Note: Descriptions are shown in the official language in which they were submitted.
The present invention relates to the covering of
a wound, lesion or the like on an animal body with an ad~
herent, skin-like collagen membrane to effect protection
therefor during the healing process. The invention also
pertains to an iontophoretic process whereby collagen fibrils
are electrochemically linked with each other and to the wound
or lesion site to provide such membranes.
The present invention further relates to the ion-
tophoretic administration of topical or systemic ionizable
or polar medicaments to a mammalian body, which medicaments
are responsive to an e~ectric field, and more especially, to
the administration of denatured or undenatured proteins, with
:,
~ or without a metallic component, to a wound, lesion or the ~
~i .
like, under the influence of an electric field, most preferably
a weak electric field. Additionally, the invention is relevant
to therapeutic treatments of mammalian bodies by the applica-
tion of minute electrical currents thereto. The invention also
- relates to articles adapted for use in practicing the pxesent
method.
The need to provide protection for a wound, lesion
or the like on an animal body during the healing thereof has
long been recognized. Bandages, surgical dressings and coat- ~ -
ings are often used for this purpose. More recently,
surgical grafting techniques have been developed to avoid
the oxygen impermeability problems encountered with extensive
use of bandage-like protective coatingsO Although skin
grafting is quite successful when the patient'sown skin
is used, grafts from donors often give rise to rejection
_ - -2-
' ,
3~?~
problems preventing the proper therapeutic eEfects. Thus,
other proteinaceous materials such as collagen have been
employed in oxygen-permeable protective materials~:
In recognition o:E the highly favorable, inherent ,~
characteristics of collagen which render it adaptable for
providing protective films for wounds, lesions and the like,
I have developed a process for the formation of adherent
films disclosed in my U.S. Pa-tent No. 3,563,228 issued
~ February 16, 1971. Briefly described, -that earlier patent `.
; 10 relates to the app.lication of an electric field, of
.
suitable polarity, to a dispersion of undenaturated collagen
fibrils to cause electrochemical-linking between the fibrils
of the.dispersion. The collagen, thus applied, is also
capable.of linking to native collagen fibrils exposed at the
wound site to effect a highly adherent, protective surface
thereover.
In recognlzing the advance over the prior art .
provided by my:U.S~. Patent No. 3,563,228, it would be ~:
deslrable to provide these adherent, skln-like protective
coatings but without the need for application of an external -~
power source to provide the iontophoreti.c impetus thereEor,
it being appreciated that the electric apparatus are often .:
bulky and, oftentimes require the patient to.be treated at
some central location. Accordingly, it is.desirable to be ;~
able to provide~these protective coatings by continuous ~;
treatment of the patient without significant restrictions .
upon ambulation or the necessity of confinement. ~
':
;' ' . , :. '~
-- 3 --
- ' :
; '.i
.
Further along these lines, the utility of an
electric field in medical treatment is, of course, well ~;
known. For example, it has been commonplace to provide
bandage-like articles with electrodes comprised of dis-
similar metallic materials to create a galvanic cell for
various types of clinical treatment. These ar~icles,
conventionally termed voltaic plasters, have been devised
for the iontophoretic administration of certain medicaments
through a patient's skin. Note, for example, United States
Patent Nos. 116,562, No. 175,974, No. 222,276, No. 393,741
and No. 1,967,927.
The prior art voltaic plasters suffer numerous
significant disadvantages, however. Perhaps the most impor-
~; tant are the tendencies towards metal poisoning and/or for
electro~de burns due to the materials employed, chiefly based
upon copper and zinc as the dissimilar materials for the
galvanic cell.
Currently, when it is desired to iontophoretically
administer topical medicaments, external power sources are
employed. Note, e.g. United States Patent No. 3,163,166,
as well as my earlier United States Patent No. 3,563,228.
Moreover, all prior art methods based upon the
application of an electric field to the body have hitherto
employed substantial voltages and/or currents which not
only tend to be discomforting to the patient, bu~ can
actually traumatize the area proximate the point of application.
Consequently, it is most desirable to provide a
therapeutic iontophoretic treatment of mammalian bodies
, ,; :
;3 3~;
.
.
which optimi~es the healing effect thereo while minimizing
the highly deleteriou~ side ef~ects and eliminating the
need for bulky external power sources.
This object is achieved, in accordanae with th~
invention, by providing a bandage adapted.for application to
a mammalian body having a wound, lesion or the like~ which
comprises:
(a) a bandage substrate adapted for applica~ion to
the body; .
~b~ a single metallic electrode, at least a part
of this electrode being in direct contact with the body; and
(c) collagen and/or an ionizable or~polar medicament
in electrically co-operative relationship with the electrode.
The bandage is capable in use of forming a galvanic
couple between the single electrode and the body when applied
.~ over the wound, lesion or the like, and producing~ without useof an external power source, a local current effective for
ontophoresis or for applying a small electric charge to the
~ body.
: 20 Optionally~ should it be desired to efect such a
protective coating more rapidly than is possible by employing
only the inherent electrical characteristics of the body to
be treated, an auxiliary power source may be supplied. In
accordance with this embodimént, such an auxiliary power supply
is in~orporated integrally with a bandage or dressing substrate
:bèaring the collagen to be electrochemically-linked. This
,
- power source comprises a galvanic couple which employs, inter
alia, natural body fluids as an electrolyte. The galvanlc
interaction between
electrodes will create an electric ~ield which provides the
iontophoretic impetus for electrochemical-linking of the
applied collagen to yield an adherent, skin-like protective
layer thereof over the tissue area to be treated.
Surprisingly, it has also been ascertained that
ionizable or polar medicaments may be effectively admin-
istered to a mammalian body, when there is provided an
iontophoretic impetus derived, in part, from these
naturally-occuY~ring local charges on the body to ~e treated
; 10 in concert with a similar compatible electrode borne upon
or comprising a bandage or bandage-like substrate. This
embodiment is efficacious for the administration of any
îonizable or polar medicament responsive to an electric
field; proteinaceous medicaments, or derivatives thereof,
being preferred. The proteinaceous medicaments may be
either undenatured or denatured, e.g., the protein component
of mild or strong silver protein, alginates, and the like. ;
Additionallyj there may be present various matallic salts
or compounds, partlcularly when a denatured protein iS ,
2~ employed~ That metallic ion most preferred is silver,;
albeit, other medicinally-effective metallic ions may be
incorporated.
The bandage or bandage-like device employed to
deliver the medicament to the mammalian body has an integral
~, 25 electrode of, e.g., foil in electrically-cooperative rela- ;~
tionship with the medicament thereon. Aluminum is the most
." ' ~
preferred electrode material; howe~er, the electrode might
~ be fabricated from any of a number of known active materials~ -~
;- -6-
.. ,. ~:
,
When the device, comprised of the electrode and
medicament, is applied to a mammalian body, natural body
fluids or, optionally, administrated isotonic or other
electrolytic fluids, will establish the appropriate electric ~-
current and concomitant field for delivery of the medicament
deep within the wound, lesion, or the like, on ~he body.
The medicaments envisioned for use in conjunction with this
invention comprise, but are not limited to, anti-infective,
analgesic, bacteriostatic, and like ionizable or polar
compounds, provided the compound is responsive, in terms
of migration, to an electric field.
In yet another embodiment, it has been further
surprisingly discovered that highly beneficial therapeutic
effects may be realized from the application of exceedingly
slight or minute electrical currents, for periods from as
short as about 10 minutes to longer term treatments ranging
up to a few weeks, the period of time and amount of electri-
cal current applied generally varying inversely. The
thera~utic effects are realized by applying a current
within the range of from about 0.001 to about 1,000 micro-
amperes (~iA), and most preferably from about 2.5 to about
S00 microamperes, at a voltage of from about 0.01 to about
3.0 volts. The beneficial effects observed range from
healing of wounds, lesions, or the like by the linking of
exposed, damaged collagen fibrils, to actual regeneration of
tissue materials following, for example, surgery, and the
improved knitting of bone frac-tures. Attendant this thera-
peutic effect is a substantial diminution in pain commonly
.
': , ' " " :
3~
I encountered in these situations.
FIG. 1 is a top elevation view of a bandage
according to one embodiment of the present invention;
FIG. 2 is a side elevation view of the bandage
of FIG. 1;
FIG. 3 is a side elevation view, similar to that
of FIG. 2, showing an alternate embodiment of the present
invention;
FIG. 4 is a botkom elevation view of a bandage
according to yet another embodiment of -the present inven-
tion; and
` FIG. S is a slde elevation view of the bandage of
FIG. 4.
`:
,::
In order to more fully elucidate upon the objects
15 and advantages of the present invention, the following
detailed description will be given in terms of various pre- ~-
ferred embodiments and exemplified~with respect thereto.
; ~ The same are intended, however, to be illustrative and in
; no wise limitative.
Furthermore, as used in the context of the present
I invention, the term bandage is meant to include all
; varieties of surgical dressings, regardless of physical
, configuration, which may be applied over a wound site to
: ~,
effect treatment therefor. Thus, the present invention t
envisions utility extending from the rather small adhesive
~;l bandages to large dressings o~ several squate feet which
~ -8- ~
.`'~s~ ;,.i,.,':
,.. .. . .
may be applied to burn victims.
The first embodlment to be described makes use
of the inherent, negative electrlcal potential of an animal
body to provide the necessary iontophoretic impetus for
electrochemical-linking of collagen fibers contained in a
dispersion applied proximate the area to be treated. To
achieve these ends, a collagen dispersion is prepared in
the same ma~ner as that described in U. S. Patent No.
3,563,228, save for the fact that the collagen concentra-
- lO tion in the instant dispersion is greater than the pre-
ferred 0.25% to 1% by weight concentration recited therein,
e.g., up to about 50% by weight concentration, but most
desirably having the consistency of soft table butter.
More specifically, the instant collagen suspension may be
' 15 prepared from bovine deep flexor tendon which has been
cleaned and trimmed of fat and other extraneous matter,
frozen, and subsequently sliced perpendicular to the longi-
tudinal axis of the tendons to a suitable length of about
,
O.001 mm to 0.5 mm, pref~erably from 0.2 mm to 0.5 mm, albeit ;
such a length is not critical. The collagen ~ibriis may
, ~ ~
then be disaggregated by treatment with proteolytic enzyme
such as commercial ficin. This treatment may be achieved,
for example, by gentle aggitation for approximately 1 hour
at 35F in an aqueous solution of ficin. These fibrils ~ ~
25 are then washed with distilled water and treated with ;
aqueous sodium chloride solution of appro~imately 1~ con-
centration for about 1 hour in two or three successive
treatments. See further said U. S. Patent No. 3,563/228.
,
g _
. . .
- , . .:;: .~ . : :, , ~ ,: .. .. ,, : . . ,: ~, : . -- : ,. :
3L.h~ Y~
Having thus been prepared, these fibrils are added to a
mixture of equal parts of ethanol and water, optionally
containing approximately 0.2% cyanoacetic acid if long-term
storage is anticipated; this mixture is then aggitated at a
temperature approaching the freezing point thereof and sub-
sequently homogenized by a conventional homogenizer.
Optionally, the collagen dispersion may be produced accord- f
ing to the teachings of either U. SO Patent No. 3,368,911
-
or the process of Battista as described in the ~ournal of
10 Applied Poly~er Science, 11, 41-498 (1967).
Such a dispersion of, for example, 10% collagen
concentration, will exhibit a paste-like or syrupy consistency, -
~; sometimes similar to that of soft butter. This paste or dis-
persio;~ is then enhanced for better conductivity by additions
of saline (usually in amounts ranging from between 0.1% to
1.0~ by weight), such as sodium ~hloride or potassium chloride,
` preferably in amounts to render the paste isotonic; that is,
; 0.9~. Metallic salts corresponding to those indigenous to
; the animal body may also be added in similar minute quantities,
~ 20 e.g. in amounts ranging between about 0.01~ and 10~ by weight.
:.. i :
~`I Selection of these salts, specifically to be rich in positive
ions, is well within the purview of the skilled artisan.
.', .
~} This paste may then be applied locally over the ~
.", ~
area to be treated. An electrical field will be established
I~ 25 between the collagen paste dispersion and the animal body;
`f the paste will exhibit an overall positive char~e while the
:.~1 . ` '.:
~ areas surrounding the wound site will exhibit an effective
. ,~, j ~
-~ negati~e electrical potential. However, the relative
~f
1 0-
1 .
. ~
,., ~, :
electrical potential thus established is relatively slight
and, thus, the desi~ed electrochemical-linking of the
collagen fibrils proceeds rather slowly. Accordinglyl it
may be desirable to provide an auxiliary power source,
operatin~ in conjunction with the body's inherent electri-
cal characteristics, to enhance this action.
Figures 1-3 illustrate another embodiment of the
present invention wherein a galva~ic couple is employed to
achieve the necessary electrical impetus for electrochemical-
linking. Figure l illustrates a bandage, generally design-
nated as 10, bearing electrodes ll and 12. The bandage may
be selected from numerous commercial varieties well known ~;
; to tnose skilled in the art and is necessary only to pro-
vide a suitable substrate upon which the galvanic electrodes
may be deposited, as well as a suitable quantity of collagen.
Preferably, the bandage will be comprised of a liquid
~; impervious top layer 13, as shown in Figures 2 and 3,
possessing an area 14 wherein a plurality of perforations
.. ...
I~ 16 are located~ Characteristics such as flexibility,
`, 20 absorbency, etc., will be dictated by individual cases and
t .:
~ are well known to the skilled artisan.
"., .
Electrodes ll and 12, which form the galvanic ~;
; couple, may be fabricated from strips of suitable electro-
, chemical material, such as metal. The electrodes may be
`. ! . .
25 adhered to the upper surface of the bandage in any desired
manner, such as adhesive paste. Optionally, these electrodes
may be fabricated by dispersing the desired electrochemi-
cally-active material in a volatile carrier to form a for-
- 1 1 -
mulation which may then be applied to the bandage. A
quantity of dry electrolyte 18 is disposed intermediate ~ ~-
electrodes 11 and 12.
As viewed in Figure 2, a collagen coating, such
as that fully described hereinabove, designated as 20, is
applied to the opposite side of the bandage and dried.
; Electrode 12 is caused to be maintained in electrical
contact with the collagen coating by internally disposed
conductive member 19, although electrode 12 may be over-
wrapped about the end of the bandage thereby providing this
desired electrical contact. Electrode 11 is caused to be
electrically insulated from both electrode 12 and the
collagen coating 20 and lS overwrapped about the bandage
10 or otherwise caused to make electrical contact with the
15 skin of the animal to be treated at a location apart from ~
the wound area, W. ~;
It is necessary that electrode 12 exhibits a
:i
positive standard reduction potential with respect to
~` electrode ll to efect the proper polarity therebetween;
that is, current should flow from electrode 12, through the
coated collagen layer to the tissue area of interest, and
thence to electrode 11, through electrolyte 18 and back to
electrode 12 to complete the electrical circuit, as depicted
'l in Figure 2. Thus, if the positive strip 12 is made of a
metal which may be strongly attacked by electrolysis, it may
, ,.
enter the wound, lesion, etc.. Accordingly, while the
electrode 12 may be fabricated from any harmless metal,
such as, aluminum, it is preferred that this positive
r- - -12-
:: - ",
..:: :.,:; :: .;: ,~:
- , , :,,.,-,~", ,:, ::: .
electrode be made from carbon. As regards the composition
of electrode 11, any metallic material meeting the fore-
going standard reduction potential criterion and one which
further exhibits a harmles~ effect on the body may be
-, suitably employed.
The bandage according to this embodiment may b-
activated by applying a few drops of water to the perforated
area 14 which will we-t both the electrolyte 18 and the
dried collagen dispersion coating 20. Optionally, the -
body's own fluids, such as blood or serum, may be employed
to these endsO Once this has been achieved, galvanic
action between the two electrodes will assist the inherent
~ ~egat~ve potential o the animal body by providing a current
-~ of proper polarity and attendant electric field to aug~ent
~/ 15 that naturally existing~ Accordingly, collagen in the
:
hydrated coating will electrochemically-link according to
the lines of electric force, E, and the fibrils will form
a film or membrane linked with damaged fibrils of the wound
to effect an adherent, skin-like protective coating.
` ! : :
~ An alternate embodiment of the topic bandage is
depicted in Figure 3 wherein there is now incorporated a
:,. . . .
discrete region 22 which is porous in nature. In this
embodiment, the material from which the bandage is fabricated
; .
~; is such ~hat the~collagen dispersion described supra may
~` 25 be impregnated therein; for example, foamed polyurethane,
,
Otherwise, this bandage will operate identical to the ~;
description for the bandage described in Figures 1 and 2.
3~
Further, it will be obvious to the skilled artisan
that the bandage depicted in Figures 1-3, and described
above, need not employ the saline or metallic salt com-
ponents in the collagen dispersion during initial processing
thereof. The action of the galvanically generated electric
field will, in some cases, be sufficient to supplant the
requirement of these constituents by using the body's own
fluid components~
Another, and the most preferred embodiment in
10 accordance with the present invention is illustrated in ~ ~;
Figures 4 and 5~ In Figure 4, there is shot~ a bandage
generally designated as 40 bearing an area 42 which is a
-; film of electrochemically-active material. Borne upon the
film 42 is a film of collagen 44. The electrical potential
is derived fxom a single active electrode, 42, which i.s in
~; contact with ~he skin of the patient to be treated proximate -~
~' the wound area. The electrode 42 is chosen to ensure
~f~
it possesses negative electrical characteristics with respect
i
to the collagen film, as shown in Figure 5.
- 20 The materialsl selection for electrode 42 is
;~l restricted primarily upon considerations such as standard
reduction potential to ensure the electrode maintains a
negative potential with respect to the collagen film; the
, , ~
:, ' . ~;
, .
~ -14~
~, /
" : . :,: .. , : .: : :: : - : ~ : :
3i~
'~ `.
propensity for dissolution, to minimize the introduction of
the electrode material within the wound area, as well as
other considerations well known to the skilled artisan.
Preferred electrode materials are, for example, aluminum,
5 mild silver protein and zinc. However, when zinc is
employed, due to its galvanic activity, it is preferable to
form electrode 42 as a narrow strip adjacent collagen film
44, in contradistinction to the film shown in Figure 4,
wherein the electrode is adjacent the entire periphery of
collagen film 44.
~`~ Particularly beneficial results may be realized
upon employing a mild silver protein film for electrode 42.
~, ~ild silver protein, a colloidal solution prepared by the
:.~ . ,.
interaction of protein and silver oxide and containing about
15 l9 to 23% silver, is a well known bacteriostatic agent. `~
Only a small fraction of the silver is in an ionizable
,::
" state and, thus, mild silver protein is not irritating but,
, ln fact, is somewhat demulcent. For a more comprehensive
~, understanding of the uses and~effects of mild silver protein,
see Goodman and~Gillman. The Pharmacological Basis of
Therapeutics, 3rd Edition, McMillan, 1969.
The mild silver protein membrane may be fabricated
~!
to exhibit either a propensity to disintegrate in moisture
or, with good wet strength to preclude such occurrence.
25 Accordingly, the electrode material itself may take an
active role in the healing process~
Another of the preferred electrode materials is
; aluminum, a relatively innocuous material with little
_ f 5~
:
tendency to dissolve when the bandage is employed. A
bandage similar to that depicted in Figure 5 was fa~ricated
for purposes of experimentation. The bandage 40 has an ~;
upper, liquid imper~ious layer 46 and conveniently possesses
a pressure sensitive adhesive (not shown) on the obverse
side in order to facilitate adherence of the bandage to ~he
area for treatment. This test employed a conventional
bandage commercially marketed undex the trademark CURAD.
A thin foil of aluminum, for example, 0.002 to 0.003 inches
thick, was adhered over a gau2e area 50 of the bandage. A
paste of collagen was prepared in accordance wiih the process
described above and deposited over the electrode 42 by
means of a doctor blade. The collagen membrane, 44, may ~ r~
?.~
''!^`~ be either supported or unsupported, and may be processed to
yield the collagen dispersible or insoluble in water, as
desired. Once the bandage was assembled as shown in Figure
5, a drop of saline solutîon was placed upon the collagen
~l~ film. Potentiometric tests were performed upon the bandage
at that time and indicated a voltage of 0.5 volts between
the electrode and collagen film, and a current of 400 micro-
amperes.
Other bandages were fabricated in similar fashion
. .
employing electrode materials as set forth in Table I. The
voltage and current developed by each of these bandages is - ;
25 likewise set forth in Table I~ ~
,:
, :
-16- ~ ;
.. . .
,.. . ,.-. . ., .; , :: :. ,.. -., . .. : : . . , -:~:
. -.- , . . , . . .. ,....... , ~.. .. .
.3
TABLE I
Electrode MaterialVoltage (V)Current (ua?
Aluminum 0.5 400
Zinc 1.2 200
Tin O.S 50
Titanium 0.15 25
Tantalum 0.1* 2.5
*reverse polarity
` :,:,,:
It has been observed that the collagen dispersion
`I 10 borne upon the bandage substrate electrochemically-links
~i in a very short amount of time under the influence of the
electrical potential derived from the galvanic source. More-
over, the collagen film adherently and tenaciously attaches
i to the wound site through both mechanical and chemical link-
-l 15 ~ages with the exposed, damaged collagen fibrils of the
wound.~ Accordlngly, it has further been observed that the
handage~substrate~itself may be removed in~a relatively
short amount of time, leaving ~ehind this highly adherent,
skin-Iike collagen film. Moreover, it has been observed `~
that the collagen film thus applied to the wound site, upon
limited dehydration, will contract somewhat and tend to
close the wound in a natural manner. These, and other
benefits, are realized upon application of materials totally
~` -17-
acceptable to the animal undergoing treatment and, accord-
ingly, rejection is rare.
Moreover, various modifications may be made to
the bandage and/or collagen dispersion of the present inven-
tion. For example, mild silver protein may be mixed with
; the collagen dispersion to form a paste of enhanced electro-
~; chemical activityO Further, the conductivity of mild silver
protein has been found -to be enhanced by a rine spray or
il .
~^ mist of ammonia prior to use. Thus, the relative electrical ;~ ~
. ,
~ 10 potential between electrodes and~or the collagen f.ilm is '
`; ; ,~ ' : .
capable of a wide range of selection in order that the
bandage be adapted ~or tailor-made operation. This is
particularly true as the electrochemical-linking phenomenon
~ is a strong function of electrical potential and may be
$
15 advanced or retarded based upon materials selection. ~^
It has also been determined that the notable
benefits of practicing the presènt invention may be realized -~
: ~ ;
- ~ by impregnating simple tissue paper with the appropriate
collagen dlsperslon, with or without additions, rather than ; ;~
``~ 20 ~depositing the~collagen upon a conventional bandage sub-
strate. The impregnated paper, whether readily disinte-
gratable or possessing wet strength, may then be utilized ~
for treatment, optionally in combination with any of the ~;
galvanic sources described above. In like vein, the collagen
dispersion, with~or without additions, may be dried to a
film, supported or unsupported, and used without need of any
substrate. These~embodiments may prove highly ~eneficial ~``
for treatment of exte~nsive wound areas such as, for example,burns
"`
Also, the collagen film may be electrically
linked prior to its application to the wound area. Thus,
the pre-linked film or membrane may be placed over the area
to be treated and one of the foxegoing galvanic sources
; 5 applied to effect linking between the collagen membrane and
damaged collagen fibrils of the wound.
~nother embodiment of the present invention per-
~ains, broadly, to methods for the iontophoretic administra-
~;`` tion of various ionizable or polar medicaments to a mammalian
body and a delivery system therefor based upon a bandage
such as the one described above~ More specifically, the ~
present invention is particularly adapted for the administra- ;
tion o~ various pxoteinaceous and/or biocompatible metallic
medicaments, or derivatives thereof, to a mammalian body
~, 15 from a bandage or bandage-like article under the }nfluence
;~ .~- of an electric field established between the bandage and the
body.
~, It is observed that prior art voltaic plasters
,
~,;
suffer numerous disadvantages, the most significant being
~` 20 risk of metal poisoning and/or electrode burns to the body
being treated due to the construction of the bandage from
highly active dissimilar metals as the galvanic electrode
materials, and an inability to effectively deliver a wide
range of medicinally effective medicaments. Both of these
significant drawbacks are overcome by the present invention,
by providing an integral electrode on a bandage substrate hav-
ing a quantity of medicament also borne thereon. When applied to
mammalian body, natural body fluids or applied isotonic
fluids will create a voltaic effect whereby the medicament
is caused to migrate deeply within a wound, lesion, or the
like, to elecit its desired pharmacologic response.
In part, the improvement derived from the present
invention is coupled with the recognition that a mammalian
body possesses a slight, inherent negative electric charge,
~ particularly at areas proximate the site of a wound, lesion ~ :
.~ or the like. Thus, by appropriate design of a delivery
` 10 device, materials may be employed which advantageously
.~ utilize this electrica~ characteristic thereby overcoming
the need for disslmilar electrodes to effect the galvanic ::
'i!~ cell while yet providing for the generation of a suitable ~.
-. electric field fox :the iontophoretic impetus. The improve-
ment in the iontophoretic administration of medicaments in
accordance with the present invention lies also, in part, in
administering a broad range of ionizabIe or polar compounds ~ :
responsive to the applied el.ectric field. ~`
. : ~ : ;
;~~ : Whlle numerous anionic, cationic, and polar medi-
20~ caments, including certain amphoteric medicaments, are
envisioned within the scope of the present invention, the
preferred are proteinaceous medicaments, eithex undenatured
: or denatured. Thus, these preferred medicaments include
-,~"
. the protein component of mild or strong silver protein, ~.
: 25 alginates, and the like. Additionally, various effective
metallic salts may be employed in the iontophoretic admini- :
: stration method according to the present invention in con~
junction with the;protein or derivative thereof. It has
: "
_~o_ :
, :
:
been determined that the proteinaceous medicament may be
employed alone when the protein component is not denatured.
;; When, however, that protein component is denatured, it is
particularly beneficial to employ a metallic salt, most ;~
preferably a silver salt. However, other medicinally-
~- effective equivalent metallic salts might be utilized. ~-
~; Likewise, other medicaments including, particularly,
Dexamethasone Sodium Phosphate, Methylprednisolone Sodium
~ Succinate, Flurandrenolide, and Amphotericin, are preferred
;~ 10 compounds for use in conjunction with the present invention.
These compounds may be employed individually or in admixture, -~
with or without the additional presence of metallic salts,
or denatured or undenatured mild silver proteins. Moreover,
.,
other various steroids, antibiotics, and antifungal com-
pou~ds, or the like, may also be employed, together or separ-
ately as might be desired. Further medicinally-effective
..
compounds and preparations may be selected from -s~ecific ;
pharmacological efects, such selection being within the scope
of those skilled in the art.
The most preferred proteinaceous medicament is
the antiseptlcally-effective mild silver protein, which is a
colloid of silver with protein, containing on the order o
about 10 to 25~ silver. This material is readily available,
commercially; and is described in "The Merck Index", Merck
25 & Co., Inc., 5th Edition, 1940, page 458. However, other -
anti-infectious, analgesic, bacteriostatic, and like
proteinaceous compounds may be employed to this end.
In electrically-cooperative relationship with the
_ -21-
3~
medicament is an electrode, which may assume any of a
number of physical configurations. Most preferably is a
metallic foil, although any electrochemically-active material
may be utilized and may be deposited in the form of a liquid j`
such as, for example, dispersion, and subsequently dried.
The electrode material should be selected from those known
to be compatible with the mammalian body for the obvious -~
reasons including toxicity, irritation, etc. As will become
more apparent hereinbelow, a salient distinction between
the bandage of the present invention and those of the prior
,. }
-~ art is the absence of a galvanic couple of active metallic
j ~ ,
`1 components on the bandage su~strate to which has been
attributed the significant problems of electrode burns and/
~,'JI~or metal poisoning indigenous to the latter. That is, the
instant-bandage employs but a singular electrochemically~
aetive material for the eleetrode, regardless of the physical ~ `
, ,~
state or configuration thereof, i.e.~ a bandage such as illus~
`~ trated in Figures 4 and 5. Of course, for the iontophoretic
administration of certain of;the medicaments within the scope
.. . ~
of the present invention, particularly those not heretofore
, : . j
iontophoretically administered (espeeially proteinaceous and ~ ;
protein/metallic medicaments), a conventional galvanic ;~
couple might be employed, e.g., a bandage such as illustrated
in Figures 1-3. However, in seleetion of the appropriate
materials for the couple, the skilled artisan will readily ~`
appreciate that less active metallie eomponents than
utilized in prior art devices may well be ehosen due to the
augmentive nature of the instant bandage respecting the
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33~
inherent electrical characteristics of the mammalian body
to which the bandage will be applied.
; The most preferred electrode is a foil of aluminum
metal. Other electrode materials include, for example,
5 copper, zinc, tin, and titanium, each of which will provide ~
an effective positive charge with respect to the mammalian ~;
- body. Should the medicament utilized require a net negative
charge to provide the desired iontophoretic impetus of
~` proper polarity, such materials as tantalum might be utilized
0 Regardless of the electrode material or configura-
tion thereof, it is essential that the electrode be in
electrically-cooperative relationship with the medicament
to be iontophoretically administered. As a consequence
when the bandage is activated by electrolytic fluids such
as, for example, body fluids or administered isotonic
saline, voltaic interaction wlll establish an electric
field between the electrode and underlying wound site and
generate a corresponding electric current, whereby the
~;
medicament is caused to migrate deeply within the wound in ~
;!~ : ~ ,. . ...
20~ response thereto.
The present invention envisions utility extending
-from small adhesive bandages to large dressing of several
square feet which may be applied to, for example, burn
victims. Exemplary of a particularly suitable bandage is
that of Figure 4, denoted generally as 40, which is com~
:~ .
prised of, e.g., a 6" x 2" substrate 46, having a medial ~;
portion and terminal portions. The medial portion has
adhered thereto a foil of, for example, aluminum metal,
_ _~3--
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3~
denoted as 42. The foil optimally comprises approximately ~ ~
one half of the total surface area of the bandage substrate; ~; -
~' however, these dimensions are not critical provided the
electrode material has sufficient surface area to provide
; 5 the required iontophoretic effective electric current.
The central portion of the electrode 42 has
I~ coated thereon, or adhered thereto, a quantity of the -~
;~ desired medicament 44. Preferably, the medicament is
applied as a paste or liquid to some absorbent material ~
~, 10 such as tissue paper or sterile cloth or gauze. The medica~ ;-
ment is allowed to dry and the porous carrier adhered to
, the foil electrode.
`1 An optional embodiment employs a commercially- -
available surgical bandage, such as those marketed under the
trademark "CURAD". As opposed to the bandage of Figure 4,
which may be made in relatively large dimensions, and ~
wherein the terminal portions may or may not be coated with ~`;
an adhesive substance, this altexnate embodiment is designed ~ `
.
~ ~for application to rather small cutst abrasions or the like.
:.
The bandage is comprised of a plastic or polymeric substrate
having a medial portion and adhesively coated end portions
with an absorbent gauze adhered to the substrate in the -
medial portion. Two foil electrodes, such as 42' shown in
Figure 4, are also borne upon the substrate and are caused
25 to partially~overlap the medial gauze area. The desired ~ -~
medicament may be applied to the gauze pad and allowed to
dry.
~` A bandage in accordance with this latter embodiment
'. ~
_
-24- ;
- `'- :.
was prepared in order to ascertain the effectiveness of the
iontophoretic administration of mild silver protein to a
human body. The bandage employed is approxlmately 7.5 cm
long and 2.5 cm wide. The gauze pad accounts for approxi-
5 mately 30% of the total surface area of the bandage and iscoated with a solution of mild silver protein (USP) made
isotonic with 0.9% sodium chloride. After the medicament
has dried, two rectangular strips of aluminum oil having
dimensions of about 2.5 cm x 2.0 cm are adhered to the
bandage substrate, partially overlapping the coated gauze
area such that approximately 15~ of each aluminum foil
strip is in direct contact with the coated gauze pad.
This bandage was placed on a human body over a
minor wound. A drop o isotonic saline was administered to ~`~
lS the coated gauze pad in order to establish voltaic action
between the aluminum foil electrodes and the body. The
electric potential was measured to be about 3/4 of a volt,
and the current generated about 10 microamperes. In response
to the electric field thus generated, the silver protein
.
medicament~migrated deeply within the wound at a rate much
greater than wére the electric field absent.
A similar bandage was prepared employing as a
;substrate, a commercially-available bandage, marketed under
the name "Air-Vent Tape Clear", by Johnson & Johnson.
;25 This bandage, measuring about 9.0 cm x 2.6 cm, was placed
with the adhesive side-up, upon which was adhered, in the -~
central portion thereof, a foil of aluminum me~al measuring
about 4.5 cm x ~2.0~cm x 0.0254 mm. The adheslve of the
,:
3~ r
bandage provided suficient area for firm attachment of the
foil thereto, leaving a sm~ll peripheral strip of adhesiye
exposed along the longitudinal edges of the foil due to
its narrower transverse dimension relative to that of the
bandage.
Sterile tissue paper, measuring 2.4 cm x 2.4 cm,
was soaked in a 10% solution of mild silver protein made
.
isotonir with 0.9% sodium chloride. The tissue was removed ;~
: :
from this solution and permitted to dry. Subsequently, the
impregnated tissue was placed over the aluminum foil, the
exposed adhesive from the bandage providing means for firm ;~
`~ attachment.
This bandage was applied over a cut on a human
~' body, perspiration and wound serum providing the re~uisite
15 poly-electrolyte. The voltage of the resultant electric ~;
field was measured at about l volt; the current varied
between 5 and 15 microamperes as the iontophoretic process ~;;
proceeded to carry the medicament deeply within the wound.
Depending upon the configuration of the electrodes,
.. ~
and their rel;ative placement with respect to the medicament
coating, various bandages have been tested and have been
.
found to develop between about 1/2 and 1 volt potential,
and between about 2 and about 15 microamperes current, for
aluminum foil electrodes. Obviously, various other elec- ;
trode materials will provide differing electrical charac~
teristics.
Yet another embodiment envisioned within the
scope of the present invention regards the use of soft,~;
-~ -26- -
' ,
hydrogel rnaterials, such as those disclosed in, for example,
United States Patent No. 2,976,576, Re. 27,401,
No. 3,220,960, No. 3,503,942, No. 3,639,524, No. 3,699,089,
No. 3,721,657 and No. 3,966,847. These materials, which
will swell and retain, by hydration, solutions of the
desired medicaments, may be employed as carriers therefor
in lieu o~ the saturated tissue or sterile gauze materials.
Otherwise, the bandage is identical in all respects to those
enumerated above.
While the foregoing embodiments have been predicated
basically upon the administration of various medicaments
or collagenous dispersions or suspensions from, for example,
a bandage substrate, the scope of the present invention is
indeed quite broader. For example, it has been learned that
very beneficial therapeutic effects may realized upon the
application of very minute electrical currents to a mammalian
body. In conjunction with this embodiment, as there is no
: .
need to deliver an anclllary medicament or the like, the
appropriate electric field may be provided by, for example,
a bandage substrate such as that described above, and illus_
trated in Figures 1-5, but without the need to provide the
coating of collagen or medicament. Consequently, the device
becomes exceedingly simple in design and may be comprised
of merely an adhesive upon which is borne an appropriate
~ ~:
electrode or electrodes. Indeed, since the fundamental
purpose of the adhesive substrate is to serve as a convenient
support for the collagen dispersion or medicament, as well
27
- ~.
., .. - .~., . . . :.:~,.:. .: ,;, . , .,, : .,.. . . . , . ~
-~ as the electrodes, even the substrate may be eliminated ~-
and the appropriate electro-chemically-active electrodes
implanted or otherwise fixed on the mammalian body to be
treated.
Regardless, however, of the basic electrode con- `~
figuration employed, it has been ascertained that the ~`
application of currents within the range of from about
0.001 to about 1,000 microamperes, and preferably from
about 2.5 to about 500 microamperes, at a volta~e in the
range of from about 0.01 to about 3.0 volts, maximi~es the
therapeutic efects desired whileconcomitantly diminishing -
all of the unwanted side efects attendant the use of
conceptually similar methods and articles. These beneficial ~ ~;
therapeutic effects range from the linking of damaged
collagen fibrils at the site of the wound, lesion, or the
like, to an observable regeneration o~ certain tissues
following, for example, surgery. It has also been observed ~ `
that bone ractures may be promoted to enhanced knitting
by application o these minute currents. Consequently,
the range o benefits derivable by practicing the present
invention is indeed exceedingly broad.
`, ,'.
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