(O)O- or a bond;
Lal is a bond, -N(Ra)C(O)N(Ra)- or-N(Ra)C(O)O-;
wherein Ra is hydrogen or Cl-C4 alkyl;
Rlo is a bivalent Cl-C6 alkylene, or phenyl group, R4 and ~7 are independently a bivalent C2-C6 alkylene;
y is an integer from 1 to 10, preferably 1 to 5;
R5 and R6 are independently Cl-C4 alkyl;
R8 and Rg are independently C1-C24 alkyl, and X is an ophthalmically acceptable counterion.

Typical ancl preferred s~uctures of the above monomers have the following forrnulae:

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CH3 CH3 fH3 CH3 H2C = C--Cll--O--(CH2)3--SliO--S~--(CH2)3--11--Cl8H37 Cl (II) 3-methacryloxypropyltetramethyldisiloxanylpropyldimethyloctadecylammonium chloride (MADAC), H2c = c ~ Icl o (cH2)3 s!o Sl (CH~)3--11~ CH3 C1~3 (III) .

H2C= C~lC2--O--(CH2)3~SiO--51--~CH2)~ 3 C H C ~3 ~:CH3 H H f H3 f H3 CH3 ¢~H2 =C~ O--CH2CH2NIIl-- (CH2)3--SiO--Si _ (C~12)3--N~ C18H37 C1~3 (V) ~,~o 0 1H3 1H3 1H3 The novel monomers of the present invention used to produce the organosilicon polymers are a further embodiment of this invention. A description of a typical procedure for producing ~hese novel monomers is reproduced hereinafter. Below is a synthe~ic scheme for the production of the MADAC monomer of the formula II (a typical and preferred ;, monomer) used in producing the water soluble polyrners and contact lense materials of the present invention.

Step 1 A compound of the f~rmula lIA
, l L~ fH3 f H3 ~f H2C = C--Cl--O-- (CH2~3--Si--Cl (IIA) `l .

~ 2 1 is reacted with a compound of the formula IIB
"1 :

5~13 `' Cl--~i ~ (CH2)3--Gl (IIB) ~j . j in the presence of water to produce a compound of the formula IIC

1 f H3 f H3 f H3 ,, . H2C = C--11--O-- (CH2)3--SliO--Sl--(cH2)3--Cl (lIC) and HCl as a by-product.

,~ Step 2 The compound of the formula (IIC) is reacted with an excess of NH3, to produce a compound of the formula IID

H3 ¦ f H2C = C--lC~--O-- (CH2)3--SiO--Si--~CH2)3--NH2 (IID).

Step 3 Said compound of the formula IID is reacted with an excess of CH3Br to produce f ~ a compouud of the folmula IE

i, f H3 CH3 f H3 ,, H2C = C--11--O-- (CH2~3--SiO--Si--(CH2)3--N(CH3)2 (IlE).

Step 4 The compound of ~he formula IlE is quaternized with Cl8H37Cl to produce a-¦ compound of formula lI (MADAC) I

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.1 I H3 IH3 l~13 l~13 H2C = C--C--O-- (CHz~3--S1O _S1--(CH2)3--N _ C~gH37 C1 (Il)- :

The reaction conditions in Step l may be varied, but it is usually carried out preferably from about ambient temperatures to about 40C in an aqueous solution, which may be slightly acidic.
, The reaction with the amine in Step 2 is preferably carried out in an aqueous solution at a temperature from about 0C to about ambient temperature and preferably from about 0C
to about 20C. I'his reaction is ordinarily carried out at atmosphelic pressure, however, it can be carTied out under high pressure at even higher temperatures, if necessary.

Step 3 is preferably caTried out at a reaction temperature of from about room tempera~ure to up to about 40C in a suitable organic solvent, especially an inert organic solvent, such as toluene, benzene, etc.
.1 .. 1 Step 4 may be carried out in a solvent, preferably at room or ambient temperature. The ,i solvents include such organic solvents as toluene, benzene and other inert, typically used '1 so'vents. The reaction conditions vary depending upon the nature of the reactants, solvents employed, pressure conditions, etc. The above conditions represent the typical conditions employed.
~.' The other monomers of the generic formula (I) can be produced by following the same reaction scheme used to prosluce the MADAC monomer as set forth in Steps (l) to (4 1 ~ above.
.
.ij The quaterniæd monomers of the generic formula (I) set forth above, may be homo- or ¦ ~ co-polymerized to produce the ~mal polyrner structure. The monomers are typically polymerized in an inert atmosphere, such as nitrogen or argon, free of oxygen. The polymerization may be initiated by way of initiators, such as peroxides or azobisisobutyro-~` nitrile (AIBN) in amounts sufficien~ to initiate the reaction, i.e. typically from about O.Ol to 0.5 weight % based on the weight of the monomer. The reaction may be carried out in the presence of a solvellt, such as an alcohol, toluene, benzene, tetrahydrofuran or a ketone, such as methylethyl ketone. The reaction may be carried out by heating the 'I

A
reaction solution at elevated temperatures and preferably at temperatures from about 4ûC
to about 150C or the reflux temperature of the solvent. The temperature varies depending upon the monomers and other materials present in the reaction solution.

The reaction may also be carried out by subjecting the reaction solution to a UV source to produce the fimal product. The reaction is carned out for a time sufficient to complete the polymerization, which reaction may proceed for time periods up to about 100 hours or more. The initiator used in the polymerization reacdon is dependent upon the type of energy source used and may be different if a UV source is used as opposed to a thermal energy source.
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The above monomers of formula (I) may be homopolymerized or they may be copolymerized with suitable comonomers. This copolymerization reaction thus includes the reaction of the quaternary ammonium group-containing organosilicon monomers with one or more comonomers.
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`~ The copolymers may contain copolymeric units having a generic structure depicted as -M-. The copolymeric units can be added to achieve the desired physical pr~perties, enhance the solubility in aqueous or nonaqueous media, achieve better miscibility in various solvents or to improve the dispersibility of the polymer.

The first type of M units is represented by vinylaromatics, e.g. styrene, lower aLt~enes or lower aLIcadienes, such as ethylene, butadiene and the like. The second type of M units is illustrated by vinyl acetamide, vinyl amines, vinyl amine quaternized with hydroxy-~' ethylenes or similar water solubilizers or wi~h hydrophobes such as alkyls, e.g. dodecyls, or vinylbenzyl amine quaternized with three long chain aLtcyl hydrophobes or with three lower alkyl or hydroxyaLlcyl hydrophiles. Other units include, f~r example, vinyl acetate, vinyl alcohol, acrylic acid, acrylate and methacrylate esters; acrylamide and acrylamide derivatives, including quaternized acrylamide; N-vinylimidazole and derivatives thereof, including quaternized N-vinylimidazoles; 4-vinylpyridine and derivatives thereof, including quaterniæed 4-vinylpyridines; N-vinylpyrrolidone and derivatives thereof; vinyl-benzyl ethers of polycthylene glycols and their monoalkyl ethers. These units are all known in the art as are the methods for their incorporation into copolymers. Mixtures of j two or more M units may, of ~ourse, be used. The term "lower" used in the context of this il invention de~mes radicals or groups having preferably up to 7 carbon atoms, more preferred up to 4 carbon atoms.

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Generically, the M UllitS can be grouped as 2 to 6 carbon aLkylenes or alkenylenes, having pendent therefrom, from O to 2 substituent groups selected from aryls, aLIcaryls, and araL~cyls of 6-8 carbons, aLcyls of 1-4 carbons, amides, hydroxyls, carboxylic acids, and their esters, preferably lower aL~cyl esters, nitrogen-containing S or 6 atom heterocyclics i! and amine and ether-substituted aryls, alkaryls and araL~cyls.
, ``i' The M copolymer units may be vinylbenzyl amines quaternized by hydrophilic groups such as hydroxyaLlcyls of from 1 to 4 carbon atoms, p~Nticularly vinylbenzyl amines quaterniæd with three 2-hydroxyethylenes (i.e. with a triethanolamine s~ucture). Such units are represented s~ruc$urally as .;;
H-CH2}
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~-~X CH2--N~(CH2)a ~ 3 X e ~ ~

. ., wherein a is 2 through 4 inclusive and most preferably 2.

Another group of copolymer units M contemplated herein are vinylbenzyl e~ers of poly-(ethylene glycol)s or their mono-lower alkyl ethers, particularly methyl ethers. Such units are represented structurally as --(CH-CH
j-l I

- [~CH2 C2H4)b-R

wherein b is 1 through 10 inclusive, preferably 1 through 4 inclusive, and R" is hydroxy or `~ lower aL~coxy, such as alkoxy having from 1 to 4 carbons, e.g. methoxy, ethoxy, propoxy or butoxy, most generally methoxy.
As can be seen from the above, any compatible copolymer unit can be polymeriæd with ,~ 2~,5'~
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the monomers (I) to incorporate the antimicrobial quaternary group-containing organosilicon monomers (I) of the present invention into the polymer structure as long as the monomers do not deleteriously affect the objective purposes of the present invention, which is primarily to achieve antin~icrobial effects, for disinfecting contact lenses, etc.
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The polymers of the present invention may be crosslinked with various crosslinking agents. Examples of such crosslinking agents are allyl compounds e.g. allyl methacrylate, diallyl itaconate, monoallyl itaconate, diallyl maleate, diallyl fumarate, diallyl succinate, diallyl phthalate, triallyl cyanurate, triallyl isocyanurate, diethylene glycol bis-allyl carbonate, triallyl phosphate, triallyl tn~nellitate, allyl vinyl ether, N,N-diallylmelamine;
vinyl compounds, e.g. divinyl benzene, N,N'-methylene bis acrylamide, ethylene glycol i, dimethacrylate, neopentylglycol dimethacrylate, tetraethylene glycol dimethacrylate, :~ hexamethylene bis maleimide, divinyl urea, bisphenol A bis methacrylate, divinyl adipate, ~l glycerin trimethacrylate, trimethylolpropane triacrylate, trivinyl trimellitate, l,S-penta-diene, 1,3-bis(4-methacryloxybutyl) tetramethyl disiloxane, divinyl ether and divinyl ; sulfone; hydroxyl reactive compounds such as polyvalent isocyanates, e.g. hexarnethylene , diisocyanate, isophorone diisocyanate, toluene diisocyanate; polyaldehydes, e.g.
glutaraldehyde and glyoxal; polyacids, e.g. glutaric acid and oxalic acid; polyepoxides, e.g. butane diepoxide, vinylcyclohexane dioxide and butanediol diglycidyl ether; polyols ; l (acid catalysis), e.g. dimethylol urea and diethylene glycol.

, The amounts of such crosslinking agents are dependent upon the purpose desired and usually about 0.01 to lû weight % of the crosslinking agent, based upon the weight of the monomers may be used.

i The polymers o~ the presene invention preferably have average molecular weights ranging 1I from about 2,û00 to about 1,000,000 for the homo- or co-polymer. The average molecular weight as used herein means the weighl average molecular weight (Mw) as determined by '~Z light scattering measurement.
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The number of recurring units, i.e. the mers units, ranges from about 10 mers to about 3,000 mers for the quaternary ammonium group-containing organosilicon monomers in ' the homopolymers or in the case of copolymers, the total number of units of all the ` comonomers ranges from 10 mers to about 3,000 mers.

~l The homopolymer of the monomers of the present invention as represented by the ,1 ~ X 5 ~

~ j l 1 1 -~i polymerized MADAC monomer of Formula (II) above, is expressed by the following formula:
:

~ _H2C--C--)nCH3 CH3 CH3 c o(CH2)3 s!o si--(CH2)3--N ~ C.8H37 ` ~H3 1H3 1~,3 .,1 .
wherein n is an integer of 10 to about 3000 and X is an ophthalmically acceptable counterion. As can be seen from the above, the polymeri7ation takes place at the reactive alkene terminal portion of tne MADAC monomer. The n group varies between about 10 mers up to about 3,000 mers as previously mentioned. The comonomers M, similarly react at the alkene portion of the quaternary ammonium group-containing monomer structure.

The polymerization and copolymerization methods discussed above relate to the homo-polymerization or copolymerization of the quaternary ammonium group-containing organosilicon monomers, but the monomers may be homopolymeIized or copolymerizedbefore being quaternized and then subsequently quaternized. For exarnple, the product as set forth in Step 3 (prior to the quaternizing step), may be polymerized and the resulting polymer subsequently quaternized as in Step 4 for producing the monomer as discusæd above.

The polymers of the present invention are primarily used in ophthalmic solutions for cleaning lenses, particularly soft lenses, where penetration of the antimicrobial component into the soft gel structure is to be avoided. However, the liquid composition c~n be used on hard contact lenses and any surface where antimicrobials and preservatives are typ;cally employed. Further, the polymers of t'ne present invention can be used to produce contact lenses which are strong9 flexible, highly oxygen perrneable, wettable and optically clear.

To produce solid structures, such as contact lenses, preferably higher molecular weight polymers are employed, ~nd especially crosslinlced polymers are preferably used, which are crosslinked to a degree sufficient to attain the desirable properties as discussed above.
The final lenses thus produced have sufficient antimicrobial properties to help kill bacteria and other microorganisms which grow on the lenses, but are not toxic or harmful to the eyes.

.1 2 ~

' ~, The aqueous solutions for disinfecting e.g. soft contact lenses provided herein are :~ compatible, from pharmacological and chemical standpoints, with typical ingredients ii normally included in the antimicrobial or disinfectant solutions for contact lens care, and clo not significantly alter the toxicity of the system. They have very low mammalian cli toxicity and are chemically stable, odorless and non-volatile, and exhibit a broad spectrum ! of anti-bacterial activity against a wide range of microorganisms which pose a danger to ^~ the eye, as exemplified by Pseudomonas aeruginosa. 'lrhey are nontoxic and non-irritating to the tissues of the eye in the concentrations and frequency of u se contemplated herein.
..
The compositions of this invention also are compatible with other ingredients usually ' found in ophthalmological eye care solutions. They are easily handled and applied, do not foam, and can be and are chemically stable in a wide range of pH's. However, it is ~q preferable to apply the solutions at a pH of 7, plus or minus one unit, and in an isotonic solution, so that there will be no adverse effects to the eye from osmotic pressure due to an l imbalance in the ionic strength of the solution.
.,i ~i In the practice of the present invention, in respect to the sterilization of contact lenses, the ; i, active quaternary ammonium group-containing organosilicon polymer is present in the solution in amounts sufficient to impart antimicrobial or disinfecting prope~ties to the solution against pathogens, i.e. in an amount sufficient to destroy or inhibit multiplication ' of bacterial microorganisms such as Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Aero~acter aerogenes, while at the same time not causing irritation to the eye or damage to the lens.

The antimicrobial polymers of ~he present invention may be present in small ~nounts such as 0.001 weight %, based on the weigh~ of the aqueous disinfectant solution, when used as a disinfectant to clean hard surfaces, such as contact lenses. The upper limit is dictated by factors which may cause eye irri~ation ovér long periods of time andlor damage to the soft , contact lenses, when used for that purpose. An upper limit is e.g. about 0.5 weight %, but a practical range is from about 0.002 weight percent to about 0.1 weight %, based upon the weight of the aqueous disinfectan~ solution.

~, A typical disinfectant solution useful in the practice of this invention, may contain in addition to the active ingredient, buffers, stabilizers, and isotonizing agents. These ;l additional materials should be non-toxic and should not distort or otherwise damage the :' 2 ~

, - 13-., contact lens and they should not lower or raise the pH below 5.5 or above 8.5 since this can have an adverse effect on ocular tissue.
. . .
;~; Other disinfectants can be used in the disinfectant composition to enhance the sterilizing , or disinfecting effects, if desired.
. :
The disinfectant liquid compositions of the present invention can be used in a variety of compositions where the antimicrobial effects of the polymer are desired. The description . ~ of the utilities in the specification and claims should therefore not be construed as 9'~l precluding the utility of such compositions or polymers in areas or fields of uses o~her than specifically described herein.
, ~t'' The following examples are given by illustration only and are not designed to limit the essential inventive concept as broadly disclosed herein. Temperature are given in degrees ~ Celsius. The first three examples will illus~rate concrete procedures for producing the ;':3 antimicrobial polymers of the present invention.
.,.~, E~ample 1: To a dry, 250 milliliter, th~ee-neck flask equipped with a condenser, nitrogen inlet and magnetic stirrer, are added 10.02 g of 50% 3-methacryloxypropyltetramethyl-disiloxanylpropyl-dimethyloctadecylammonium chloride (MADAC) in methanol, 5.01 gN,N-dimethylacrylamide, 0.10 g 2-hydroxy-2-methyl- 1-phenyl-propan- 1-one and 100 ml methanol. The mixture is stiIred and purged five minutes with nitrogen. The outlets are then sealed and the reaction system is subjected to ultraviolet ligh~ at ambient temperature for 96 hours. At ~he end of 96 hours the methanol is removed via rotary evaporation. The residue is purifled by stirring in 200 ml hexanes for 18 hours. The resulting solids are filtered and the p~ification process is repeated two more times.

_ample 2: To a dry, 250 milliliter, three-neck, waterjacketed flask e~quipped with a condenser, nitrogen inlet9 magnetic stirrer and constant-temperature water circulator, are added 10.02 g of 50% 3-methacryloxypropyltetramethyldisiloxanylpropyldimethylocta-decylammonium chloride (MADAC) in methanol, 5.06 g N,N-dimethylacrylamide, 0.12 g Vazo 52 ~pentanenitrile-2,4-dimethyl-2,2-azobis) and 100 ml methanol. The mixture is stirred and purged five minutes with nitrogen. The outlets are then sealed and the reaction system is heated to 60C for 96 hours. At the end of the reaction, the methanol is removed via rotary evaporation. The residue is stirred in 200 ml hexanes for 18 hours. The resulting solids are filtered and the purification process is repeated for two more times.

21:~S~3 ~ - 14-i:

Example 3: To a dry 250 milliliter, three-neck waterjacketed flask equipped with a condenser, nitrogen inlet, magnetic stirrer and constant-temperature water circulator are - added 10.03 g of 50% 3-me~hacryloxypropyltetramethyldisiloxanylpropyldimethylocta-decylammonium chloride (MADAC) in me~hanol, 5.03 g N-vinyl pyrrolidone, 0.10 g Vazo 52 and 100 ml methanol. The mixture is stirred and purged five minutes withnitrogen. The outlets are ~hen sealed and the reaction system is heated to 60C for 96 - ~ hours. At the end of the reaction, the methanol is removed via rotary evaporation. The residue is stirred in 200 ml hexanes for 18 hours. The resulting solids are ~lltered and the .1 purification process is repeated two more times.
: .
The following Examples 4-6 represent examples in which the solutions of the polymers of Examples 1-3 are tested for their preservative effilcacy and cytotoxicity. The formulations and results are shown in Tables 1 and 2, respectively.
.
Examples 4-6: Solutions are prepared from the polymers described in Examples 1 through 3. Table 1 indicates the concentration of each solution and solvent. Each solution is tested : ' for preservative efficacy and cytotoxicity. The results o~ the microbial and toxicity tests A' are shown in Table 2.
;l Table 1 (Formulations of Examples 4-6) "
, Example PolYmer Used Concentration Solvent 4 Example 1 0.025% Saline, Isotonic `, 5 Example 2 0.025% Saline, Isotonic , 6 Example 3 0.025% Saline Isotonic ,~, l'able 2 (CytotoxicitY and Preservative Tests Results) Pseudomonas Aspergillus Aeru inosa * Fumi~atlls*

Example CytotoxicitY 24Hours 7 Days 24 Hours 7 Days 4 Negative Negative Negative 103 103 S Negative Negative Negative 103 103 6 Negative Negative Negative 103 103 ,'1 2 ~
`:`i . `, ;,1 :
* Initial inoculum is 106 for all tests.
.! , Example 7 illus~ates a typical procedure for preparing contact lenses from the quaternary ammonium group-containing organosilicon monomers of the present invention.

Example 7: Contact lenses are prepared from the following ~ormula~ion: 9.8S g 2-i~ hydroxyethyl methacrylate, O.OS g ethyleneglycol dirmethacrylate, 0.10 g 3-methacryloxy-propyltetramethyl-disiloxanylpropyldimethyloctadecylammonium chloride (MADAC) and -1 0.05 g 2-hydroxy-2-me~hyl-1-phenyl-propan-1-one. The formulation is stirred to eEfect solution and cured via actinic irradiation. After a two-hour cure, the resulting lenses are 1 clear and colorless.

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Claims

1. An antimicrobial quaternary ammonium group-containing polymer comprising in its structure repeating monomer units of the formula I

(I) wherein R1, R2 and R3 are independently hydrogen, C1-C7 alkyl, or -COOR13 with R13 being hydrogen or C1-C4 alkyl;
z1 and z2 are independently 0 or 1;
La is -C(O)O-, -C(O)N(Ra)-, or a bond;
La1 is a bond, -C(O)O-, -C(O)N(Ra)-, -O-, -OC(O)O-, -N(Ra)C(O)N(Ra)- or -N(Ra)C(O)O-; wherein Ra is hydrogen or C1-C8 alkyl;
R10 is a bivalent C1-C20 aliphatic, C3-C25 cycloaliphatic or C6-C20 aryl group, each of which may be substituted with up to five halogen atoms, or (CH2CH(Ra)O)j, wherein j is an integer from 1 to 50;
R4 and R7 are independently a bivalent group selected from C2-C10 aliphatic, such as C2-C8 alkylene, C1-C4 alkylene-(oxy-C1-C4 alkylene)g, C1-C4 alkylene-OCH2-(hydroxy C1-C4 alkylene)-CH2, cycloaliphatic up to 25 carbon atoms and aryl up to 25 carbon atoms, wherein g is an integer from 1 to 10;
y is an integer from 1 to 10;
R5 and R6 are independendy C1-C8 alkyl, C6-C25 aryl, or C6-C25 cycloaliphatic which may be substituted by one or more halogen, hydroxy, C1-C4 alkyl, carboxy or C1-C12 perhaloalkyl groups, or R5 and R6 may be -Si(OSiCH3)3;
R8 and R9 are independently C1-C24 alkyl, C3-C24 cycloaliphatic or C6-C25 aryl, which groups may be each substituted with from 1 to 11 groups selected from hydroxy, C1-C4 alkyl, carboxy, C1-C12 perhaloalkyl, and halogen, or R8 and R9 may also be (CH2CH2O)xH units, where x is an integer from 1 to 10, and X is an ophthalmically acceptable counterion.

2. An antimicrobial quaternary ammonium group-containing polymer according to claim 1 in which the counterion X is selected from the group consisting of halogen, hydroxyl, acetate, SO42-, CO32- and PO43-.

3. An antimicrobial quarternary ammonium group-containing polymer according to claim 1 in which the polymer is a homopolymer containing repeating monomer units of the formula I.

4. An antimicrobial quaternary ammonium group-containing homopolymer according to claim 3 of the formula wherein n is an integer of 10 to about 3000 and X is an ophthalmically acceptable counterion.

5. An antimicrobial quaternary ammonium group-containing homopolymer according to claim 4 in which X is Cl.

6. An antimicrobial quaternary ammonium group-containing polymer according to claim 1 in which the polymer is a copolymer of a monomer of formula I and at least one suitable comonomer.

7. An antimicrobial quaternary ammonium group-containing polymer according to claim 6 in which the comonomer is selected from the group consisting of vinyl aromatics, lower alkenes, lower alkadienes, vinyl acetamide, vinyl amines, vinyl acetate, vinyl alcohols, acrylic acid, acrylate and methacrylate esters, acrylamides, N-vinylpyridine andderivatives thereof, N-vinylpyrrolidone and derivatives thereof, and vinyl benzyl ethers of polyethylene glycols and their monoalkyl ethers.

8. An antimicrobial quaternary ammonium group-containing polymer according to claim 1 in which the polymer is crosslinked with a suitable crosslinking agent.

9. An antimicrobial quaternary ammonium group-containing polymer according to claim 1 in which the polymer has an average weight molecular weight of 2000 to about 1000000.

10. A liquid composition comprising a solvent and an antimicrobially effective amount of the antimicrobial quaternary ammonium group-containing polymer of claim 1.

11. A liquid composition according to claim 10 in which the solvent is water.

12. An aqueouls ophthalmic solution comprising an antimicrobially effective amount of the antimicrobial quaternary ammonium group-containing polymer of claim 1.

13. A method for cleaning and disinfecting contact lenses which comprises treating the contact lenses with an aqueous solution containing an antimicrobially effective amount of the antimicrobial quaternary ammonium group-containing polymer according to claim 1.

14. A contact lens made from the antimicrobial polymer of any one of claims 1, 3, 6 or 8.

15. An antimicrobial quaternary ammonium group-containing monomer of the formula I:

(I) wherein R1, R2 and R3 are independently hydrogen, C1-C7 alkyl, or -COOR13 with R13 being hydrogen or C1-C4 alkyl;
z1 and z2 are independently 0 or 1;
La is -C(O)O-, -C(O)N(Ra)-, or a bond;
La1 is a bond, -C(O)O-, -C(O)N(Ra)-, -O-, -OC(O)O-, -N(Ra)C(O)N(Ra)- or -N(Ra)C(O)O-; wherein Ra is hydrogen or C1-C8 alkyl;
R10 is a bivalent C1-C20 aliphatic, C3-C25 cycloaliphatic or C6-C20 aryl group, each of which may be substituted with up to five halogen atoms, or (CH2CH(Ra)O)j, wherein j is an integer from 1 to 50;
R4 and R7 are independently a bivalent group selected from C2-C10 aliphatic, such as C2-C8 alkylene, C1-C4 alkylene-(oxy-C1-C4 alkylene)g, C1-C4 alkylene-OCH2-(hydroxy C1-C4 alkylene)-CH2, cycloaliphatic up to 25 carbon atoms and aryl up to 25 carbon atoms, wherein g is an integer from 1 to 10;
y is an integer from 1 to 10;
R5 and R6 are independently C1-C8 alkyl, C6-C25 aryl, or C6-C25 cycloaliphatic which may be substituted by one or more halogen, hydroxy, C1-C4 alkyl, carboxy or C1-C12 perhaloalkyl groups, or R5 and R6 may be -Si(OSiCH3)3;
R8 and R9 are independently C1-C24 alkyl, C3-C24 cycloaliphatic or C6-C25 aryl, which groups may be each substituted with from 1 to 11 groups selected from hydroxy, C1-C4 alkyl, carboxy, C1-C12 perhaloalkyl, and halogen, or R8 and R9 may also be (CH2CH2O)xH units, where x is an integer from 1 to 10, and X is an ophthalmically acceptable counterion.

16. An antimicrobial monomer according to claim 15 of the formula II

(II)

17. An antimicrobial monomer according to claim 15 of the formula III

18. An antimicrobial monomer according to claim 15 of the formula IV

(IV)

19. An antimicrobial monomer according to claim 15 of the formula V

(V)

20. A method of producing an antimicrobial monomer of the formula II

(II) by (1) reacting a compound of the formula IIA

(IIA) with a compound of the formula IIB

(IIB) in the presence of water to produce a compound of the formula IIC

(IIC) (2) reacting the compound of the formula (IIC) with an excess of NH3, to produce a compound of the formula IID

(IID) (3) reacting said compound of the formula IID with an excess of CH3Br to produce a compound of the formula IIE

(IIE) and (4) quaternizing the compound of the formula IIE with C18H37Cl to produce a compound of formula II.

21. A method of producing an antimicrobial quaternary ammonium group-containing polymer which comprises homopolymerizing or copolymerizing, with a suitable comonomer, an antimicrobial monomer of the formula I

(I) wherein R1, R2 and R3 are independently hydrogen, C1-C7 alkyl, or -COOR13 with R13 being hydrogen or C1-C4 alkyl;
z1 and z2 are independently 0 or 1;
La is -C(O)O-, -C(O)N(Ra)-, or a bond;
La1 is a bond, -C(O)O-, -C(O)N(Ra)-, -O-, -OC(O)O-, -N(Ra)C(O)N(Ra)- or -N(Ra)C(O)O-; wherein Ra is hydrogen or C1-C8 alkyl;
R10 is a bivalent C1-C20 aliphatic, C3-C25 cycloaliphatic or C6-C20 aryl group, each of which may be substituted with up to five halogen atoms, or (CH2CH(Ra)O)j, wherein j is an integer from 1 to 50;
R4 and R7 are independently a bivalent group selected from C2-C10 aliphatic, such as C2-C8 alkylene, C1-C4 alkylene-(oxy-C1-C4 alkylene)g, C1-C4 alkylene-OCH2-(hydroxy C1-C4 alkylene)-CH2, cycloaliphatic up to 25 carbon atoms and aryl up to 25 carbon atoms, wherein g is an integer from 1 to 10;
y is an integer from 1 to 10;
R5 and R6 are independently C1-C8 alkyl, C6-C25 aryl, or C6-C25 cycloaliphatic which may be substituted by one or more halogen, hydroxy, C1-C4 alkyl, carboxy or C1-C12 perhaloalkyl groups, or R5 and R6 may be -Si(OSiCH3)3;
R8 and R9 are independently C1-C24 alkyl, C3-C24 cycloaliphatic or C6-C25 aryl, which groups may be each substituted with from 1 to 11 groups selected from hydroxy, C1-C4 alkyl, carboxy, C1-C12 perhaloalkyl, and halogen, or R8 and R9 may also be (CH2CH2O)XH units, where x is an integer from 1 to 10, and X is an ophthalmically acceptable counterion.