United States Patent [191 . Gettings et al.

[54] OPTHALMIC FLUID DISPENSING

[11]
[45]

Patent Number:
Date of Patent:

5,013,459
May 7, 1991
514/63
514/29

4,614,675

9/1986 Ona 6161. .......................... .. 427/387

METHOD

4,615,882 10/1986 51661161

4,631,273 12/1986 Blehm et a1.

[75] Inventors: Richard L- Gettings, Freeland;

William C. White, Midland, 130111 0f
MiCh.
_ _

4,631,297 12/1986 13611166 61 a1.

4,648,978 3/1987 Makinen et a].
4,682,992
4,721,511

521/78
.. 210/762
55/279
. . . . .. 8/188

7/1987 Fuchs ........... ..

1/1988 Kupits . . . . . . . . . . ..

[73] Ass1gnoo=
[21]

Dow Corning Corporation, Midland,

Mich.

4,772,593 9/1988 w11111611 e181.

4,781,974 11/1988
4,822,667 4/1989

514/63
.. 428/288
. . . . .. 428/265

136116116116 .... ..
Goad et a1. . . ..

APPI' N- 433,817
' .

4,835,019

5/1989 w11116 61 a1. ...................... .. 427/387

[22] H1
[51]

9 9 1989
210/469; 210/501; 210/505; 210/5l0.1;
514/840

FOREIGN PATENT DOCUMENTS

1217004
wO86/01457

Int. Cl.5 .............................................. .. C02F 1/50

US. Cl. .................................. ..

V1987 Canada I
1/1987 PCT Inf] AppL I

1386876 3/1975 United Kingdom _

1433303 4/1976 11111166 Kingdom .

[58]

Field of Search ............. .. 210/668, 679, 755, 764,

[56]

210/807, 192, 282, 291, 251, 416.1, 416.2, 416.3, 466-469, 501, 504, 505, 510.1; 55/ 274; 514/ 631 839 840 References Cited
us. PATENT DOCUMENTS
2/1971
5/1973
2/1974

OTHER PUBLICATIONS Applied Microbiology, vol. 24, NO. 6, Dec. 1972, A. J. Isquith et al., Surface Bonded Antimicrobial Activity of an Organosilicon Quaternary Ammonium Chloride".
Primary ExaminerTom Wyse
Ammey Agent 0 ?rm-hm I" Decesare
[57]
.

3,560,385
3,730,701
3,794,736

R0111 ...................... .. 252/49.6

Isquith et a1.
Abbott et a].

....... .. 71/67

ABSTRACT
. . '.

3,817,739 6/1974 4115156116161.

3,360,709 1/1975 Abbott et a1_

....... .. 71/67
424/134

424/78

A 131611? afld devlce f_ dlpens}ng 3" quemls ?llld

whtch 1s destred to be mamtamed m a ster1le condiuon.

3,865,728 2/ 1975 Abbott et a1. $951,798 4/ 1976 l'laldopoulos

410051023 V1977 Hacker - - - - ~ - -

210/501 210/469
- - ~ 1 - - 252/99

The method includes storing a quantity of aqueous ?uid such as ophthalmic saline solution in a reservoir within
a portable container having, an outlet. A porous ?lter

4461518
4,259,103

1/ 1979 We a a1 """ "

3/1981 Malek et al. ....

424/52
. . . . . . . .. 7l/67

medium is arranged within the container adjacent the

. . .

4,282,366 8/1981 Eudy .................. .. 556/413

4,371,577
4,394,378
4,406,892

met, and the aqua? Phthalm1c ?ud 5 cafsed 0

pass from the reservoir through the porous medlum and
.10 the outlet. The porous medium has covalently
bonded thereto an antimicrobially effective amount of

2/1983 Sam at a]_

7/1983
9/1983

_____ __ 423/96
. . . .. 424/184
. . . .. 424/184

Klein . . . . . . . . . . .
Eudy . . . . _ . . . . . .

414721327

9/198:

Neefe """""""" 6 6 66 6 6 "

- - - ll

264/19

which is an organosilane. The organosilane can also be

$155153;$181511..
4,557,854
4,564,456

bonded to the inner and outer surfaces of the portable

. . . .. 252/174
. . . .. 210/698

12/1985
l/l986

Plueddemann . . . . .
l-loman . . . . . . . .. . . .

wmamer

4,567,039

1/1986 Stadnick .............................. .. 132/70

40 Claims, 1 Drawing Sheet

US. Patent

May 7, 1991

5,013,459

5,013,459

compounds are used to treat aquarium ?lters. PCT

OPTHALMIC FLUID DISPENSING METHOD

BACKGROUND OF THE INVENTION'
This invention relates to a method of dispensing an

Application No. 8601457, published Jan. 15, 1987,

teaches that microorganisms on multi-cellular plants
and fruit can be killed by the application thereto of an aqueous mixture of a surfactant and an organosilicon

opthalmic ?uid from a portable container which in

cludes a porous ?lter medium having bonded thereto an

quaternary ammonium compound. U.S. Pat. No._ 4,564,456, issued Jan. 14, 1986, discloses organosilanes
vas anti-scale agents in water systems. In a particular

antimicrobial agent in order to eliminate contamination

by microbial growth.
An antimicrobial is an agent that destroys or inhibits

application of an antimicrobial organosilicon quater

nary ammonium compound, a paper substrate is ren

the growth of microorganisms. The major classes of microorganisms are bacteria, fungi including mold and mildew, yeasts, and algae. Microorganisms can be
found in the air, the waters, the human body, soil,
wastes, and on all surfaces. The organisms are deposited

dered resistant to the growth of microorganisms in U.S. Pat. No. 4,282,366, issued Aug. 4, 1981. In U.S. Pat. No.
4,504,541, issued Mar. 12, 1985, an antimicrobial fabric is disclosed which is resistant to discoloration and yel
.. lowing by treatment of the fabric with a quaternary

from the air. food and drink spills, dust, dirt and tracked
in soil, and from human excreta such as sweat, urine,

ammonium base containing an organosilicon com

pound. U.S. Pat. No. 4,781,974, issued Nov. 1, 1988,

relates to wet wiper towelettes having an antimicrobial agent substantive to the ?bers of the web and being an

and feces. Organisms grow and multiply when there is

available a nutrient source of food such as dirt, organic

or inorganic material, and living tissue. For growth and 20 organosilicon quaternary ammonium compound. In multiplication, organisms also require warm tempera U.S. Pat. No. 4,467,013, issued Aug. 21, 1984, such tures, and moisture. When these conditions exist, micro compounds are disclosed to be useful in surgical drapes, organisms thrive and ?ourish. Microbial growth, how gowns, dressings, and bandages. Organosilicon quater ever, leads to many problems such as unpleasant odors nary ammonium compounds have been employed in ranging from stale to musty and mildew-like, to putrid carpets, in U.S. Pat. No. 4,371,577, issued Feb. 1, 1983; and foul smelling, resembling ammonia. The growths applied to walls, added to paints, and sprayed into also produce unsightly stains, discoloration, and deteri shoes, in U.S. Pat. No. 4,394,378, issued July 19, 1983; oration of many surfaces and materials in which they applied to polyethylene surfaces and used in pillow come into contact. A more serious disadvantage of ticking in U.S. Pat. No. 4,721,511, issued Jan. 26, 1988; microbial growth is the production of pathogenic mi in ?exible polyurethane foams of ?ne-celled, soft, resil croorganisms, germs, their metabolic products and their ient articles of manufacture in U.S. Pat. No. 4,631,297, somatic and reproductive cell parts, which contribute issued Dec. 23, 1986; and mixed with a surfactant in to the spread of disease, infection, and disorders. British Pat. No. 1,386,876, of Mar. 12, 1975. Some gen Antimicrobial agents are chemical compositions that eral, more domestic type applications of these com
are used to prevent such microbiological contamina

tions by inhibiting, killing and/or removing them and neutralizing their effects of deterioration, defacement,
odor, disease or other negative effects. Particular areas

pounds, has included their use in a dentifrice as in U.S.

Pat. No. 4,161,518 issued July 17, 1979; in a novel laun

dry detergent in U.S. Pat. No. 4,557,854, issued Dec. 10,

1985; as a hair conditioner in U.S. Pat. No. 4,567,039, issued Jan. 28, 1986; and in a soft contact lens disinfec 40 tant solution in U.S. Pat. No. 4,615,882, issued Oct. 7,

of application of antimicrobial agents and compositions are, for example, cosmetics, disinfectants, sanitizers, wood preservation, food, animal feed, cooling water, metalworking ?uids, hospital and medical uses. plastics and resins, petroleum, pulp and paper, textiles, latex,
adhesives, leather and hides, and paint slurries. In the

1986. In U.S. Pat. No. 4,614,675, issued Sept. 30, 1986, properties can be influenced by mixing the organosili
con quaternary ammonium compounds with certain

area of medical applications, antimicrobials are often 45 siloxanes. Other typical uses of organosilicon quaternary am used as powders, in lotions, creams, ointments and/or monium compounds in accordance with the prior art delivered in a variety of solvents or directly as over-the can be seen from U.S. Pat. Nos. 4,005,028, issued on Jan. counter or ethical drugs to alleviate, mediate, cure and 25, 1977, and relating to hard surface rinse aids and /or protect people or other animals from disease or cosmetic conditions. Of the diverse categories of antimi 50 detergents. Contact lenses are treated with an organosi

crobial agents and compositions, quaternary ammonium

compounds represent one of the largest of the classes of
antimicrobial agents in use. At low concentrations, qua ternary ammonium type antimicrobial agents are bacte

lane in U.S. Pat. No. 4,472,327, issued Sept. 18, 1984. In U.S. Pat. No. 4,682,992, issued July 28, 1987, glass

spheres are treated with the compounds and employed ' .-as ?lters. The compounds are used to treat swine dysen

riostatic, fungistatic, algistatic, sporostatic, and tubercu

lostatic. At medium concentrations they are bacteri

cidal, fungicidal, algicidal, and viricidal against lipo

philic viruses. Organosilicon quaternary ammonium salt
compounds are well known as exempli?ed by U.S. Pat. No. 3,560,385, issued Feb. 2, 1971, and the use of such compounds as antimicrobial agents is taught, for exam ple, in a wide variety of patents such as U.S. Pat. Nos.

tery in U.S. Pat. No. 4,772,593, issued Sept. 20, 1988; applied to a polyester fabric in U.S. Pat. No. 4,822,667, issued Apr. 18, 1989; and adhered to a polyamide ?la ment in US. Pat. No. 4,835,019, issued May 30, 1989. In Canadian Patent No. 1,217,004, granted Jan. 27, 1987, 60 organosilane quaternary ammonium compounds are
formulated into bleaches that are applied to hard sur

faces such as bath tubs, wash basins, toilets, drains, and ceramic tile floors. 3,730,701, issued May 1, 1973, and 3,817,739, issued Among the numerous attempts to alleviate the prob June 8, 1974, where the compounds are used to inhibit lems of microorganisms on surfaces have involved the 65 algae; 3,794,736, issued Feb. 26, 1974, and 3,860,709, use of soaps, detergents, and surface cleaners. The treat issued Jan. 14, 1975, where they are employed for steril ments, however, have for the most part included an izing or disinfecting a variety of surfaces and instru unbound category of antimicrobial which is not actually ments; and 3,865,728, issued Feb. 11, 1975, where the

5,013,459

bonded to the surface sought to be treated, and there

category of bound antimicrobial is an alkoxysilane qua

fore is_consumed by the microorganisms, with the result that the unbound antimicrobial is depleted and washed away during routine cleansing. As this diffusion contin ues, the concentration of the active ingredient becomes diluted below effective levels, with the result that the microorganisms sought to be inhibited, adapt and build
up a tolerance, becoming immune to what was once an

ternary ammonium compound, and such alkoxysilane

quaternary ammonium compounds have been found to be more effective at reducing the number of microor

ganisms, and inhibiting microbially generated odors,

than conventional organotin compounds and other or

ganic quaternary ammonium compounds. The silanes of

the present invention when delivered from simple water
solutions immobilize on surfaces and bond thereto to

effective treatment dose. Such unbound diffusible anti microbials have therefore been found to be limited in

their ability to offer broad spectrum control of microor ganisms, in contrast to the bound type of antimicrobial which remains chemically attached to the surface to which it is applied providing for a surface that prevents recolonization by the microflora associated therewith. Diffusing types of antimicrobials also often suffer from the propensity to transfer percutaneously, giving rise to sensitization and irritation immunological responses, and raising serious questions as to their ultimate fate 20 within the body and body systems.
The unbound antimicrobials of the prior art are not

provide a coating of immobilized antimicrobial, unlike conventional materials. In the present invention, this bound characteristic of alkoxysilane quaternary ammonium compounds, as well as their capabilities of performing at effective kill levels beyond prior art types of compositions, is taken advan
tage of in the treatment of surfaces, in order to reduce

or substantially eliminate the incidence of microorgan isms, germs, their metabolic products and their somatic and reproductive cell parts, which contribute to the spread of such microbes.
It is not new to disinfect aqueous solutions in an at

the equivalent of the bound antimicrobial organosi

tempt to rid the solutions of bacterial growth. For ex

ample, U.S. Pat. No. 1,204,171, issued Nov. 7, 1916, lane of the present invention because the unbound anti discloses a sanitary drinking tube which includes a body microbials do not perform substantially the same func~ tion, in substantially the same way, to produce substan 25 of disinfecting material. Water is said to be drawn through the disinfecting material and ?ltered or ren tially the same results, as do the bound silanes of the dered free from contamination, although the exact na present invention. The function differs because the ture and construction of the disinfecting material is not bound antimicrobial is permanent whereas the unbound disclosed. In U.S. Pat. No. 4,483,771, issued Nov. 20, types are easily washed away or rubbed from the sur face. The compounds of the present invention are not 30 1984, a liquid ?lter of multiple layers is taught, one layer of which is impregnated with an antibiotic bacteria only durable but retain their antimicrobial activity after

some ten laundering cycles, and only slightly diminish

in their activity after as many as twenty-?ve laundering cycles. The bound silanes of the present invention retain an effective kill level of microorganisms. The manner in which the bound silane functions differs from the un
- bound types, since the bound silane attaches itself to the

destroying material such as penicillin, iodine, tetracy

cline, kanamycin, or sulfonamides. A dispenser for sa line solution is taught in U.S. Pat. No. 4,463,880, issued

Aug. 7, 1984. The saline dispenser includes a disinfec tant soaked pad, although the composition of the disin
fectant is not disclosed. In contrast, the present inven tion in one embodiment is directed speci?cally to op thalmic solutions and to the treatment of such solutions

surface to which it is applied, whereas the unbound

types are mere coatings which are not substantive. This

to prevent reinfestation, and enables one to utilize the intrinsic antimicrobial activity 0 the silane treated sur

is signi?cant since the silane antimicrobial will continue 40 with a bound silane antimicrobial. Such a bound anti microbial avoids the negative effects that traditional unbound antimicrobials possess. For example, it is known that many preservatives cause eye irritation to face to kill transient microbes, long after the unbound many people, and the foregoing unbound antimicrobials types of antimicrobials have been depleted of their ac tivity. Further, the bound silanes of the present inven 45 of the type noted immediately above in the 171, 77l, and 880 patents would be no exception. In fact such tion destroy, reduce, and inhibit the growth and multi unbound antimicrobials would in all likelihood possess plication of bacteria, fungi, and other pathogenic micro irritation levels well in excess of the levels experienced organisms, by the disruption of cell membranes, a mech with current preservative type compounds. This is par anism absent from conventional unbound antimicrobial materials. The results produced by the bound silanes is 50 ticularly signi?cant when it is considered that opthal mic solutions are traditionally administered in the form not the same as the results produced by the unbound of drops directed to the area of the human eye. This types, since the bound silanes provide a prolonged anti highly sensitive area of the human anatomy is prone to microbial activity and continue to kill and inhibit the

proliferation of potentially destructive microorganisms,

-' irritation, and hence the presence of any leachable ma

versus mere temporary and super?cial protection of 55 terial in a ?lter medium used to treat such solutions which may tend to cause irritation to the eye should be fered by the unbound category of material. Thus, it avoided. Hence, the bound silane antimicrobial of the should be apparent that the method of the present in present invention offers signi?cant advantages in that vention in employing the bound antimicrobially active

organosilicon quaternary ammonium compounds is far

removed from methods that have been previously dis closed by the prior art.
Bound antimicrobials kill organisms on contact and

once the silane is chemically bonded to a surface such as a porous ?lter medium, the silane is substantive to that

surface and is not carried away from the surface to the eye along with the ?lter effluent. In addition, the silane

of the present invention maintains the ophthalmic solu continue to kill organisms without being diffused or tion in a sterile condition in the container, and causes leached from the surface. Thus, the bound antimicrobial leaves behind an effective level of active ingredient and 65 any excess draining back into the container following administration to be re-sterilized. The addition of other is able to control a broad spectrum of microorganisms

including gram negative and gram positive bacteria, mold, mildew, fungi, yeast, and algae. An exemplary

preservatives for the ophthalmic solution is therefore eliminated.

5,013,459

The 171, 771, and 880 patents discussed above all suffer from the additional disadvantages in that the
disinfectants and antibiotics disclosed therein are wash able from the ?lter surfaces, and while some of the microorganisms may be killed to some extent, the solu

emulsions. Often, the ?lter may not be suf?cient for microbial decontamination, and therefore it has been found to be advantageous to bond the organosilane to the outer surfaces of the portable container as well as to the inner surfaces thereof. This internal and external
container treatment is adapted for use in addition to the -

tion sought to be preserved would actually become

contaminated with the disinfectant or antibiotic. In

treatment of the porous ?lter with the organosilane. In

severe cases, it may even become necessary to include

leaching from the ?lter surfaces, the disinfectants would present the problem of raw toxicity to the eyes and skin, and a limited spectrum of activity. The antibiotics on the other band, would create allergenic response sensi tivities, a general chemical incompatability with the solution sought to be preserved, and the lack of a broad spectrum activity against a variety of microbial contam inates. Microorganisms also possess the capability of
quickly adapting to most antibiotics. .

an organosilane bound porous material in the bottom of the container reservoir for added microbial decontami nation. This is most practically carried out with a po
rous material in the form of beads or ?bers. . These and other features, objects, and advantages, of

the present invention will be apparent when considered

n

"in light of the following detailed description thereof.

IN THE DRAWINGS FIG. 1 is a pictorial representation shown in cross section of a liquid dispensing device in accordance with the present invention.
FIG. 2 is a pictorial representation of the de\ . illus

SUMMARY OF THE INVENTION This invention is directed to a method of dispensing

an aqueous ?uid which is desired to be maintained in a

sterile condition by storing a quantity of aqueous fluid

in a reservoir within a portable container having an

outlet. The aqueous fluid is preferably an opthalmic

?uid such as a saline solution which is free of preserva'

trated in FIG. 1 and shown partially in cross-xenon.

The device is oriented in a fashion to assimilate the position of the device when it is tilted with the hand of the user in order to apply drops of solution contained therein.

tives. A porous ?lter medium is arranged within the

container adjacent the outlet, and the aqueous ophthal

mic preservative free saline solution is caused to pass from the reservoir through the porous medium and to the outlet. The porous ?lter medium has covalently bonded thereto an antimicrobially effective amount of

DETAILED DESCRIPTION OF THE INVENTION

an organosilicon quaternary ammonium compound, and the organosilicon quaternary ammonium compound is an organosilane having the formula selected from the group consisting of
35

Ammonium compounds in which all of the hydrogen atoms on nitrogen have been substituted by alkyl groups
are called quaternary ammonium salts. These com

pounds may be represented in a general sense by the

formula: '

The nitrogen atom includes four covalently bonded substituents that provide a cationic charge. The R groups can be any organic substituent that provides for 45 a carbon and nitrogen bond with similar and dissimilar R groups. The counterion X is typically halogen. Use of wherein, in each formula, quaternary ammonium compounds is based on the hy Y is R or R0 where each R is an alkyl radical of 1 to drophilic portion of the molecule which bears a positive 4 carbon atoms or hydrogen; charge. Since most surfaces are negatively charged, a has a value of O, l or 2; 50 solutions of these cationic surface active agents are R is a methyl or ethyl radical;
R" is an alkylene group of 1 to 4 carbon atoms;

R', R" and Rvare each independently selected from a group consisting of alkyl radicals of 1 to 18 carbon atoms, CHZC6H5, --CI-l2C2OI-I, CH2OI-l, and

readily adsorbed to the negatively charged surface. This af?nity for negatively charged surfaces is exhibited by 3-(trimethoxysilyl)propyldimethyloctadecyl ammo

nium chloride hereinafter referred to as TMS. This (CH2),;NHC(O)R', wherein it has a value of from 2 55 compound is manufactured by the Dow Corning Cor to 10 and R" is a per?uoroalkyl radical having from 1 to poration, Midland, Mich., and has the formula: 12 carbon atoms; and x is chloride, bromide, ?uoride, iodide, acetate or CH3 tosylate. The porous ?lter medium may be constructed of 60

various materials, however, the ?lter is preferably con

structed of a ?ber strand such as of rayon, wool, nylon,

cotton, silk, cellulose triacetate, polypropylene, poly carbonate, ?berglass, and polyester. The method is
applicable to a wide variety of ?uids in general, but is 65 most convenient for the treatment of ?uids such oph thalmic solutions, saline salt solutions, water delivered

2) a,

5.,

medicines, surgical irrigation ?uids, water, milk, and

In the presence of moisture, this antimicrobial agent imparts a durable, wash resistant, broad spectrum bio

5,013,459

static surface antimicrobial ?nish to a substrate. The

inventor that even though the prime mode of coupling

to the surface system is by the route described above, it is also believed by the inventor that the alkoxy groups
on the silicon atom may also participate in their own right to bind to the surface.
Preferred for this invention is a reactive surface con

organosilicon quaternary ammonium compound is

leach resistant, nonmigrating, and is not consumed by

microorganisms. It is effective against gram positive and gram negative bacteria, fungi algae, yeasts, mold,
rot, and mildew. The quaternary ammonium complex

provides durable, bacteriostatic, fungistatic, and algi

' static surfaces. It can be applied to organic or inorganic surfaces as a dilute aqueous or solvent solution of

taining some small amount of water. By reactive, it is meant that the surface must contain some groups which

0.1-1.5 percent by weight of active ingredient. After the alkoxysilane is applied to a surface, it is chemically
bonded to the substrate by condensation of the silanol groups at the surface. The pure compound is crystalline whereas methanol solutions of the compound are low

will react with some of the silanols generated by hydro lysis of the silanes of this invention.
R in the silanes of this invention are alkyl groups of 1
to 4 carbon atoms. Thus, useful as R in this invention are

the methyl, ethyl, propyl and butyl radicals. In the

above formulas RO can also be R. R can also be hydro

ethyl radical. Because of the presence of these alkyl radicals, the prior art teaches that the materials must be sheets, blankets, bedspreads, carpet, draperies, ?re hose fabric materials, humidi?er belts, mattress pads, health 20 stabilized with a corresponding solvent. Thus, methoxy groups require methanol and ethoxy groups require care apparel, mattress ticking, underwear, nonwoven ethanol, for example. disposable diapers, nonwoven fabrics, outerwear fab

viscosity, light to dark amber liquids, soluble in water, alcohols, ketones, esters, hydrocarbons, and chlorinated hydrocarbons. The compound has been used in applica tions such as, for example, socks, ?ltration media, bed

gen thus indicating the silanol form, i.e. the hydroly

zate. The value of a is 0, 1 or 2 and R is'a methyl or

rics, nylon hosiery, vinyl paper, wallpaper, polyure

thane cushions, roo?ng materials, sand bags, tents, tar paulins, sails, rope, blood pressure cuffs, athletic and casual shoes, shoe insoles, shower curtains, toilet tanks, toilet seat covers, throw rugs, towels, umbrellas, uphol stery ?ber?ll, intimate apparel, wiping cloths, and medi
cal devices such as blood pressure cuffs.

R for purposes of this invention is an alkylene group of 1 to 4 carbon atoms. Thus, R" can be alkylene groups

such as methylene, ethylene, propylene, and butylene.

R', R"", and R" are each independently selected from
a group which consists of alkyl radicals of l to 18 car

bons, CH2C6H5, CH2CH2OH, -CI-l2OH, and

(CH2),NHC(O)R'. x has a value of from 2 to 10 and R is a per?uoroalkyl radical having from 1 to 12 car

The silanes useful in this invention have the general formula

bon atoms. X is chloride, bromide, ?uoride, iodide,

acetate or tosylate. Preferred for this invention are the silanes of the
35

general formula

Ra

Ra

--

It should be noted that generically, these materials are quaternary ammonium salts of silanes. Most of the silanesfalling within the scope of this invention are 40 R is methyl or ethyl; a has a value of zero; R" is propy known silanes and references disclosing such silanes are lene; R' is methyl or ethyl; R"" and R" are selected numerous. One such reference, US Pat. No. 4,259,103, from alkyl groups containing 1 to 18 carbon atoms issued to James R. Malek and John L. Speier, on Mar. wherein at least one such group is larger than eight 31, 1981, discusses the use of such silanes to render the carbon atoms and x is either chloride, acetate or tosy surfaces of certain substrates antimicrobial. British Pa 45 late. tent No. 1,433,303, issued to Charles A. Roth shows the Speci?c silanes within the scope of the invention are use of ?llers treated with certain silanes to be used in represented by the formulae:

paints and the like to give antimicrobial effects. Numer

ous publications have disclosed such silanes, for exam

ple, A. J. Isquith, E. A. Abbott and P. A. Walters, Ap

plied Micrabi'ology, Vol. 24, No. 6, Dec., 1972, pages

859-863. '

For purposes of this invention, the silanes can be used neat or they can be used in solvent or aqueous-solvent solutions. When the silanes are used neat, the inventive process is preferably carried out in a system in which some small amount of water is present. If it is not possi
ble to have a system with some small amount of water

present, then a water soluble or water-dispersable, low

molecular weight hydrolyzate of the silane may be used. What is important is the fact that the durability of
any effect produced by the silane as part of a product
requires that the silane molecule react with a surface to a certain extent. The most reactive species, as far as the

silanes are concerned, is the ESiOI-I that is formed by 65 hydrolysis of the alkoxy groups present on the silane. The ESiOH groups tend to react with the surface and bind the silanes to the surface. It is believed by the

9
-continued

5,013,459.

10

agent on a given substrate. A comparison of the inten sity of retained blue color to a color standard is used as a check to determine if the treatment has been applied

properly.
One method consists of preparing a 0.02 to 0.04

weight percent solution of bromphenol blue in distilled

water. This solution is made alkaline using a few drops

The treatment can be applied to the porous filter medium in the form of an emulsion including water, the
silane, and a water immiscible liquid. The water immis cible liquid, or volatile as used in the emulsion, is a

'of saturated N32C03 solution per 100 milliliters of the solution. Two to three drops of this solution are placed
on the treated substrate and allowed to stand for two

minutes. The substrate is then rinsed with copious

amounts of tap water and the substrate is observed for a

silicone oil which is highly volatile, and low in viscosity

anes, cyclic siloxanes such as dimethylsiloxane cyclic tetramer, and phenylmethyl ?uids such as linear poly phenylmethylsiloxanes. Preferred for this invention are those silicone oils having a viscosity at twenty-?ve degrees Centigrade ranging from about 0.65 cs to about one thousand cs. A particularly preferred range is from
about 0.65 cs to about 20 cs, although those silicone oils of viscosities of 50 cs, and 350 cs, can be employed. These silicone oils are more particularly described and set forth in detail in US. Pat. No. 4,631,273, issued Dec.

and molecular weight. For example, there may be em test is used. The sodium salt of bromphenol blue is ployed trimethylsiloxy endblocked polydimethylsilox: -"ing depleted from a standard solution by complexing with
the cations on a treated substrate. The change in brom

blue stain and it is compared to a color standard. For a spectrophotometric determination, the follow

phenol blue concentration is determined spectrophoto

metrically or by comparison with color standards whereby the level of substrate treatment by the cationic silane is determinable.

phenyl, an alkoxy radical having the formula R""O-,

The method consists of preparing a 0.02 weight per cent standard solution of bromphenol blue in distilled water. It is made alkaline with a few drops of saturated Na2CO3 solution per 100 milliliters of bromphenol blue solution. The color of this solution is purple. The blank 23, 1986, the disclosure of which is incorporated herein solution is adjusted to yield a 10 to 12% transmittance by reference. Such silicone oils are siloxanes which are reading when measured in 1 cm cells using a spectro low molecular weight cyclics and polysiloxanes having photometer set at 589 nm by the following method. Fill the general formula 30 a container % full of distilled water and add 2 ml of the 0.02% standard bromphenol blue solution for every 50 ml of distilled water. Add 0.5 ml of a 1% Triton wherein R is an alkyl radical of l to 3 carbon atoms, X-100 surfactant (manufactured by Rohm and Haas,
wherein R" is an alkyl radical of l to 4 carbon atoms or hydrogen; R" is an alkyl radical of 1 or 2 carbon atoms or the phenyl group; R' has the same meaning as R; Q is a substituted or unsubstituted radical composed of

Philadelphia, Pa., USA) aqueous solution for every 50 ml of water. Mix, and using the spectrophotometer, determine the maximum absorbance. Adjust the upper
zero to 100% transmittance with distilled water. Check

carbon and hydrogen, or carbon, hydrogen and oxygen, or carbon, hydrogen and sulfur, or carbon, hydrogen
and nitrogen; w has a value of from 1 to 500; 2 has a value of l to 25 and y has a value of 3 to 8.

the percent transmittance of the working bromphenol

blue solution at the maximum absorbance setting. Ad just the blank solution to 10 to 12% transmittance with
either water or bromphenol blue standard solution as necessary.

The samples of treated substrate can be tested by placing 0.5 gram samples of the substrate standard in a emulsion containing the organosilane. Such microemul 45 ?ask large enough for substantial agitation of the sample sions and their preparation are described in US. Pat. and the test solution. Add 50 ml of the working solu No. 4,842,766, issued June 27, 1989. Solutions with tion. Agitate for 20 minutes on a wrist-action shaker. particle sizes less than 0.150 microns are disclosed Fill the test curvette with the test solution. Centrifuge if which are either oil-in-water or water-in-oil microemul particulate matter is present. Measure the % transmit sions including the organosilane and at least one surfac tance at the wavelength set forth above. The transmit tant. The 766 patent relating to the microemulsions is tance is compared against a standard curve prepared by considered incorporated herein by reference. preparing several substrate samples of known concen Various procedures are employed in order to test the
dance with the present invention in the form of a micro

The organosilane may also be employed in accor

organosilanes of the presentinvention. For example, the

"tration of the cationic silane. For example, samples

presence of the chemical on a substrate can be deter 55 containing a known amount of cationic silane at, for

mined by complexing a standardized solution of bromo phenol blue in water with the quaternary nitrogen of

example, 0%, 0.25%, 0.50%, 0.75% and 1% are read spectrophotometrically and a curve is plotted.

The antimicrobial activity of a treated surface is nor the organosilane and recording the color change spec mally evaluated by shaking a sample weighing 0.75 trophotometrically. Results of this test can be used in order to determine whether the organosilane has bound 60 grams in a 750,000 to 1,500,000 count Klebsiella pneumo
itself to a particular surface. Such a test procedure is set
forth below. .

niae suspension for a one hour contact time. The suspen

sion is serially diluted, both before and after contact, and cultured. The number of viable organisms in the The anion of an aqueous sodium salt of bromphenol suspensions is determined. The percent reduction based blue can be complexed with the cation of polymerized silanes of this invention while on a substrate. The blue 65 on the original count is determined. The method is intended for those surfaces having a reduction capabil colored complex, substantive to a water rinse, is qualita ity of 75 to 100% for the specified contact time. The tively indicative of the presence of the cation on the results are reported as the percent reduction. Media substrate thus indicating the extent of antimicrobial

11

5,013,459

used in this test are nutrient broth, catalog No.

0003-01-6 and tryptone glucose extract agar, catalog No. 0002-01-7 both available from Difco Laboratories, Detroit, Mich, U.S.A. The microorganism used is Kleb

siella pneumoniae American Type Culture Collection;

Rockville, Md. U.S.A., catalog No. 4352. The proce
dure used for determining the zero contact time counts

is carried out by utilizing two sterile 250 ml. screw-cap Erlenmeyer ?asks for each sample. To each ?ask is added 70 ml of sterile buffer solution. To each ?ask is 10

This complex molecule has three active areas. The

added, aseptically, 5 ml of the organism inoculum. The

?asks are capped and placed on a wrist action shaker.

presence in the molecule of the long chain aliphatic alkyl group Cid-I37 which is non-polar and oil-like,

They are shaken at maximum speed for 1 minute. Each

?ask is considered to be at zero contact time and is

determines the hydrophobic/oleophilic properties of

the molecule. The molecule attaches itself to surfaces via the methoxy silane functionality which serves as the anchor. or coupler, whereas the quaternary ammonium salt functionality portion of the molecule which is cat

immediately subsampled by transferring 1 ml of each

solution to a separate test tube containing 9 ml of sterile buffer. The tubes are agitated with a vortex mixer and then 1 ml of each solution is transferred to a second tube

ionically charged, performs the antimicrobial or micro

containing 9 ml of sterile buffer. Then, after agitation of

the tubes, 1 ml of each tube is transferred to a separate

sterile petri dish. Duplicates are also prepared. Sixteen ml of molten (42 C.) tryptone glucose extract agar is
added to each dish. The dishes are each rotated ten

organism killing function. It is this unique and complex arrangement which sets the organosilicon compounds of the present invention apart from the conventional organic antimicrobial materials of the prior art. Regarding the activity of the compounds of the pres
BACTERIA: Gram (); Escherichia COll, Klebsiella pneumoniae, Klebsiella oxytoca, Pseudomonas aeruginosa, Pseudomonas ?uorescens. Proteus mirabz'lis, Proteus vul

ent invention, such compounds have been found to be times clockwise and ten times counterclockwise. The dishes are then incubated at 37 C. for 24 to 36 hours. 25 effective against a number of microorganisms, such as

The colonies are counted considering only those be

tween 30 and 300 count as signi?cant. Duplicate sam

ples are averaged. The procedure used for determining

the bacterial count after 1 hour is essentially the same as that used to determine the count at the zero contact

garis, Salmonella typhi, Salmonella typhimurium, Salmo

nella cholera suis, Enterobacter cloacae, Enterbacter aero

time. The only difference is that pour plating is per

formed at the 100 and 10" dilutions as well as at the

genes, Morganella morgam'i, Aeromonas hydrophila, Cit

robacterfreundii, Citrobacter deversus, Serratia marcesc ens, Serratia liqutfaciens, Xanthomanas campestris,
35

10*2 dilution. Percent reduction is calculated by the formula

Acinetobacter calcoacett'cus; Gram (+): Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus mutans, Streptococcus pyogenes, Streptococcus fecalis, Micrococcus

lutea, Bacillus sp. (vegetative cell); Fungi: Aspergillus

niger, Aspergillus ?avus, Aspergillus sydowi, Aspergillus

where A is the count per milliliter for the flask contain ing the treated substrate; B is zero contact time count per milliliter for the ?ask used to determine A before the addition of the treated substrate and C is zero
contact time count per milliliter for the untreated con 45

versicolor, Aspergillus terreus, Penicillium chrysogenum, Penicillium variabile, Penicillium funiculosum, Penicil

Iium pirtophilum, Poria placenta, Aureobasidium pullu

Ians, Gloeophyllum trabeum. Chaetomium gobosum, Tri

choderma viride, Trichophyton mentagrophytes; Fungi (yeasts): Candida albicans, Candida pseudotropicalis,
Saccharomyces cerevisiae.
The treatment disclosed herein can be carried out

trol substrate. The foregoing Shake Flask Test measures antimi crobial substrate activity. An alternative test sometimes

with the quaternary ammonium compounds of this in

employed is the Agar Plate Graphing Technique

vention per se. Often, however, it is desirable to extend which again affords a measure of antimicrobial sub 50 the compounds of this invention by incorporating therein hydrocarbon or halohydrocarbon substituted strate activity, in which treated swatches of fabric are siloxanes of the formula placed on agar impregnated with Klebsiella pneumoniae.

Antimicrobial activity is measured by the existence of a zone of inhibition and diffusability in the agar. Immobia
lized antimicrobials will not show a zone.

55

It is also possible to measure antimicrobial solution

activity and this is performed in accordance with the procedures of the Minimum Inhibitory Concentration Test (MIC) in which the level of chemical required to inhibit the growth of microorganisms in a system is detennined, typically employing organisms such as Staphylococcus aureus, Klebsiella pneumoniae, and Asper

in which R is a hydrocarbon or halohydrocarbon radi~ cal and a varies from 0 to 3. The incorporation of such siloxanes in no way effects the property of the quater nary ammonium compound so that the claims of this
invention are construed to cover both the use of quater

gillus niger.

One species of organosilane and the preferred or ganosilicon quaternary ammonium compound in accor 65 anes. For example, surfaces can be treated with an aque ous solution of a mixture of 10 mols of monomethyl dance with the present invention is 3-(trimethoxysilyl) trimethysilane and 1 mol of Cl-C1gH37Me2N+(CH2) propyldimethyloctadecyl ammonium chloride of the 3Si(OMe)3. It has also been found that combinations of formula:

nary ammonium siloxaneper se and mixtures or copoly mers of such siloxanes with said hydrocarbon substi tutes siloxanes or halohydrocarbon substituted silox

13

5,013,459

14

1 mol C1_C1sH37Me2N+(CH2)3Si(OMe)3 and 0.5 mol

of 3-chloropropyltrimethoxysilane give effective silox

ane coatings. The use of hydrocarbon and halohydro

carbon siloxane extenders often give cheaper, more durable, more oleophilic or oleophobic surface treat
ments, than the pure quaternary siloxane. The process of the present invention can be best de scribed with reference to the accompanying drawing in

nate the problem of microbial contamination and buildup of microorganisms, both the inner and outer surfaces of the container 10 should be treated with the organosilane in order to bind the organosilane to these surfaces. This treatment should include especially the area surrounding the outlet 19, particularly the cap 15,
as well as the container walls 11. In the case of ophthal

which the container for dispensing an ophthalmic solu tion is shown generally at 10 in FIGS. 1 and 2. The
liquid dispenser 10 will be seen to include a ?exible wall 11 which forms a reservoir for storing saline solution 12.

>mic applications of the present invention, such treat ment avoids the contamination caused by touching the
cap to the eye area upon administration of the contents of the container to the eye. Such surface coverage of the container interior and exterior walls is set forth in

In accordance with the presentinvention, the solution is preferably free of preservative. Container 10 has an upper section 13 which includes exterior threads, and the exterior threads mate with the interior threads 14 of the container cap 15. Cap 15 can also be integrally con structed with container wall 11, if desired. Cap 15 en
closes and forms a chamber 18 which houses a porous

Example I. Treatment may be further enhanced by

adding directly to the contents of the reservoir 12 a

loose organosilane bound porous material. This concept is shown in Example III. Wetting agents such as ?uoro carbon, nonionic, and cationic surfactants, may also be combined with the organosilane in the treatment pro
cess, and this embodiment.is set forth in Example II.

Example IV is directed to the concept of employing the ?lter medium. The ?lter medium is retained in the organosilane in the most effective amount which is chamber 18 by a screen mesh support 17 which is posi shown to be at least in excess of about 0.5 percent by tioned and held within the cap 15 by an interior lip 20. weight of the organosilane based on the total weight of An outlet 19 extends axially of cap 15 and provides the surface being treated, and preferably in an amount communication between the reservoir 12 of saline ?uid and the exterior of the container 10. As the container is 25 of about 0.75 percent by weight. tilted by the hand 22 of the user in the direction of EXAMPLE I arrows 16, as shown in FIG. 2, drops 21 of saline solu
tion are directed to the area of the eye of the user. When

Containers of polyethylene, polypropylene and glass

were treated by exhaustion while immersed in 140 de gree Fahrenheit tap water, 1% by weight solution of a

the container is returned to its upright position as shown in FIG. 1, excess saline solution in outlet 19 drains back into reservoir 12 through the porous ?lter medium 18. The device also includes a cover for the outlet which is not shown in the drawings. Treatment of the porous ?lter medium 18 with the

42% active 3-(trimethoxysily1)propyldimethyloctade

cyl ammonium chloride for four hours. Samples were
dried-in a forced air oven at 90 degrees Centigrade for

organosilicon quaternary ammonium compounds of the

present invention results in a covalent bond which

two hours. Glass beads, cigarette ?lters of cellulose triacetate, #1 Whatman ?lter paper, and styrene maleic
anhydride (SMA) beads were treated as above. Bromo

chemically unites the organosilicon antimicrobial com

pound to the surfaces of the porous ?lter medium. This provides that the bound antimicrobial will not leach into the reservoir or pass into the eye with the drops 21,
as do conventional unbound type antimicrobials and

phenol blue tests for intensity of color and uniformity of

treatment were performed by immersion to treated and control substrates for ?ve minutes immersion and at ambient room temperature. The #1 Whatman ?lter paper and the cigarette ?lters were tested by a padding test, the beads and plastic containers were tested by the dynamic shake ?ask test.

disinfectants. This is particularly signi?cant in the pres

ent instance in that the various opthalmic solutions intended herein are delivered to the highly sensitive
area of the human eye.

In the padding test, the bacteriostatic activity of fab

45 ric or an antibacterial agent applied to a standard fabric

The wall 11 of the portable container 10 is con structed of a ?exible material in order that the container wall may be squeezed to force the contents of the con

is evaluated. Test and control fabric swatches are inocu

lated with the test organism. Immediately after inocula

tion and after six hours of contact time, the bacteria are eluted from selected swatches by shaking in a known tainer from the reservoir 12 through the porous ?lter medium 18 and into the outlet 19. The ?exible material 50 amount of solution. The number of bacteria present in the two solutions is determined. The percent reduction is preferably one of polyethylene, polypropylene, and after the six hour contact is calculated and reported. acrylic polymers. The porous ?lter medium 18 may be one of a variety of materials suitable for liquid ?ltration __This method is based on AATCC Test Method lOO. The results of the tests of Example I are shown in among which are those ?lter materials constructed of a Table I. ?ber strand such as rayon, wool, nylon, cotton, silk, cellulose triacetate, polypropylene, polycarbonate, ? TABLE I berglass, and polyester. The porous ?lter medium can Analytical (mug % Reductionz
also be of a cellular structure of a foam material such as

polyurethane, polystyrene, polyvinyl chloride, polyeth

ylene, and polypropylene. In addition, the porous ?lter
medium may be a high surface area particulate material such as silica, ceramic, sintered metal, and sintered glass. Other materials which can be used for the porous ?lter medium are paper, mesh screen, and glass beads.
60

Inten-

Shake

Sample
PE Bottle
PP Bottle
Glass Bottle

sity1
Treated
Control Treated Control Treated Control Treated
Control

Uniformity
complete
None Complete None complete None complete
None

Padding
NR6
NR NR NR NR NR NR
NR

Flask
1005
05 1005 05 NR NR 100
0

2
4 3 4 2 4 2
4

struction is the preferred embodiment.

Glass containers can also be used but the ?exible con 65 Glass Beads

In addition to treatment of the porous ?lter medium 18 with the organosilane, and in order to further elimi

SMA Beads

Treated
Control

2
4

Complete
None

NR
NR

100
0

15
TABLE I-continued
Analytical (BPA)
Inten-

5,013,459
% Reduction2
Shake

EXAMPLE III Contaminated Solution Test Using Various

Sample
Whatman #1 Treated Control

sity1
' 1 4

Uniformity
Complete None

Padding
1003 0

Flask
NR NR

Bottle/Substrate-Filter/Substrate Con?gurations
5

All test substrates were treated as in Example I. A

phosphate buffer solution of a 24 hour culture of Klebsi

CTA Filter

Treated
Control

l
4

Complete
None

1004
0

100
0 10

ella pneumoniae at 1.4x 1O5/ml was prepared. Twenty

milliliters of this inoculum was placed into test con

IIntensity: l - Dark Purple, 2 - Medium Purple, 3 - Light Purple. 4 - No Retention.

2Klebsiella Pneumoniae, one hour.

"Eight Circles.
Tented nplrt and placed in bottom of tube for padding.
we grains cut in small pieces.
NR - not run.

PE = Polyethylene PP = Polypropylene

tainer con?gurations and agitated on a rotary shaker for one hour. Plate counts were performed using standard plate count procedures. The results of these tests are shown in Table III. TABLE III
Microbial Plate Counts

CTA = Cellulose Triacetate

15

Sample

% Reduction
Treated Control Treated Control Treated Control Treated Control Treated Control Treated Control Treated Control Treated Control Treated Control 99.99 0 99.98 0 99.98 0 100 0 100 0 100 0 100 0 100 0 100 0

The test protocol above provides data from which it

can be concluded that all of the test substrates were

PE Bottle 2 oz. PP Bottle 2 oz.

uniformly treated with the test compounds and that

surfaces were antimicrobial. 20

Glass Bottle 2 oz.

PE Bottle 2 oz.

EXAMPLE II To minimize treatment time and to optimize unifor mity, a test using a wetting agent was conducted. Sub strates as in Example I were treated by exhaustion by 25 immersion in ambient room temperature tap water with a 1% by weight solution of a 42% 3-(trimethoxysilyl)

0.5 g Glass Beads

PP Bottle 2 oz. 0.5 g Glass Beads Glass Bottle 2 oz. 0.5 g Glass Beads PE Bottle 2 oz. 0.5 g CTA Filter PP Bottle 2 oz. 0.5 g CTA Filter Glass Bottle 2 oz. 0.5 g CTA Filter

propyldimethyoctadecyl ammonium chloride for l min

ute, 5 minute, 10 minute and 20 minute intervals. Sam ples were dried in a forced air oven at 90 degrees Centi- 30 grade for two hours. The treatment bath contained

0.05% by weight of a ?uorocarbon surfactant Zonyl

FSN. The surfactant can be any nonionic or cationic

8 Material including orgenosilane placed in container.

wetting agent.
Bromophenol blue tests were performed and the re sults of these tests are shown below in Table II. TABLE II
1 Minute 5 Minutes

The test protocol of Example III and Table III pro

vides data from which it can be concluded that the

control bottles and ?lter con?gurations did not affect

BPA Analytical Ratings/Treatment Immersion Times

10 Minutes 20 Minutes

Sample
PE Bottle
PP Bottle

Intensityl Uniformity Intensity Uniformity Intensity Uniformity Intensity

Treated
Control

Uniformity
Complete
None

4
4

None
None

3
4

Pools
None

3
4

Complete
None

2
4

Treated
Control

4
4

None
None

3
4

Pools
None

3
4

Complete
None

2
4

Complete
None

Glass Bottle
Glass Beads

Treated
Control Treated Control Treated
Control

3
4

Pools
None Pools None None
None

2
4

complete
None

2
4

complete
None Complete None Complete
None

2
4

Complete
None Complete None Complete
None

SMA Beads

3 4 4
4

3 4 3
4

Pools None Pools

None

3 4 2
4

2 4 2
4

Whatman #1
CTA Filter

Treated
Control

2
4

Complete
None

1
4

Complete
None

1
4

Complete
None

1
4

Complete
None

Treated
Control

2
4

Complete
None

1
4

Complete
- None

1
4

Complete
None

1
4

Complete
None

1Intensity: l - Dark Purple. 2 - Medium Purple, 3 - Light Purple, 4 - No Retention.

55 microbial growth; that sanitizing levels of reduction were reached with all treated samples; and that the use of thetreated glass beads or CTA ?lter inserts signi? cantly improved the microbial kill.
EXAMPLE IV The test protocol of Example I] and Table II pro- 60 The substrate for ?ltering materials was Filterol , vides data from which it can be concluded that the CTA cigarette ?lter. This test was conducted to deter wetting agent enhances room temperature exhaustion mine an optimal treatment level. The Filterol CTA such that all substrates were uniformly treated within 10
?lters were treated as in Example I except that a con minutes. The Whatman #1, and CTA ?lters were uniformly 65 centration series of 0.25%, 0.5%, 0.75% and 1% of 42% active 3-(rimethoxysilyl)propyldimethyloctadecyl am treated in one minute, the SMA and glass beads and the monium chloride by weight of the substratewas em PE and PP bottles in 10 minutes, and the glass bottle in ployed in the exhaustion procedure. A 20 minute ex 5 minutes.

17

5,013,459

18

haustion period was employed. Analytical checks of the post exhaustion bath showed no detectable active ingre dient. All samples were tested with bromophenol blue,

were placed in a rinsed one pint French square bottle. The treated test system and untreated control were placed into a series of these bottles and shaken on a

reciprocal shaker at ambient room temperature (21 C.) and the Shake Flask Test was performed as outlined above. Results of these tests are set forth in Table IV. 5 for 0 minutes, 1 minute, 5 minutes, 10 minutes and 20 minutes. Water sam les were analyzed for B-trimethox
TABLE IV . . P . .

>

ysilylproplydimethyl

octadecyl

ammomum

chloride

Amy"?!
Fl 1
Sample

% Transmission

120

M'rb'l$cal % Reduction
12 8

blue colorimetric test. Each of the samples were sub

using the quaternary ammonium sensitive bromophenol , , .

Filzggl %
pi1mo1
Filterol
Fh'erol @

ozsggfhs
(150% TMS
0.75% TMS
90% TMS
.

14b
14,0
15.0
16-0

'7
405
99.6
99-6

l0 jected to Bit of the above protocol. Samples were dried

between cycles. It was found that 2x of the 5 minute
rinse ridded the system of unreacted material and all
microbiolog ical tests were run with that system.
' Staphylococcus aureas, Escherichia coli and Pseudomo

Table IV indicates that the preferred level of treat- 15.. "115 aemginosa were cultured Per the preservative ch31

ment with the organosilane TMS to provide desired

efficacy as an antimicrobial ?lter medium is in excess of

lehge Test Requh'emems 1" the 115- Pharmacopla- C111"

lures were stahdal'dlzed so_ that one drop eohfalhed

at least about 0.50% by weight of the organosilane,

belweeh _105 and 106 Orgamsms- A

"Yphe 0_y

preferably about Q_75%_

EXAMPLE v

20 liters of broth was placed aseptically into 9 milliliters

broth (Difco) was prepared and sterilized. Five milli

were Inserted and {OPS arranged unqler aseptw Conch

polyethylene dropper bottles. Tips and ?lter assemblies

t t d '.d tions. A drop of the moculum was aspirated into the test

Simulated In Use Test-Antimicrobial Package System

A t t 1 k t

1on9 ' ?lmed xsllgoljrgp>f g8 .y toe a iiyoirg 20m?! 1:51?wet B 2:.mg agen . SOY 1mm es d 90f, ~ony amp es were me a

t. Ola pa: 3g? 5y? em .vras 9on5 rllc ab. {10 pr? .e optima F3115 guf'gpnthor mltgatm mlcgl tla contarin' 25 3 10.11.10 e 11. gnthecon (timer fromtl .0 etlnp y'nil', uge'i. o z?ionblp 15: sdyihem 0 con a.m.ma 10; as 1. e. p0 ed of. 650%.; at is)? (receiving Cctm avml' nanoncigvas heuste. ' tag/3S bsys er. gfmfporlgnqs welre game. 33; 5X 2315109131 6 ylydweltgh 10 t1 d 0150 u 30

bottles. Separate bottles were checked for microbial presence at 24 hours, 14 days, and 28 days. Standard retrieval and counting techniques were used for the ?uid. One milliliter was removed for serial dilution. The tips and ?lters were aseptically removed, placed in tubes of tryptic soy broth, incubated for 24 and 48 hours, and checked for growth turbidity, and recorded
as (+) or (). Identi?cations of the organisms were made. All tests were run in triplicate. The results are Shown in Table V_

TABLE V
MICROBIOLOGICAL TEST
SIMULATED IN-USE TEST - ANTIMICROBIAL PACKAGE sYsTEM

Fluid Tests/CFU/ml
Organism
Staphloccoccus aureus

Tip
28 Days
0 o o

Filter
24 hr.
-_ _

Run
l 2 3

TR
X x x

UNTR

0 hr.
2.6 X l0H 2.6 X 104 2.6 X 101

24 hr.
O o o

14 Days
0 o 0

24 hr.
_

48 hr.
_ -

48 hr.
_ _

1 2 3
Escherichia coli 1 2

X x X
x x x

16x10" 2.6><i041 215x104

3.56 >< 102 3.56 X 1042 3.56 X 10*2

>3><107 >3><107 >3><107

3.1 X 102 2.6 X 102

>3><107 >3><l07 >3><1O7

o 0 o

>3><l07 >3><107 >3><107

o o

++ + +
_ -

+++ +++ +++

_ _ ~

+++ +++ +++

_ _ _

+++ +++ +++

_ _,

2.7 X 102

l 2 3
Pseudomona aeuroginosa 1 2 3 x X x

X x x

356x1042 356x102 356x1042

3.84 x 1043 3.84 X 1043 3.84 X 1043

>3><1O7 >3><107 >3><107

3.1 x 101 6.8 X 101 4.3 x 101

>3><107 >3><107 >3><l07

0 0 o

>3><107 >3><1o7 >3><1o7

o 0 o

+ ++ +
_ _

+++ +++ +++

_

+++ +++ +++

_ _

+++ +++ +++

_ _

I 2 3

x x X

184x10 >3><107 184x10 >3><107 184x103 >3><l07

>3><107 >3><1o7 >3><10"

>3><1O7 >3><1o7 >3><107

++ + ++

+++ +++ +++

+++ +++ +++

+++ +++ +++

= Inoculum drop had 1.35 X 105 CFU organisms present. Divided _by 5 ml equals 2.6 x 10 CFU/ml. 2 = lnoculum drop had 2.78 x 10 CPU organisms present. Divided by 5 ml equals 3.56 X 10 CFU/ml. 3 = lnoculum drop had 1.92 X 105 organisums present. Divided by 5 ml equals 3.84 X 10 CFU/ml.
TR = Treated. UNTR = Untreated.

C. in a forced air oven and put through a rinse cycle. Each of the test bottles were aseptically assembled with the CTA ?lter 18 inserted into the neck of the 60

delivery nipple and inserted into the neck of the bottle. Controls and treated samples were all treated identi cally. Various ?lter substrates such as urethane foam,

The treated bottle systems in Table V showed rapid reduction of the test organisms as evidenced by the absence of growth of the S. aureus in the 24 hour ?uid sample, and the absence of growth on the tip or in the ?lter matrix. This is evidenced by the 2-2.5 log reduc cotton fabric, and paper, were treated as above, and 65 tion of E. coli in the 24 hour ?uid sample; the absence of inserted as needed for testing. growth at 14 days and absence of growth on the tip or To assure durability of the treatment, a deionized in the ?lter matrix, and the 3 log reduction of P. water rinse cycle test was undertaken with the treated aeuroginosa in the 24 hour ?uid sample, absence of substrates. Four hundred milliliters of deionized water

19

5,013,459

20

growth at 14 days, and absence of growth on the tip or in the ?lter matrix. All positive growth was con?rmed to be the appropriate test organism. The criteria of the

U.S. Pharmacopia preservative challenge test was

met (3 log reduction in 14 days with no increase after 28 days), demonstrating that the system will preserve a

5. The method of claim 4 in which excess aqueous ?uid in the outlet returns to the reservoir through the porous ?lter medium upon release of the container wall. 6. The method of claim 5 wherein the porous ?lter medium is constructed of a ?ber strand selected from

the group consisting of rayon, wool, nylon, cotton, silk,

packaged ?uid from bacterial organisms sourced from

outside. ' '

cellulose triacetate, polypropylene, polycarbonate, ? berglass, and polyester.

7. The method of claim 5 wherein the porous ?lter medium is a cellular foam material selected from the

It will be apparent from the foregoing that many other variations and modi?cations may be made in the

compounds, compositions, and methods described

herein without departing substantially from the essen tial features and concepts of the present invention. Ac cordingly, it should be clearly understood that the forms of the invention described herein are exemplary
only and are not intended as limitations on the scope of

group consisting of polyurethane, polystyrene, polyvi nyl chloride, polyethylene, and polypropylene.
8. The method of claim 5 wherein the porous ?lter medium is a high surface area particulate material se ; lected from the group consisting of silica, ceramic, sin~ tered metal, and sintered glass. 9. The method of claim 5 wherein the porous ?lter medium is constructed of a material selected from the

the present invention. That which is claimed is:

1. A method of dispensing an aqueous sterile ?uid

comprising storing a quantity of aqueous sterile ?uid in a reservoir within a portable container having an outlet, arranging a porous ?lter medium within the container

group consisting of paper, mesh screen, and glass beads. 10. The method of claim 1 wherein the aqueous sterile ?uid is selected from the group consisting of ophthal mic solutions, saline salt solutions, water delivered med

adjacent the outlet, and causing the aqueous sterile ?uid

icines, surgical irrigation ?uids, water, milk, and emul

510115.

to pass from the reservoir through the porous medium 25 11. The method of claim 1 in which the organosilane to the outlet, the porous medium having covalently is bonded to the outer surfaces of the portable container. bonded thereto an antimicrobially effective amount of 12. The method of claim 11 in which the organosilane an organosilicon quaternary ammonium compound, the is bonded to the inner surfaces of the portable container. organosilicon quaternary ammonium compound being 13. The method of claim 12 in which the container an organosilane having the formula selected from the reservoir includes a porous material therein and the porous material has the organosilane bonded thereto. group consisting of consisting of 14. The method of claim 13 wherein the porous mate

rial having the organosilane bonded thereto is selected from the group consisting of beads and ?bers.
35
and

15. The method of claim 14 wherein the ?ber is a strand selected from the group consisting of rayon,

wool, nylon, cotton, silk, cellulose, triacetate, polypro

pylene, polycarbonate, ?berglass, and polyester.

16. The method of claim 1 in which the organosilane
is present in an amount in excess of about 0.5 percent by weight based on the total weight of the surface treated
. Ra

with the organosilane.

17. The method of claim 16 in which the amount of

wherein, in each formula,

Y is R or R0 where each R is an alkyl radical of l to 45 18. The method of claim 1 in which the porous me 4 carbon atoms or hydrogen; dium includes a wetting agent in addition to the or alias a value ofO,1, or 2; ganosilane, the wetting agent being selected from the

the organosilane is about 0.75 percent by weight.

R is a methyl or ethyl radical; R is an alkylene group of l to 4 carbon atoms; R', R" and RV are each independently selected from a group consisting of alkyl radicals of l to 18

group consisting of nonionic surfactants, cationic sur factants, and ?uorocarbon surfactants. 19. The method of claim 1 wherein the organosilane

is 3-(trimethoxysilyl) propyldimethyloctadecyl ammo

nium chloride of the formula

carbon atoms, --CH2C6H5, CH2CH2OH, CH

20H, and -(CHz)xNHC(O)R"', wherein it has a value of from 2 to 10 and R is a per?uoroalkyl radical having from 1 to 12 carbon atoms; and X is chloride, bromide, ?uoride, iodide, acetate or

55

tosylate.
2. The method of claim 1 wherein the aqueous ?uid is an ophthalmic saline solution which is free of preserva tives. 3. The method of claim 2 wherein the wall of the portable container is constructed of a ?exible material in order that the container wall may be squeezed to force the contents of the container from the reservoir through the porous ?lter medium and into the outlet. 4. The method of claim 3 in which the ?exible mate

20.. A method as claimed in claim 1 wherein the or

ganosilicon compound has the formula

rial is selected from the group consisting of polyethyl

ene, polypropylene, and acrylic polymers.

21

5,013,459

22

wherein each R is an alkyl radical of 1 to 4 carbon atoms or hydrogen; a has a value of 0, 1 or 2; R is a methyl or ethyl radical; R" is an alkylene group of 1 to 4 carbon

cellulose triacetate, polypropylene, polycarbonate, ? berglass, and polyester.

27. The device of claim 25 wherein the porous ?lter medium is a cellular foam material selected from the

atoms; R', R and Rvare each independently selected

from a group consisting of alkyl radicals of l to 18

carbon atoms, -CH2C6H5, CH;CH3OH, CHZOH,

and (CH1)xNl-lC(O)R"', wherein x has a value of from 2 to 1 and Ri is a per?uoroalkyl radical having from 1 to 12 carbon atoms; X is chloride, bromide, ?uoride, iodide, acetate or tosylate. 21. A method as claimed in claim 1 wherein the or

group consisting of polyurethane, polystyrene, polyvi nyl chloride, polyethylene, and polypropylene.
28. The device of claim 25 wherein the porous ?lter
medium is a high surface area particulate material se

lected from thev group consisting of silicon, ceramic, sintered metal, and sintered glass.
29. The device of claim 25 wherein the porous ?lter medium is constructed of a material selected from the

ganosilicon compound has the formula

group consisting of paper, mesh screen, and glass beads.

' 30. The device of claim 22 in which the organosilane ._ is chemically bonded to the outer surfaces of the porta

(R0)3_,,s|iR" N
R'a

22. A device for dispensing an aqueous sterile fluid comprising a portable container having a reservoir in
communication with an outlet, a porous ?lter medium

ble container. 31. The device of claim 30 in which the organosilane is chemically bonded to the inner surfaces of the porta ble container. 32. The device of claim 31 in which the container
reservoir includes a porous material therein and the

porous material has the organosilane chemically bonded

thereto. 33. The device of claim 32 wherein the porous mate

within the container adjacent the outlet, the aqueous sterile ?uid passing from the reservoir through the po
rous medium to the outlet, the pourous medium having covalently bonded thereto an antimicrobially effective amount of an organosilicon quaternary ammonium

rial having the organosilane chemically bonded thereto

is selected from the group consisting of beads and ?bers. 34. The device of claim 33 wherein the ?ber is a strand selected from the group consisting of rayon,

compound. the organosilicon quaternary ammonium compound being an organosilane having the forumla
selected from the group consisting of
30

wool, nylon, cotton, silk, cellulose triacetate, polypro

pylene, polycarbonate, ?berglass, and polyester.

35. The method of claim 1 in which the organosilane
is present in an amount in excess of about 0.5 percent by

weight based on the total weight of the surface treated

with the organosilane. .

35

36. The device of claim 35 in which the amount of the

organosilane is about 0.75 percent by weight.

37. The device of claim 22 in which the porous me
_ dium includes a wetting agent in addition to the or

ganosilane, the wetting agent being-selected from the

wherein, in each formula,
Y is R or R0 where each R is an alkyl radical of l to 4 carbon atoms or hydrogen; a has a value of O, l or 2; R is a methyl or ethyl

group consisting of nonionic surfactants, cationic sur factants, and ?uorocarbon surfactants. 38. The device of claim 22 wherein the organosilane is 3-(trimethoxysilyl) propyldimethyloctadecyl ammo nium chloride of the formula
45

radical;
R" is an alkylene group of 1 to 4 carbon atoms;

R', R"" and Rvare each independently selected from

a group consisting of alkyl radicals of 1 to 18 car

bon atoms, CH2C6H5, CHZCHZOH, :CHZOH, and (CHz)xNl-IC(O)R"', wherein x

has a value of from 2 to 10 and R is a per?uoroal

kyl radical having from 1 to 12 carbon atoms; and X is chloride, bromide, ?uoride, iodide, acetate or
39. The device of claim 22 wherein the organosilicon tosylate. 23. The device of claim 22 wherein the container 55 compound has the formula
includes a wall constructed of a ?exible material in

order that the container wall may be squeezed to force the contents of the container from the reservoir through the porous ?lter medium and into the outlet. 24. The device of claim 23 in which the ?exible mate

rial is selected from the group consisting of polyethyl

ene, polypropylene, and acrylic polymers.

25. The device of claim 24 in which excess aqueous atoms; R, R"" and Rvare each independently selected ?uid in the outlet returns to the reservoir through the porous ?lter medium upon release of the container wall. 65 from a group consisting of alkyl radicals of l to 18 carbon atoms, CH2C6H5, CH2CH2OH, --CH2OH, 26. The device of claim 25 wherein the porous ?lter and -(CHZ)XNHC(O)R"", wherein x has a value of from medium is constructed of a ?ber strand selected from 2 to 10 and Rw'is a per?uoroalkyl radical having from 1 the group consisting of rayon, wool, nylon, cotton, silk,

wherein each R is an alkyl radical of l to 4 carbon atoms or hydrogen; a has a value of O, 1 or 2; R is a methyl or ethyl radical; R" is an alkylene group of l to 4 carbon

23

5,013,459 '

24
/

to 12 carbon atoms; X is chloride, bromide, ?uoride,

iodide, acetate or tosylate.

(RO)3_,SiR" g
R'?
_
1O

\ X9
_'

40. The device of claim 22 wherein the organosilicon

compound has the formula

25

35

45

55

65