U.S. patent number 3,728,213 [Application Number 05/172,880] was granted by the patent office on 1973-04-17 for antibiotic paper.
This patent grant is currently assigned to American Cyanamid Company. Invention is credited to Charles Frank Hinz.
United States Patent |
3,728,213 |
Hinz |
April 17, 1973 |
**Please see images for:
( Certificate of Correction ) ** |
ANTIBIOTIC PAPER
Abstract
Cellulose fibers possess strong antibiotic properties (including
antiviral properties) when they have a uniform content of a small
amount of a 2-(C.sub.8 -C.sub.18 substantially straight chain)
pseudourea. The fibers remain antimicrobial when in addition they
contain a normally water-soluble thermosetting wet strength resin
in thermoset state. Antibiotic bandages, diapers, bed sheets,
boxes, surgeons' gowns, etc. can be prepared from paper composed of
these fibers.
Inventors: |
Hinz; Charles Frank (East
Norwalk, CT) |
Assignee: |
American Cyanamid Company
(Stamford, CT)
|
Family
ID: |
22629582 |
Appl.
No.: |
05/172,880 |
Filed: |
August 18, 1971 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
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773954 |
Nov 6, 1968 |
|
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42479 |
Jun 1, 1970 |
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Current U.S.
Class: |
162/161; 47/9;
162/158; 424/404; 424/443; 424/447; 514/588 |
Current CPC
Class: |
A61L
15/28 (20130101); A61L 15/46 (20130101); A61L
15/28 (20130101); D21H 21/36 (20130101); C08L
1/02 (20130101) |
Current International
Class: |
A61L
15/20 (20060101); A61L 15/16 (20060101); D21h
005/22 (); D21h 003/12 () |
Field of
Search: |
;162/158,161,190
;424/322,326,27-29 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
Primary Examiner: Bashore; S. Leon
Assistant Examiner: Smith; William F.
Parent Case Text
This is a continuation-in-part of my copending applications, Serial
Nos. 773,954 and 42,749, respectively, filed November 6, 1968 and
June 1, 1970, and now both abandoned.
Claims
I claim:
1. Cellulose fibers having a uniformly adsorbed effective content
within the range of 0.01 percent - 3 percent based on the dry
weight of the fibers as agent inhibiting the growth of
microorganisms thereon of a 2-(C.sub.8 -C.sub.18 substantially
straight chain alkyl) pseudourea.
2. Fibers according to claim 1 wherein the pseudourea is
2-n-dodecylpseudourea.
3. Antimicrobial paper consisting essentially of fibers according
to claim 1.
4. Infants' diapers consisting essentially of a substantially
square assembly of a batt of fibers according to claim 1 and two
sheets of wet strength paper, one of which is sized and the other
is unsized, said batt being positioned between said sheets of
paper.
5. A process for the manufacture of antimicrobial paper which
comprises forming an aqueous suspension of cellulose papermaking
fibers, adding thereto a small but effective amount as
antimicrobial agent of a salt of a 2-(C.sub.8 -C.sub.18
substantially straight chain alkyl) pseudourea, forming said fibers
into a wet web, and drying said web at a temperature between about
190.degree. F. and 250.degree. F. to form paper.
6. A process according to claim 5 for the manufacture of paper
which comprises forming an aqueous suspension of cellulose
papermaking fibers, adding thereto sufficient of an acid solution
of a 2-(C.sub.8 -C.sub.18 substantially straight chain alkyl
polypseudourea) to deposit on said fibers an effective amount
thereof within the range of 0.01 percent - 3 percent based on the
dry weight of said fibers as antimicrobial agent, adding to said
suspension 0.1 percent - 3 percent of a water-soluble cationic wet
strength resin, forming said fibers into a web, and drying said web
at a temperature between about 190.degree. F. and 250.degree.
F.
7. A process according to claim 6 wherein the wet strength resin is
a thermosetting resin containing amine-reactive substituents.
Description
The present invention relates to cellulose fibers and fibrous
cellulose structures having antimicrobial properties. More
particularly, the invention relates to cellulose fibers, water-laid
cellulose webs (including paper) and articles made therefrom having
antimicrobial properties resulting from the presence therein of a
uniformly adsorbed content of an ionic pseudourea, and to methods
for the manufacture of said fibers and webs. For convenience, the
term "antimicrobial" is hereafter used to describe the inhibiting
of the life of all microbes including fungi, bacteria, protozoa and
viruses.
Antimicrobial paper is paper composed of fibers which have an
effective content of an agent which inhibits the growth thereon of
some or all of the forms of life just mentioned. In the past, the
principal use of such paper has been as mulch paper (paper which is
spread on the ground to inhibit the growth of weeds and the
evaporation of water), but such paper is coming to find important
use for such purposes as bandages, boxes for bandages and other
surgical equipment, diapers, surgical drape sheets, hospital gowns
and bed sheets, and as the base for surgical adhesive tape. Such
items are commonly supplied in sterile form, and during their
period of use they must resist microbial growth. Paper which
possesses antiviral properties is urgently desired, for example in
connection with the care of patients with head colds, influenza and
mumps.
Because of the long period of time during which it must maintain
its integrity in the warmth and humidity of the environment, mulch
paper must be highly and comparatively permanently resistant to
microbial attack. Mulch paper is moist during much of its life at a
temperature most favorable to the growth of microorganisms, and is
subject to severe tearing forces (e.g., by the wind) from time to
time. Mulch paper desirably maintains its identity and strength
during the growing season and nevertheless should ultimately
succumb to attack by microorganisms, i.e., it should be greatly
weakened or disintegrated by them within two to three months after
being plowed under ground at the end of the growing season. PaPer
used for bandages, hospital sheets, surgical drape sheets and
underwear should likewise possess wet strength.
The discovery has now been made that cellulose fibers which have an
adsorbed content of a long chain alkyl pseudourea of borderline
solubility such that it is substantially insoluble in water as the
free base but is soluble in acid possesses antimicrobial properties
alone and in the presence of wet strength resins in thermoset
state, and these properties are retained when the paper is exposed
to moist conditions for long periods of time at elevated
temperatures such as are encountered in outdoor weathering. I have
found that in preferred embodiments such as when the paper is
sufficiently antimicrobial to strongly resist the growth of
microbial life under incubating conditions, the fibers carrying a
pseudourea of the type described remain substantially sterile.
The present invention in preferred embodiments provides
improvements as follows:
1. Bulk fibrous cellulose ("cotton wool") carrying a pseudourea (or
pseudothiourea) of the type described possesses antimicrobial
properties when used as surgical and dental packing in wounds, and
when employed as packing material in boxes has the property of
maintaining the inside of the boxies substantially sterile with
respect to yeasts, bacteria, protozoa, and lipophilic viruses. 2.
Paper comprising the aforesaid fibers possesses similar
antimicrobial properties and remains substantially sterile when
employed as diaper material for babies, surgical drape sheets,
hospital gowns bed sheets, etc.
3. The paper strongly resists attack by microorganisms found in
agricultural fields, and this activity is not masked when the paper
has an effective amount of a normally water-soluble wet strength
resin in thermoset state. Moreover, the paper is readily permeable
by water, and hence permits rain to penetrate into the ground, and
is accordingly well-suited for use as mulch paper. The paper is
substantially unaffected by the action of microorganisms when
allowed to remain for three to five months on fields under
temperature and humidity conditions highly conducive to the rapid
growth of microorganisms (temperatures of 70.degree. F.- 90.degree.
F. and relative humidity in excess of 50 percent).
The microbial life against which the paper of the present invention
possesses activity include the bacteria, (including
sulfate-reducing bacteria), yeasts, fungi, and green algae, and
lipophilic viruses.
The pseduoureas referred to have the formula
R represents a C.sub.8 -C.sub.18 substantially straight chain alkyl
substituent. Suitable substantially straigh chain alkyl
substituents include octyl, dodecyl, hexadecyl and octadecyl. The
aforesaid pseudoureas dissolve in water containing a stoichiometric
excess of hydrochloric acid, acetic acid, formic acid,
trichloroacetic acid, nitric acid, phosphoric acid or other strong
acid. The molecule as a whole is cationic.
The amount of pseudourea present in cellulose fibers and in the
paper of the present invention depends upon the specific
antimicrobial activity of the pseudourea present, the vitality of
the microorganisms present, and the degree of antimicrobial
activity which it is desired that the fibers (or paper, paperboard,
etc. which have a content thereof) should possess. As a rule of
thumb, I have found that in most instances, cellulose fibers
possess perceptible antimicrobial activity when they contain as
little as 0.1 percent of the pseudourea based on the dry weight of
the fibers. On the other hand, I have found that the fibers need
not contain more than about 3 percent by weight of the pseudourea
for them to possess very satisfactory antimicrobial activity. My
results to date indicate that satisfactory results are obtained
when the fibers contain between about 0.3 percent and 0.5 percent
by weight of the pseudourea as in this range the fibers (and the
paper) possess very satisfactory antimicrobial activity yet
over-use of the pseudourea is avoided. The optimum amount of
pseudourea that need be present in any instance to procure the
desired antimicrobial activity can be readily found by laboratory
trial.
The pseudoureas referred to above are most conveniently applied by
forming an aqueous suspension of cellulose fibers and adding to the
suspension one or more of the aforesaid pseudoureas as a
water-soluble salt. The pseudourea component of the salts are
rapidly and substantively absorbed by the fibers and the amount of
pseudourea which is present in the fibers of the final product can
be determined by calculation based on Kjeldahl nitrogen
analysis.
Thereafter the suspension is processed into paper or paperboard in
any customary manner. The fibers are formed into a web web by
flowing the suspension over a foraminous substrate, and the web is
dried at an elevated temperature into the desired form.
For the manufacture of cotton wool the fibers in the suspension may
be allowed to accumulate on the foraminous substrate so as to form
a wet web of substantial thickness which may be dried, and the
resulting batt carded so as to separate the fibers into a fluffy
wool-like product.
For processing into paper, the suspension is formed into a wet web
at some normal basis weight and the wet web is dried over
steam-heated rolls.
In many instances when the end product is paper or paperboard, it
is desired that such product possess wet strength properties. These
properties can be imparted by adding any of the known cationic
thermosetting wet strength resins for paper along with the
pseudourea, or by applying the wet strength resin subsequently, for
example at the size press, the paper being subsequently heated to
develop the wet strengthening properties of the resin. Suitable
resins include the melamine-formaldehyde resin colloid of Maxwell
et al. U.S. Pat. No. 2,345,543, the polyamine-epichlorohydrin
resins of Daniel et al. U.S. Pat. No. 2,595,935, and the
polyamidepolyamine-epichlorohydrin resins of Keim, U.S. Pat. No.
2,926,154.
It may be desired that the paper and paperboard of the present
invention possess superior dry strength without possessing
permanent wet strength (to facilitate disposal of the paper after
use). This can be accomplished by adding a water-soluble cationic
or non-ionic dry strengthening agent along with pseudourea.
Suitable polymers for this purpose are disclosed in Woodberry, U.S.
Pat. Nos. 2,959,514 and 3,258,393.
The invention will be further illustrated by the following examples
which illustrate embodiments of the invention and are not to be
construed as limitations thereon.
EXAMPLE 1
The following illustrates the manufacture of antimicrobial
cellulose fibers resulting from the presence thereon of a small
amount of water-insoluble pseudourea.
Aliquots are taken from an aqueous neutral suspension of
well-beaten cellulose papermaking fibers at a consistency 0.6
percent and to these are respectively added sufficient of 10
percent by weight solutions of:
1. n-Decylpseudourea hydrochloride
2. n-Dodecylpseudourea nitrate
3. n-Dodecyl-N,N-dimethylpseudourea acetate
4. n-Hexadecylpseudourea trichloroacetate
to provide up to 0.5 percent of the urea derivative (as the free
base), based on the dry weight of the fibers. The pH of the
aliquots is then adjusted to 6, and the suspensions are gently
stirred for a minute to permit the pseudourea to be adsorbed by the
fibers. The pH of the suspension simultaneously decreases.
The resulting suspensions are formed into thick water-laid webs on
a laboratory handsheet machine which are oven-dried at 190.degree.
F., and the resulting webs are hand-carded using a textile carder.
Fluffy resilient masses are obtained which resemble surgical cotton
wool.
Samples of the cotton wool are respectively sprayed with
suspensions of:
1. Aerobacter aerogenes
2. Bacillus cereus var. mycoides
3. Pseudomonas aeruginosa
4. Chaetomium globosum
5. i Penicillium citrinum
6. Penicillium expansum
7. Trichoderma viride
8. Aspergillus flavus
9. Fusarium moniliforme
10. Aspergillus niger
in a standard laboratory nutrient medium (agar-agar medium
containing protein as source of nitrogen, carbohydrate, and
calcium, magnesium, potassium and iron salts of the type normally
present in said medium) to provide nutritional requirements for the
microbial life thereon. The samples are allowed to stand for three
days at 30.degree. C. and 75 percent relative humidity, to permit
the fibers to exert their biocidal properties, and then are
incubated on sterile agar plates, in comparison with control
samples of cotton wool which contain no antimicrobial agent, to
determine the extent to which the microbial life has been arrested.
At the end of the incubation period the plates carrying the test
cotton wool are substantially or completely free from
microorganisms, whereas the control plates carry heavy growths of
microorganisms.
EXAMPLE 2
The following illustrates the manufacture and use of mulch paper
according to the present invention.
Into a furnish composed of a 50:50 mixture of hard wood and soft
wood papermaking fibers at pH 4.5 at a consistency of 0.6 percent,
as it passes through the machine chest in a paper mill, is metered
a 5 percent by weight solution of n-dodecylpseudourea hydrochloride
at a sufficient rate to provide 0.5 l percent of
n-dodecylpseudourea (as the free base) based on the dry weight of
the fibers and a solution of the melamine-formaldehyde wet strength
acid colloid of Maxwell et al. U.S. Pat. No. 2,345,543 at the same
rate. The furnish is processed into paper at a basis weight of 50
lbs. per 25" .times. 40"/500 ream, and the paper is dried at
190.degree. F.-250.degree. F. for about 1 minute. Kjeldahl nitrogen
analyses of the paper show that the dry paper contains 60 percent
-70 percent by weight of the dodecylpseudourea which had been
added. From experience it is known that most of the remainder was
adsorbed by the cellulose fibers, which were lost with the white
water.
The resulting paper is transported to a pineapple plantation and is
rolled upon the ground by an automatic pineapple seedling planter.
Pineapple seedlings are then planted through approximately 1 inch
diameter holes punched through the paper.
The paper largely prevents the growth of weeds around the
seedlings, does not support microbiological growth during the
period that the pineapples are growing, resists tearing when wet,
and shortens the vegetation period of the pineapples. The paper
loses virtually all its strength and disintegrates to fibrous state
within three months after being ploughed under the ground.
EXAMPLE 3
The procedure of Example 2 is repeated except that the paper is
applied as a mulch for watermelons, cauliflower, cabbage, celery,
parsnips and tomatoes grown in a Florida soil. Similar results are
obtained.
EXAMPLE 4
The following illustrates the remarkable antimicrobial properties
possessed by a preferred paper of the present invention.
A sample of the paper of Example 2 is pressed upon a sterile Petri
dish of agar upon which has previously been sprinkled an aqueous
suspension of Aspergillus niger and other fungal spores. The dish
is incubated at 30.degree. C. along with a control dish which
contains no paper. After 48 hours the control dish carries a heavy
growth of fungi, but the paper in the test dish shows no growth
whatever.
EXAMPLE 5
A strip of the paper of Example 3 11/2inches .times. 2 inches is
folded so as to form a strip approximately 1/2 inch .times. 2
inches. The strip is placed at the midpoint across a strip of
adhesive plaster 2 inches .times. 2 inches, which is then cut to
form a bandage of the bandaid type 1/2 inch .times. 2 inches. The
bandage is applied over a cut and abraded area on the leg of a
warm-blooded animal. The area heals without infection.
EXAMPLE 6
The following illustrates the virustatic and virucidal efficiency
of the pseudoureas against typical lipophilic viruses.
A
Virus Used: Influenza B (National Institute of Health's
Massachusetts Strain RMK-3)
80 mg. of 2-n-dodecylpseudourea acetate is dissolved in 200 ml. of
warm distilled water giving a solution containing 400 p.p.m. of the
agent. To 4.5 ml. of this solution is added 0.5 of the virus and
shaken to form a uniform solution. The solution is maintained at
22.degree. C. for 10 minutes. Several dilutions are made to below
10.sup..sup.-1 biocide concentration and inoculated into rhesus
monkey kidney cultures. A control is prepared consisting of 0.5 ml.
of the virus in 4.5 ml. of Earl's lactalbumin hydrolysate
medium.
The virucidal effectiveness of the solution is determined by the
hemadsorption test wherein 3 days after inoculation the cell
culture tubes are washed twice with 1.0 ml. of phosphate-buffered
saline solution and 1 ml. of 0.4 percent guinea pig erythrocytes is
added to each tube. The tubes are incubated for 20 minutes at
4.degree. C. and washed again with 1.0 ml. of the saline solution.
The erythrocytes adsorbed the monkey kidney cells that are infected
with influenza.
The procedure is repeated except that
2-n-dodecyl-N,N-dimethylpseudourea dihydrogen phosphate is used in
place of the acetate.
The virus potency (log TCID.sub.50 /ml.) is 5.2 for the control and
2.2 for each of the tests with the pseudourea salts, where TCID
represents Tissue Culture Infection Dose.
Each of the pseudourea salts is toxic to the virus concentrations
at 10.sup..sup.-1. ##SPC1##
Example 7
The following illustrates the manufacture of an infant's diaper
according to the present invention.
To an aqueous suspension of cellulose papermaking fibers at pH 4.5
and a consistency of 0.6 percent is added sufficient of an aqueous
solution of n-(2-decyl)pseudourea acetate to provide 2 percent
based on the dry weight of the fibers. The fibers are formed into a
web on a screen and the web is allowed to air dry. The web is
carded to form cotton wool which is formed into a batt about 18
inches .times. 18 inches .times. 1/4 inch. The batt is placed
between two sheets of wet strength paper 18 inches .times. 18
inches, one of which is sized and the other is unsized. The edges
of the two sheets are bound together with pressure-sensive adhesive
tape.
Example 8
The following illustrates the antimicrobial effect of increasing
amounts of a preferred antimicrobial agent as a function of the
kinds of microbial life present.
A water-leaf paper sheet (paper containing no additive) of 40 lb.
basis weight per 25" .times. 40"/500 ream is immersed in a 0.05
percent by weight solution of 2-n-dodecyl pseudourea ("PU") and
removed. Surplus solution is allowed to drain off. The resulting
wet web is dried for one minute on a laboratory drum drier having a
drum temperature of 240.degree. F. and contains about 0.05 percent
of the pseudourea by weight. The procedure is successively repeated
with solutions of increasing strength, yielding papers of the
psedudourea content shown in the table below.
The papers are then tested for their antimicrobial power against
fungus (Aspergillus niger), and on a bacterium (Aerobacter
aerogenes).
Results are as follows.
Growth After 48 % PU Hours at 80.degree.F. No. In Paper Fungus
Bacterium Control None Heavy Heavy 1 0.05 Mod. Mod. 2 0.1 Do.
Slight 3 0.2 Little Little 4 0.3 None None 5 0.5 Do. None 6 1.0 Do.
Do.
Since 2-dodecylpseudourea is known to be a virucide, and since the
above results show that this compound is adsorbed on paper in
strongly biologically active form, it is expected that the paper
described possesses strong antiviral properties as well.
Example 9
The following illustrates the manufacture of highly antimicrobial
paper of excellent wet strength properties according to the
invention.
To an aqueous suspension of unbleached softwood kraft fibers at 0.6
percent consistency and pH 6 in ordinary (non-aseptic) laboratory
water is added with gentle stirring sufficient of a 5 percent by
weight solution of 2-n-dodecylpseudourea hydrochloride to supply
3/4 percent of this compound based of the dry weight of the fibers.
There is then added sufficient of a 1 percent solution of a
water-soluble cationic thermosetting glyoxylated 95:5 molar ratio
acrylamide:diallyl dimethyl ammonium chloride copolymer to supply 1
percent of the polymer based of the dry weight of the fibers.
The suspension is then formed into handsheets at 50 lb. basis
weight which are dried for one minute on a drying roll having a
surface temperature of 220.degree.F.
The resulting paper carries about 0.6 percent and 0.8 percent by
weight of the respective agents, and has a TAPPI wet tensile of 9
lb. per inch.
A 6" .times. 6" sheet of the paper is then inoculated with stock
laboratory cultures so as to place on the sheet cultures of a
bacterium and a fungus, and the sheet is allowed to airdry at
80.degree.F. for 30 minutes. The sheet is then rolled in a plastic
sheet and allowed to incubate in the dark for 48 hours. The sheet
is then incubated and is found to be sterile.
Example 10
An experimental child's diaper (a commercial cloth diaper having
pinned to the center a "pillow" composed of a batt of cellulose
papermaking fibers between two sheets of wet strength paper, the
fibers in the batt and the paper containing 1 percent of
n-n-dodecylpseudourea by weight) is placed about a baby in
approximately customary manner and left in position until soiled.
The soiled pillow is removed and a sample incubated at 80.degree.F.
No microbial growth develops.
* * * * *