Note: Descriptions are shown in the official language in which they were submitted.
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PREPOLYMER COMPOSITIONS COMPRISING
AN ANTIMICROBIAL AGENT
BACKGROUND OF THE INVENTION
Field of the Invention
This invention is directed to prepolymer compositions comprising a compatible
antimicrobial agent. These compositions provide for in situ formation of
antimicrobial
polymeric films on mammalian skin which films are useful as wound dressings,
wound
bandages, surgical incise drapes, wound closure materials which replace or are
an adjunct
to sutures, and the like.
This invention is also directed to kits of parts comprising such prepolymer
compositions and an applicator means for applying the composition to mammalian
skin.
The following publications, patent applications and patents are cited in this
application as superscript numbers:
' Hawkins, et al., "Surgical Adhesive Compositions", U.S. Patent No.
3,591,676,
issued July 6, 1971
Halpern, et al., "Adhesive for Living Tissue", U.S. Patent No. 3,667,472,
issued
June 6, 1972
Blum, et al., "In vitro Determination of the Antimicrobial Properties of Two
Cyanoacrylate Preparations", J. Dent. Res., X4(3):500-503 (1975)
Barley, et al., "Methods for Treating Non-Suturable Wounds by Use of
Cyanoacrylate Adhesives", International Patent Application Publication No. WO
93/25196, published December 23, 1993
Barley, et al., "Methods for Treating Suturable Wounds by Use of Sutures and
Cyanoacrylate Adhesives", U.S. Patent No. 5,254,132, issued October 19, 1993
Khan, et al., "Preparation of a Skin Surface for a Surgical Procedure", U.S.
Patent No. 5,547,662, issued August 20, 1996
' Byram; et al., "Methods to Inhibit Acute Radiation Induced Skin Damage",
International Patent Application Publication No. WO 96/34610, published
November 7, 1996.
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Cardarelli, et al., "Film Forming Antimicrobial Material ", U.S. Patent No.
4,374,126, issued February 15, 1983
Askill, et al., "Methods for Draping Surgical Incision Sites Using a
Biocompatible Prepolymer", U.S. Patent Application Serial No. 08/941,097 filed
October 8, 1997 as Attorney Docket No. 026446-108
'° Dell, "Film-Forming Composition Containing an Antimicrobial Agent
and
Methods", U.S. Patent No. 4,542,012, issued September 17, 1985
" Greff, et al., "Prepolymer Compositions Comprising an Anti-Microbial Agent",
U.S. Patent Application Serial No. 08/947,109 filed October 8, 1997 as
Attorney
Docket No. 026446-087
'z Brink, et al., "Film-Forming Emulsion Containing Iodine and Methods of
Use",
U.S. Patent No. 5,173,291, issued December 22, 1992
'3 Hagen, et al., "A Comparison of Two Skin Preps Used in Cardiac Surgical
Procedures", AORN Journal, X2(3):393-402 (1995)
'4 Ritter, et al., "Retrospective Evaluation of an Iodophor-Incorporated
Antimicrobial Plastic Adhesive Wound Drape", Clinical Orthopedics and Related
Research, pp. 307-308 (1988)
'S Osuna, et al., "Comparison of an Antimicrobial Adhesive Drape and Povidone-
lodine Preoperative Skin Preparation in Dogs", Veterinary Surgery, 21(6):458-
462(1992)
'6 Matsumoto, "Chapter 3: Bacteriology and Wound Healing", in "Tissue
Adhesives
in Surgery", Medical Examination Publishing Company, Inc., Flushing, New
York, USA, pp. 106-113 (1972)
" Modern Plastics Encyclopedia, 1997
'8 Mixon, "Surgical Drape havinglncorporated therein a Broad Spectrum
Antimicrobial Agent", U.S. Patent No. 5,069,907, issued December 3, 1991
'9 Greff, et al., "Methods and Compositions for Treating Dermatoses" U.S.
Patent
Application Serial No. 08/963,265 filed concurrently herewith as Attorney
Docket
No.026446-067
zo "Kits Containing Cyanoacrylate Compositions Comprising an Antimicrobial
Agent", U.S. Patent Application Serial No. 08/962,869, filed concurrently
herewith as Attorney Docket No. 026446-111
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All of the above publications, patent applications and patents are herein
incorporated by reference in their entirety to the same extent as if each
individual
publication, patent application or patent was specifically and individually
indicated to be
incorporated by reference in its entirety.
Biocompatible prepolymer compositions, such as compositions comprising
cyanoacrylate esters, have been disclosed for a variety of topical uses on
mammalian skin
including use as a replacement or adjunct for sutures or staples in closing
the dermal layer
of an incision after surgery.'~Z~S Other disclosed topical uses of such
prepolymer
compositions include inhibition of acute radiation-induced skin damage' as
well as in the
in situ formation of a surgical incise drape.9 Other suitable prepolymer
compositions
include compositions comprising prepolymers other than cyanoacrylate and
povidone-
iodine."
In each case, when topically applied to mammalian skin, the biocompatible
prepolymer composition polymerizes to form a coherent polymeric film which
adheres to
the skin.
Notwithstanding the beneficial properties associated with such prepolymer
compositions and their suitability for topical applications, these
compositions do not
possess a sufficiently broad and/or active spectrum of antimicrobial activity
including
activity against microbial spores and, accordingly, cannot assure reductions
in microbial
populations on mammalian skin surface either under or adjacent the polymeric
film
formed in situ on the skin.3~'6
Many of the uses of prepolymer compositions enumerated above would, however,
significantly benefit by an antimicrobial property in the polymer film. For
instance,
when used as a surgical (incise) drape, such films would reduce microbial
populations
under and adjacent the drape including those at the incision site and,
accordingly, would
reduce the risk of post-operative infection. Such is the basic premise of
commercial
surgical drapes containing an antimicrobial agent impregnated directly into
the drape or
in an adhesive layer attached thereto where it was hoped that this agent would
be released
onto the skin surface to inhibit microbial growth.'3,'4 Osuna, et al.'S
report, however, that
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when the antimicrobial agent is incorporated into the adhesive layer, the
adhesive does
not release sufficient amounts of the impregnated agent to be, by itself,
antimicrobial.
Without being limited to any theory, it is believed that the antimicrobial
agent is too
strongly bound onto/into the adhesive to be released onto the skin and/or that
there is
insufficient skin surface contact between the adhesive and the skin to effect
release of a
sufficient amount of antimicrobial agent.
As noted above, most prepolymer compositions do not possess antimicrobial
activity and, accordingly, in situ formation of a polymeric film on mammalian
skin which
film possesses antimicrobial properties necessitates, of course, that an
antimicrobially
effective amount of an antimicrobial agent be incorporated into the prepolymer
composition and that sufficient amounts of this agent be released from the
polymeric film
onto the skin to achieve an antimicrobial effect. The incorporation of such an
antimicrobial agent into the composition is problematic at best because
several disparate
criteria must be simultaneously met. First, the antimicrobial agent must be
soluble or
dispersible in the prepolymer composition at the concentrations necessary to
effect
antimicrobial properties. Second, the antimicrobial agent employed must not
cause
premature polymerization of the prepolymer composition. Third, the
antimicrobial agent
employed must not prevent in situ polymerization of the prepolymer composition
when
applied to the skin. Fourth, the antimicrobial agent must be compatible with
the intended
use of the polymeric film by not inhibiting formation of a flexible, durable
film. Fifth,
the impregnated antimicrobial agent must be released from the polymerized film
in situ
on the patient's skin in sufficient amounts to be antirnicrobial.
Because of these disparate properties, antimicrobial agents have not been
incorporated into prepolymers but, rather, solutions or emulsions of the
formed polymer
are employed and these solutions/emulsions are then applied to the patient's
skin. In such
cases, subsequent evaporation of the solvent leaves a polymer film on the skin
which film
is permeated with the antimicrobial agent.g~'°''2 Alternatively, the
antimicrobial agent
may be incorporated into a polymer melt's and then extruded as a film which is
applied to
the skin. Since the polymer is preformed prior to application to the skin,
these
solutions/emulsions reduce the effective adherence of the polymer filin to the
skin and,
accordingly, could lead to premature lifting or removal of the film from the
skin.
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Moreover, the use of water and other solvents in the emulsion or solution
leads to slow
drying times for the film with the concurrent difficulty in determining when
or if the
solvent has evaporated sufficiently to provide a polymer film on the patient's
skin.b
Replacement of water in such aqueous formulations with a quick drying organic
solvent
such as acetone, isopropanol, etc. leads to noxious/flammable vapors in the
operating
room and, in many cases, these solvents cause skin irritation. In any event,
the use of
such emulsions or solutions requires application of relatively large
quantities of these
compositions onto the skin in order to account for the portion which
evaporates
therefrom.
Still, in another alternative, commercially available embodiment (e.g.,
IOBANTM),
a polymeric film is coated with an adhesive layer having an antimicrobial
agent
incorporated into the adhesive. Such films, however, suffer from poor contact
of the
adhesive layer with the skin and subsequently reduced antimicrobial effects.
Additionally, notwithstanding the use of the adhesive, the polymeric film can
lift during
surgical procedures which has an adverse effect on infection rates.'s
In addition, there is a need for a polymeric film with an antimicrobial aimed
at
prevention or treatment of specific dermatological problems. An example of
this need is
the requirement for antifungals in topical products used for incontinence,
where the
incidence of fungal infection is extremely high.
In view of the clear benefits associated with the incorporation of an
antimicrobial
agent directly into the prepolymer composition, there is an ongoing need to
formulate a
prepolymer composition comprising an antimicrobial agent, mixtures of
antimicrobials
and specific therapeutic antimicrobials.
SUMMARY OF THE INVENTION
This invention is directed to prepolymer compositions comprising a
polymerizable biocompatible prepolymer composition and an antimicrobially
effective
amount of an antimicrobial agent. These compositions provide for in situ
formation of an
antimicrobial polymeric film on mammalian skin. The specific antimicrobial
employed
is compatible with the prepolymer composition insofar as the antimicrobial
neither causes
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premature polymerization nor prevents polymerization, rather a flexible,
adhesive and
durable polymer film is formed in situ on mammalian skin by this composition.
Moreover, the antimicrobial agent is expected to be released from the
polymeric film in
antimicrobially effective amounts thereby imparting antimicrobial properties
to the
polymeric film.
Accordingly, in one of its composition aspects, this invention is directed to
an
antimicrobial prepolymer composition which comprises:
(a) a polymerizable biocompatible prepolymer composition; and
(b) an antimicrobially effective amount of an antimicrobial agent with the
proviso that the biocompatible prepolymer composition is neither a
cyanoacrylate
prepolymer composition nor a silicone prepolymer composition and the
antimicrobial
agent is not a complex of iodine molecules.
Preferably, the polymerizable biocompatible prepolymer composition is selected
from the group of prepolymers consisting of urethane acrylate, (C,-C6 alkyl)
(C,-C6)
alkacrylate (e.g., methyl methacrylate), (C,-C6 alkyl) acrylate, (C,-C6
hydroxyalkyl)
acrylate, (C,-C6 hydroxyalkyl) alkacrylate, styrene, a-methyl styrene, vinyl
acetate, one
and two component epoxy materials, mixtures thereof, and the like.
Antimicrobial agents include, by way of example, antibacterials, antifungals,
antibiotics, antivirals and antiparasitics. Preferably, such antimicrobial
agents are
selected from the group consisting of acyclovir, amphotericin B, bacitracin,
butoconazole
nitrate, carbol-fuchsin solution, chloramphenicol, chlortetracycline
hydrochloride,
ciclopirox olamine, clindamycin phosphate, clotrimazole, econazole nitrate,
erythromycin, gentamycin sulfate, gentian violet, haloprogin,
iodochlorhydroxyquin,
ketoconazole, mafenide acetate, metronidazole, miconazole nitrate, mupirocin,
naftifine,
neomycin sulfate, nitrofurazone, nystatin, oxiconazole nitrate, silver
sulfadiazine,
sulconazole nitrate, tetracycline hydrochloride, tolnaftate, undecylenic acid
and zinc
undecylenate, benzyl benzoate, crotamiton, lindane, permethrin, pyrethrins,
quaternary
ammonium compounds, e.g., cetrimide, biguanide compounds such as chlorhexidine
and
its salts, e.g., chlorhexidine gluconate, and chlorophenols, e.g. MICROBAN~
(Microban
Products).
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Preferred antimicrobial agents are chlorhexidine and its salts, neomycin
sulfate,
bacitracin, miconazole nitrate, naftifine, acyclovir and lindane.
The antimicrobial prepolymer compositions may further comprise an effective
amount of a polymerization inhibitor, a biocompatible plasticizer, and a
polymerization
initiator.
This invention is also directed to a kit of parts useful for applying the
antimicrobial prepolymer compositions described herein onto mammalian skin. In
particular, such a kit of parts comprises (a) a container comprising therein
an
antimicrobial prepolymer composition as described above and (b) an applicator
means for
applying the composition onto mammalian skin.
This invention is also directed to a kit of parts which comprises the
prepolymer
stored in a first container and the antimicrobial agent stored in a second
container. At the
appropriate point in time the contents can be mixed together to form the
composition
described above. Preferably, the first or second container comprises an
applicator means
1 S such that upon mixing of the components the composition can be applied to
mammalian
skin. Alternatively, a separate applicator means can be employed in the kit.
In a further
embodiment the kit may comprise further containers containing additional
components.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
This invention is directed, in part, to biocompatible prepolymer compositions
comprising a polymerizable biocompatible prepolymer and an antimicrobially
effective
amount of an antimicrobial agent. However, prior to discussing this invention
in further
detail, the following terms will first be defined.
Definitions
As used herein, the following terms have the following meanings:
The term "polymerizable biocompatible prepolymer compositions" refer to
polymerizable monomers, oligomers or mixtures thereof including single or
multi-
component systems. The prepolymer composition will polymerize in situ on
mammalian
skin to form an adherent, water-insoluble polymeric layer over the skin. The
prepolymer
and resulting polymeric film are biocompatible with the skin as measured by
the lack of
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moderate to severe skin irritation and the resulting polymer film is
substantially non-toxic
and can be removed from the skin by conventional means, e.g., sloughing off
with the
epidermal layer of the skin or by removal with a suitable biocompatible
solvent (e.g.,
acetone and isopropanol).
S Included within the term "polymerizable biocompatible prepolymer
compositions" are both single and mufti-component systems. Single component
prepolymer compositions include those wherein a single prepolymer is capable
of
polymerizing under suitable polymerization conditions (e.g., free radical
conditions) to
provide for a polymer film on mammalian skin. Such single component systems
include
well known reactive vinyl groups which form a biocompatible polymer such as
urethane
acrylate, (C,-C6 alkyl) (C,-C6 alkacrylate, (C,-C6 alkyl) acrylate, (C,-C6
hydroxyalkyl)
acrylate, (C,-C6 hydroxyalkyl) alkacrylate, styrene, a-methyl styrene, vinyl
acetate,
mixtures thereof, and the like. Specific examples of such single component
systems
include methyl methacrylate, hydroxyethyl methacrylate, styrene, and the like.
Additionally, such single component systems can also comprise polymerization
inhibitors, polymerization initiators, colorants, perfumes, etc.
Mufti-component prepolymer compositions include those wherein two or more
components are employed to co-react under suitable polymerization conditions
to provide
for a polymer film on mammalian skin. An example of a two component system is
a
diepoxide and a diamine specifically exemplified by bis-phenol A diglycidyl
ether and
ethylene diamine.
Preferred prepolymers for use in this invention include, by way of example
only,
urethane acrylate, (C,-C6 alkyl) methacrylate, (C,-C6 alkyl) acrylate, (C,-C6
hydroxyalkyl) acrylate, (C~-C6 hydroxyalkyl) alkacrylate, styrene, a-methyl
styrene, vinyl
acetate, one and two component epoxy materials, mixtures thereof, and the
like.
Specifically excluded from the compositions of this invention are prepolymers
comprising an iodine containing antimicrobial agent. Such prepolymer
compositions are
described in commonly assigned U.S. Patent Application Serial Nos. 08/912,681,
filed on
August 18, 1997, and 08/947,109 filed on October 8, 1997 as Attorney Docket
No.
026446-087 and entitled "Prepolymer Compositions Comprising an Antimicrobial
Agent
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both of which are incorporated herein by reference in their entirety. Also
excluded are
silicone prepolymers.
The polymerizable biocompatible prepolymer compositions described herein
polymerize on mammalian skin tissue without causing histotoxicity or
cytotoxicity.
The term "antimicrobial agent" refers to agents which destroy microbes (i.e.,
bacteria, fungi, viruses, parasites, microbial spores, and the like) thereby
preventing their
development and pathogenic action. Preferred antimicrobial agents include, by
way of
example, antibacterials, antifungals, antibiotics, antivirals and
antiparasitics.
Examples of suitable antimicrobial agents include acyclovir, amphotericin B,
bacitracin, butoconazole nitrate, carbol-fuchsin solution, chloramphenicol,
chlortetracycline hydrochloride, ciclopirox olamine, clindamycin phosphate,
clotrimazole, econazole nitrate, erythromycin, gentamycin sulfate, gentian
violet,
haloprogin, iodochlorhydroxyquin, ketoconazole, mafenide acetate,
metronidazole,
miconazole nitrate, mupirocin, naftifine, neomycin sulfate, nitrofurazone,
nystatin,
oxiconazole nitrate, silver sulfadiazine, sulconazole nitrate, tetracycline
hydrochloride,
tolnaftate, undecylenic acid and zinc undecylenate, benzyl benzoate,
crotamiton, lindane,
permethrin, pyrethrins, quaternary ammonium compounds, e.g., cetrimide,
biguanide
compounds such as chlorhexidine and its salts, e.g., chlorhexidine gluconate,
and
chlorophenols, e.g. MICROBAN~ (Microban Products).
The term "biocompatible plasticizes" refers to any material which is soluble
or
dispersible in the prepolymer composition and does not adversely affect the
polymerization of the prepolymer when applied to the skin, which increases the
flexibility of the resulting polymer film coating on the skin surface, and
which, in the
amounts employed, is compatible with the skin as measured by the lack of
moderate to
severe skin irntation. Suitable plasticizers are well known in the art and
include those
disclosed in Modern Plastics Encyclopedia, 1997", the disclosure of which is
incorporated herein by reference in its entirety. Specific plasticizers
include, by way of
example only, citrate plasticizers, phthalate plasticizers, and the like.
The term "polymerization inhibitor" refers to well known free radical
inhibitors of
prepolymers including materials such as hindered phenols, hydroquinone, 4-
methoxyphenol, amines and the like. The polymerization inhibitor is typically
employed
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in amounts effective to inhibit polymerization of the prepolymer composition
until
application of the composition onto the mammalian skin and initiation of
polymerization
as herein described. Preferably, the polymerization inhibitor is employed from
about
0.01 to about 0.1 weight percent based on the total weight of the composition.
S The term "initiator" refers to those well known polymerization initiators
which
are typically incorporated into the composition to initiate polymerization of
the
prepolymer. Such initiators include, by way of example, thermal initiators,
light
activated (e.g., UV) initiators, and the like. Examples of thermal initiators
include
peresters, peroxycarbonates, peroxides, azonitrile compounds, and the like.
Promoters or
accelerators such as metal salts and amines may be used with the initiators.
The specific
thermal initiator is preferably selected to initiate polymerization of the
prepolymer at
ambient skin temperatures {e.g., ~35°C) or slightly above with
additional heating.
Examples of light activated initiators include benzoin alkyl ethers,
benzophenone,
Darocur 1173 (available from Ciba Geigy, Ardsley, New York, USA),
camphorquinone,
and the like.
Preferably, the initiator is a light activated initiator and, after
application of the
prepolymer composition to mammalian skin, a light source is passed over the
skin to
initiate polymerization. Even more preferably, the light activated initiator
is
biocompatible with the skin as measured by the lack of moderate to severe skin
irritation.
Comn_ocity ions
This invention is based on the novel and unexpected discovery that the
antimicrobial agents described herein are compatible with prepolymer
compositions
forming a composition which, upon polymerization, provides for an
antimicrobial
polymeric film. Compatibility is assessed by the fact that these antimicrobial
agents are
dispersible or soluble in the prepolymer composition at antimicrobially
effective
concentrations and when so employed, do not cause premature polymerization of
the
prepolymer composition and do not prevent effective polymerization of the
prepolymer
composition when applied to mammalian skin. Moreover, the polymerizable
prepolymer
composition comprising such antimicrobial agents forms a flexible, durable
polymer film
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having the antimicrobial agent incorporated therein which antimicrobial agent
will
release in sufficient amounts to provide antimicrobial properties to the film.
The compositions of this invention are prepared by adding an antimicrobial
agent
to the prepolymer. The antimicrobial agent is preferably added to the
prepolymer as a
S powder and is dispersed or dissolved in the prepolymer composition. Mixing
is
employed to obtain a homogeneous solution or suspension. It is understood that
the order
of addition is not critical.
The amount of antimicrobial agent added to the composition is a sufficient
amount such that the resulting polymeric film is antimicrobial. Preferably,
from about
0.5 to about 30 weight percent of the antimicrobial agent and more preferably
from about
1 to 25 weight percent is added to the composition based on the total weight
of the
composition.
The specific amount of antimicrobial agent required to effect antimicrobial
properties in the resulting polymeric film can be readily measured by
conventional in
vitro assays measuring zones of microbial growth inhibition around the film.
Zones of
inhibition of at least 1 millimeter and preferably 3 millimeters from the edge
of the film
when tested in the manner of Example 3 below evidence that the polymeric filin
is
antimicrobial. Assessing the amount of antimicrobial agent required in the
polymeric
film to effect such a zone of inhibition is well within the skill of the art.
The composition of the antimicrobial and the polymerizable biocompatible
prepolymer can be formulated to a specific viscosity to meet disparate demands
for the
intended application of the composition. For example, relatively low
viscosities are often
preferred where application is to be made to a large surface area (e.g.,
abdominal
surfaces). This preference results from the fact that these forms are less
viscous and,
accordingly, will permit more facile large surface area application of a thin
film.
Contrarily, where application is to be made to a specific position on the skin
(e.g., elbow
surfaces, knee surfaces and the like), higher viscosity materials are
preferred to prevent
"running" of the material to unintended locations.
Accordingly, these compositions preferably have a viscosity of from about 10
to
50,000 centipoise at 20°C. For low viscosity applications, viscosity
ranges of from about
10 to 1,500 centipoise at 20°C are preferred. More preferably, the
biocompatible
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prepolymer employed in the composition is almost entirely in monomeric form
and the
composition has a viscosity of from about 10 to about 500 centipoise at
20°C.
A thickening agent is optionally employed to increase the viscosity of the
composition which thickening agent is any biocompatible material which
increases the
viscosity of the composition. Suitable thickening agents include, by way of
example,
polymethyl methacrylate (PMMA), polymers of the respective prepolymer or other
preformed polymers soluble or dispersible in the composition, a suspending
agent such as
fumed silica and the like. Fumed silica is particularly useful in producing a
gel for
topical application having a viscosity of from about 1500 to 50,000.
Thickening agents are deemed to be biocompatible if they are soluble or
dispersible in the composition and are compatible with the skin as measured by
the lack
of moderate to severe skin irritation.
The prepolymer compositions of this invention can optionally include a
biocompatible plasticizer and such plasticizers are preferably included from
about 10 to
40 weight percent and more preferably from about 10 to 30 weight peicent based
on the
weight of the composition absent the antimicrobial agent.
Additionally, the prepolymer compositions described herein preferably include
a
polymerization inhibitor and a polymerization initiator in effective amounts
to prevent
premature polymerization but provide for in situ polymerization on mammalian
skin. For
example, an effective amount of a polymerization inhibitor is preferably
included in the
composition to inhibit premature polymerization of the composition. Likewise,
the
polymerization initiator is included in the composition in effective amounts
to initiate
polymerization when the composition is placed under polymerization conditions
(e.g.,
light). As above, such initiators include thermal initiators, light activated
initiators and
the like and in situ polymerization of the prepolymer composition on mammalian
skin
preferably occurs within 0.5 to 5 minutes.
The biocompatible prepolymer compositions may additionally contain one or
more optional additives such as colorants, perfumes, rubber modifiers,
tackifiers,
modifying agents, etc. In practice, each of these optional additives should be
both
miscible/dispersible and compatible with the prepolymer composition and the
resulting
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polymer. Compatible additives are those that do not prevent the use of the
prepolymers
in the manner described herein.
In general, colorants are added so that the polymer layer formed on the skin
will
contain a discrete and discernable color. Perfumes are added to provide a
pleasant smell
to the formulation. Rubber modifiers are added to further enhance the
flexibility of the
resulting polymer layer. The amount of each of these optional additives
employed in the
composition is an amount necessary to achieve the desired effect.
When employed, each of these additives are incorporated into the composition
and the resulting composition mixed until homogeneous.
Ttili tv
The methods described herein are useful in forming in situ an antimicrobial
adherent polymer film on the skin surface of a mammalian patient. Such
mammalian
patients preferably include humans as well as, for example, domestic animals
exemplified
by horses, cows, dogs, sheep, cats, etc. and any other mammalian species.
The polymer film finds particular utility in inhibiting microbial
contamination
thereunder and in the areas immediately adjacent thereto. Accordingly, such
polymeric
films can be used to topically cover small wounds on skin surfaces which
wounds do not
penetrate through the dermal layer of the skin as, for example, in the manner
described in
Barley, et a1.4 When so employed, the antimicrobial biocompatible prepolymer
composition is applied over the wound. Upon polymerization, an antimicrobial
polymeric film is formed over the wound which provides for antimicrobial
properties at
the wound surface while also preventing exogenous contaminants from entering
the
wound.
Additionally, the polymeric films formed from the antimicrobial prepolymer
compositions described herein can also be used in the in situ formation of a
surgical
incise drape in the manner described by Askill, et a1.9 When so employed, the
in situ
formed film adheres to the mammalian skin surface to provide for a surgical
incise drape
which does not lift during surgery and has antimicrobial properties.
In any event, an antimicrobial polymeric drape is formed over the selected
site by
applying a biocompatible prepolymer composition of this invention to the skin
surface at
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the selected site. As noted above, this composition comprises polymerizable
biocompatible monomers and/or reactive oligomers (prepolymers) which, upon
application to the skin polymerizes in situ to form an antimicrobial
biocompatible
polymeric film.
Still further, the polymeric films formed from the antimicrobial prepolymer
compositions described herein can be used in methods for treating active
dermatoses
(e.g., dermatitis, psoriasis and eczema).'9 In such methods a polymerizable
prepolymer
composition is applied to the topical surface of the dermatosis and then the
prepolymer is
polymerized in situ on this surface so as to form a coherent polymeric film
over the
dermatosis.
When so used, the antimicrobial polymeric film will only adhere to the skin
for a
period of about 1-4 days after which time it sloughs off. This occurs because
the
polymeric film adheres only to the uppermost portion of the epidermal layer
which is
continuously in the process of being sloughed off and replaced by the
underlying cells.
Accordingly, the antimicrobial polymeric film need not be removed after in
situ
formation. However, if immediate removal of the polymeric film is required,
such can be
removed with a suitable biocompatible solvent, e.g., acetone or isopropanol.
Kits
In view of the many different uses for topical application onto mammalian
skin,
this invention also encompasses a kit of parts useful for applying the
antimicrobial
prepolymer compositions described herein onto mammalian skin. In particular,
such a kit
of parts comprises (a) a container comprising therein an antimicrobial
biocompatible
prepolymer composition as described above and (b) an applicator means for
applying the
composition onto mammalian skin.
The container comprises any compatible material which stores the prepolymer
composition without degradation of the container or prematurely polymerizing
the
prepolymer. Such materials include, by way of example, inorganic materials
such as
glass (including amber glass), metals, ceramics, and the like as well as
organic materials
such as polyolefins including fluorinated polyolefins, and the like.
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Suitable applicator means include brushes, rollers, aerosols, swabs, wipes,
and the
like.
In one embodiment, the container and applicator means are combined into a
single article such as a brush affixed to the terminal portion of the
container wherein
means are employed to prevent premature release of the prepolymer composition.
For
example, the brush may be overlaid with a removable impermeable barrier. When
application of the prepolymer composition is intended, the barner is simply
removed.
Alternatively, a frangible barrier may be used and broken or crushed to
release the
material for mixing prior to use.
In another embodiment, the container and applicator means are separate
articles
designed to mate with each other. For example, the prepolymer composition
could be
stored in an amber vial sealed with a screw cap and the applicator means
includes a screw
mechanism which mates with a complimentary screw mechanism on the top of the
vial.
When application of the prepolymer composition is intended, the cap is removed
from the
1 S vial and the applicator is attached.
In still another embodiment, the container itself comprises a two-component
system. Such two component systems can be used, e.g., with two-component epoxy
prepolymer systems wherein the first component is segregated from the other.
For
example, a diepoxide composition is added to one component of the container
and a
diamine added to the other. At the time of use, the components are then mixed
to provide
for a polymerizable prepolymer composition of this invention.
Alternatively, the two-component system can be used to store the antimicrobial
agent in one component of the container and the prepolymer composition in the
other
component. At the appropriate time, the components can be mixed to provide for
a
prepolymer composition of this invention. Multiple component systems can also
be used
(e.g., a three component system comprising a two component epoxy prepolymer
composition and the antimicrobial agent each stored in separate compartments
segregated
from each other until time of use).
Kits similar to those described above have been described in U.S. Patent
Application No. 08/962,868,2° filed concurrently herewith, as Attorney
Docket No.
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026446-111 and entitled "Kits Containing Cyanoacrylate Compositions Comprising
an
Antimicrobial Agent." This application is herein incorporated by reference in
its entirety.
The following examples illustrates certain embodiments of the invention but is
not meant to limit the scope of the claims in any way.
EXAMPLES
In the examples below, all temperatures are in degrees Celsius (unless
otherwise
indicated) and all percents are weight percent (also unless otherwise
indicated) except for
percent inhibition which is true mathematical percentage. Additionally, the
following
abbreviations have the following meanings. If an abbreviation is not defined,
it has its
generally accepted meaning.
CFU - colony forming
units
g - grams
hrs. - hours
min. - minutes
ml - milliliters
mm - millimeters
SAB-DEX - Sabouraud Dextrose
TSA - trypticase soy
agar
EXAMPLE 1
This example illustrates the preparation of two separate prepolymer
compositions, one comprising chlorhexidine diacetate as the antimicrobial
agent and the
second comprising tetracycline hydrochloride as the antimicrobial agent. In
this
example, ambient conditions were employed unless otherwise noted.
Specifically, 47.5 g acrylate urethane prepolymer (available under the
tradename
LOCTITE 3104, from Loctite Corp., Rocky Hill, Connecticut) was combined with
2.5 g
dimethylamino ethylacrylate and 0.25 g. camphorquinone (both available from
Aldrich
Chemical Co., Milwaukee, Wisconsin). This composition was covered to exclude
light
and then mixed until homogenous and the camphorquinone was dissolved. This
composition is referred to as "Composition A."
0.5 g chlorhexidine diacetate (Aldrich) was added to 4.5 g of Composition A.
This was covered to exclude light and mixed until a uniform dispersion was
formed. This
composition is referred to as "Composition B."
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0.05 g tetracycline hydrochloride (Sigma Chemical Co., St. Louis, Missouri)
was
added to 4.95 g of Composition A, covered to exclude light and mixed until the
tetracycline hydrochloride was dissolved. This mixture is referred to as
"Composition
C."
Small samples of approximately 1 to 2 g of each of Composition A, B, and C
were placed between two approximately 4 by 6 inch sheets of PARAFILM (American
National Can, Neenah, Wisconsin) and pressed to achieve approximately 3 inch
zones of
composition. These sheets were then exposed to white light of approximately
250 watts
(halogen lamp) at a distance of about 12 inches, and cure times were measured.
Compositions A and B cured within 30 seconds and Composition C cured within 60
seconds.
EXAMPLE 2
This example illustrates in vivo application onto mammalian skin of a
prepolymer
composition of Example 1.
Specifically, following the procedure of Example 1 above, an antimicrobial
prepolymer composition is prepared containing chlorhexidine diacetate as the
antimicrobial agent (such as Composition B, above). Approximately 2 g of this
composition is applied onto the calf of a human female subject using a flat
metal blade to
spread the mixture into a smooth, flat film. This film is covered with a thin
transparent
plastic film (such as is used to wrap foods) and is exposed at about a 12 inch
distance to
white light of about 250 watts (halogen Lamp) for sixty seconds. The polymeric
film
cures tack-free in about 2 minutes, at which time the transparent plastic film
can be
removed from the polymeric film. After about 1 to 3 days, the polymeric film
will
dough off the calf. The skin under the polymeric film is normal in appearance
with no
redness or irntation.
EXAMPLE 3
The following example illustrates how the antimicrobial effects of a polymeric
film of this invention can be determined.
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A. Per ,paration of the InoculLm
Specifically, the surfaces of two TSA plates, 100 x 15 mm, are inoculated with
stock cultures (maintained on TSA slants) with the following microorganisms
using a
sterile inoculating loop: Staphylococcus aureus (ATCC No. 6538) and
Staphylococcus
epidermidis (ATCC No. 12228). The plates are incubated at 30° to
35°C for 24 hrs. The
surfaces of two SAB-DEX agar plates are streaked with Candida albicans and
incubated
at 20-25 °C for 48 hrs.
The cultures are harvested with sterile saline. Each culture suspension is
collected
in a sterile container and sufficient sterile saline is added to reduce the
microbial count to
obtain a working suspension of approximately 1 x 10$ CFU's per ml.
The specific microorganisms recited above are selected for inclusion herein
because they are common human skin pathogens (bacteria and fungus).
B.
Each of the three test microorganisms is used to inoculate individual TSA
plates
by streaking them with sterile cotton tip applicators saturated with the
appropriate
suspension. The plates are allowed to dry.
C. Inhibition Study
Films of polymerized prepolymer comprising chlorhexidine diacetate or
tetracycline hydrochloride are formed as in Example 1 and are cut into
approximately 11
to 13 mm2 pieces. The pieces are placed in the center of the appropriate
inoculated TSA
plates (the tetracycline hydrochloride film is not tested with Candida
albicans). An
untreated 25 mm filter disk is cut in half, and one half is placed in the
center of the
appropriate inoculated TSA plate while the other half is place in the center
of non-
inoculated TSA plates, to serve as a negative control. Two inoculated plates
of each
microorganism are also used as positive controls without the test article.
These plates are
then incubated for 3 days at 30° to 35 °C. After incubation, the
plates are removed and
examined for any signs of microbial growth inhibition.
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Zones of inhibition extending at least 1 mm from the antimicrobial films
evidence
that the antimicrobial is leaching from the film and imparting antimicrobial
properties to
the film.
From the foregoing description, various modifications and changes in the
composition and method will occur to those skilled in the art. All such
modifications
coming within the scope of the appended claims are intended to be included
therein.
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