U.S. patent application number 10/666947 was filed with the patent office on 2005-10-13 for transcutaneous infusion of carbon dioxide for local relief of pain and other ailments.
This patent application is currently assigned to Capnia, Incorporated. Invention is credited to Rasor, Julia S., Rasor, Ned S..
Application Number | 20050228337 10/666947 |
Document ID | / |
Family ID | 22681216 |
Filed Date | 2005-10-13 |
United States Patent
Application |
20050228337 |
Kind Code |
A1 |
Rasor, Ned S. ; et
al. |
October 13, 2005 |
Transcutaneous infusion of carbon dioxide for local relief of pain
and other ailments
Abstract
The invention relates to devices for transcutaneous and
transmucosal application of carbon dioxide in the form of a gas and
in the form of a capnic solution (such as carbonated water) for the
relief of pain, including musculoskeletal disorders, neuralgias,
rhinitis and other ailments. Gaseous carbon dioxide is applied to
the skin for at least three minutes, and the capnic solution may be
held on the skin for at least three minutes, which provides relief
of symptoms.
Inventors: |
Rasor, Ned S.; (Cupertino,
CA) ; Rasor, Julia S.; (Los Gatos, CA) |
Correspondence
Address: |
TOWNSEND AND TOWNSEND AND CREW, LLP
TWO EMBARCADERO CENTER
EIGHTH FLOOR
SAN FRANCISCO
CA
94111-3834
US
|
Assignee: |
Capnia, Incorporated
Los Gatos
CA
|
Family ID: |
22681216 |
Appl. No.: |
10/666947 |
Filed: |
September 17, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10666947 |
Sep 17, 2003 |
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09795648 |
Feb 28, 2001 |
|
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6652479 |
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60185495 |
Feb 28, 2000 |
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Current U.S.
Class: |
604/23 |
Current CPC
Class: |
A61M 2202/0225 20130101;
A61M 2202/0007 20130101; A61H 33/14 20130101; A61M 15/0033
20140204; A61M 2210/0618 20130101; A61M 2202/0225 20130101; A61M
2202/064 20130101; A61P 27/16 20180101; A61H 2033/145 20130101;
A61P 25/02 20180101; A61M 37/00 20130101; A61M 15/009 20130101;
A61M 15/0065 20130101 |
Class at
Publication: |
604/023 |
International
Class: |
A61M 037/00 |
Claims
What is claimed is:
1. A device for transcutaneous application of carbon dioxide
comprising: A container adapted for removable application to a
subject's skin, to form a pocket between the subject's skin and the
sheet; An activatable source of carbon dioxide, adapted to be
placed inside the pocket; Whereby, when activated, the source of
carbon dioxide releases carbon dioxide into the pocket to deliver a
dose of carbon dioxide to the subject's skin.
2. The device set forth in claim 1 wherein the container comprises
a gas impermeable sheet defining a perimeter and further comprises
an adhesive placed around the perimeter adapted for removable
application to the subject's skin.
3. A device as set forth in claim 1 further comprising: A vent in
the container.
4. A device as set forth in claim 2 further comprising: A vent in
the sheet.
5. A device as set forth in claim 1 wherein the activatable source
of carbon dioxide comprises an agent that generates the gas by a
chemical reaction.
6. A device as set forth in claim 5 further comprising a porous
envelope inside the gas and liquid impermeable envelope that
contains the agent.
7. A device as set forth in claim 1 wherein the activatable source
of carbon dioxide comprises a small cylinder containing the gaseous
agent attached to the container, in operable communication with the
pocket and adapted to release carbon dioxide into the pocket.
8. A device as set forth in claim 7 further comprising: A vent in
the container.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. patent application
Ser. No. 09/795,648, filed on Feb. 28, 2001, which is incorporated
by reference herein (which claims the benefit of U.S. Provisional
Patent Application No. 60/185,495, filed on Feb. 28, 2000).
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention relates to methods and apparatus for delivery
of carbon dioxide (CO.sub.2), and other physiologically active
agents to individuals.
[0004] Alternative methods and devices for delivering carbon
dioxide and other gases to individuals are described in U.S. patent
application Ser. No. 09/614,389 filed Jul. 12, 2000 and 09/708,186
filed Nov. 7, 2000, which are incorporated by reference herein.
Those applications describe the use of CO.sub.2, or other
therapeutic gas or agents, and associated transmucosal dispensing
apparatus for providing controlled amounts of gas to the nose,
mouth and/or eye for use in the relief of headaches, allergic
rhinitis and asthma, among other ailments, and for the potentiation
of the actions of certain drugs and/or physiologically active
agents.
[0005] The present invention, however, relates to methods and
apparatus for transcutaneous application of CO.sub.2 (i.e., applied
to the skin) and transmucosal application of CO.sub.2 (i.e.,
applied to a mucous membrane) in both the form of a gas and in the
form of aqueous solutions (such as carbonated water).
[0006] 2. Related Art
[0007] Subcutaneous Applications of CO.sub.2
[0008] CO.sub.2 is a known therapeutic agent and subcutaneous
application has been found to relieve a variety of ailments.
[0009] A West German group conducted a 3-year clinical treatment
program involving local subcutaneous injection of gaseous CO.sub.2
[A. Grosshans and H. Gensch, Z. gesamte inn. Med., Jahrig. 42
(1987) Heft 23]. The 335 patients treated had the following
indications:
[0010] 1. Cervico-cranial syndrome, in particular pains in the
neck, contractions of the neck, headache including migraine and
vertigo;
[0011] 2. Cervico-brachial syndrome;
[0012] 3. Lumbalgia with and without root-irritation syndrome;
[0013] 4. Other muscular-skeletal pain conditions (degenerative
changes, muscular contractions and others).
[0014] The treatments consisted of daily or twice-weekly injections
of 100-200 ml of CO.sub.2 gas under the skin, in the body regions
indicated, for a period of 2-5 weeks (10-15 injections). An
.about.8 cm diameter gas emphysemum arose with a mild hyperemia of
the skin at the injection site which disappeared within 3-5 minutes
after the injection. Improvement of the indicated disorder occurred
after 4-5 treatments. Of the total patients treated, 171 became
difficulty-free or were substantially improved, 157 were improved
with some remaining distress and 7 had no improvement.
[0015] Mineral Baths
[0016] Effervescent mineral water baths have been known from
antiquity to the present as being effective for relieving
musculoskeletal, neural and rheumatic pain. In general, it has been
assumed that the dissolved mineral components were responsible for
the therapeutic effects of the baths. However, the experimental
evidence developed by the inventors suggests that the effectiveness
of such baths arises from the high CO.sub.2 content of the mineral
water rather than from its other dissolved components.
SUMMARY OF THE INVENTION
[0017] The inventors discovered that results similar to those
obtained by subcutaneous injection of CO.sub.2 could be obtained by
transcutaneous application of CO.sub.2. This application could be
made either by applying the CO.sub.2 in the form of gas, or
alternatively, in the form of aqueous solutions (i.e., carbonated
water).
[0018] Application of the CO.sub.2 may be transcutaneous (through
the skin) or transmucosal (through a mucous membrane). For example,
gaseous CO.sub.2 or an aqueous solution of CO.sub.2 may be applied
to external skin surfaces for relief of various ailments.
Furthermore, an aqueous solution of CO.sub.2 may be sprayed into
the nose, mouth and/or upper respiratory passages for relief of
various ailments as an alternative to the application of gaseous
CO.sub.2 which was described in U.S. patent application Ser. Nos.
09/614,389 and 09/708,186.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] FIG. 1 shows a device used to test absorption of carbon
dioxide.
[0020] FIG. 2 shows the carbon dioxide absorbed by a wet paper
towel in an experiment using the device of FIG. 1.
[0021] FIG. 3 shows the device of FIG. 1 used on a human
subject.
[0022] FIG. 4 shows a device for applying carbonated water to a
selected portion of a subject's external skin surface.
[0023] FIG. 5 shows a subject utilizing a spray bottle containing
carbonated water.
[0024] FIG. 6 shows a device used for obtaining a quantitative
measurement of absorption of carbon dioxide in carbonated water
through the skin of a human subject.
[0025] FIG. 7 shows the results of an experiment using the device
of FIG. 6.
[0026] FIG. 8 shows the results of the same experiment as in FIG.
7, but taken immediately after the subject had been exercising.
[0027] FIG. 9 shows the results of the experiment of FIG. 8 fifteen
minutes after the measurements shown in FIG. 8.
[0028] FIG. 10 shows a therapeutic application of gaseous carbon
dioxide to an affected area of a subject.
[0029] FIG. 11 shows another therapeutic application of gaseous
carbon dioxide to an affected area of a subject using a cup
device.
[0030] FIG. 12 shows a subject submerging an affected body part
into carbonated water.
[0031] FIG. 13 shows a first embodiment of a "patch" for
application of CO.sub.2 with a peelable closure.
[0032] FIG. 14 shows the embodiment of a "patch" for application of
CO.sub.2 with the peelable closure removed and the patch applied to
the skin.
[0033] FIG. 15 shows a second embodiment of a "patch" for
application of CO.sub.2.
[0034] FIG. 16 shows a third embodiment of a "patch" for
application of CO.sub.2.
DETAILED DESCRIPTION OF THE DRAWINGS
[0035] Transcutaneous application of gaseous CO.sub.2 has been
found to relieve ailments previously treatable by subcutaneous
injections of gaseous CO.sub.2.
[0036] Application of Gaseous CO.sub.2
[0037] One of the inventors undertook tests between Jan. 3 and Feb.
6, 2000 to determine whether beneficial results obtained by
subcutaneous injection of CO.sub.2 could be obtained by the less
invasive means of transcutaneous diffusion. Since the above-cited
subcutaneous treatments occurred over periods of days to weeks, the
inventor reasoned that continuous chronic infusion, via a
transcutaneous "CO.sub.2 patch", might give equivalent relief of
distress if the period of the 100-200 ml dose infusion was applied
over 24 hours or more, i.e., at a rate as low as .about.0.1
ml/minute.
[0038] To determine the inherent rate of absorption and diffusion
of CO.sub.2 in a "passive" aqueous medium a preliminary in vitro
experiment was performed. The apparatus and method employed for
measuring the rate of CO.sub.2 absorption by a surface is
illustrated in FIG. 1. The device was placed on a table top 150,
and comprised a source of CO.sub.2 in the form of a cylinder 101
and a flow regulator 110, including a pressure regulator 112 and
flow meter 113. Polyethylene tubing 115 of approximately 0.2
cm.sup.2 lumen connected the cylinder 101 to a glass funnel 120
having a maximum area of 80 cm.sup.2. An additional length of
tubing 125 was used for measurement of changes in gas volume. This
gas volume measurement means used in the experiment could be
eliminated in a device intended to administer CO.sub.2 to a
patient's skin surface. The entire system was purged of air by
prolonged CO.sub.2 flow. The additional length of tubing 125 was
purged first, then a bolus of low-volatility (forepump) oil 130 was
inserted into its open end and the end plugged. The funnel 120 was
then purged with its open end resting on a portion of the selected
test surface 140 immediately adjacent to the portion to be tested,
and with the purge flow escaping at its edge. At zero time the
purge flow was terminated, the plug in the tube 125 end was removed
and the funnel was slid onto the test portion of the surface
without breaking the seal between the funnel edge and the wet
surface. The displacement of the oil bolus 130 within the 0.20
cm.sup.2 lumen of the tube 125 was then observed as CO.sub.2 gas
was removed from the closed system via absorption in the surface
140; i.e., each cm of displacement corresponded to absorption of
0.20 cc of gas by 80 cm.sup.2 of test surface.
[0039] As a control, the system was first tested by placing the
funnel 120 on a non-absorbing test surface 140 without water. No
movement of the bolus 130 occurred, which indicated that there was
no significant absorption or evolution of gas within the
system.
[0040] Next, the funnel was placed on test surface 140 of a 0.4-mm
thick water-soaked paper towel having about the same thickness as
skin. FIG. 2 shows the observed rate of absorption of gaseous
CO.sub.2 into the surface of the towel, i.e., a monotonic
quasi-exponential approach of the absorbed gas volume to the amount
apparently required to saturate the water in the towel with
CO.sub.2. The near linearity of the second (logarithmic) plot in
FIG. 2 shows that the volume of gas changes quasi-exponentially as
saturation is approached. The observed initial rate of absorption
determined from several such tests fell in the range 0.6-1.2
ml/min, and saturation occurred at 4-10 ml, for the 80-cm.sup.2
area test surface. If the vascular bed of the skin suppresses
saturation by removing CO.sub.2 as fast as it diffuses into the
skin, these rates would suggest that a 100-200 cc transcutaneous
dose CO.sub.2 would be delivered in 1{fraction (1/2)} to 5{fraction
(1/2)} hours. The inventors thus concluded that the rate was
sufficient for a "CO.sub.2 patch" to be feasible. Significantly,
the time constant for the exponential saturation was found to be
about three to five minutes, which was about the same as the
reported time for disappearance of the gas emphysemum in the
previously described subcutaneous gaseous CO.sub.2 injections.
[0041] Finally, as shown in FIG. 3, an attempt was made to measure
the rate of transcutaneous absorption of CO.sub.2 into a human body
using the same system. An area of skin on the right anterior thigh
sufficiently large for two positions of the funnel 120 applicator
was washed thoroughly and soaked with water for fifteen minutes.
The funnel 120 was purged of air by prolonged CO.sub.2 flow (for
about 10 minutes) while seated on the wet skin in the upper thigh
position 160, and then was slid to the lower thigh position 170 at
zero time. In several such tests, each over a period of about 10
minutes, no significant flow was observed, which suggested that
there was no measurable absorption of CO.sub.2 by the skin within
the sensitivity of the method. In other words, it appeared that
less than <0.1 ml of gas was absorbed. However, after all such
tests, when the funnel 120 containing CO.sub.2 was removed, a
hyperemia was observed over the region of skin in contact with
CO.sub.2, corresponding to that of moderately severe sunburn. This
reddening requires about three to five minutes to develop in
contact with CO.sub.2, and a similar period to subside after
removal of the CO.sub.2. There were no observed aftereffects. In a
control experiment, the inventors found that no reddening of the
skin appeared when only air was applied for ten minutes. Therefore,
the inventors concluded that some quantity of CO.sub.2, sufficient
to cause the observed vascular effects, must have diffused into the
skin. Therefore, the inventors continued with their experiments to
determine if a transcutaneous application of CO.sub.2 would reduce
local pain.
[0042] Application of Capnic Solutions
[0043] Treatment of Pain by Transcutaneous Infusion of CO.sub.2
[0044] To determine if pain could be treated using gaseous
CO.sub.2, a 73-year-old female subject was selected, who was
diagnosed with fibromyalgia. The subject was experiencing chronic,
highly localized pain over an area of approximately two to three
centimeters in diameter on both her outer thighs. The area was
exquisitely sensitive to touch. In addition to the localized pain,
the subject also had more general pain along the path of the
sciatic nerve which occurred identically in both legs.
[0045] The experiment employed an open-cylinder procedure shown in
FIG. 4. The interior diameter of the cylinder 410 measured
approximately 5 cm. The cylinder was placed over the area of
localized pain on one thigh 420. The cylinder was then filled
approximately 2 cm deep with carbonated water 430. After the
application of carbonated water 430, the area of application was
observed to be reddened to the degree described above in the
Preliminary Experiments section when gaseous CO.sub.2 was applied
to the skin. In this experiment a PVC pipe was used as the
cylinder, although in practice other materials could be used,
provided that the resulting device was able to hold the water in
position over the treatment area for the desired time.
[0046] The subject stated, within 2-3 minutes after the application
of the carbonated water, that the localized pain was fully
relieved, and that the general pain was partially suppressed over
about a 15-cm length along the sciatic nerve path in her thigh. The
pain in the other leg was not affected. The device was then removed
from the subject's thigh. About {fraction (11/2)} hour after the
application, the subject stated that the localized pain had
returned somewhat, but still was far less than that in the other
leg. The general pain then was about the same in both legs.
[0047] In part as a result of the foregoing experiment, the
inventors believe that carbonated water baths may be used
effectively for treatment of musculoskeletal, neural and other
rheumatic pains by immersion of the affected portions of the body
or the whole body into fresh carbonated water for at least three
minutes.
[0048] Treatment of Allergic Rhinitis by Transmucosal Application
of Capnic Nasal and Oral
[0049] Because of the observed similarity of the physiological
effects of gaseous CO.sub.2 and a capnic solution (carbonated
water) applied to the skin, the inventors believed that a capnic
solution might be effective for treatment of upper respiratory
indications for which infusion of gaseous CO.sub.2 is effective.
With reference to FIG. 5, to test this hypothesis, a 70-ml
commercially marketed plastic "squeeze" bottle 510 for dispensing a
physiological saline spray was 3/4 filled with fresh effervescing
carbonated water. The carbonated water spray was then sprayed into
the nose of a subject 520 who was suffering a mild allergic
rhinitis attack. The inflammation and allergic distress were
relieved immediately in a manner similar to that found when gaseous
CO.sub.2 was infused into the subject's nose. During the course of
a day as allergic rhinitis attacks reoccurred, the carbonated water
spray and gaseous CO.sub.2 infusion were used alternately and their
relative effectiveness assessed. The subject concluded that the two
methods of treatment were equally effective for relief and
suppression of allergic rhinitis symptoms.
[0050] Other subjects tried the spray once and also found it to
give effective treatment. Those subjects resisted its further use,
however, because all subjects found that the spray injection
treatment is highly disagreeable compared with the gas infusion
treatment and is no more effective. The disagreeable aspects cited
were the discomfort associated with a liquid being sprayed up the
nose and the messiness of the effluent liquid from the nose after
the spray. Nevertheless, the carbonated nasal spray is a distinct
alternative for treatment of the upper respiratory distress
indications, and shares many of the advantages of a gaseous
CO.sub.2 infusion treatment including effectiveness, ease of use,
rapid relief on demand, unlimited dose, low cost, and freedom from
aftereffects and other contraindications associated with the use of
drugs. It is also possible to use the carbonated spray orally to
deliver the dose of carbon dioxide to the mucous membranes in a
similar manner.
[0051] The carbonated spray may offer superior treatment for
patients suffering from dry nasal membranes along with allergy
symptoms, i.e., the conditions for which the several saline nasal
spray products presently are marketed. As with those products, a
buffered isotonic solution should be used to minimize tissue volume
changes by osmosis, but the solution should be carbonated by
dissolving the maximum amount of CO.sub.2 in it that is consistent
with a practical operating pressure. The inventors found that the
degree of carbonation of commercially marketed carbonated water
corresponds to an acceptable CO.sub.2 pressure in the spray bottle
(1-2 lb/in.sup.2 at room temperatures). Furthermore, it has been
found that the carbonated water can be stored for an indefinitely
long period when the screw cap (not shown) of the dispenser 510 is
tightly closed. Multiple effective doses of the spray are obtained
until almost complete exhaustion of the spray bottle contents.
[0052] Measurement of the Electrical Potential Accompanying the
Transcutaneous Application of a Capnic Solution
[0053] With reference to FIG. 6, the inventors also undertook an
experiment to obtain a quantitative indication of the extent and
effect of transcutaneous infusion of CO.sub.2 effected by applying
a capnic aqueous solution (carbonated water) to the skin. In this
experiment the inventors used a cylinder 605 of about 5 cm interior
diameter, similar to that shown in FIG. 4, to apply about 2 cm of
the capnic solution 610 to a subject's anterior thigh 620. The
inventors then measured, using a digital logger 650, the resulting
electrical potential difference between the liquid and the
subject's body. As shown in FIG. 6, the potential difference was
measured between a stainless steel electrode 630, immersed in a
liquid pool (e.g. capnic solution) applied to the skin of the
anterior thigh, and a large (15.times.25 cm) aluminum plate 640 (as
indifferent electrode) applied to the moistened skin of the
posterior thigh 620.
[0054] In all tests a hyperemia occurred over the area of contact
between the skin and the applied pool of carbonated water. The skin
was reddened to about the same degree and within about the same
time of three to five minutes as was described in connection with
the application of gaseous CO.sub.2 to the skin. In control
experiments comprising application of distilled water to the
subjects' skin such reddening did not occur. Therefore, the
inventors concluded that the hyperemia occurred as a result of
CO.sub.2 infusion into the skin.
[0055] FIGS. 7-9 show the changes in body/liquid potential
difference after distilled water and carbonated water were applied
simultaneously to adjacent regions of the skin of the anterior
thigh. Both carbonated water and distilled water electrodes are
spontaneously positive relative to the body electrode, i.e., such
as to inhibit transport of carbonate or bicarbonate ions into the
body from the capnic solution, or to expel them from the body into
the distilled water.
[0056] Many observations have shown that the carbonated water
potential and its change with time always are substantially greater
than those for distilled water and that the changes are
approximately equal to the cell resting potential (60-90 mv).
Furthermore, as can be seen in FIG. 7, the potential is directly
related to the concentration of the carbonated water (the "stale"
solution shows no bubbles while the "fresh" solution effervesces
and deposits bubbles onto the skin). There was an increase in
potential when the carbonated water was agitated which suggests
that the decrease in potential with time arises in part from a
CO.sub.2 concentration gradient in the carbonated water. No change
occurs when the distilled water is agitated.
[0057] The decrease in carbonated water potential with time can
arise from a decrease in its CO.sub.2 concentration due to CO.sub.2
diffusion into the skin, from a concentration gradient within the
solution, and from an increase in the CO.sub.2 concentration in the
skin. The increase in potential upon agitation of the solution
indicates that diffusion is primarily into the skin rather than
into the atmosphere. Although not shown here, the CO.sub.2 dose
into the skin can be determined as a function of the decrease in
the concentration of CO.sub.2 in the agitated solution by various
methods of measurement (e.g., conductivity, cell potential, pH or
titration). By correlation of such measurements with the observed
decrease in liquid/body potential, that decrease could be used as a
convenient clinical method for dose determination.
[0058] The changes in distilled water potential can arise from
changes in concentration of body fluids in the skin and in the
applied liquid due to interdiffusion of the distilled water and the
body fluid components, for example, by osmosis.
[0059] FIG. 8 shows data taken under the same conditions as those
in FIG. 7 except that they are taken immediately after exercise. It
can be seen that the potentials and associated changes with time
are more than twice as large as those in FIG. 7. The data in FIG.
9, taken 15 minutes after those in FIG. 8, show a reversion to the
behavior observed before exercise in FIG. 7. In addition, it can be
seen that the application of CO.sub.2 actually decreases the
potential of the liquid applied on the skin in an adjacent region,
whether that liquid is carbonated or distilled water. In summary of
the results of many such tests:
[0060] 1. The liquid/body potential difference appears to be a
quantitative measure of the concentration and delivered
transcutaneous dose of CO.sub.2 via carbonated water applied to the
skin.
[0061] 2. The .about.3 minute exponential decay time of the
liquid/body potential changes corresponds to the time for reddening
of the skin by applied CO.sub.2 and for the reddening of the skin
to disappear, suggesting a 1:1 correlation of the observed
potential and the physiological effects of CO.sub.2
application.
[0062] 3. Other factors affecting the underlying muscle, such as
exercise, affect the liquid/body potential.
[0063] 4. After the initial topical application of carbonated
water, subsequent applications of carbonated water to the skin in
one region of an underlying muscle affects the liquid/body
potential in adjacent and non-adjacent regions of that muscle,
suggesting that the effects of transcutaneous infusion of CO.sub.2
are not confined to the skin in the immediate region of
application.
[0064] The inventors conclude that a possible explanation for the
observed results of the experiments described above is that the
application of CO.sub.2 to the skin changes the local electrical
potential through a response of the local and adjacent tissue in
opposition to an increase in the local physiological concentration
of CO.sub.2. This conclusion is supported by the observed reduced
absorption of CO.sub.2 in a physiologically active tissue, shown in
FIG. 3, as compared with that in an equivalent passive system as
shown in FIG. 2. This proposed mechanism is confirmed by the
observed development of an electrical potential in opposition to
the transport of carbonate and bicarbonate ions into the tissue as
shown in FIGS. 7-9, and by the increase in this reaction potential
due to increased partial pressure of CO.sub.2 in the tissue
resulting from exercise as shown in FIG. 8. Whatever the actual
mechanism, the response to the application of CO.sub.2 apparently
is associated with a reduction of pain in the local and adjacent
region of CO.sub.2 application. Implications for Therapeutic Use of
CO.sub.2
[0065] Gaseous CO.sub.2
[0066] In therapeutic use, a subject would apply gaseous CO.sub.2
to an affected area of the body. Application could be accomplished
by a number of different apparatus. In the simplest application
shown in FIG. 10, a dispensing device 1000 such as that shown in
U.S. patent application Ser. Nos. 09/614,389 and 09/708,186 for
infusion of the nose, mouth or eyes could be used to bathe the
affected area in CO.sub.2. The flow rate for the devices of U.S.
patent application Ser. No. 09/614,389 is as low as 2 to 10 cc/sec,
although higher flow rates are possible with the same device. As
shown in FIG. 10, the user could place a hand 1010 over the area
forming a pocket between the hand and the area of skin. By infusing
the CO.sub.2 into the pocket, the rate at which the CO.sub.2 is
dispersed into the surrounding air will be reduced. Alternatively,
as shown in FIG. 11, a cup 1100 or similar apparatus of appropriate
size and shape could be used in conjunction with the source of
CO.sub.2 1110 to retain the gas over the treated area. Preferably,
the cup would be of a gas impermeable material to limit the loss of
CO.sub.2. Of course, the funnel apparatus used in the inventors'
experiment to measure the rate of transcutaneous absorption of
CO.sub.2 could also be used with minimal modifications to
accomplish the same purpose. With the cup or funnel, after
placement on the affected area, the cup or funnel would be purged
of air by a prolonged flow of CO.sub.2. Unlike the experiment
described previously, it would not be necessary to move the device
after the purging procedure. The time of CO.sub.2 application could
vary from a few minutes to, if an attached cup or funnel device was
used, a few hours.
[0067] The gas used for treatment should be essentially pure, that
is, by volume, at least 50% carbon dioxide, preferably at least 70%
carbon dioxide and more preferably 95% or greater. For certain
applications, gases other than CO.sub.2, drugs, surfactants or
other substances could be incorporated into the flow.
[0068] Aqueous Solutions of CO.sub.2
[0069] As suggested above, an aqueous solution of CO.sub.2 can be
used to relieve both localized and general pain through submersion
of the affected areas. As shown in FIG. 12, the general procedure
would be to place fresh, carbonated water (not shown) into a
container or tub 1200 of appropriate size and have the subject
submerge the area(s) to be treated in the carbonated water, for
example, the hand and wrist 1210. The subject could vary the time
of submersion from a few minutes, preferably at least three
minutes, to a few hours, depending upon the severity of the pain
and individual response to the treatment. Submersion of the whole
body or substantially the whole body, i.e., the entire body except
the head to allow for breathing, may be appropriate for certain
treatments.
[0070] As an alternative, which is shown in FIG. 4, depending upon
the size and location of the treated area, a device such as that
used to test the subject response could be used. In other words,
the fresh, carbonated water 430 could be contained in a CO.sub.2
"patch," for example an open container or cylinder 410, and the
container placed on the skin over an affected area.
[0071] For application to mucous membranes, such as the nose, mouth
or ears, as shown in FIG. 5 the fresh carbonated water can be
placed in a standard "squeeze" bottle 510, such as is used for
nasal spray, or a modification thereof. To use, the subject would
open the bottle, placed the bottle into a nostril or other orifice,
and squeeze to produce a spray of the capnic solution. The bottle
would then be closed tightly to preserve the carbonated water for
later use.
[0072] CO.sub.2 Patches
[0073] FIGS. 13-16 show "patch" embodiments by which CO.sub.2 or
other gaseous agents can be applied to the skin to relieve pain in
a region of the body. FIG. 13 shows a patch 1300 with a peelable
closure 1305 to contain and protect its active contents before use.
FIG. 14 shows the patch 1300 with the peelable closure removed and
applied to the skin to relieve pain in a region of the body. The
patch 1300 consists of a cavity 1310 enclosed by a gas and liquid
impermeable plastic envelope 1320 having an adhesive rim 1330 for
attachment of the edge of the cavity to the skin 1335, thereby
forming a gas-tight seal and chamber 1340. The chamber 1340 is
filled with a sponge or other liquid-containing medium 1350 soaked
with a gas-containing liquid. When the patch is in use this liquid
is in contact with the skin and delivers a dose of the dissolved
gaseous agent to the underlying tissue by transcutaneous diffusion
as describe herein.
[0074] An electrode 1360 can be used to monitor the dose and its
effect on the tissue by measurement of the electrical potential
between this electrode and a conventional ECG electrode (not shown)
elsewhere on the body, as described and shown in connection with
FIGS. 7-9. Although an electrode as shown could be included for use
in a clinical setting, it need not be a part of a patch intended
solely for more general use.
[0075] As an alternative to the liquid containing medium 1350, the
patch 1300 shown in FIGS. 13 and 14 the gas-containing liquid in
the chamber 1340 can be replaced by an agent that generates the gas
by a chemical reaction such as a mixture of solid citric acid and
water-containing microcapsules, which when crushed together release
a substantial quantity of carbon dioxide gas that then can diffuse
through the skin as described. To facilitate diffusion of the gas
from the chamber 1340 into the skin in this embodiment it is
desirable to wet the skin before application of the patch or
otherwise before the gas is applied to the skin. As shown in FIG.
16, as an alternative to microcapsules, the chamber 1340 may
include a porous envelope 1345 inside the gas and liquid
impermeable
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