CA1142297A

CA1142297A - Compounds of sterilizing activity

Info

Publication number: CA1142297A
Application number: CA000326426A
Authority: CA
Inventors: Rupert A. Selway; John G.B. Howes; John K. Andrews
Original assignee: Smith and Nephew Pharmaceuticals Ltd
Current assignee: Smith and Nephew Pharmaceuticals Ltd
Priority date: 1978-04-26
Filing date: 1979-04-26
Publication date: 1983-03-01
Also published as: JPS5513778A; AU4663579A; BE875885A; IT7922177A0; ZA792004B; IT1202915B; DE2916698A1; FI791365A; LU81195A1; CH641818A5; ES479987A1; FR2424290A1; NL7903292A; FR2424290B1; AU526968B2; SE7903657L; US4304894A

Abstract

ABSTRACT
Watersoluble terpolymers based on three monomer units all of formula:
(or possibly the 5-membered ring analogue) wherein the N-substituents are respectively (A)low-low e.g.
dimethyl (B)low-medium e.g. methyloctyl and (C)low-higher e.g.
methyllauryl or methylcetyl, in molecular size; B:C being usually 5:1 to 0.333:1 (preferably 2:1 to 1:1) in weight ratio, and species less surprisingly effective sterilizing activity e.g. against Candida while (a) not accumulating in soft contact lenses, whereby they can be used as an overnight nonirritant aqueous sterilant solution at concentrations below 0.1 weight percent e.g. 0.05 or less and (b) not penetrating skin or like membrane whereby aqueous formulations can be uses as topical disinfectants without systemic side-effects.

Description

2;~7 .. 1 _NOV:EL COMPOUNDS OF STE:RILIZING ACTI~TITY", This invention relates to a novel class of watersoluble polymeric materials exhibiting quaternary ammonium groups, and to the use of the bactericidal properties of such materials in the preparation of sterilizing solutions for storage of 5 prostheses such as contact lenses, Contact lenses have for many years been made of hard polymeric material based predominantly on polymeric methyl methyacrylate. More recently, lenses have alternatively been made of soft material, whether rubbery hydrophobic material 10 such as the silicone-based lenses or hydrophilic material such as the gel-based lenses using e. g. hydroxyethylmethacrylate or like monomers to produce alone or with compatible comonomers a water-swellable polymer These lenses are removed each night and placed in a ;~ ~ 15 sterilizing solution For hard lenses, or for hydrophobic soft lenses, the main criterion of such solution is that it shall maintain - sterility, at least insofar as that term is understood ophthalmically For hydrophilic soft lenses, however, additional criteria apply; thus the solution shall not be such as to affect the water 20 content of the lens ( and thus its dimensions ) or, more import-antly, shall not contain any dissolved material which can be absorbed by the lens and lead to irritation or damage when the lens is subsequently worn.

,~ . , ' *

;: - ,. '~

1~4ZZ~7 Unfortunately, common bactericidal materials such as chlorhexidine or benzalkonium chloride do exhibit a tendency to accumulate in a soft contact lens with consequent irritation to the wearer, Because of this, the upper practical concentration 5 which can be used without unacceptable irritation is one at which their biocidal activities are considerably diminished, as explained below.
U. S. Patent 3539684 describes water-soluble polymeric quaternary ammonium compounds, active against Aerobacter , 10 aerogenes and useful to sterilize cooling water towers, ponds, reservoirs or swimming pools to inhibit algal or bacterial growth. These compounds are said to be based upon monomer units.of formula ~
, - 'l '' : ~ ~ ~ca2-x -: / \
Rl R2 . .
: ~ :
although there is some doubt about this, and the analagous lS 5 membered rin~ structure ~ ~ , ' ` .

- : :

:: . . ~, . -:. - ~ . : ..
~, . . .. .

2~97 X

has been proposed, Nonetheless, for convenience herein the above 6 membered ring structure will also be used to define the novel products of the present invention.
In the formula, X is any convenient anion and basically 5 Rl is a small alkyl group (e, g, CH3) and R2 a large (e. g. C8), The in~entors also envisage copolymers of two such monomers, one where Rl and R2 are both small alkyl groups and the other where one such group is small and one large.
In one aspect of the invention we have now discovered that 10 by modifying such a polymer structure still further so as to provide a terpolymer ( or higher order polymer) with three indent-ifiably distinct pairs of substituted on the nitrogen atom a novel water-soluble polymer can be made which is useful for example in a sterilizing solution for contact lenses, especially soft ~`
15 hydrophilic contact lenses, but which also provides tbe other uses outlined in this specification.
In one aspect the present invention provides a water-soluble polymeric material wherein a major amount, and ~:
; ' . . .
r .Z~.
......~.. ~ - " ; , . , , . ~ - . .

.. ~: . : : - :
- , . .
- . , .~ ~ ~ . . . . . . .

.. . . . . . . .

` ~ "` 1142~

preferably at least ~0~0 by weight of the monomer units consist of (A) (B) and (C) units, as defined below, the 0-1070 remainder by weight being units of one or more compatible monomers capable of copolymerisation, and no component (A) (B) or (C) being present in an amount less than 2% by weight:

A:

~ ~_ .CH2 : R /. R .
. ' _ ' '~ ,' '' '_ .

D ~ ~ _ Cllz -.. . . . .
C:_~ CE~

-.
, , , ~, j" ., "., . "~

~, . , . . . ,.. ..
, . .. ~ . . , . , , ll~Z~97 wherein X is any compatible anion allowing water-solubility, R is unsubst~tuted alkyl, or monohydroxyalkyl, the alkyl group in each case containing from one to four carbon atoms, Rl is elther (a) unsubstituted alkyl or monohydroxy- -alkyl the alkyl group in each case containing at least six carbon atoms or (b) a carbocyclic or heterocyclic mononuclear unsubstituted aryl group separated from the nitrogen atom by an unsubstituted or alkyl substituted alkylene group, containing in total up to six carbon ~
atoms, R2 is different from Rl, and (1) where Rl is defined as unsubstituted alkyl or monohydroxyalkyl the alkyl group in each case containing at least six carbon atoms then R2 is either a carbocycli~ or heterocyclic mononuclear unsubstituted aryl group,separated from the nitrogen atom by an unsubstituted alkylene group containing in total up to six carbon atoms, or is unsubstituted alkyl or mono-hydroxy alkyl, the alkyl group in this case containing at least eight carbon atoms, and always at least one more carbon atom than Rl when defined as at (a) above, or (ii) where Rl is -a carbocyclic or heterocyclic mononuclear unsubstituted aryI group separated from the nitrogen atom by an unsubstituted alkylene group containing in total up to six carbon atoms, then R2 is unsubstituted alkyl or monohydroxy alkyl, the alkyl group in each case containing at least six carbon atoms.
The R groups may be the same or different. They are usually all the same and all methyl~
The Rl groups are preferably chosen from C6 to C20 un-substituted n-alkyl groups, and more preferably from the C6-C10 groups. Specifically, an unsubstituted n-octyl gr~up is preferred for Rl.

. - 5 -li~2~2~7 The R2 groups are preferably chosen from C8 to C20 unsubstituted n-alkyl, more preferably from the C8 to C16 groups and most specifically are the unsubstituted n-lauryl (C12) or n-cetyl (C16) groups.
X may be F , Cl , Br , I , CH3S~4 or CH3C~ , but is most preferably Cl .
Preferably the` polymer is a strict terpolymer, i.e. not a higher order copolymer.
The content of units of A can be very low e.g. down to 10 15% although often it is as least 40~, for example from 50 to 90%, weight percent.
The weight percent ratio between B and C is usually between 5:1 and 1:1, although a ratio of from 5:1 to 0.333:1 is suitable, from 3:1 to 0.5:1 is more preferable`and from 2:1 to 1:1 is optimal. - - -The content of units B is usually above 3% and can befrom 5 to 30~ weight percent or more. The contents of units of C
is usually above 3% and usually from 3 to 25%; 5% to 20%, weight percent however, is especially useful. However, these are only 20 rough guidelines and viable terpolymers can be produced outside these restricted ranges.
While the novel class of,nolymer described above is a major -aspect of the invention, the use of such polymer in aqueous solu-tion as a sterilizing agent e.g. for contact lenses is another aspect of the invention.

.

Z2~7 . `

The invention therefore further consists in an aqueous sterilizing solutic>n especial1y but not e~clusively for contact lenses, especially hydrophilic soft contact lenses, which contains one or more of the watersoluble linear polymeric compounds defi~ed 5 above. In commercial practice 0. 01% maximum would be especially preferred, but the amount used should exert its effect in a reasonable overnight sterilizing time, e. g. 4 hours maximum.
Thus, 0. 02% or even 0. 05% solutions are sti~l valuable, especially since we have found the active biocidal agent of this solution to 10 have a lower tendency to migrate into and bind to the lens material.
which we believe is due to its large mol~cular size compared to that of chlorhexidine or benzalkonium chlorides, Also, because it can be u8ed at higher concentrations without irritation it exhibits useful antifungal effects as well, without the use of an l 5 antifungal micro~ial agent e. g. an organic mercurial.

The novel terpolymers of the invention are of course claimed per se In use, for the purposes outlined herein, we have found that in most cases it is advisable, and in many cases necessary, to avoid low-molecular ~veight terpolymers, or terpolymers containing a low molecular weight fraction Thus, a terpolymer as described above freF from species of molecular weight less than lO, 000, or preferably less than 20, 000, is a preferred form of the invention, especia71y for the medical and disinfectant uses envisaged Any necessary removal of low X

~l~Z~7 ~ ~ `

molecular weight species can be effected by any conventional method such as dialysis, Freedom from low molecular weight species is believed to confer the desired properties of non-penetration of skin and non-inclusion into gel-type contact lenses.
The preparation and use of polymers according to the invention will be further described with reference to the foLlowing examples, the first of which describes a typical preparation and some of the remainder of which compare the properties of the terpolymer as defined above to those of various two-component polymers, or of terpolymers, outside the scope of the present invention, Preparative Example Preparation of a typical polyquaternary copolymer containing methyl and n-lauryl ~roups ;~ 15 Diallyl methyloctyl ammonium chloride (3, Og), diallyl methyl lauryl ammonium chloride (1, 5g) and diallyl dimethyl ~, ammonium chloride (5, 5g) were dissolved in distilled water (lOml) : in a 100 ml flask, t butyl hydroperoxide (O, 6g) was added, ~ :
and the resultant solution held at 75 degrees under a nitrogen 20 blanket for 45 hrs, . ~ The viscous solution so obtained was poured slowly into : .
: ~ acetone (1, 2L) with stirring and the semi-solid precipitatetriturated with fresh acetone until fully solidified, filtered and dried at lOû deg centrigrade, The resultant solid was redissolved : ' .

~.

in water (13ml) and the solution placed in a closed visking tube, and was dialysed against 200 ml of distilledi water for 24 hours.
This process was repeated using four further 200 ml aliquots, by which time no material could be demons~rated in the dialyzate.
5 The resultant solution was freezed dried to give 6. 2 gms of a pale buff solid polymer For convenience the polymer is described as "30:1 5 octyl lauryl", to specify the weight percentage of fatty quaternary monomers employed.
lO Examples of properties of materials All the products made were tested by a microbial 'Die Off' Test, in which an aqueous solution of t~e test polymer was inoculated with a 106 organism/ml challenge of one of four test organisms, A.t times 2, 4 and 24 hours after inoculation, an 15 aliquot of test solution was removed and subc~lltured into recovery medium to test for surviving organisms.
Example 1 All of the terpolymers of the invention, and the typical comparison terpolymers and bipolymers were bactericidal against 20 a 106 organism/ml challenge Or the following ~acteria:
Staphylococcus aureus NCTC 6571 ~St. a) :::
Escherichia coli NCTC 86 (E: c) Pseudomonas aerugin NCTC 6750 (Ps a) Table 1 shows the earliest ~ample time at which no viable bacteri;t ~ .
::

.. ......

:`. ' ~ . ' . :'~ :: : :
., . ~ , ~

`` 114~2~7 .
were removed from test solution of a range of the polymers.
ln this and in all subsequent examp~es of the invention there were used terpolymers the repeatillg units of which include unsubstituted n-alkyl groups e. g. 1 - methyl, 8 = n-octyl, 12 = n-lauryl, 16 = n-cetyl TABLE 1.
~ . . _ ........................... ., MONOMER UNITS TIME (Hrs) To reduce a 106jml . challenge to less than 1 .
WEIGHT _ p~ RCENTAGES - . ~

A ¦(R,R B (R,Rl) C, (R,R2) S~.a. ¦E.c. Ps.a.
_ _ ` 75 1,1 25 1,12 O _ _ ~ 2 ~ 2~ 2 1,1 50 1,12 O _ ~ 2` < 2C 2 1,1 10 1,8 5 1,12 ~ 2 ~ 2. ~ 2 1,1 20 1,8 10 1,12 < 2 < 2< 2 25 I,8 112Jl,12 ~<2 L2 Thus, all terpolymers and comparison bipolymers in the above Table, tested as 0 01% aqueous solutions show good bactericidal activity. Because all these test matérials showed such good bactericidal activity, further examples were corapared using the 10 yeast Candida Albicans (London School of Hygiene and Tropical Medicine No, 3153) as being a better challenge organism for comparison purposes, ' .

...

:, . ~ . ~ , . .

~1 ~2Z~7 ampl c 2 Various terpolymers according to the invclltion were tested against a 106/ml challenge of Candida Albicans as in E~ample 1. The results are given in Table 2.
TABLI~ 2 Test M~ er lln s ~ample Time (Hrs) Solu-tion ~ ht - Percentages After inocula-~ion (l~/v) A (R,R) B (R,Rl) C (R,R2) 2 4 24 . _ . , ~ . . . ~.
0.1% 85 1,1 5 1,8 lo 1,12 .. + ~ . _ 0.05% . _ _ + + _ 0.1% ~5 1,1 lo 1,8 5 1,12 + . _ . 0.05% _ _ + + . _ 0.1% 85 1,1 7.5 1,8 7.5 1,12 + . + _0.05% . . . + . + : _ __ 0.1% 85 1,1 12 1,8 3 1,12 + . + _ 0.05% _ _ _ _ + + _.-* 0.1% ~o 1,1 15 1,8 5 1,.12 + _ _ 0.05% . ~ . + _ .o.ïo~0 77.5 1,l l5 1,8 7.5 1,12 + + _: 0.05% . . . + + + .
_ , ~ _~
* 0.1% 70 1,1 20 1,8 lo 1,12 + _ ._ : : 5% . . ... + + ! _ `~ ... .... _ _ _ ~::* o.l~ 65 1,1 20 1,8 15 1,12 + _ _ 0.05% + + _ :* o.~ 62.5 1,l 25 1,8 l2.5 l,l2 _ _ _ 0.05~ _ . + _ _ * 0.1% 551,1 30 1,8 15 1,12 + _ _ ~ - 0.05% . + ~ _ :~ ~ _ _ .. .
: 0.1% 501,1 25 1,8 25 1,12 . + + _ - Viable challenge organisms recovered = Some challenge organisms recovered - = No viable challenge organisms recovered '` 11~22~7 1~11 examples tested showed some alltifugal activity, but some were notably more active than others (noted * in Table 2).

Exarnple 3 Different terpolymers within the general scope of the S invention were tested against a 106/ml challenge of Candida Albicans, as in Example 2. Results are given in Table 3.

. . .~
Test Monomer UnitsSample Tirne (Hrs)

3~~tion W i~ht - Percentages After inocula-tion Stren~ A (R,R) B (R,Rl) C (R,R2) 2 . 4 24 0.1% 85 1,1 10 1,8 5 1,16 _ + _ 0.05% _ _ _ _ + ~ ~
O.lyo 85 1,1 7~ 1,8 7~ 1,16 + + _ 0.1% 85 1,1 i2 1,8 3 1,16 ~ + + , . _ __ __ . , __ ._. . _ 0. 1% 70 l,l 20 1,8 10 1, 16 . ~ . ` ~ _ 0. 05% .~ ~ _ .
: ~ ~ , :0.1% 62.5 1,1 25 1,8 12-~ 1,16 ~ ~ - _ : 0.05~ . _ _ ~ _ ~ _ :~
:
; (Key as for Table 2) All examples tested showed some Antifugal activity, though not as marked as that of some of the terpolymers in Table 2.

.... .

ZZ~7 Example 4 Further dif~erent terpoly~ners within the general scope of the inventi.on were tested as in Example 3.

est I Monomer Units Sample Time ~tion Weight - Percenta~;es trength A ~R,R) B (R,Rl) C (R,R2) 2 4 24 . . . . .
0.1% 70 1,1 10 1,12 20 1,16 + _ _ 0.05% . . . * + + ;~
0.1% 70 1,1 20 1,12 10 1,16 + _ 0.05% . . . . .+ ~ _ ~.
0.1% 55 1,1 30 1,12 15 1,16 ~ ; _ .~.. . . 0.05% _. . ...~.. ~ .... . .. :+ + : _ 0. 1% 55 1, 1 15 1, 12 30 1, 16 + + _ 0.05~6 _ __I ~ _ (Key as for Table 2) , S All examples tested showed some antifugal activity.

Example 5 Four further terpolymers of the "octyl-lauryl"type described in Example 2 were tested~ flgainsta106/ml. Candida Albicans challenge, ~s before. Results were as shown in Table S

~14Z29~

Test Monomer Units Sample Time ~;Tution Weight - Percentages (Hours) Strength % A (R,R) B R,Rl) C (R,R2) 2 4 24 0 02 60 1,1 20 I,B 20 1,1 0.0147.5 1,1 7.5 1,8 35 ~ ~,12' + _ j 0 0l 5o ,1~7.5 1, 12~5 1 ?~12 + +

~ 0.0162,5 ,~25 -1,8 1~.5 1,12 t : 0.0117.5 1,1`55 1,8 27.5 1,12 ~ _ _ '~: 0~ _ _ _ _ . ~ '- ":

: , .
Key as before. A dot entry signifies no information available or deducible .
.
. . .

11~225~7 Example 6 (Comparative) Certain terpolym~rs outside the scope of the invention were tested as before against Candida Albicans In thi s example " HE " means that 2 -hydroxy- ethyl radical 5 isused in place of radical R2. Thus the terpolymer in question is deficient by not possing a true R2 radical.
A]so "PEG" - means a polythylene glycol radical (CH2 CH20) n where n is about 4. 72 on average. This also does not fit the definition of R2, R1, or R.

1~ Lonomer llnits W~ lt Percentaee l Samplë Time ~Hrs) _ 1 A (R~R) B ;R,~1) C (R,R2) 2 ; 4 _ 24 ~_ .; . ~ ~' l . . , . _ .
1,1 10 1,8 51,HE + + _ 1,1 10 1,8 5l?HE + + _ ;~
l,1 10 1,8 51,HE + + _ 1,1 10 1,16 51, PEG + + _ _ . . ..

.
- All examples were tested as O.1% solutions. Only slight antifungal activity was demonstrated.

.
Example 7 (Comparative) Other bipolymers containing n-octyl ~groups were tested 15 against a 106/ml challenge Or Candida Albicans. Results are given in table 7 11422~7 MONO~IF.R UNIT~ SAMPLE TI~E (Hrs) _ . .
WEIGHT PERCENTAGES .
A ¦ (R,R) I B l(F~,Rl) ~ C (R,R2) 2 ~ 4 ¦ 24 90 1,1 10 1,8~ O _ + ~ _ 85 1,1 15 1,8O _ ~
80 1,1 20 1,8O _ ~ ~ ' _ 75 1,1 25 1,8O _ ~ ~
50 1,l 50 1,8O _ ~ + . ~ -- . .
All examples tested as 0.1% aqueous solutions. Some antifungal activit~ was demonstrated. No viable organisms were recovered after 24 hours exposure to the test bipolymer.

Example 8(Comparative) S Other bipolymers were chosen to reproduce as exactly as possible the polymer types of Example 5, i.e. with the same weight of protruding chains by omission of one or other substituted unit and its weight replacement by the remaining unit. The polyrner compositions, and results against a 106 Candida Albicans challenge lO are shown in Table 8 it being understood that lines 1 and 2 of this Table describe two bipolymers structurally equivalent to each other and to that described in line 1 of Table 5: lines 3 and 4 to line 2 thereof;!~lines 5 and 6 to line 3; and lines 7 and 8 to line 4 of Table 5.

1 1 4 2 ~ 9 _ ___ . . __ Tcst Monomer Units Sam~le Time .
Sollltion W lght - Percentages ~Hours~
v,~ 0 A (R,R) B (R,Rl) C (R,R2) 2 4 24 . . _ . _ __ .
0.01 55.32 1,1 ~.68 1,8 O 1,12 + +

0 1O ~ . . . ; . . . + +
0.01 62.791,1 O 1,8 36,21 1,12 + +
0.02 . . , . _ _ 0.10 . .
¦ O- 139'33 I1 60. 7 1 I,a ~ 1~,12 1 + +

0.10 50,R3 I,lO 1,8 ~9.17 1,12 + _ _ .
0.01 ~ .06 ~: 55.9 ~, O l,l + _-O 01 7 09 l,l o 1 8 42.91 1,1 0.O 59.56 1,140.44 l,S O 1,12 + +

Ø2 67.22 1,1 O 1,8 32,7~ 1,12 t ~ 114Z297 From a comparison of Tables 8 and 5 it can be deduced that 1he "octyl-lauryl" terpolymer is always more active than the "octyl" bipolymer and usually more active than the corresponding "lauryl" bipolymer, except for the 3:1 terpolymer and other less 5 preferred ranges.

The invention described above, and in particular the numerical limitations and their relationship to the results obtained on testing, will be more fully described with reference to the accompany~ng drawings in which:
10 Fig. 1 is a graph of weight percentage of R,R1 monomer units against that of R,R2 monomer units.
~ig. 2-7 are dlagrammatic graphs indicating how results change if theter~olymers defined by the points on fig. 1 are used at different strengths and for different times.

In Fig. 1, each terpolymer is marked with a solid circ]e, triangle or square, it being understood that if two or more polymers of the same weight ratios are shown they are slightly displaced equally around tlleir true position. Circles denote "octyl-lauryl" terpolymers; triangles "octyl-cetyl" and squares 20 " lauryl- cetyl"

From the tables it will be seen that all or substantially all the terpolymers are active enough to kill all the challenge organisms a~ter 24 hours; this accordinglv does not figure on the ; : ., . ;

114229'7 graph. From the tables morcover, it can be secn that the strongest conditions otherwise measured are for terpolymer at 0.10% concentration for four hours. In instanccs where this leads to a complete or substantially complete kill of the Candida organism, 5 the point position is shown surrounded by an enclosure of the same shape. Thus, it is quite clear by inspection that the "octyl-lauryl"
terpolymer (circles) is the most effective, especiall~r at higher "octyl" and "lauryl" contents; some "octyl-cetyl" (triangles) or "lauryl-cetyl" (squares) terpolymers are active, but usually at 10 low contents of the se constit~lents .

Figs. 2 to 7 show on a reduced scale only those examples whicll are active at a variety of other conditions. At 0.01% for four hours thrce examples are active (fig. 2), at 0.02% for four hours, four (fig. 3); and at 0.05% for four hours, nine (fig.4).
15 Similarly at 0.02% for two hours only two are active (fig. 5); two are active at 0.05% (fig. 6); and by 0.01% at twc~ hours, four are active (fig. 7). Tentatively therefore from these graphs we can sllr]nise that time of contact is more controlling than concentration: or in other words that with attractively weak solutions a four hour time 20 scale (easily available with overnight lens sterilization) is ample~

.
For completeness, it is noted that at 0.10% and four hours, 13 compounds are active? while at 0.01% and two hours, only one is namely the 55: 27; 5 " octyl-lauryl" teT polymer .

11422~7 The compounds shown, and their activities are not randc mly distributed and appear to take up ~ome population or clusters.
These can be delimited either by reference to the absolute composition of the polymer, or preferably to the relative proportions of its 5 components.

,.
As to the first, the content of B has already been stated to be usually above 3/9 preferably 5-30%, and that of C usually above 3/0, preferably 3-25%, most preferably 5-20%. Thus from a consideration of figure 1 it can be seen that the rectangle DEFG defines 10 a customary- range of compositions and that the rectangle HJKL defines a preferred range. However, there are useful and active compounds out side the se range s .
' The co~tent of A is usually but not always at least 400/O, preferrably 50 to 90/0. These limits are shown, in the form of diagram 15 given, as diagonal lines MN, PQ, RS respectively.

~' ~: . ' ' ' .
As to the second, relative co1ltents of B to C are shown as lines sloping upward from the origin. OQ is 5: 1, OT 3: 1, OV 2: 1, ~: ~
; OW 1: 1, OX 0: 5: 1 and OP 0 . 333: 1 . Initially thi s invention wa s considered to be usually confined between a. 5 :1 and 1. i rat io, but 20 we now believe that from 5 :1 to 0 . 333: 1 is also a use~ul definition and indeed figs. 2 to 7 show the trapezium PRSQ defined by 5:1 to 0.333:1 as B:C, and 50-90YO A as a useful overall preîerred area.
Again this is not exclusiYe of other active compounds.

.
. - ~ . .

2Z9~ .

Within the ranges given, those from 3: 1 to 0.5: 1 are preferred, especiallythose from 2:1 to 1:1, which contain most of the valuable compositions.

The terpolymers defined above and exemplified, which are 5 themselves novel . com~ounds, generally possess the following advantage s:
a) they do not accumulate in a soft contact lense to an undesired extent to lead to irritation even at concentrations of 0.10%, possibly because of the molecular size and shape; moreover, many 10 examples are effective in four hours at 0.05% or less, considerably weaker solutions than those used for chlorhexidine or benzalkonium salts .
b) they are not generally absorbed through the skin and other biological membranes again possibl~r due to molecular size and s~pe;
15 thus the chance of system~ic toxicity is greatly reduced.

These properties suggest that the compounds of the present invention can also be used for topical application for humans, for ~; example skin sterilizing agents, ~ for the treatment of micrabial infections of skin or of mucous membranes They could be 20 formulated with pharmacologically acceptable carrier, e.g. liquids, ointments, or lations. Such new medical uses constitute a further aspect of the inveltion.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A water soluble polymeric material wherein at least 90% by weight of the monomer units consist of (A), (B) and (C) units, as defined below, the 0-10% remainder by weight being units of one or more compatible monomers capable of copolymerisation, and no component (A), (B) or (C) being present in an amount less than 2% by weight:

A

B C

wherein X is any compatible anion allowing water-solubility, R is unsubstituted alkyl, or monohydroxy alkyl, the alkyl group in each case containing from one to four carbon atoms, R1 is either (a) unsubstituted alkyl or monohydroxy alkyl, the alkyl group in each case containing at least six carbon atoms, or (b) a carbocyclic or heterocyclic mononuclear unsubstituted aryl group, separated from the nitrogen atom by an unsubstituted alkylene group, contain-ing in total up to six carbon atoms, R2 is different from R1, and (i) where R1 is unsubstituted alkyl or monohydroxy alkyl, the alkyl group in each case containing at least six carbon atoms, then R2 is either a carbocyclic or heterocyclic mononuclear unsubstituted aryl group separated from the nitrogen atom by an unsubstituted alkylene group, containing in total up to six carbon atoms or is unsub-stituted alkyl or monohydroxy alkyl, the alkyl group in this case containing at least eight carbon atoms, and always at least one more carbon atom than R1 as defined at (a) above, or (ii) where R1 is a carbocyclic or heterocyclic mononuclear unsubstituted aryl group separated from the nitrogen atom by an unsubstituted alkylene group containing in total up to six carbon atoms, then R2 is unsubstituted alkyl or monohydroxy alkyl, the alkyl group in each case containing at least six carbon atoms.

2. A water soluble polymer as claimed in claim 1, wherein-substantially all of the monomer units consist of (A), (B) and (C) as defined therein.

3. A water soluble polymer as claimed in claim 2, wherein the R groups are all methyl.

4. A water soluble polymer as claimed in claim 3, wherein the R1 group is chosen from C6 to C20 unsubstituted n-alkyl groups.

5. A water soluble polymer as claimed in claim 3, wherein R1 is n-octyl.

6. A water soluble polymer as claimed in claim 3, wherein R2 is chosen from C8 to C20 unsubstituted n-alkyl groups.

7. A water soluble polymer as claimed in claim 6, wherein R2 is n-lauryl or n-cetyl.

8. A water soluble polymer as claimed in claim 3, wherein X- is Cl-.

9. A water soluble polymer as claimed in claim 3, free from species of molecular weight less than 10,000.

10. A water soluble polymer as claimed in claim 3, free from species of molecular weight less than 20,000.

11. A water soluble polymer as claimed in claim 3, wherein the weight ratio between R, R1-substituted monomer units and R, R2-substituted units is from 5:1 to 0.333:1.

12. A water soluble polymer as claimed in claim 11, in which the said weight ratio is from 3:1 to 0.5:1.

13. A water soluble polymer as claimed in claim 12, in which the said weight ratio is from 2:1 to 1:1.

14. A water soluble polymer as claimed in claim 13, in which R is methyl, R1 is octyl and R2 is lauryl.

15. A water soluble polymer as claimed in claim 14, in which the weight percentage giving the said weight ratio are 55:27.5 or substantially those percentages.

16. A water soluble polymer as claimed in claim 14, in which the weight percentages giving the said weight ratio are 20:20 or substantially those percentages.

17. A method of sterilizing a surface in which it is brought into contact with an aqueous solution of a water soluble polymer as claimed in claim 3.

18. A method of sterilizing a contact lens in which an aqueous solution containing not more than 0.1 weight percent of the polymer as claimed in claim 3 in which R is methyl, R1 is n-octyl and R2 is n-lauryl or n-cetyl, is contacted with the contact lens for not more than 4 hours.

19. A sterilizing solution containing not more than 0.1 of a polymer as claimed in claim 3.

20. A contact lens sterilizing solution containing not more than 0.05% of a polymer as claimed in claim 3 in which R is methyl, R1 is n-octyl and R2 is n-lauryl or n-cetyl.