U.S. patent number RE29,909 [Application Number 05/821,963] was granted by the patent office on 1979-02-13 for method of cleansing contaminated wounds.
This patent grant is currently assigned to Deknatel Inc.. Invention is credited to Leonard D. Kurtz.
United States Patent |
RE29,909 |
Kurtz |
February 13, 1979 |
Method of cleansing contaminated wounds
Abstract
Aqueous detergent solutions of block copolymers of ethylene
oxide and propylene oxide having the structure: ##STR1## and an
ethylene oxide to propylene oxide ratio of at least 4:1 have been
found to be surprisingly useful in the cleansing of contaminated
wounds in that they do not impair the wound's ability to resist
infection. Surgical scrub solutions of these detergent solutions
containing in addition antiseptic agents provide cleansing
solutions which both eliminate bacteria and provide the desired
cleansing action without impairing the wound's ability to resist
infection.
Inventors: |
Kurtz; Leonard D. (Woodmere,
NY) |
Assignee: |
Deknatel Inc. (Long Island,
NY)
|
Family
ID: |
23828764 |
Appl.
No.: |
05/821,963 |
Filed: |
August 4, 1977 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
Reissue of: |
460451 |
Apr 12, 1974 |
03997458 |
Dec 14, 1976 |
|
|
Current U.S.
Class: |
514/772; 424/672;
424/78.06; 510/132; 568/623; 568/625 |
Current CPC
Class: |
A61K
31/77 (20130101); A61K 31/79 (20130101); C11D
1/722 (20130101); A61K 31/79 (20130101); A61K
31/77 (20130101) |
Current International
Class: |
A61K
31/79 (20060101); A61K 31/79 (20060101); A61K
31/74 (20060101); A61K 31/74 (20060101); A61K
31/77 (20060101); A61K 31/77 (20060101); C11D
1/722 (20060101); C11D 1/722 (20060101); C11D
001/72 (); C11D 003/48 () |
Field of
Search: |
;252/89,106
;424/78,80,150 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
Primary Examiner: Willis, Jr.; P.E.
Attorney, Agent or Firm: Larson, Taylor and Hinds
Claims
It is claimed:
1. In the cleansing of contaminated wounds with a surgical scrub
solution, the improvement which comprises employing as the surgical
scrub solution an aqueous detergent solution which does not impair
the wound's ability to resist infection, consisting of an aqueous
solution of at least about 10% by weight of a block copolymer of
ethylene oxide and propylene oxide having the structure: ##STR3##
wherein the ratio of (C.sub.2 H.sub.4 O).sub.a+c to .sub.b is at
least about .Badd..[.4:1.]. .Baddend..Iadd.3:1 .Iaddend.said
copolymer having an average molecular weight of about 5,000 to
15,500.
2. The improvement of claim 1 wherein the molecular weight of the
copolymer is about 5,000 to 13,500.
3. The improvement of claim 1 wherein the molecular weight of the
copolymer is about 5,000 to 13,500 and (C.sub.2 H.sub.4 O).sub.a
**.sub.c is about 80%.
4. The improvement of claim 3 wherein the copolymer has a molecular
weight of 8,350. .Iadd. 5. The improvement of claim 1 wherewith the
ratio of (C.sub.2 H.sub.4 O).sub.a+c to .sub.b is at least about
4:1. .Iaddend..Iadd. 6. The improvement of claim 5 wherein the
molecular weight of the copolymer is about 5,000 to 13,500.
.Iaddend..Iadd. 7. The improvement of claim 5 wherein the molecular
weight of the copolymer is about 5,000 to 13,500 and (C.sub.2
H.sub.4 O).sub.a+c is about 80%. .Iaddend..Iadd. 8. The improvement
of claim 7 wherein the copolymer has a molecular weight of 8,350.
Description
FIELD OF THE INVENTION
This invention relates to the cleansing of contaminated wounds.
More particularly the invention is directed to use of certain
nonionic surfactant solutions in the cleansing of wounds.
BACKGROUND OF THE INVENTION
Recommendations for immediate care of the soft tissue injuries
include cleaning the area surrounding the wound and the wound
itself. Practices vary somewhat in the selection of and use of the
cleansing agent for cleansing the skin and the wound. The use of
detergents of surfactants for wound cleaning, outside of a very few
exceptions are ordinarily avoided because of their harmful effects
on wound healing. In other words, despite the fact that many
detergents are highly effective cleaning agents and do an excellent
job in removing foreign substances from a wound they are
nevertheless "toxic" in the sense that they impair the wound's
tissue's ability to resist infection. Of special note is the fact
that other standards or measurements of toxicity, for instance,
oral toxicity, intravenous toxicity and skin sensitivity have not
been found to bear a direct relationship to the ability of a
detergent to impair a wound's ability to resist infection. A number
of detergents acknowledged or classed as non-toxic on the basis of
other studies unfortunately prove toxic to wound healing, that is,
do in fact impair the wound's ability to resist infection.
Among the commercially available surgical scrub solutions which
have been used by surgeons are pHisoHex and Betadine. The harmful
effects of even these solutions have been reported and confirmed by
studies in Custer, J., Edlich, R. F., Prusak, M. Madden, J., Panek
and Wangensteen, O. H. "Studies in the management of the
contaminated wound V. An assessment of the effectiveness of
pHisoHex and Betadine surgical scrub solutions." Amer. J. Surg.
121:572, 1971. These surgical scrub solutions are mixtures of an
antiseptic agent and a surface active detergent, the antiseptic
agent being employed to destroy the viable bacteria in the wound
while the surface active agent is utilized as a cleansing agent to
remove foreign bodies from the wound surface. It was found that
treatment of the contaminated wounds in guinea pigs with either of
these surgical scrub solutions increased the wound's susceptibility
to bacterial infection. In fact, the incidence of infection after
treatment of the contaminated wounds with these surgical scrub
solutions was higher than the infection rate of wounds subjected to
0.9% sodium chloride solution. The antiseptic agents in the
surgical solutions while exerting a favorable influence on
contaminated wounds fails to eliminate the harmful effect of the
detergents.
As a consequence of the increasing evidence on the harmful effects
of detergents on wounds, most surgeons today simply irrigate the
wound with large amounts of 0.9% sodium chloride solution.
Needless to say a need exists in the cleaning of contaminated
wounds for a cleaning agent which possesses the desired effective
cleansing action without the adverse effects on wound healing that
characterize prior art detergent-containing surgical scrubs. It is
one object of the invention, therefore, to satisfy this need.
Another object of the invention is to provide a new
detergent-containing surgical scrub solution which provides
antiseptic benefits without impairment to wound healing.
SUMMARY OF THE INVENTION
This and other objects of the invention are obtained by selecting,
as the cleansing solution in the cleansing of contaminated wounds,
an aqueous detergent solution containing as the detergent a block
copolymer of ethylene oxide and propylene oxide having the
structure: ##STR2## where b is below about 25% and (C.sub.2 H.sub.4
O).sub.a+c is at least 75%, preferably up to 95% of the total
weight of the copolymer, said copolymer having an average molecular
weight of about 5,000 to 15,500. The preferred block copolymers of
the invention have a molecular weight of about 5,000 to 13,500 and
a (C.sub.2 H.sub.4 O).sub.a+c, i.e. an ethylene oxide content of at
least 75% .Iadd.(i.e. a ratio of at least 3:1). .Iaddend.It is
important to note that while the molecular weight of the copolymers
has not been found to be a particularly important determinant of
the toxicity of the detergents in body wounds, the content of
ethylene oxide is critical and an important causal factor of
toxicity. It has been surprisingly discovered that if a copolymer
having an ethylene oxide content of at least 75% is selected as the
surfactant in cleansing of contaminated wounds there is no
impairment of the wound's natural resistance to infection. This is
in sharp contrast to the results obtained with solutions of
copolymers having less than 75% ethylene oxide content where high
incidences of infection in wounds receiving these copolymers is
encountered.
In another embodiment of the invention a novel surgical scrub
solution is obtained comprising an aqueous detergent solution
containing as a surfactant the above described block copolymer and
an antiseptic.
DETAILED DESCRIPTION OF THE INVENTION
The block copolymers of the invention are commercially available
members of a family comprised of an almost unlimited number of
nonionic surfactants commonly referred to as Pluronic Polyols. The
pluronic Polyols are a series of block copolymers that consist of
water-soluble poly(oxyethylene) groups at both ends of a
water-insoluble poly(oxypropylene) chain. The first step in making
the surfactants of the present invention is the controlled addition
of propylene oxide to the two hydroxyl groups of a propylene glycol
nucleus. The resulting polyoxypropylene glycol becomes
water-insoluble at a molecular weight of 900. The hydrophobe is
then tailored to the desired molecular weight and ethylene oxide
added to sandwich the hydrophobic base between hydrophilic
poly(oxyethylene) group which are controlled in length. The
surfactants of the present invention is that narrow group in which
the ethylene oxide addition is controlled to constitute at least
75% by weight of the final molecule. Illustrative of commercially
available Pluronic Polyols suitable for use in the invention are
polyol products of BASF Wyandotte Corporation designated F38, F68,
F88, F98 and F108. Particularly preferred in Pluronic Polyol
F68.
In brief, the surfactants may be prepared employing the following
illustrative general procedure:
A stainless steel reaction chamber is first purged with nitrogen
and propylene glycol and sodium hydroxide and heated to 120.degree.
C with gentle agitation until the sodium hydroxide has dissolved.
Propylene oxide is added as fast as it will react, maintaining a
temperature of 120.degree. C., until the desired molecular weight
is obtained. Then the desired amounts (75% or greater) of ethylene
oxide is added at such a rate as to maintain the desired reaction
temperature of 120.degree. C. When all the ethylene oxide has been
added, the reaction chamber may be stripped of low-boiling olymers.
The reaction mixture is then neutralized, usually with phosphoric
acid, to a pH of 7 .+-. 1. The neutral salts are removed
mechanically by filtration and the product is cooled.
A more detailed disclosure of the preparation of the surfactants
can be found, for instance, in U.S. Pat. No. 2,674,619, hereby
incorporated by reference.
The surfactants of the invention are all water-soluble exhibiting a
solubility in water of greater than 10 grams per 100 ml. Thus, the
cleansing solutions employed in the invention may be prepared by
simply dissolving the copolymer in water. The concentration of the
copolymer in the water may vary with the only important critera
being that it be present in deterge amounts, that is, in sufficient
concentrations to detergent or effect cleansing action. In general,
concentrations of at least about 10%, usually up to about 25% by
weight have been found suitable.
If desired, the cleansing solutions of the present invention may
include other materials commonly employed in surgical scrub
solutions. For instance, and in accordance with another aspect of
the present invention, a novel surgical scrub solution is provided
by including in the detergent solution of the invention an
antiseptic. The antiseptic can be any of the known antiseptic
agents, particularly those conventionally included in surgical
scrub solutions. Such antiseptic agents include, for example, ethyl
alcohol, benzalkonium chloride, chloramine, iodine, iodophors such
as polyvinylpyrrolidoneiodine, and the like. The surfactants of the
invention form stable, soluble complexes with elemental iodine as
has been described in deHavarre, M. G. and Bailey, H. G. "The
interference of nonionic emulsifiers with preservatives. "J. Soc.
Cosmet. Chem. 7:427, 1956. The present invention contemplates using
aqueous solutions of complexes of the copolymer and iodine as
surgical scrub solutions wherein the surfactant copolymer provides
the cleansing action and the iodine eliminates the bacterial
pathogens. The antiseptic agents in the scrub solutions is employed
in effective amounts usually ranging from about 0.5 to 5.0 percent
by weight.
Any of the various cleansing or scrubbing techniques known in the
art for cleansing of wounds may be employed in the invention such
as swabbing or scrubbing with gauze, sponges, surgical cotton and
the like moistened with the cleansing solution, simple irrigation
of the wound with the solution and the like.
The following examples are included to further illustrate the
present invention. In all of the examples the standardized
preparation of the animal, the technique of wounding, and the
bacterial culture procedure was that reported in Edlich, R. F.,
Tsung, M. S., Rogers, W., Rogers, P. and Wangensteen, O. H.
"Studies in the management of the contaminated wound. I. Technique
of closure of such wounds together with a note on a reproducible
model." J. Surg. Res. 8:585, 1968. Two standardized incisions,
parallel and equidistant from the vertebral column, were made in
each guinea pig. Five minutes after wounding, a predetermined
number of a strain of Staphylococcus aureus (ATCC No. 12,600) was
delivered to the wound. A designated solution (0.1 ml.) was
instilled into the wound 5 minutes later. Five minutes after the
topical treatment, the edges of the wounds were approximated with
microporous tapes. Four days after treatment, the inflammatory
responses of the wounds were determined.
In each case the inflammatory responses assessed were the presence
of gross infection and wound induration. Induration about the wound
was determined by palpating the wound with a gloved finger and
measuring the width of the indurated margin of each wound in
millimeters. The wound was then opened and inspected for evidence
of purulent exudate. For confirmation of the presence of bacteria,
a culture was taken by swabbing the wound with a cotton-tipped
applicator. The induration measurements were analyzed using
Student's test for varied differences. The significance of the
gross infection score and positive culture data was determined by
the sign test.
EXAMPLE I
The effect of topical application of 1 ml of 10% solutions of
Pluronic Polyols of varying molecular weight, with a wide range of
ethylene oxide content, on guinea pig wound's resistance to
infection was studied. Utilizing standarized wounds contaminated
with a designated number of bacteria, the influence of the polyol
on the wound's resistance to infection was ascertained by comparing
the infection rate of contaminated wounds subjected to one polyol
to the incidence of infection in controlled contaminated wounds
subjected to another polyol. The wound culture results, the wound
induration and the incidence of infection in the treatments are all
shown in Table 1 below.
Table 1
__________________________________________________________________________
Influence of Molecular Weight of Pluronic Polyols on Their Toxicity
in Surgical Wounds Inoc- Inflammatory Response ulum Pluronic Polyol
Gross Infection Culture No. (no. Molec- (% (% Ani- bac- ular FO:PO
Induration posi- posi- mals* teria Weight Ratio (mm) (P) tive) (P)
tive)
__________________________________________________________________________
9 10.sup.6 8,350 4:1 5.8 .+-. 1.8 <0.01 11.1 NS 100.0 14,000 4:1
7.0 .+-. 2.3 33.3 100.0 18 10.sup.7 8,350 4:1 5.6 .+-. 1.6 <0.01
61.1 NS 100.0 14,000 4:1 7.1 .+-. 1.6 83.3 8 10.sup.8 8.350 4:1 9.5
.+-. 1.8 NS 100.0 NS 100.0 14,000 4:1 8.9 .+-. 1.1 100.0 100.0 10
10.sup.6 5,000 4:1 5.3 .+-. 1.8 <0.05 50.0 NS 100.0 14,000 4:1
6.3 .+-. 1.9 66.7 100.0 12 10.sup.7 5,000 4:1 8.3 .+-. 1.3 <
0.05 90.0 NS 100.0 14,000 4:1 9.6 .+-. 1.3 100.0 100.0 11 10.sup.5
5,000 1:4 5.6 .+-. 1.2 NS 72.7 NS 100.0 1,630 1:4 5.6 .+-. 1.9 72.7
100.0
__________________________________________________________________________
.sup.a Not significant *guinea pigs
The results of Table 1 show that the incidence of gross infection
in contaminated wounds after the application of a high molecular
weight polyol did not differ significantly from the infection rate
of wounds treated with a polyol with the same ethylene
oxide:propylene oxide ratio (EO:PO ratio) and a lower molecular
weight. However, the width of indurated margins of wounds treated
with a polyol with a molecular weight of 14,000 was significantly
greater than the width of indurated edges of wounds subject to a
polyol with the same EO:PO ratio (4:1) and a lower molecular weight
5,000 and 8350). The molecular weight of the Pluronic polyols with
low ethylene oxide content had no significant influence on the
tissue's inflammatory response. The width of the indurated margins
of wounds receiving Pluronic polyols with a 1:4 EO:PO ratio and a
wide range of molecular weights did not differ significantly.
EXAMPLE II
Utilizing Pluronic polyols with similar molecular weights, the
incidence of infection of wounds treated with polyols containing
80% ethylene oxide (by weight) was compared to Pluronic polyols
containing 20% and 50% ethylene oxide (by weight). The results of
the comparison are shown in Table 2.
Table 2
__________________________________________________________________________
Influence of Ethylene Oxide Content of Pluronic Polyols on Their
Toxicity in Surgical Wounds Inoc- Inflammatory Response ulum
Pluronic Polyol Cross Infection Culture No. (no. Molec- (% (% Ani-
bac- ular EO:PO Induration posi- posi- mals* teria) Weight Ratio
(mm) (P) tive) (P) tive)
__________________________________________________________________________
14 10.sup.5 5000 1:4 5.8 .+-. 2.4 <0.01 71.0 <0.05 100.0 5000
4:1 4.4 .+-. 2.5 28.0 100.0 21 10.sup.5 4600 1:1 5.0 .+-. 1.0
<0.01 52.4 <0.05 100.0 5000 4:1 4.3 .+-. 0.6 14.3 100.0
__________________________________________________________________________
*guinea pigs
The data of Table 2 shows that the incidence of infection of wounds
treated with a polyol containing 80% ethylene oxide was
significantly lower than the infection rate of the wounds receiving
a polyol with an EO:PO ratio of either 1:1 or 1:4. The width of the
indurated edges of the wounds receiving a polyol with a 4:1 EO:PO
ratio was significantly smaller than the width of the indurated
edges of wounds treated with Pluronic polyols containing less
ethylene oxide.
EXAMPLE III
The effect of a 10% aqueous solution of a Pluronic polyol (0.1 ml)
having a molecular weight of 8,350 and a EO:PO ratio of 4:1 on a
wound's resistance to infection was compared with 0.9% sodium
chloride solution at different bacteria contamination levels. The
results are shown in Table 3 below.
Table 3
__________________________________________________________________________
Effect of a Pluronic Polyol.sup.a Exhibiting an 80% Ethylene Oxide
Content on the Wound's Resistance to Infection Inoc- Inflammatory
Response Culture ulum Gross Infection (% No. (no. Induration (%
posi- Animals* bacteria) Treatment (mm) (P) positive) (P) tive)
__________________________________________________________________________
16 10.sup.5 Pluronic 5.3 .+-. 1.5 NS.sup.b 12.5 NS 100.0 0.85% NaCl
5.7 .+-. 1.6 25.0 100.0 25 10.sup.6 Pluronic 6.6 .+-. 2.6 NS 20.0
NS 100.0 0.85% NaCl 6.5 .+-. 2.0 28.0 100.0 27 10.sup.7 Pluronic
6.6 .+-. 1.7 NS 40.8 NS 100.0 0.85% NaCl 7.1 .+-. 1.8 40.8 100.0
__________________________________________________________________________
.sup.a Molecular weight 8.350, EO:PO ratio 4:1. .sup.b Not
significant. *guinea pigs
The data of Table 3 shows that the incidence of gross infection of
wounds treated with the polyols of the invention containing an
ethylene oxide content of 80% did not differ significantly from the
control wounds subjected to 0.9% sodium chloride.
Pluronic polyols of the present invention having an EO:PO ratio of
4:1 and a molecular weight of 8,350 was added to Betadine
antiseptic solution to prepare a surgical scrub solution. Betadine
antiseptic solution contains the idophor
polyvinylpyrrolidone-iodine. The therapeutic value of the resulting
Pluronic polyol-Betadine antiseptic solution mixture was compared
with the commercially available Betadine surgical scrub solution in
the treatment of contaminated wounds. Betadine surgical scrub
solution contains an anionic detergent and the
polyvinylpyrrolidone-iodine. The results of the tests are shown in
Table 4 below.
Table 4
__________________________________________________________________________
Therapeutic Value of Surgical Scrub Solutions Containing a Pluronic
Polyol in the Treatment of the Contaminated Wound Inoc-
Inflammatory Response Cul- ulum Gross Infection ture No. (no.
Surgical Scrub Solution (% (% Ani- bac- Antiseptic Induration posi-
posi- mals* teria) solution Detergent (mm) (P) tive) (P) tive) (P)
__________________________________________________________________________
PVP-Iodine Nonionic 4.3 .+-. 0.5 0.0 50.0 12 10.sup.6
pluronic.sup.a <0.01 <0.05 <0.05 PVP-Iodine Anionic 7.8 +
2.6 66.6 100.0
__________________________________________________________________________
.sup.a 4:1 EO:PO ratio and 8,350 MW. *guinea pigs
The results of Table 4 establish that the therapeutic value of the
Pluronic polyol-Betadine antiseptic solution mixture was
significantly greater than the commercially available Betadine
Surgical Scrub solution in the treatment of contaminated wounds.
None of the wounds treated with the polyol-Betadine antiseptic
mixture exhibited infection as compared to the 66.6% of the wounds
receiving Betadine surgical scrub solution. The efficacy of the
polyol-Betadine antiseptic agent scrub was further apparent from
the culture data. Staphylococcus areus was recovered from all
wounds treated with the betadiene surgical scrub solution. Only 50%
of the wounds treated with Pluronic-Betadine antiseptic solution
exhibited Staphylococcus aureus. The difference between the
incidence of sterile cultures in the two treatment groups is
significant at the 0.05 level of confidence.
EXAMPLE IV
72 guinea pigs were anesthetized, shaved, and depilated. Each
animal then received two standardized, paravertebral incisions of 3
cm. length down to the panniculus carnosus. After wounding the
animals were divided into two large groups and each wound in a
specified group received 0.02 ml of inoculum containing either 1.0
.times. 10.sup.6 or 10.sup.7 bacteria. The bacteria employed were a
penicillin sensitive strain of S. aureus (ATCC No. 12,600). Within
each large group the animals were further divided into four
treatment groups. Wounds in a designated treatment group received
0.1 ml of a 10% solution of either Pluronic polyol F-68, F-98 or
F-87, having the molecular weight and percent ethylene oxide set
out in the table below. Wounds in the fourth treatment group
received 0.1 ml of isotonic saline and served as controls. After
the solutions had remained on the wounds for 15 minutes, the wound
edges were approximated with microporous tape and the animals were
sacrificed and the inflammatory responses of their wounds
evaluated. The inflammatory responses assessed were wound
induration and the presence of purulent exudate. An estimate of the
number of viable bacteria present in each wound was also made.
______________________________________ Compound % Ethylene Oxide
Molecular Weight ______________________________________ F-87 70%
7700 F-68 80% 8000 F-98 80% 13,500
______________________________________
The results of the study are shown in Table 5 below.
Table 5
__________________________________________________________________________
Induration Gross Infection Viable Bacteria Inoculum Treatment (mm)
(p) (% pos.) (p) (10.sub.6) (p)
__________________________________________________________________________
10.sup.6 Saline* 5.2 .+-. 0.9 -- 17 -- 5.43 .+-. 0.60 -- F-68 5.0
.+-. 0.9 NS 33 NS** 5.63 .+-. 1.14 NS F-98 6.2 .+-. 1.3 NS 50 NS
5.64 .+-. 0.84 NS F-87 5.6 .+-. 0.9 NS 67 0.05 6.00 .+-. 1.01 NS
10.sup.7 Saline 10.5 .+-. 1.9 -- 100 -- 6.72 .+-. 0.29 -- F-68 10.3
.+-. 1.2 NS 100 NS 6.83 .+-. 0.29 NS F-98 8.9 .+-. 1.1 NS 100 NS
6.72 .+-. 0.29 NS F-87 11.8 .+-. 1.6 NS 100 NS 7.05 .+-. 0.28 0.01
__________________________________________________________________________
*0.9% **not significant
Table 5 shows that Pluronic polyols containing 70% of ethylene
oxide by weight impairs the wound's ability to resist infection.
This finding is in sharp contrast with the results encountered in
treating the contaminated wounds with Pluronic polyol F-68 and
F-98. Contaminated wounds subjected to therapeutic treatment with
these pololys had an infection rate which did not differ from the
infection rate of contaminated wounds subjected to 0.9% saline.
* * * * *