Transcutaneous infusion of carbon dioxide for local relief of pain and other ailments
The invention relates to methods 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. The capnic solution may also be sprayed onto mucous membranes such as the nose for relief of symptoms such as allergic rhinitis.
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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 INVENTION1. Field of the Invention
This invention relates to methods and apparatus for delivery of carbon dioxide (CO2), and other physiologically active agents to individuals.
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 CO2, 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.
The present invention, however, relates to methods and apparatus for transcutaneous application of CO2 (i.e., applied to the skin) and transmucosal application of CO2 (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).
2. Related Art
Subcutaneous Applications of CO2CO2 is a known therapeutic agent and subcutaneous application has been found to relieve a variety of ailments.
A West German group conducted a 3-year clinical treatment program involving local subcutaneous injection of gaseous CO2 [A. Grosshans and H. Gensch, Z. gesamte inn. Med., Jahrig. 42 (1987) Heft 23]. The 335 patients treated had the following indications:
- 1. Cervico-cranial syndrome, in particular pains in the neck, contractions of the neck, headache including migraine and vertigo;
- 2. Cervico-brachial syndrome;
- 3. Lumbalgia with and without root-irritation syndrome;
- 4. Other muscular-skeletal pain conditions (degenerative changes, muscular contractions and others).
The treatments consisted of daily or twice-weekly injections of 100-200 ml of CO2 gas under the skin, in the body regions indicated, for a period of 2-5 weeks (10-15 injections). An ˜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.
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 CO2 content of the mineral water rather than from its other dissolved components.
SUMMARY OF THE INVENTIONThe inventors discovered that results similar to those obtained by subcutaneous injection of CO2 could be obtained by transcutaneous application of CO2. This application could be made either by applying the CO2 in the form of gas, or alternatively, in the form of aqueous solutions (i.e., carbonated water).
Application of the CO2 may be transcutaneous (through the skin) or transmucosal (through a mucous membrane). For example, gaseous CO2 or an aqueous solution of CO2 may be applied to external skin surfaces for relief of various ailments. Furthermore, an aqueous solution of CO2 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 CO2 which was described in U.S. patent application Ser. Nos. 09/614,389 and 09/708,186.
Transcutaneous application of gaseous CO2 has been found to relieve ailments previously treatable by subcutaneous injections of gaseous CO2.
Application of Gaseous CO2One of the inventors undertook tests between Jan. 3 and Feb. 6, 2000 to determine whether beneficial results obtained by subcutaneous injection of CO2 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 “CO2 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 ˜0.1 ml/minute.
To determine the inherent rate of absorption and diffusion of CO2 in a “passive” aqueous medium a preliminary in vitro experiment was performed. The apparatus and method employed for measuring the rate of CO2 absorption by a surface is illustrated in
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.
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.
Finally, as shown in
To determine if pain could be treated using gaseous CO2, 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.
The experiment employed an open-cylinder procedure shown in
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 1½ 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.
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.
Treatment of Allergic Rhinitis by Transmucosal Application of Capnic Nasal and Oral SprayBecause of the observed similarity of the physiological effects of gaseous CO2 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 CO2 is effective. With reference to
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 CO2 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.
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 CO2 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 CO2 pressure in the spray bottle (1-2 lb/in2 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.
Measurement of the Electrical Potential Accompanying the Transcutaneous Application of a Capnic SolutionWith reference to
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 CO2 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 CO2 infusion into the skin.
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
The decrease in carbonated water potential with time can arise from a decrease in its CO2 concentration due to CO2 diffusion into the skin, from a concentration gradient within the solution, and from an increase in the CO2 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 CO2 dose into the skin can be determined as a function of the decrease in the concentration of CO2 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.
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.
In summary of the results of many such tests:
- 1. The liquid/body potential difference appears to be a quantitative measure of the concentration and delivered transcutaneous dose of CO2 via carbonated water applied to the skin.
- 2. The ˜3 minute exponential decay time of the liquid/body potential changes corresponds to the time for reddening of the skin by applied CO2 and for the reddening of the skin to disappear, suggesting a 1:1 correlation of the observed potential and the physiological effects of CO2 application.
- 3. Other factors affecting the underlying muscle, such as exercise, affect the liquid/body potential.
- 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 CO2 are not confined to the skin in the immediate region of application.
The inventors conclude that a possible explanation for the observed results of the experiments described above is that the application of CO2 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 CO2. This conclusion is supported by the observed reduced absorption of CO2 in a physiologically active tissue, shown in
In therapeutic use, a subject would apply gaseous CO2 to an affected area of the body. Application could be accomplished by a number of different apparatus. In the simplest application shown in
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 CO2, drugs, surfactants or other substances could be incorporated into the flow.
Aqueous Solutions of CO2
As suggested above, an aqueous solution of CO2 can be used to relieve both localized and general pain through submersion of the affected areas. As shown in
As an alternative, which is shown in
For application to mucous membranes, such as the nose, mouth or ears, as shown in
CO2 Patches
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
As an alternative to the liquid containing medium 1350, the patch 1300 shown in
In the patch embodiment shown in
The quantity of CO2 required to achieve saturation of the skin is very small, so the required volume of carbonated water or gas-generating agent in the patch, or of gas in the cylinder, is easily contained in a conveniently-sized patch.
While preferred embodiments of the present invention are described above and in the following claims, it is contemplated that various modifications may be made without departing from the spirit and scope of the invention. Furthermore, many of the features of the various embodiments described herein can be combined or added to other devices to obtain the optimum combination of features for particular applications and markets.
Claims
1. A method for transcutaneous delivery of carbon dioxide to an individual comprising the steps of:
- Selecting a portion of the individual's skin; and
- Applying a quantity of carbonated water to the selected portion of the individual's skin.
2. The method of claim 1, wherein the applying step further comprises submerging the selected portion of the individual's skin in the carbonated water.
3. The method of claim 1, wherein the applying step further comprises the steps of:
- Placing a selected quantity of carbonated water in a container that defines an opening, said opening adapted to be sealed against the selected portion of the individual's skin; and
- Placing the opening over the selected portion of the individual's skin and orienting the container such that the carbonated water contacts the selected portion of the individual's skin.
4. The method of claim 2, wherein the applying step further comprises submerging the selected portion of the individual's skin in the carbonated water for at least three minutes.
5. The method of claim 3, wherein the applying step further comprises applying the carbonated water to the selected portion of the individual's skin for at least three minutes.
6. The method of claim 1, wherein the container is large enough to receive substantially all of the individual's body, and wherein the selected portion of the individual's skin comprises substantially all of the individual's transcutaneous skin surface, and the applying step further comprises:
- Submerging the selected portion of the individual's skin in the carbonated water.
7. The method of claim 6, wherein the applying step further comprises, submerging the selected portion of the individual's skin for at least three minutes.
8. A method for transcutaneous delivery of carbon dioxide as in claim 1 wherein the selecting step further comprises:
- selecting a portion of skin adjacent to an area of the individual's body that is experiencing pain.
9. A method for transcutaneous delivery of carbon dioxide as in claim 1 wherein the applying step further comprises:
- Placing a selected quantity of carbonated water in an absorbent material; and
- Placing the absorbent material against the selected portion of the individual's skin.
10. A method for transcutaneous delivery of carbon dioxide as in claim 9 wherein the applying step further comprises placing the absorbent material against the selected portion of the individual's skin for at least three minutes.
11. A method for transcutaneous delivery of carbon dioxide as in claim 1 wherein the portion of the individual's skin further comprises a mucous membrane.
12. A method for transcutaneous delivery of carbon dioxide as in claim 8 further comprising placing carbonated water into a container from which a spray of carbonated water may be generated; and the applying step further comprises spraying a quantity of carbonated water on the selected portion of the individual's skin.
13. A method for transcutaneous delivery of carbon dioxide as in claim 11 further comprising placing carbonated water into a container from which a spray of carbonated water may be generated; and the applying step further comprises spraying a quantity of carbonated water on the mucous membrane.
Type: Application
Filed: Sep 17, 2003
Publication Date: Jun 5, 2008
Applicant: Capnia, Incorporated (Los Gatos, CA)
Inventors: Ned S. Rasor (Cupertino, CA), Julia S. Rasor (Los Gatos, CA)
Application Number: 10/666,562