KR20140035378A - Method of producing substances with supersaturated gas??transdermal delivery device thereof??and uses thereof - Google Patents

Abstract

The present invention generally relates to non-invasive transdermal delivery devices for portable mechanical devices for non-invasive transdermal administration of gases, small to large water soluble (hydrophilic) pharmaceutical agents, vitamins and other therapeutic agents. The components of such a delivery device, a method of preparing a material comprising a supersaturated amount of dissolved gas, as well as a method of administering a therapeutic agent using such a delivery device and a method of treating a disease or condition using such a delivery device Also disclosed.

Description

Manufacture of materials with supersaturated gas, percutaneous delivery devices thereof and methods of use thereof

Delivery of agents through the skin to achieve a therapeutic effect is commonly known as transdermal drug delivery. Percutaneous drug delivery systems are dosage forms that facilitate the delivery of therapeutic agents through the blood circulation as well as systematically into the surviving epidermal and / or dermal tissue of the skin for local therapeutic effects. . Percutaneous delivery of therapeutic agents offers a number of advantages over the injectable and oral routes. For example, percutaneous delivery of a therapeutic agent increases the bioavailability of the agent by avoiding gastrointestinal uptake and hepatic first pass metabolism, improves the therapeutic efficiency of the agent by providing controlled constant administration of the agent, Providing continuous administration of the medicament maintains stable plasma levels of the medicament, reduces pharmacological administration due to better absorption of the medicament, and provides better overall treatment value and increased patient compliance through greater dosing flexibility. Disadvantages of transdermal delivery include, for example, difficulty in administering a therapeutic agent having a molecular weight greater than 500 Daltons or the use of a therapeutic agent having a very low or high partition coefficient.

Percutaneous drug delivery systems may have an active or passive design. Typical formulations of passive transdermal drug delivery systems include, for example, ointments, creams, gels and transdermal patches. Manual systems require careful selection of the base and the addition of permeation enhancers and are applied to the skin surface to deliver a specific dose of medicament into the blood stream. Due to the impermeable nature of the skin, passive transdermal drug delivery systems have typically been used with lipophilic therapeutics.

Active transdermal drug delivery systems use mechanical energy to increase the delivery of therapeutics across the skin by altering the skin barrier (primarily the stratum corneum) or by increasing the energy of the drug. Such active systems are for example microneedles and microdermabrasion that punctures or otherwise physically ruptures the stratum corneum, photochemical waves using chemicals to alter the stratum corneum, and to drive charged drugs through the skin. Iontophoresis using low voltage currents, electroporation and reverse electroporation using short high voltage electric pulses to create temporary aqueous pores in the skin, and sonophoresis using low frequency ultrasonic energy to rupture the stratum corneum. Heat ablation using heat to make the skin more permeable and increase the energy of the medicament and magnetophoresis using magnetic energy to increase the drug flux across the skin.

There are two important layers of skin: the dermis and the epidermis. The outermost epidermis is approximately 100 to 150 micrometers thick, has no blood flow, and contains therein a layer known as the stratum corneum. This layer is important for percutaneous delivery because its composition provides water retention and foreign body protection. Just below the epidermis, the dermis contains a system of capillaries that carry blood throughout the body. If the drug is able to penetrate the stratum corneum, the drug can enter the blood stream. Sweat ducts and hair follicles are also pathways of entry into the blood system, but these pathways have been considered somewhat insignificant. See, for example, Aulton Pharmaceutics: The Science of Dosage Form Design (2d edition, Churchill Livingston, Harcourt publishers, 2002).

The percutaneous route has been one of the most successful and innovative focuses for the study of drug delivery. More than 35 therapeutic agents are currently approved for sale in the United States, and approximately 16 active ingredients are approved for use worldwide. However, there is still a need for a better way to deliver therapeutics by the transdermal route. For example, currently available transdermal delivery systems are limited to small molecular weight drugs with very small daily doses that often involve a variety of patient discomforts. The present disclosure discloses a transdermal delivery system using a device for administering a vapor comprising liquid particles comprising a supersaturated amount of dissolved therapeutic agent entering the circulatory system via the glands pores and the vascular system.

Accordingly, aspects herein disclose percutaneous devices. The transdermal delivery device disclosed herein can include a pressure cylinder, a permeation valve, an exchange chamber, and a processing chamber. The components can be installed in a housing.

Another aspect of the present disclosure discloses a steam generating assembly in an exchange chamber. The steam generation assembly disclosed herein can include a permeation valve and a fluid chamber assembly. The steam generation assembly disclosed herein may optionally include a control switch assembly.

Another aspect of the present disclosure discloses a method of making a material comprising a supersaturated amount of dissolved gas. The method of making a material disclosed herein includes disposing a material as disclosed herein in an airtight container and exposing the material to a gas, the gas being capable of dissolving the material at 25 ° C., 1 atm. Dissolve into the material in greater amounts than it is. The gas may be carbon dioxide. The final substance supersaturated with the dissolved gas may then be administered to an individual to treat a condition as disclosed herein. In another aspect, the present disclosure discloses the use of a material comprising a supersaturated amount of dissolved gas to prepare a drug. Such drugs may then be administered to an individual to treat the conditions disclosed herein.

Another aspect of the present disclosure discloses a method for transdermally administering a therapeutically effective amount of a therapeutic agent to an individual. The method of transdermal administration disclosed herein comprises administering to an individual a substance comprising a supersaturated amount of dissolved gas using a transdermal delivery device disclosed herein. In another aspect, the method of transdermal administration disclosed herein comprises administering to an individual a substance comprising a supersaturated amount of dissolved gas and a therapeutic agent at a rate set by a permeate valve using a transdermal delivery device disclosed herein. do. Administration of gases and / or therapeutic agents usually treats signs associated with the condition. In an aspect, the present disclosure discloses the use of a material comprising a supersaturated amount of dissolved gas to treat a condition using the percutaneous device disclosed herein. Embodiments also include the use of a transdermal delivery device disclosed herein for transdermally administering a therapeutically effective amount of a therapeutic agent to an individual.

Another aspect of the present disclosure discloses a method of treating a condition using the percutaneous device disclosed herein. The method of treating a condition disclosed herein comprises administering to a body part of an individual suffering from the condition a composition comprising a substance comprising a supersaturated amount of dissolved gas using a transdermal delivery device as disclosed herein. And administration of the composition reduces the signs associated with the condition. A method of treating a condition disclosed herein uses a percutaneous delivery device as disclosed herein to administer a composition comprising a supersaturated amount of dissolved gas and a substance comprising a therapeutic agent to a body part of an individual suffering from the condition. Also comprising the steps, administration of the composition reduces the signs associated with the condition. The material may be a liquid aerosol, foam, emulsion, gel, sol or other material that may be supersaturated in the amount of dissolved gas. Conditions include, but are not limited to, ischemia, hypertension, cardiovascular disorders, treatment of diabetic disorders, wounds, chronic inflammation, arthritis, migraine, cellulite disorders, pale skin disorders and cosmetic disorders. In an aspect, the present disclosure discloses the use of a substance comprising a supersaturated amount of dissolved gas to treat a condition. The percutaneous device disclosed herein may be used to administer material over a set time period at a set rate based on gas cylinder pressure and permeate valve rate. Embodiments also include the use of a transdermal delivery device disclosed herein for transdermally administering a therapeutically effective amount of a therapeutic agent to an individual to treat a condition of the individual.

The drawings are illustrations of different embodiments of the subject matter disclosed herein. Each illustrated embodiment is not intended to limit the scope of the subject matter disclosed herein, but rather is illustrative of its scope and spirit. Similar components in the figures share the same reference numerals.

1 is a block flow diagram of components of an exemplary delivery device described herein.
2 is a cross-sectional view of an exemplary housing.
FIG. 3A shows an exemplary permeate valve and fluid chamber configuration, FIG. 3B shows another exemplary permeate valve and fluid chamber configuration, and FIG. 3C shows another exemplary permeate valve and fluid chamber including an actuator assembly. It is a figure which shows a structure.
4A is a perspective view of an exemplary transdermal delivery device, FIG. 4B is a cross-sectional view of an exemplary transdermal delivery device, and FIG. 4C is a cross-sectional view of another exemplary transdermal delivery device including an actuator.
5A is a cross-sectional view of an exemplary permeate valve with the gas cartridge not fully engaged with the through member, and FIG. 5B shows the gas cartridge associated with the through member.
6 is a cross-sectional view of an exemplary control switch assembly.
7 is a cross-sectional view of an exemplary fluid chamber assembly.

The average diameter of most human glands provides adequate space for most drug molecules to pass through. According to various studies, the mean density of pores varies considerably between individuals and body parts. Palms, palms and fingers and soles, soles and heel have an average of 2,700 holes per square inch of raised friction skin surface. This compares to approximately 400 holes per square inch of the remainder of the skin surface of the body. The total number of pores distributed throughout the body has been estimated at 1,600,000 to 4,000,000. The size of the glands has been found to vary by five times among individuals, but the average pore size in human skin is 50 microns. The dimensions of the coil running down from the opening in the epidermis are about 2 to 5 mm long, about 60 to 80 microns in diameter, and have a tube with a slightly smaller diameter.

The present disclosure discloses a lightweight phage mechanical device designed to transdermally administer a therapeutic agent to an individual. The device may produce a vapor that contains a supersaturated amount of dissolved gas that is delivered non-invasively through the skin via orifice and vascular systems contained within the skin, such as, for example, sweat glands and vascular systems. In normal operation, a removable cartridge containing compressed gas, such as, for example, carbon dioxide, is attached to the port of the permeation valve. The permeate valve can reduce the pressure and thus the speed of the gas at a predetermined rate without mechanical adjustment. This adjustment of the gas pressure can also reduce the temperature of the gas.

If the gas is a therapeutic agent, this low pressure ambient temperature gas can then be passed to a fluid chamber assembly containing a liquid such as, for example, water, a physiologically buffered solution or other suitable liquid, where it is dissolved into the liquid and the gas Produces a supersaturated liquid. This therapeutic agent is then administered to the individual by evaporating the supersaturated liquid and applying vapor to the skin surface where liquid particles comprising the supersaturated amount of dissolved therapeutic agent enter the body via the skin pores. If the therapeutic agent is not a gas, this low pressure ambient temperature gas can be passed to the fluid chamber assembly containing the liquid and the therapeutic agent, where the gas dissolves into the liquid to produce a therapeutic liquid comprising a supersaturated amount of dissolved gas. do. This therapeutic agent may then be administered transdermally to the individual as a vapor.

Aspects of the present disclosure disclose partly a transdermal delivery device. A flow diagram of such a device is shown in FIG. Such a device may include at least one compression cylinder 102, at least one permeation valve 104, a fluid chamber 106, and a processing chamber 108. Each of these components may be directly connected or may include additional components therebetween. For example, a button to actuate the valve may be positioned between the permeate valve 104 and the fluid chamber 106. Other additional valves or ports may also be included.

The percutaneous delivery device disclosed herein can include a housing (eg, see housing 200 of FIG. 2) and a vapor generation assembly, the housing surrounding the vapor generation assembly. Such devices can be designed to be lightweight, handheld portable devices that provide a practical and comfortable sensation to the user during operation of the device. The overall shape of the transdermal delivery device disclosed herein is generally cylindrical in shape, although other geometries may be used. In one embodiment, the percutaneous delivery device disclosed herein has a length less than about 20 inches (50.8 cm), a length less than about 18 inches (45.72 cm), a length less than about 16 inches (40.64 cm), and about 14 inches ( Less than 35.56 cm), less than about 12 inches (30.48 cm), less than about 10 inches (about 25.4 cm), or less than about 8 inches (20.32 cm), and 2 inches (5.08 cm) Less than 1.5 inches (3.81 cm), less than 1 inch (2.54 cm) or less than 0.5 inches (1.27 cm). In an aspect of this embodiment, the transdermal delivery device disclosed herein can be less than about 12 inches (30.48 cm) long and about 1 inch (2.54 cm) wide.

The housing disclosed herein includes a cartridge holding vessel (eg, FIG. 2) detachably coupled to an outer body shell (see, eg, outer body shell 202 of FIG. 2), one or more inner compartments and an outer body shell. Cartridge holding container 212]. The outer shells disclosed herein can be made of any durable material that provides durability, safety and portability, including metals or metal alloys, high strength plastics or composite materials. The shape of the outer shell is designed to receive the steam generating assembly disclosed herein and provide a practical and comfortable sensation when gripped by the user's hand during operation of the device.

The housing disclosed herein may optionally include a fluid chamber assembly access cover detachably coupled with the outer body shell. The fluid chamber access cover disclosed herein is designed to provide access to the fluid chamber assembly disclosed herein. The fluid chamber assembly access cover disclosed herein is designed to be detached from an outer body shell of a transdermal delivery device. Such detachment allows the user to, for example, remove the fluid chamber assembly or its components as well as to reattach the fluid chamber assembly or its components. In one embodiment, the fluid chamber assembly access cover disclosed herein is designed to be completely removed from the housing of the transdermal delivery device to allow access as disclosed herein. In another embodiment, the fluid chamber assembly access cover disclosed herein is designed to achieve access to the fluid chamber assembly as disclosed herein, but remains attached to the outer body shell of the housing. By way of non-limiting example, the fluid chamber assembly access cover may include a threaded portion that can be screwed or unmapped onto the threaded portion of the outer body shell. In this arrangement, the access cover can be completely removed from the housing. As another non-limiting example, the fluid chamber assembly access cover includes a track and groove arrangement with an outer body shell that allows the access cover to slide back and forth from the open position to the closed position. Such an arrangement may be designed to allow complete removal of the access cover, or may include a stop that prevents complete removal but provides access as disclosed herein. As another non-limiting example, the fluid chamber assembly access cover may include a hinge assembly with an outer body shell that causes the access cover to swing open or closed. In this arrangement, the access cover is typically attached to the housing. Other arrangements for allowing access as disclosed herein are known in the art.

One or more interior compartments disclosed herein are designed to accurately maintain the steam generating assembly or components thereof in a manner that ensures proper operation of the transdermal delivery device. The interior compartment compares an open end delivery outlet (see, eg, open end delivery outlet 206 of FIG. 2) and a steam generation assembly compartment (see, for example, steam generation assembly compartment 208 of FIG. 2). It may include a limited. Such compartments may include internal pedestals to enhance structural integrity of the apparatus and / or footings to ensure proper placement and function of the steam generating assembly or components thereof disclosed herein.

The cartridge holding vessel disclosed herein may include an outer lid shell (see, eg, outer lid shell 214 of FIG. 2) and an inner cartridge compartment (see, eg, inner cartridge compartment 216 of FIG. 2). Can be. The cartridge holding vessel disclosed herein is designed to properly position, mount, and secure the compressed gas cartridge to the lance housing of the permeate valve during operation of the percutaneous delivery device.

The cartridge holding container disclosed herein can be detachably coupled to an outer body shell of the housing. In another embodiment, the cartridge can be embedded within the device and then provide a single use where the device can be discarded. The cartridge holding container disclosed herein may be designed to be completely removed from the housing of the transdermal delivery device to achieve a non-engaged position as disclosed herein. In another embodiment, the cartridge holding container disclosed herein achieves a non-engaged position as disclosed herein but is still designed to be attached to the housing. As a non-limiting example, the cartridge holding container may include a threaded portion that can be screwed or unthreaded onto the threaded portion of the outer body shell. In this arrangement, the cartridge holding container can be completely removed from the housing, where the compressed gas cartridge is inserted into the inner cartridge compartment. The cartridge holding container is then screwed back onto the housing in a manner that allows for proper insertion of the cartridge into the device. As another non-limiting example, the cartridge holding container includes a hinge assembly having an outer body shell that allows the cartridge holding container to be positioned in a manner that allows the compressed gas cartridge to be properly inserted into the device. In this arrangement, the cartridge holding container is typically attached to and held in the housing. Other arrangements are known in the art to allow for proper cartridge insertion and cartridge holding vessel attachment as disclosed herein.

The cartridge holding container disclosed herein may be detachably coupled with the outer body shell of the percutaneous delivery device. This is accomplished in that the cartridge holding container disclosed herein can be in one of two operating positions. In the non-engaged position (or in a detached or open position), the cartridge holding vessel disclosed herein causes the compressed gas cartridge to be disposed within the interior cartridge compartment of the cartridge holding vessel and on the permeate valve disclosed herein for the compressed gas cartridge. Reveal the lance housing present at and / or do both. In the engaged position (or attached or closed position), the cartridge holding vessel disclosed herein discharges compressed gas from the cartridge and induces the discharged gas into a permeate valve through which the gas permeates through the valve at a predetermined rate. It is designed to position, mount and secure the compressed gas cartridge to the lance housing of the permeate valve.

The housing disclosed herein may optionally include a leg stand or other protrusion (see eg leg stand 204 of FIG. 2) attached to the outer body shell. The leg stands disclosed herein may typically be located near the end where the open end delivery outlet is located. The leg stands disclosed herein can be designed to incline the fluid container assembly to provide an inclination of less than 30 ° relative to the horizontal position of the transdermal delivery device to facilitate mixing of gas and liquid. The leg stand may also be retractable into the outer body shell for ease of storage.

Thus, in one embodiment, the housing disclosed herein is a cartridge detachably coupled with an outer body shell, an open end delivery outlet comprising a processing chamber, a vapor generation assembly compartment comprising a fluid exchanger, a permeation valve and an outer body shell. A retention vessel, wherein the vapor generation assembly compartment is interposed between the open end delivery outlet and the cartridge retention vessel. The open end delivery outlet is designed to receive an individual body part, such as a finger, toe or foot. Alternatively, the open end delivery outlet may simply be disposed above or near the skin surface. The steam generating assembly compartment itself may be subdivided into different compartments designed to receive the component parts of the steam generating assembly disclosed herein.

In another embodiment, a housing disclosed herein includes an outer body shell, an open end delivery outlet, a vapor generation assembly compartment including a fluid chamber assembly compartment and a permeate valve, a cartridge holding vessel detachably coupled with the outer body shell; The linear arrangement of the inner compartment is an open end delivery outlet next to the fluid chamber assembly compartment next to the permeation valve.

An exemplary apparatus is shown in FIG. 2, and the housing 200 includes an outer body shell 202, a leg stand 204, an open end delivery outlet 206, a steam generating assembly compartment 208, a permeate valve compartment ( And a cartridge holding container 212 detachably coupled to the outer body shell 202 and an outer cover shell 214, and an inner cartridge compartment 216.

The percutaneous device may optionally include a compressed gas cartridge that may be housed in the cartridge holding container 212. Compressed gas cartridges disclosed herein are typically large enough to contain sufficient gas under pressure to produce a volume of supersaturated liquid with sufficient dissolved gas to produce a vapor that provides a therapeutic effect. The therapeutic effect can in some cases be achieved with one dose of supersaturated gas. Compressed gas cartridges disclosed herein typically have a pressure in excess of 40 psi (about 275 kPa) at 21.1 ° C, or a pressure in excess of 104 psi (about 717 kPa) at 54.4 ° C, regardless of the pressure at 21.1 ° C. Gas or any liquid having an absolute vapor pressure of greater than 40 psi (about 275 kPa) at 37.8 ° C. For example, a compressed gas cartridge may be about 400 kPa (about 58 psi) at 21.1 ° C., about 600 kPa (about 87 psi) at 21.1 ° C., about 800 kPa (about 116 psi) at 21.1 ° C. or about 1000 kPa at 21.1 ° C. Holds 16 g, 8 g or 1.3 g of food or medical grade gas under a pressure of (about 145 psi). In one embodiment, the compressed gas cartridge contains 16 g of food or medical grade carbon dioxide at 21.1 ° C. under about 800 kPa (about 116 psi). The compressed gas cartridge may have a disposable design. Such disposable compressed gas cartridges typically include a permeable seal that can be penetrated for discharging the gas. For example, as disclosed herein, the lance from the permeate valve penetrates the permeate seal of the compressed gas cartridge, thereby compressing it into and through the permeate valve from the cartridge in a manner that ensures constant gas flow from the percutaneous delivery device. Allow the release of gases.

Non-limiting examples of gases useful for operating the transdermal delivery devices disclosed herein include food or medical grade gases, including food or medical grade carbon dioxide, food or medical grade oxygen, food or medical grade helium, and food or medical grade argon. Include. The compressed gas cartridges disclosed herein may be threaded or non-threaded. The threaded compressed gas cartridge may be secured to the pressure-temperature regulator assembly without the aid of a cartridge holding vessel as disclosed herein. Threadless non-formed pressurized gas cartridges may be secured to the permeate valve using cartridge holding vessels as disclosed herein. The compressed gas cartridges disclosed herein may have a standard industrial design, or may have a custom design useful only for the transdermal delivery device disclosed herein. In one embodiment, the threaded or non-threaded compressed gas cartridge includes a body, an internal gas compartment, and a punctureable seal. In another embodiment, the threaded or non-threaded compressed gas cartridge includes a body, a neck, an internal gas compartment, and a punctureable seal.

Aspects of the present disclosure partially disclose steam generating assemblies. The steam generation assembly disclosed herein includes a permeate valve and a fluid chamber assembly. The steam generation assembly disclosed herein may optionally include a control switch assembly. In one embodiment, the steam generation assembly disclosed herein includes a permeate valve and a fluid chamber assembly, but no control switch assembly. In another embodiment, the steam generation assembly disclosed herein includes a permeation valve, a control switch assembly and a fluid chamber assembly.

In one embodiment, as shown in FIG. 3A, fluid chamber assembly 302 may be connected to permeate valve 304 using tube 306. A compressed gas cartridge (not shown) may be attached to permeate valve 304 at thread attachment point 308. The first barb connector 310 and the second barb connector 312 can be used to connect respective components to the tub 306. Tube 306 may be formed of any suitable material such as, for example, plastic or metal. In addition, the tube 306 may be connected to a barb or other lockable connection using a gasket or o-ring. In other embodiments, the tube may simply be welded or attached directly to the component without the use of barbs.

As shown in FIG. 3B, the fluid chamber assembly 302 and the permeation valve 304 may be directly connected without the use of a tube. Here, male thread 314 on fluid chamber assembly 302 may be screwed onto female thread 316 on permeate valve 304. Inverse thread configurations can also be used. In another embodiment, the fluid chamber assembly 302 and the permeation valve 304 may be manufactured in one piece without the need for manual attachment.

FIG. 3C shows a system including a vapor generation assembly 318 that includes a fluid chamber assembly 302 and a control switch assembly 320 connected to a permeate valve 304 as in FIG. 3A. The control switch assembly 320 is an optional feature that may or may not be used with the devices described herein.

As shown in FIG. 3A, the permeation valve 304 may be directly associated with two components. The first connecting device 322 is typically screwed into the permeation valve 304 and used to associate it with the fluid chamber assembly 302 and finally the delivery area. The second connecting device 324 is also screwed onto the permeate valve 304 and is typically used to interface the compressed gas cylinder with the permeate valve 304.

In one embodiment, as shown in FIGS. 4A-4C, the transdermal delivery device 400 includes a housing 402 having a leg stand 404 and a fluid chamber access cover 406. The fluid chamber assembly access cover 406 opens to the open end delivery outlet 408 and fluid chamber assembly 410 shown. The fluid chamber assembly access cover has a track and groove arrangement 412 with the housing 402 that allows the access cover 406 to slide back and forth. In another embodiment, the hinge 414 allows the access cover 406 to swing upward to reveal the open end delivery outlet 408 and the fluid chamber assembly 410.

The cartridge holding container 416 can be detached from the percutaneous delivery device 400 to expose the front end of the permeate valve 418 where the lance 420 is located. The cartridge holding container 416 may hold the compressed gas cartridge 422. The cartridge holding container (not shown) has a threaded portion that can be screwed on or disengaged from the threaded portion of the outer body shell 320.

In some embodiments, the fluid chamber assembly access cover 406 may have a window 424 that can be used to view the contents within the fluid chamber 426 when the fluid chamber assembly access cover 406 is closed. In such embodiments, at least a portion of the fluid chamber 426 adjacent the window 424 may be transparent.

3C is a cross-sectional view of an alternative transdermal delivery device 428 that includes additional components, a control switch 430 that may be the control switch assembly described in FIG. 6 or may be of a different design but with similar functionality. The control switch 430 allows control of the instant of delivery of the therapeutic agent or the duration of delivery. This is in contrast to a device without a control switch 430 that will drain the contents of the cartridge 422 until exhaustion. In other words, control switch 430 causes the device to be turned on and off.

The permeate valve as disclosed herein includes at least one permeate member. The permeate valve disclosed herein is designed to reduce the pressure of the gas coming from the compressed gas cartridge. In some cases, the permeation valve can increase the temperature of the gas so that the gas can dissolve when the gas enters the fluid chamber assembly as disclosed herein. The permeate valves disclosed herein can include a lance as well as a permeate member. The valve itself may be formed of a metal alloy, high strength glass reinforced nylon or other lightweight material that can withstand the high and low temperatures applied by the gas when the gas leaves the compressed gas cartridge. The permeation valve disclosed herein may further comprise an adapter for connecting it to another portion of the instrument assembly. Exemplary permeation valves useful for operating the percutaneous delivery device disclosed herein include, for example, Compressed Gas Cartridge Permeation Dispensers having a predictable permeation rate. a Predictable Permeation Rate, "US Pat. No. 7,857,167, which is incorporated herein by reference for all that it discloses with respect to a permeate valve.

In one embodiment, the permeation valves disclosed herein can be set to reduce the pressure of the compressed gas to less than about 40 psi (about 275 kPa) at 21.1 ° C. In an aspect of this embodiment, the permeation valve is, for example, about 35 psi (about 241 kPa), about 30 psi (about 207 kPa), about 25 psi (about 172 kPa), about 20 psi (about 138 kPa) or about It can be set to reduce the pressure of the compressed gas to 15 psi (about 103 kPa). In another aspect of this embodiment, the permeation valve is, for example, less than 40 psi (about 275 kPa), less than 35 psi (about 241 kPa), less than 30 psi (about 207 kPa), less than 25 psi (about 172 kPa), It may be set to reduce the pressure of the compressed gas to less than 20 psi (about 138 kPa) or less than 15 psi (about 103 kPa). In another aspect of this embodiment, the permeation valve is, for example, about 15 psi (about 103 kPa) to about 40 psi (about 275 kPa), about 15 psi (about 103 kPa) to about 35 psi (about 241 kPa) , About 15 psi (about 103 kPa) to about 30 psi (about 207 kPa), about 15 psi (about 103 kPa) to about 25 psi (about 172 kPa) or about 15 psi (about 103 kPa) to about 20 psi ( About 138 kPa) to reduce the pressure of the compressed gas.

In another embodiment, the permeate valve disclosed herein will increase the concentration of the compressed gas so that when the gas moves through the permeate valve and enters the fluid chamber assembly, the gas will not freeze the liquid contained within the fluid chamber assembly. . In an aspect of this embodiment, the permeation valve is for example about 0 ° C., about 2 ° C., about 4 ° C., about 5 ° C., about 8 ° C., about 10 ° C., about 12 ° C., about 15 ° C., about 18 ° C., about The temperature of the compressed gas can be increased to 20 ° C. or about 22 ° C. In another aspect of this embodiment, the permeation valve is for example at least 0 ° C, at least 2 ° C, at least 5 ° C, at least 8 ° C, at least 10 ° C, at least 12 ° C, at least 15 ° C, at least 18 ° C, at least 20 ° C or It is possible to increase the temperature of the compressed gas to at least 22 ° C. In another aspect of this embodiment, the permeation valve is, for example, about 0 ° C. to about 22 ° C., about 2 ° C. to about 22 ° C., about 4 ° C. to about 22 ° C., about 8 ° C. to about 22 ° C., about 12 ° C. The temperature of the compressed gas to about 22 ° C., about 0 ° C. to about 18 ° C., about 2 ° C. to about 18 ° C., about 4 ° C. to about 18 ° C., about 8 ° C. to about 18 ° C., or about 12 ° C. to about 18 ° C. Increase.

In another embodiment, the permeation valves disclosed herein reduce the pressure of the compressed gas from about 15 psi (about 103 kPa) to about 40 psi (about 275 kPa) and increase the temperature of the compressed gas from about 0 ° C to about 22 ° C. Can be set to increase. In another embodiment, the pressure-temperature regulator assembly disclosed herein reduces the pressure of the compressed gas from about 15 psi (about 103 kPa) to about 40 psi (about 275 kPa) and compresses the compressed gas from about 4 ° C to about 22 ° C. It can be set to increase the temperature of. In another embodiment, the pressure-temperature regulator assembly disclosed herein reduces the pressure of the compressed gas from about 15 psi (about 103 kPa) to about 40 psi (about 275 kPa) and compresses the compressed gas from about 8 ° C to about 22 ° C. It can be set to increase the temperature of. In another embodiment, the pressure-temperature regulator assembly disclosed herein reduces the pressure of the compressed gas from about 15 psi (about 103 kPa) to about 40 psi (about 275 kPa) and the compressed gas from about 12 ° C to about 22 ° C. It can be set to increase the temperature of.

In another embodiment, the permeation valves disclosed herein can be set to reduce the pressure of the compressed gas to less than about 40 psi (about 275 kPa) and increase the temperature of the compressed gas to at least 0 ° C. In another embodiment, the permeation valves disclosed herein can be set to reduce the pressure of the compressed gas to less than about 40 psi (about 275 kPa) and increase the temperature of the compressed gas to at least 4 ° C. In another embodiment, the permeation valves disclosed herein can be set to reduce the pressure of the compressed gas to less than about 40 psi (about 275 kPa) and increase the temperature of the compressed gas to at least 8 ° C. In another embodiment, the permeation valves disclosed herein can be set to reduce the pressure of the compressed gas to less than about 40 psi (about 275 kPa) and increase the temperature of the compressed gas to at least 12 ° C.

In one embodiment, as shown in FIGS. 5A and 5B, the permeation valve assembly 500 includes a lance housing 502, a permeation member housing 504, a first attachment member 506 and a second attachment member ( 508). In some embodiments, each of the members may be formed as one single unit, and in other embodiments the members may be separate and connectable. The connection point may be sealed using o-rings 510, 510 ′ or other means such as gaskets, barbs or compression fittings.

The lance housing 502 can include a lance 512 located at an upstream end 514 of the permeate valve assembly 500. The lance 512 may pass through the compressed gas cartridge seal 516 located on the neck of the compressed gas cartridge 518 when the compressed gas cartridge comes into contact with the lance 512. Lances as disclosed herein may be of any design that can penetrate the seal of the compressed gas cartridge and allow the discharge of compressed gas from the cartridge into the permeate valve assembly 500 in a manner that ensures proper operation of the transdermal delivery device. have. Such lance designs include, for example, hollow through lance designs and solid through lance designs.

As shown in FIG. 5A, the compressed gas cartridge 518 may be screwed onto the second attachment member 508. However, the compressed gas cartridge 518 may remain sealed until the compressed gas cartridge seal 516 reaches the lance 512 as shown in FIG. 5B. Once the lance 512 punctures the compressed gas cartridge seal 516, the gas can exit the cartridge and proceed through the device.

As the air exits the compressed gas cartridge 518, the air passes through the hollow lance, around the lance member or both, and proceeds through the device. In general, the lance 512 may adjust air pressure or substantially impede the airflow. The high pressure air may then move down along the inner bore 520 through the lance housing 502 until it reaches the face 522 of the permeable member housing 504. At face 522, the high pressure air enters the permeable member housing 504 through holes in face 522. Just inside this hole, the high pressure air encounters the permeable member 526. The permeable member 526 may form a seal with the peripheral wall 528.

The use of permeable member 526 may be to adjust and / or reduce air pressure. For example, the air entering the permeable member housing 504 may be at high pressure and the air finally exiting the permeable member housing 504 on the opposite side may have a lower pressure. Permeable member 526 may be comprised of any material that is semipermeable, such as from rubber, cork, textile material, porous polymeric material, high density sintered metal or any other suitable material that provides a suitable and / or desired transmission rate. Can be.

Air gradually passes through the permeable member 526 in the rate characteristic of the material used to form the member. As permeated air exits permeable member 526, it is at a lower pressure than when entering. This lower pressure air can then travel through the permeable housing bore 530 and flow freely through the remainder of the permeate valve assembly 500.

The permeable member may also be in the form of an o-ring seal or other functional portion of the device instead of or in addition to the freestanding permeable member. For example, a permeable member or other component of a permeate valve as described in US Pat. No. 7,857,167 is incorporated herein by reference in its entirety for all that this patent discloses for permeate valves.

The first attachment member 506 and the second attachment member 508 may be the same or different depending on the requirements and configuration of the device. 5A and 5B, the first attachment member 506 is a barb connector 532 screwed thereon on the transmissive member housing 504 at the attachment portion 534. 5A and 5B, the second attachment member 508 is a threaded attachment for the opposing threaded cartridge holding container 536. In another embodiment, the cartridge holding container 536 is not necessary. There, the compressed gas cartridge 518 can be screwed directly on the second attachment member 508 because it is screwed.

In some embodiments, permeate valve assembly 500 may not include moving and / or mechanical portions (eg, springs, actuators or moving bearings). In this embodiment, transmission is fully controlled by the transmission member 526. This control can in some cases increase the safety of the device, prevent other unwanted mechanical problems, and also increase the simplicity and reduce the overall size of the device.

The permeate valve assembly may be configured to distribute the gas for an appropriate amount of time to ensure that the appropriate amount of gas is dissolved into the liquid (eg, by permeation member and / or orifice size). In one embodiment, the permeation valve assembly is adapted to dispense gas for, for example, about 3 minutes, about 5 minutes, about 7 minutes, about 10 minutes, about 12 minutes, about 15 minutes, about 18 minutes or about 20 minutes. Can be. In another embodiment, the permeation valve assembly may be adapted to dispense gas for at least 3 minutes, at least 5 minutes, at least 7 minutes, at least 10 minutes, at least 12 minutes, at least 15 minutes, at least 18 minutes or at least 20 minutes, for example. Can be. In yet another embodiment, the permeate valve assembly can be, for example, from about 3 minutes to about 5 minutes, from about 3 minutes to about 10 minutes, from about 3 minutes to about 15 minutes, from about 3 minutes to about 20 minutes, from about 5 minutes to And may be adjusted to dispense the gas for about 10 minutes, about 5 minutes to about 15 minutes, or about 5 minutes to about 20 minutes.

In some embodiments, once the compressed gas cylinder is screwed onto the permeate valve assembly and perforated by the lance, the permeation of gas through the permeate member is constant until the compressed gas is depleted from the cylinder. In other words, once the compressed gas cylinder is lanced, the gas begins to flow without interruption until it is depleted without an "off" valve.

In another embodiment, a compressed gas cylinder may be provided that is permanently and / or nonremovably attached to the device. In this embodiment, a button can be used to lance the cylinder at a given time and the cylinder can be used to complete. Upon exhaustion of the gas, the device can be discarded. This embodiment can be used as a single use device. The patient may also receive a bundle of instruments to be used and discarded once.

In another embodiment, a control switch assembly can be inserted between the permeate valve assembly and the fluid chamber to potentially and / or selectively stop the gas flow before the gas cylinder is exhausted. Such control switches as disclosed herein can include an actuator, a switch body, an inlet port and an outlet port, and can also be operated by mechanical or electronic design. The control switch assembly disclosed herein is designed to control when low pressure gas leaving the regulator assembly is allowed to enter the fluid chamber assembly.

In one embodiment, as shown in FIG. 6, the control switch assembly 600 includes an actuator 602, a switch body 604, an inlet port 606, a flow ball seat valve 608 and a flow valve insert ( 610). Inlet port 606 may be in communication with the outlet port of the permeate valve disclosed herein. However, actuator 602 may prevent the passage of gas into flow ball seat valve 608. Upon activation of the actuator 602, a channel is established between the inlet port 606 and the flow ball seat valve 608, thereby allowing gas to enter the flow ball seat valve 608. . Flow ball seat valve 608 includes a ball seat valve body 610 that receives a seat valve ball 612, a ball spring 614, and a ball seat valve outlet port 616. Activation of the actuator 602 releases the tension in the ball spring 614, which reduces the pressure on the ball 612 pressed against the o-ring 618 by the tension of the ball spring 614. As the actuator 602 is pressed, the plugged portion 620 moves down, revealing an opening 622 connecting the inlet port 606 and the ball chamber 624, where the pressure is seat valve ball. Accepting 612 can be validated. Plugged portion 620 and opening 622 are differentiated by one or more o-rings 626. Actuator 602 may be locked in an "open" position when pressed using locking mechanism 628 that engages bottom portion 630. With the pressure removed, gas can flow through the flow ball seat valve 608 and exit via the ball seat valve outlet port 616. The channels in communication with the control switch assembly 600 and the fluid chamber assembly disclosed herein allow the gas to flow into the fluid chamber assembly. This communication channel may be formed by the inlet port and flow valve insert 610 of the fluid chamber assembly as disclosed herein.

The fluid chamber assembly disclosed herein includes a fluid container, an inlet port and an outlet port. The fluid container may hold a liquid to be supersaturated by gas entering the chamber from the pressure-temperature regulator assembly. The liquid may be water, a physiologically buffered solution or any other suitable liquid. Suitable liquids allow 1) an appropriate amount of gas to be dissolved into a liquid to produce a vapor comprising liquid particles comprising a supersaturated amount of the therapeutic agent, and 2) maintain, enable or ensure the activity of the therapeutic agent, thereby To ensure that a therapeutically effective amount of a medicament is accepted by an individual upon administration. For example, carbon dioxide comes in gaseous and molecular form. It is a molecular form of carbon dioxide that can dissolve in a liquid such as water that allows for easy absorption of carbon dioxide through the skin, for example. Conversely, at higher pH, carbon dioxide tends to change into carbonic acid (H ₂ CO ₃ ) and bicarbonate ions that are not readily absorbed through the skin. The lower the pH of the liquid, the more molecular carbon dioxide is present. As such, when the gas is carbon dioxide, the pH of the liquid should be slightly acidic, such as about pH 6 or less, about pH 5.5 or less, about pH 5 or less, about 4.5 pH or less, or about pH 4 or less.

Alternatively, other substances capable of dissolving the supersaturated amount of gas may be used instead of the liquid. Non-limiting examples of such materials include, for example, colloids such as foams, liquid aerosols, emulsions, gels and sols.

Liquids disclosed herein include a therapeutic agent. As used herein, the term "therapeutic agent" is synonymous with "active ingredient" and refers to the use of any substance that provides a beneficial effect to the individual administering the therapeutic agent.

One type of therapeutic agent is a gas that is dissolved into a liquid as disclosed herein. An exemplary gas that is a therapeutic agent is carbon dioxide. The current use of gases in medicine is rapidly being explored because these molecules are important biological messengers. For example, increasing the level of carbon dioxide in the blood decreases the pH due to the conversion of carbon dioxide to bicarbonate. This reduced pH allows oxygen to dissociate more immediately from hemoglobin, called the "Bohr effect". In addition, increased levels of carbon dioxide improve circulation and blood flow by triggering draining vasodilators that dilate blood vessels in an effort to increase oxygen supply. As such, increasing carbon dioxide levels increases tissue oxygen, which in turn increases the expansion of blood vessels that allow the delivery of more nutrients to the cells, thereby increasing the supply of oxygen to the cells thereby increasing cellular metabolism. Improve. As such, increasing the level of tissue oxygen in this manner has a number of beneficial effects that promote skin health, including but not limited to promoting wound healing, improving skin feel, and providing anti-aging effects. to provide.

Another type of therapeutic agent that can be administered by the transdermal delivery device disclosed herein is a drug that can dissolve in the liquids disclosed herein or become part of the vapor upon evaporation. Approximately half of the pharmaceutical drugs currently available on the market have molecular affinity for water. This affinity manifests itself in the tendency to dissolve in water, to mix with or to absorb water. Therapeutic agents having these properties are called hydrophilic therapeutic agents and include biologics as well as small molecules or chemical drugs. Hydrophilic therapies include nicotine antihistamines, β-blockers, calcium channel blockers, nonsteroidal anti-inflammatory drugs, contraceptives, antiarrhythmic drugs, insulin, antiviral agents, hormones, α-interferons, vitamins (e.g., vitamin D) and chemicals Therapeutic agents include, but are not limited to. In one embodiment, the drug comprises one or more water soluble drugs.

Another type of therapeutic agent that can be administered by the transdermal delivery device disclosed herein is a vitamin that can be dissolved in the liquid disclosed herein or become part of the liquid particles upon evaporation.

In one embodiment, the amount of gas dissolved in the liquid is, for example, about 30,000 ppm, about 35,000 ppm, about 40,000 ppm, about 45,000 ppm, about 50,000 ppm, about 55,000 ppm, or about 60,000 ppm. In another embodiment, the amount of gas dissolved in the liquid is for example at least 30,000 ppm, at least 35,000 ppm, at least 40,000 ppm, at least 45,000 ppm, at least 50,000 ppm, at least 55,000 ppm or at least 60,000 ppm. In another embodiment, the amount of gas dissolved in the liquid is, for example, at most 30,000 ppm, at most 35,000 ppm, at most 40,000 ppm, at most 45,000 ppm, at most 50,000 ppm, at most 55,000 ppm or at most 60,000 ppm. In another embodiment, the amount of gas dissolved in the liquid is, for example, about 30,000 ppm to about 35,000 ppm, about 30,000 ppm to about 40,000 ppm, about 30,000 ppm to about 45,000 ppm, about 30,000 ppm to about 50,000 ppm, about 35,000 ppm to about 40,000 ppm, about 35,000 ppm to about 45,000 ppm, about 35,000 ppm to about 50,000 ppm, about 40,000 ppm to about 45,000 ppm, about 40,000 ppm to about 50,000 ppm or about 50,000 ppm to about 60,000 ppm.

In embodiments where the therapeutic agent may or may not be a dissolved gas, the medicament may be contained in a liquid disposed in the fluid container. In addition, the liquid disposed in the fluid container may include all of the dissolved gases that provide the therapeutic effect as well as the additional therapeutic agent.

The fluid chamber assembly may optionally include a fluid container cap that detachably couples to the fluid container disclosed herein. The ability to detach a fluid container as disclosed herein allows for refilling of the liquid as needed. For example, in applications involving the treatment of wounds, the liquid may contain both wound healing drugs such as cyclosporin, as well as dissolved molecular carbon dioxide.

The inlet port as disclosed herein is designed to receive low pressure gas flowing from the permeate valve and direct the gas into the fluid chamber assembly. Once in the fluid chamber assembly, the gas will dissolve into the liquid contained in the fluid container to produce a liquid comprising a supersaturated amount of dissolved gas molecules. As used herein, the term “supersaturated” when used with reference to “a supersaturated amount of dissolved gas molecules” is more than acceptable for liquids under ambient temperature and air pressure, typically measured at 25 ° C., 1 atm. Refer to the liquid disclosed herein containing more dissolved gas. For example, with respect to the transdermal delivery device disclosed herein, the pressure of the dissolved gas in the fluid chamber assembly is greater than the pressure of the gas outside the assembly. In one embodiment, the inlet port as disclosed herein includes a check valve, a spring and a port.

The outlet port as disclosed herein is designed to discharge a vapor comprising a supersaturated amount of dissolved gas molecules and / or therapeutic agent at ambient pressure from the fluid chamber assembly into the open end delivery outlet, where the vapor is It can be administered to. In one embodiment, the outlet port as disclosed herein includes a check valve, a spring and a poppet. Evaporation of a liquid comprising a supersaturated amount of dissolved gas is achieved when the pressure inside the liquid container is sufficient to displace the liquid through the outlet port. In an embodiment of this embodiment, the evaporation of a liquid comprising a supersaturated amount of dissolved gas results in a pressure inside the liquid container, for example, about 15 psi (about 103 kPa), about 20 psi (about 138 kPa), about 25 psi (About 172 kPa), about 30 psi (about 207 kPa), about 35 psi (about 241 kPa), about 40 psi (about 275 kPa), about 45 psi (about 310 kPa) or about 50 psi (about 345 kPa) Is achieved when In another embodiment of this embodiment, evaporation of the liquid comprising a supersaturated amount of dissolved gas results in a pressure inside the liquid container, for example, at least 15 psi (about 103 kPa), at least 20 psi (about 138 kPa), at least 25 psi (about 172 kPa), at least 30 psi (about 207 kPa), at least 35 psi (about 241 kPa), at least 40 psi (about 275 kPa), at least 45 psi (about 310 kPa) or at least 50 psi (about 345 kPa) Is achieved when In another aspect of this embodiment, evaporation of a liquid comprising a supersaturated amount of dissolved gas results in a pressure inside the liquid container, for example, up to 15 psi (about 103 kPa), up to 20 psi (about 138 kPa), 25 psi (about 172 kPa), up to 30 psi (about 207 kPa), up to 35 psi (about 241 kPa), up to 40 psi (about 275 kPa), up to 45 psi (about 310 kPa) or up to 50 psi (about 345) kPa). In another embodiment of this embodiment, the evaporation of the liquid comprising a supersaturated amount of dissolved gas results in a pressure inside the liquid container, for example from about 15 psi (about 103 kPa) to about 50 psi (about 345 kPa), about 20 psi (about 138 kPa) to about 50 psi (about 345 kPa), about 25 psi (about 172 kPa) to about 50 psi (about 345 kPa), about 30 psi (about 207 kPa) to about 50 psi (about 345) kPa), about 35 psi (about 241 kPa) to about 50 psi (about 345 kPa), about 15 psi (about 103 kPa) to about 45 psi (about 310 kPa), about 20 psi (about 138 kPa) to about 45 psi (about 310 kPa), about 25 psi (about 172 kPa) to about 45 psi (about 310 kPa), about 30 psi (about 207 kPa) to about 45 psi (about 310 kPa), about 35 psi (about 241 kPa) ) To about 45 psi (about 310 kPa), about 15 psi (about 103 kPa) to about 40 psi (about 275 kPa), about 20 psi (about 138 kPa) to about 40 psi (about 275 kPa), about 25 psi (About 172 kPa) to about 40 psi (about 275 kPa), about 30 psi (about 207 kPa) to about 40 psi (about 275 kPa), about 15 psi (about 103 kPa) to about 35 psi (about 241 kPa) , About 20 psi (about 138 kPa) to 35 psi (about 241 kPa), about 25 psi (about 172 kPa) to 35 psi (about 241 kPa), about 15 psi (about 103 kPa) to about 30 psi (about 207 kPa) ) Or about 20 psi (about 138 kPa) to 30 psi (about 207 kPa).

As disclosed herein, the vapor may comprise liquid particles and supersaturated amounts of dissolved gas molecules. The vapor may be a liquid aerosol, which is a solution comprising liquid and gas, or a colloidal composition comprising liquid and gas. When the therapeutic agent is not a dissolved gas, the vapor also includes the therapeutic agent disclosed herein.

Evaporation can produce liquid particles having an average size small enough to allow entry into the pores of the skin. In one embodiment, the average size of the liquid particles can be, for example, about 100 μm, about 75 μm, about 50 μm or about 25 μm. In other embodiments, the average size of the liquid particles may be, for example, 100 μm or less, 75 μm or less, 50 μm or less, or 25 μm or less. In another embodiment, the average size of the liquid particles is for example about 1 μm to about 100 μm, about 1 μm to about 75 μm, about 1 μm to about 50 μm, about 1 μm to about 25 μm, about 5 μm To about 100 μm, about 5 μm to about 75 μm, about 5 μm to about 50 μm, about 5 μm to about 25 μm, about 10 μm to about 100 μm, about 1 μm to about 75 μm, about 10 μm to about 50 μm or about 10 μm to about 25 μm.

The fluid chamber assembly may optionally include a pressure relief valve as a safety measure to avoid overcompressing the steam generating assembly or its components. In one embodiment, the pressure relief valve is for example a 30 psi valve, a 35 psi valve, a 40 psi valve, a 45 psi valve or a 50 psi valve. In another embodiment, a pressure relief valve may not be needed because the permeate valve is non-mechanical and provides a predetermined constant gas flow / pressure to the fluid chamber.

The fluid chamber assembly may optionally include a baffle assembly that includes one or more conical baffles or mixing elements. The baffle assembly is connected to the fluid container or fluid container cap. The baffles are positioned in the form of pillars with each baffle partially overlapping on top of the other baffles and their circular base side oriented away from the inlet port. At the periphery of this column, a narrow connecting piece places the baffle in place. As the low pressure gas enters the fluid vessel via the inlet port, the gas flow passes onto the baffle to enhance the mixing of the gas and the liquid. As such, the baffle is designed to increase and / or accelerate the amount of gas that dissolves into the liquid. In one embodiment, the fluid chamber assembly does not include a baffle assembly.

In one embodiment, as shown in FIG. 7, the fluid chamber assembly 700 includes a fluid container 702, an inlet poppet 708, an inlet spring 710, and an inlet check valve 712. And a fluid container cap 704 that houses an outlet port 714 that includes a port 706 and an outlet poppet 716, an outlet spring 718, and an outlet check valve 720. As disclosed herein, liquid 722 is disposed within fluid container 702 and is attached to fluid container cap 704 via thread 724. Threads are used for non-limiting purposes of illustration and may be replaced by any fastening means known in the art. The gas enters the fluid chamber assembly 700 via the inlet port 706, where the gas pressure causes the seal between the inlet poppet 708 and the inlet surface 726 to break and the gas enters the chamber 726. Move inlet poppet 708 relative to inlet spring 710 until it can dissolve into liquid 722. After a predetermined period of time or after a certain or predetermined amount of pressure has been formed, the liquid containing the supersaturated amount of gas dissolved gas is released when the pressure overcomes the force of the outlet spring 718 on the outlet poppet 716. And the seal between the outlet poppet 716 and the outlet port face 728 sealed with an o-ring is broken. After the seal is broken, the gas can escape as vapor.

Aspects of the present disclosure disclose, in part, methods of making a material comprising a supersaturated amount of dissolved gas. As used herein, the term "material" includes any material capable of dissolving a supersaturated amount of gas. Non-limiting examples of materials include colloids and liquids such as, for example, foams, liquid aerosols, emulsions, gels and sols. In the method disclosed herein, the material is placed in an airtight container, and the material is then exposed to a gas. At this exposure, the gas dissolves in the material in an amount greater than the material can dissolve at 25 ° C., 1 atm. The final substance supersaturated with the dissolved gas may then be administered to an individual to treat the condition as disclosed herein.

In one embodiment, the amount of gas dissolved in the material may be, for example, about 30,000 ppm, about 35,000 ppm, about 40,000 ppm, about 45,000 ppm, about 50,000 ppm, about 55,000 ppm, or about 60,000 ppm. In other embodiments, the amount of gas dissolved in the material can be for example at least 30,000 ppm, at least 35,000 ppm, at least 40,000 ppm, at least 45,000 ppm, at least 50,000 ppm, at least 55,000 ppm or at least 60,000 ppm. In another embodiment, the amount of gas dissolved in the material can be, for example, at most 30,000 ppm, at most 35,000 ppm, at most 40,000 ppm, at most 45,000 ppm, at most 50,000 ppm, at most 55,000 ppm or at most 60,000 ppm. In yet another embodiment, the amount of gas dissolved in the material is, for example, about 30,000 ppm to about 35,000 ppm, about 30,000 ppm to about 40,000 ppm, about 30,000 ppm to about 45,000 ppm, about 30,000 ppm to about 50,000 ppm, about 35,000 ppm to about 40,000 ppm, about 35,000 ppm to about 45,000 ppm, about 35,000 ppm to about 50,000 ppm, about 40,000 ppm to about 45,000 ppm, about 40,000 ppm to about 50,000 ppm, or about 50,000 ppm to about 60,000 ppm.

In another embodiment, a method of preparing a material comprising a supersaturated amount of dissolved gas disclosed herein is performed using the transdermal delivery device disclosed herein. For example, the fluid chamber assembly can be filled with a liquid or colloid as disclosed herein, and the device is activated to produce a liquid or colloid comprising a supersaturated amount of dissolved gas.

Aspects of the present disclosure further disclose, in part, methods of transdermally administering a therapeutically effective amount of a therapeutic agent disclosed herein. In one embodiment, the methods disclosed herein comprise administering to an individual a substance comprising a supersaturated amount of dissolved gas using a transdermal delivery device disclosed herein. Administration of the dissolved gas treats the symptoms associated with the condition and is therefore a therapeutically effective amount. The material may be a vapor, liquid, foam, liquid aerosol, emulsion, gel, sol or other material that may become supersaturated in the amount of dissolved gas. In an embodiment of this embodiment, the material comprising a supersaturated amount of dissolved gas is free of other therapeutic agents. In another embodiment of this example, the dissolved gas is molecular carbon dioxide. In another embodiment of this example, the dissolved gas is molecular carbon dioxide that also functions as a therapeutic agent.

In another embodiment, the method comprises administering to the individual a substance comprising a supersaturated amount of dissolved gas and a therapeutic agent using the transdermal delivery device disclosed herein. Administration of the dissolved gas and / or therapeutic agent treats the symptoms associated with the condition and is therefore a therapeutically effective amount. The material may be a vapor, liquid, foam, liquid aerosol, emulsion, gel, sol or other material that may become supersaturated in the amount of dissolved gas. In an embodiment of this example, the dissolved gas is molecular carbon dioxide. In another embodiment of this example, the dissolved gas is molecular carbon dioxide that also functions as a therapeutic agent.

Aspects of the present disclosure disclose, in part, methods of treating a condition in an individual. In one embodiment, a method of treating a condition disclosed herein comprises administering a composition comprising a substance comprising a therapeutically effective amount of dissolved gas to an individual suffering from the condition using a transdermal delivery device disclosed herein. Wherein the administration of the composition reduces the signs associated with the condition. Administration of the gas treats the symptoms associated with the condition. The material may be a vapor, liquid, foam, liquid aerosol, emulsion, gel, sol or other material that may become supersaturated in the amount of dissolved gas. In an embodiment of this embodiment, a composition comprising a material comprising a therapeutically effective amount of dissolved gas is free of other therapeutic agents. In another embodiment of this example, the dissolved gas is molecular carbon dioxide. In another embodiment of this example, the dissolved gas is molecular carbon dioxide that also functions as a therapeutic agent.

In another embodiment, a method of treating a condition disclosed herein comprises a composition comprising a material comprising a therapeutically effective amount of dissolved gas and a therapeutically effective amount of another therapeutic agent using a transdermal delivery device as disclosed herein. Administering to the individual suffering from the condition, administration of the composition reduces the signs associated with the condition. Administration of the gas and / or therapeutic agent treats the signs associated with the condition and is therefore a therapeutically effective amount. The material may be a vapor, liquid, foam, liquid aerosol, emulsion, gel, sol or other material that may become supersaturated in the amount of dissolved gas. In an embodiment of this example, the dissolved gas is molecular carbon dioxide. In another embodiment of this example, the dissolved gas is molecular carbon dioxide that also functions as a therapeutic agent.

As used herein, the term “treatment” refers to reducing or eliminating cosmetic or clinical signs associated with an individual's condition, or delaying or preventing the onset of cosmetic or clinical signs associated with an individual's condition. For example, the term “treatment” refers to a condition by, for example, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 100%. May mean reducing associated symptoms. The efficacy of the therapeutic agents disclosed herein can be determined by observing one or more cosmetic, clinical signs, and / or physiological indicators associated with the condition. Improvement of the condition may also be dictated by the reduced need for concurrent treatment. Those skilled in the art will be able to recognize appropriate signs or indicators associated with a particular condition and how to determine whether an individual is a candidate for treatment with a therapeutic agent by using the transdermal delivery device disclosed herein.

Aspects of the present disclosure provide in part for administering a therapeutically effective amount of a therapeutic agent disclosed herein. As used herein, the term "therapeutically effective amount" is synonymous with "therapeutically effective dose" and refers to the minimum dose of a therapeutic agent disclosed herein that is necessary to achieve the desired therapeutic effect and to reduce the symptoms associated with the condition. In sufficient dosages.

In an aspect of this embodiment, the therapeutically effective amount of a therapeutic agent disclosed herein is for example at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80% Reduce signs associated with the condition by at least 90% or at least 100%. In other aspects of this embodiment, the therapeutically effective amount of a therapeutic agent disclosed herein can be, for example, at most 10%, at most 20%, at most 30%, at most 40%, at most 50%, at most 60%, at most 70%, at most 80 Reduce symptoms associated with the condition by%, up to 90%, or up to 100%. In another aspect of this embodiment, the therapeutically effective amount of a therapeutic agent disclosed herein is for example about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80% , About 20% to about 20%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 30% to about 100%, about 30% to about 90%, about Signs associated with the condition are reduced by 30% to about 80%, about 30% to about 70%, about 30% to about 60% or about 30% to about 50%. In another aspect of this embodiment, the therapeutically effective amount of a therapeutic agent disclosed herein is for example at least 1 week, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least Dosage sufficient to reduce symptoms associated with the condition for 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months or at least 12 months.

The actual therapeutically effective amount of a therapeutic agent disclosed herein to be administered to an individual may include the type of condition, location of the condition, cause of the condition, severity of the condition, duration of treatment, desired degree of remission, duration of desired remission, specific therapeutic agent used, The rate of excretion of the therapeutic agent used, the pharmacodynamics of the therapeutic agent used, the nature of the other compounds to be included in the vapor, such as the individual's specific characteristics such as age, weight, general health, history and risk factors, and the individual's response to the treatment. Or by one of ordinary skill in the art by considering factors including but not limited to any combination thereof. A therapeutically effective amount of a therapeutic agent disclosed herein can therefore be determined immediately by one skilled in the art, taking into account all criteria and using its best judgment on behalf of the individual.

With respect to carbon dioxide as a therapeutic agent, 600 ppm of dissolved molecular carbon dioxide is the minimum amount needed to produce a therapeutic effect. This is equivalent to 600 parts of carbon dioxide or about 0.6% carbon dioxide and 99.4% water mixed with 1 million parts of water. In an embodiment of this embodiment, the therapeutically effective amount of the dissolved molecular CO ₂ therapeutic disclosed herein is, for example, about 600 ppm, about 700 ppm, about 800 ppm, about 900 ppm, about 1,000 ppm, about 1,500 ppm, about 2,000 ppm, about 2,500 ppm, about 3,000 ppm, about 3,500 ppm, about 4,000 ppm, about 4,500 ppm, about 5,000 ppm, about 5,500 ppm or about 6,000 ppm. In another aspect of this embodiment, the therapeutically effective amount of the dissolved molecular carbon dioxide therapeutic agent disclosed herein is, for example, at least 600 ppm, at least 700 ppm, at least 800 ppm, at least 900 ppm, at least 1,000 ppm, at least 1,500 ppm, at least 2,000 ppm, at least 2,500 ppm, at least 3,000 ppm, at least 3,500 ppm, at least 4,000 ppm, at least 4,500 ppm, at least 5,000 ppm, at least 5,500 ppm or at least 6,000 ppm. In another aspect of this embodiment, the therapeutically effective amount of the dissolved molecular carbon dioxide therapeutic agent disclosed herein is, for example, about 600 ppm to about 1,000 ppm, about 600 ppm to about 2,000 ppm, about 600 ppm to about 3,000 ppm, about 600 ppm to about 4,000 ppm, about 600 ppm to about 5,000 ppm, about 600 ppm to about 6,000 ppm, about 600 ppm to about 10,000 ppm, about 600 ppm to about 20,000 ppm, about 600 ppm to about 30,000 ppm, about 600 ppm To about 40,000 ppm, about 600 ppm to about 50,000 ppm, about 600 ppm to about 60,000 ppm, about 1,000 ppm to about 2,000 ppm, about 1,000 ppm to about 3,000 ppm, about 1,000 ppm to about 4,000 ppm, about 1,000 ppm to about 5,000 ppm, about 1,000 ppm to about 6,000 ppm, about 1,000 ppm to about 10,000 ppm, about 1,000 ppm to about 20,000 ppm, about 1,000 ppm to about 30,000 ppm, about 1,000 ppm to about 40,000 ppm, about 1,000 ppm to about 50,000 ppm Or about 1,000 ppm to about 60,000 ppm.

In an embodiment, the therapeutically effective amount of molecular carbon dioxide increases blood flow. In an embodiment of this embodiment, the therapeutically effective amount of molecular carbon dioxide is for example at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90 Increase blood flow by% or at least 100%. In other embodiments of this embodiment, the therapeutically effective amount of molecular carbon dioxide is for example about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about Blood flow is increased by 50% to about 100%, about 60% to about 100%, about 70% to about 100% or about 80% to about 100%.

In other embodiments of this embodiment, the therapeutically effective amount of molecular carbon dioxide is for example at least about 5 minutes, at least about 15 minutes, at least about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 75 minutes, about 90 minutes. At least about 105 minutes, at least about 120 minutes, at least about 135 minutes, at least about 150 minutes, at least about 165 minutes, at least about 180 minutes, at least about 195 minutes, at least about 210 minutes, at least about 225 minutes, or about 240 minutes Increase blood flow by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 100% during the abnormality. In another aspect of this embodiment, the therapeutically effective amount of molecular carbon dioxide is for example at least about 5 minutes, at least about 15 minutes, at least about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 75 minutes, about 90 At least about 105, at least about 120, at least about 135, at least about 150, at least about 165, at least about 180, at least about 195, at least about 210, at least about 225, or at about 240 About 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100% for at least a minute Blood flow by about 70% to about 100% or about 80% to about 100%.

In another aspect of this embodiment, the therapeutically effective amount of molecular carbon dioxide is for example about 5 minutes to about 30 minutes, about 5 minutes to about 60 minutes, about 5 minutes to about 90 minutes, about 5 minutes to about 120 minutes, about 5 minutes to about 150 minutes, about 5 minutes to about 180 minutes, about 5 minutes to about 210 minutes, about 5 minutes to about 240 minutes, about 15 minutes to about 30 minutes, about 15 minutes to about 60 minutes, about 15 minutes To about 90 minutes, about 15 minutes to about 120 minutes, about 15 minutes to about 150 minutes, about 15 minutes to about 180 minutes, about 15 minutes to about 210 minutes, about 15 minutes to about 240 minutes, about 30 minutes to about 60 minutes, about 30 minutes to about 90 minutes, about 30 minutes to about 120 minutes, about 30 minutes to about 150 minutes, about 30 minutes to about 180 minutes, about 30 minutes to about 210 minutes, or about 30 minutes to about 240 minutes Increase blood flow by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 100%. In another embodiment of this embodiment, the therapeutically effective amount of molecular carbon dioxide is for example about 5 minutes to about 30 minutes, about 5 minutes to about 60 minutes, about 5 minutes to about 90 minutes, about 5 minutes to about 120 minutes, About 5 minutes to about 150 minutes, about 5 minutes to about 180 minutes, about 5 minutes to about 210 minutes, about 5 minutes to about 240 minutes, about 15 minutes to about 30 minutes, about 15 minutes to about 60 minutes, about 15 Minutes to about 90 minutes, about 15 minutes to about 120 minutes, about 15 minutes to about 150 minutes, about 15 minutes to about 180 minutes, about 15 minutes to about 210 minutes, about 15 minutes to about 240 minutes, about 30 minutes to About 60 minutes, about 30 minutes to about 90 minutes, about 30 minutes to about 120 minutes, about 30 minutes to about 150 minutes, about 30 minutes to about 180 minutes, about 30 minutes to about 210 minutes or about 30 minutes to about 240 From about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, Increase blood flow by about 70% to about 100% or about 80% to about 100% The.

In another embodiment, the therapeutically effective amount of molecular carbon dioxide reduces blood pressure. In an embodiment of this embodiment, the therapeutically effective amount of molecular carbon dioxide is for example at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90 Reduce blood pressure by% or at least 100%. In other embodiments of this embodiment, the therapeutically effective amount of molecular carbon dioxide is for example about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about Blood pressure is reduced by 50% to about 100%, about 60% to about 100%, about 70% to about 100% or about 80% to about 100%.

In other embodiments of this embodiment, the therapeutically effective amount of molecular carbon dioxide is for example at least about 5 minutes, at least about 15 minutes, at least about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 75 minutes, about 90 minutes. At least about 105 minutes, at least about 120 minutes, at least about 135 minutes, at least about 150 minutes, at least about 165 minutes, at least about 180 minutes, at least about 195 minutes, at least about 210 minutes, at least about 225 minutes, or about 240 minutes Reduce blood pressure by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 100% during the above. In another aspect of this embodiment, the therapeutically effective amount of molecular carbon dioxide is for example at least about 5 minutes, at least about 15 minutes, at least about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 75 minutes, about 90 At least about 105, at least about 120, at least about 135, at least about 150, at least about 165, at least about 180, at least about 195, at least about 210, at least about 225, or at about 240 About 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100% for at least a minute Blood pressure by about 70% to about 100% or about 80% to about 100%.

In another aspect of this embodiment, the therapeutically effective amount of molecular carbon dioxide is for example about 5 minutes to about 30 minutes, about 5 minutes to about 60 minutes, about 5 minutes to about 90 minutes, about 5 minutes to about 120 minutes, about 5 minutes to about 150 minutes, about 5 minutes to about 180 minutes, about 5 minutes to about 210 minutes, about 5 minutes to about 240 minutes, about 15 minutes to about 30 minutes, about 15 minutes to about 60 minutes, about 15 minutes To about 90 minutes, about 15 minutes to about 120 minutes, about 15 minutes to about 150 minutes, about 15 minutes to about 180 minutes, about 15 minutes to about 210 minutes, about 15 minutes to about 240 minutes, about 30 minutes to about 60 minutes, about 30 minutes to about 90 minutes, about 30 minutes to about 120 minutes, about 30 minutes to about 150 minutes, about 30 minutes to about 180 minutes, about 30 minutes to about 210 minutes, or about 30 minutes to about 240 minutes Reduce blood pressure by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 100%. In another embodiment of this embodiment, the therapeutically effective amount of molecular carbon dioxide is for example about 5 minutes to about 30 minutes, about 5 minutes to about 60 minutes, about 5 minutes to about 90 minutes, about 5 minutes to about 120 minutes, About 5 minutes to about 150 minutes, about 5 minutes to about 180 minutes, about 5 minutes to about 210 minutes, about 5 minutes to about 240 minutes, about 15 minutes to about 30 minutes, about 15 minutes to about 60 minutes, about 15 Minutes to about 90 minutes, about 15 minutes to about 120 minutes, about 15 minutes to about 150 minutes, about 15 minutes to about 180 minutes, about 15 minutes to about 210 minutes, about 15 minutes to about 240 minutes, about 30 minutes to About 60 minutes, about 30 minutes to about 90 minutes, about 30 minutes to about 120 minutes, about 30 minutes to about 150 minutes, about 30 minutes to about 180 minutes, about 30 minutes to about 210 minutes or about 30 minutes to about 240 From about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, Reducing blood pressure by about 70% to about 100% or about 80% to about 100% The.

In other embodiments of this embodiment, the therapeutically effective amount of molecular carbon dioxide is for example about 4 hours or more, about 6 hours or more, about 8 hours or more, about 10 hours or more, about 12 hours or more, about 18 hours or more, or about 24 hours. Reduce blood pressure by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 100% during the above. In another embodiment of this embodiment, the therapeutically effective amount of molecular carbon dioxide is for example about 4 hours or more, about 6 hours or more, about 8 hours or more, about 10 hours or more, about 12 hours or more, about 18 hours or more or about 24 About 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100% for at least hours Blood pressure by about 70% to about 100% or about 80% to about 100%.

Aspects of the present disclosure partially disclose conditions. Conditions include incompleteness, defects, diseases and / or disorders in which remission is sought by an individual suffering from the condition. In other embodiments, the condition includes incompleteness, defects, diseases and / or disorders associated with low blood flow and oxygen delivery for which remission is sought by an individual suffering from the condition. Conditions include, but are not limited to, ischemia, hypertension, cardiovascular disorders, treatment of diabetic disorders, wounds, chronic inflammation, arthritis, migraine, cellulite disorders, pale skin disorders and cosmetic disorders. In an aspect, the present disclosure discloses the use of a substance comprising a supersaturated amount of dissolved gas to treat a condition. Typically, transdermal delivery devices are useful for cosmetic, medical and veterinary applications. An individual is typically a mammal, and the term includes humanity.

Proper flow of microcirculating oxygen enriched blood is critical for proper body function. For example, better blood flow is important for maintaining cardiovascular health. The recent dramatic increase in the incidence of cardiovascular disease, with more than one in three US adults currently suffering from this life threatening condition, has led to the prevalence of problems related to limited blood flow. The rapidly increasing incidence of obesity exacerbates this problem. In addition to top profile issues involving poor blood flow, such as heart attacks and strokes, poor blood flow can potentially cause edema, kidney damage, brain function, memory loss, sexual function, muscle performance, limb ischemia, non-oil wounds, diabetes ulcers and strokes. Potentially linked to these conditions, such as Proper flow of microcirculating oxygen enriched blood is also important in detoxifying the body while improving overall skin health from inside to outside. Additional effects of increased oxygen include reducing stress and reducing the appearance of fat, cellulite, wrinkles and wounds.

The body needs oxygen for metabolism, but low oxygen levels may not normally stimulate breathing. However, carbon dioxide may be one of the mediators of local self regulation of blood supply. If the carbon dioxide level is high, the capillaries may expand and allow greater blood flow to the tissue. Thus, in one aspect of the present disclosure, a device disclosed herein is an in vitro device that functions by transdermally delivering molecular carbon dioxide to the blood stream through the pores and glands of the skin. Supersaturated dissolved molecular carbon dioxide water vapor readily mixes in aqueous pores and sweat glands where instantaneous microcirculation is reached. Through the Bore effect (oxygen curve shift), carbon dioxide facilitates oxygen unloading when blood cells exchange water with carbon dioxide and increases blood pH in areas with lower oxygen perfusion levels, such as, for example, low blood flow. A gas exchange balancing process is initiated at decreasing microvascular levels. As red blood cells sense local oxygen demand, the increased molecular oxygen triggers the release of vasodilators from these cells to match local blood flow demands. This discharge expands the blood vessels and significantly improves the blood flow and circulation of oxygen rich blood into the area. This increased blood flow produces better oxygenated cells and tissues thereby providing nutrient support for the detoxification of many body processes and waste products. Thus, molecular carbon dioxide is a signal that ultimately instructs the body to increase blood flow and oxygen levels in areas of greatest demand.

The average density of pores varies considerably between individuals and body parts. Palms, palms and fingers and soles, soles and heel have an average of 2,700 holes per square inch of raised friction skin surface. This compares to approximately 400 holes per square inch of the remainder of the skin surface of the body. The total number of pores distributed throughout the body has been estimated at 1,600,000 to 4,000,000. Because the human palm, fingers, toes and soles have seven times more holes than other parts of the body, these zones provide for delivery of the therapeutic agents disclosed herein while the circulation system distributes oxygen-rich red blood cells in the body almost instantaneously. It is ideal for

In an embodiment, the route of administration is a transdermal route. In an aspect of this embodiment, the therapeutic agents disclosed herein are delivered transdermally to an individual's finger, toe, palm or sole. In another aspect of this embodiment, the therapeutic agents disclosed herein are delivered transdermally to the skin surface of an individual. In another aspect of this embodiment, the therapeutic agents disclosed herein are delivered transdermally to the skin surface of an individual in or near a condition.

In an embodiment, the method of treating ischemia comprises administering to a subject suffering from ischemia a composition comprising a substance comprising a therapeutically effective amount of dissolved gas using a transdermal delivery device as disclosed herein. Administration of the composition reduces the signs associated with ischemia. Ischemia is a limitation of the blood supply, usually due to factors in blood vessels, with resulting tissue damage or dysfunction. Ischemia is a hallmark of ruptured sensitivity to heart disease, transient ischemic attacks, cerebrovascular accidents, and inadequate blood supply. Ischemia in brain tissue, for example due to stroke or head injury, causes a process called liberated ischemic cascade that damages proteolytic enzymes, reactive oxygen species and other harmful chemicals and finally kills brain tissue. Ischemia is particularly prevalent in patients with diabetes and obesity, whose poor blood flow often results in an inadequate supply of oxygen to the tissues of the lower limbs, leading to skin ulcers and often non-oiled wounds leading to amputation. Better blood flow can heal these wounds and avoid many potentially lost limbs. There are various types of ischemia organized by organs that experience ischemic damage, including but not limited to cardiac ischemia, intestinal ischemia, cerebral ischemia, limb ischemia and skin ischemia. Pain is a common sign associated with ischemia, but it does not always occur. Cerebral ischemia can cause cognitive, sensory, or motor problems. Heart attack and intestinal ischemia cause nausea and vomiting. Peripheral ischemia can cause pale, bluish, discolored or blackish skin of the nose, ears, fingers, toes or other surface areas. The treatments disclosed herein can improve blood circulation and delivery of oxygen enriched blood to ischemic tissue, thereby treating ischemia.

In an aspect of this embodiment, a method of treating ischemia comprises administering to a subject suffering from ischemia a composition comprising a material comprising a therapeutically effective amount of dissolved molecular carbon dioxide using the transdermal delivery device disclosed herein. Administration of the composition reduces signs associated with ischemia.

In another embodiment, a method of treating hypertension comprises administering a composition comprising a substance comprising a therapeutically effective amount of dissolved molecular carbon dioxide to an individual suffering from hypertension using a transdermal delivery device as disclosed herein. And administration of the composition reduces the signs associated with hypertension. Hypertension is a chronic medical condition in which the blood pressure in the arteries is elevated, requiring the heart to work harder than normal to circulate blood through the blood vessels. Normal blood pressure is below 120/80 mmHg. Hypertension is said to be present when blood pressure consistently exceeds 140/90 mmHg. Hypertension includes, but is not limited to, hypertension stage I, hypertension stage II, and single systolic hypertension. Signs of hypertension include headache, dizziness, blurred vision, nausea and vomiting, chest pain, shortness of breath, heart attack, heart failure, stroke or transient ischemic attack (TIA), kidney failure, eye damage with progressive vision loss, and walking Peripheral arterial disease, aneurysm and any combination thereof that cause leg pain (limp). The treatments disclosed herein can improve blood circulation and delivery of oxygen enriched blood to the body, thereby lowering blood pressure and treating hypertension.

In an aspect of this embodiment, a method of treating hypertension comprises administering to a subject suffering from high blood pressure a composition comprising a material comprising a therapeutically effective amount of dissolved molecular carbon dioxide using the transdermal delivery device disclosed herein. Administration of the composition reduces signs associated with hypertension.

In an embodiment of this embodiment, administration of the composition is for example at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least Reduce blood pressure by 100% In another aspect of this embodiment, the administration of the composition is for example from about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to Blood pressure is reduced by about 100%, about 60% to about 100%, about 70% to about 100% or about 80% to about 100%.

In another aspect of this embodiment, the administration of the composition is for example at least about 5 minutes, at least about 15 minutes, at least about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 75 minutes, at least about 90 minutes, about For at least 105 minutes, at least about 120 minutes, at least about 135 minutes, at least about 150 minutes, at least about 165 minutes, at least about 180 minutes, at least about 195 minutes, at least about 210 minutes, at least about 225 minutes or at least about 240 minutes Reduce blood pressure by 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 100%. In another aspect of this embodiment, the administration of the composition is for example at least about 5 minutes, at least about 15 minutes, at least about 30 minutes, at least about 45 minutes, at least about 60 minutes, at least about 75 minutes, at least about 90 minutes, For at least about 105 minutes, at least 120 minutes, at least about 135 minutes, at least about 150 minutes, at least about 165 minutes, at least about 180 minutes, at least about 195 minutes, at least about 210 minutes, at least about 225 minutes or at least about 240 minutes About 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70 Reduce blood pressure by% to about 100% or about 80% to about 100%.

In another aspect of this embodiment, the administration of the composition is for example from about 5 minutes to about 30 minutes, from about 5 minutes to about 60 minutes, from about 5 minutes to about 90 minutes, from about 5 minutes to about 120 minutes, from about 5 minutes to About 150 minutes, about 5 minutes to about 180 minutes, about 5 minutes to about 210 minutes, about 5 minutes to about 240 minutes, about 15 minutes to about 30 minutes, about 15 minutes to about 60 minutes, about 15 minutes to about 90 Minutes, about 15 minutes to about 120 minutes, about 15 minutes to about 150 minutes, about 15 minutes to about 180 minutes, about 15 minutes to about 210 minutes, about 15 minutes to about 240 minutes, about 30 minutes to about 60 minutes, At least 10 for about 30 minutes to about 90 minutes, about 30 minutes to about 120 minutes, about 30 minutes to about 150 minutes, about 30 minutes to about 180 minutes, about 30 minutes to about 210 minutes, or about 30 minutes to about 240 minutes Reduce blood pressure by%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 100%. In another aspect of this embodiment, the administration of the composition is for example about 5 minutes to about 30 minutes, about 5 minutes to about 60 minutes, about 5 minutes to about 90 minutes, about 5 minutes to about 120 minutes, about 5 minutes To about 150 minutes, about 5 minutes to about 180 minutes, about 5 minutes to about 210 minutes, about 5 minutes to about 240 minutes, about 15 minutes to about 30 minutes, about 15 minutes to about 60 minutes, about 15 minutes to about 90 minutes, about 15 minutes to about 120 minutes, about 15 minutes to about 150 minutes, about 15 minutes to about 180 minutes, about 15 minutes to about 210 minutes, about 15 minutes to about 240 minutes, about 30 minutes to about 60 minutes For about 30 minutes to about 90 minutes, about 30 minutes to about 120 minutes, about 30 minutes to about 150 minutes, about 30 minutes to about 180 minutes, about 30 minutes to about 210 minutes, or about 30 minutes to about 240 minutes 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% Blood pressure is reduced by from about 100% or from about 80% to about 100%.

In another aspect of this embodiment, administration of the composition is for at least about 4 hours, at least about 6 hours, at least about 8 hours, at least about 10 hours, at least about 12 hours, at least about 18 hours or at least about 24 hours, for example. Reduce blood pressure by 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 100%. In another aspect of this embodiment, administration of the composition is for example for at least about 4 hours, at least about 6 hours, at least about 8 hours, at least about 10 hours, at least about 12 hours, at least about 18 hours or at least about 24 hours. About 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70 Reduce blood pressure by% to about 100% or about 80% to about 100%.

In another embodiment, a method of treating a cardiovascular disorder comprises administering a composition comprising a substance comprising a therapeutically effective amount of dissolved gas to an individual suffering from a cardiovascular disorder using a transdermal delivery device as disclosed herein. Wherein the administration of the composition reduces signs associated with cardiovascular disorders. Cardiovascular disease is any of a number of specific diseases that affect the heart itself and / or the vascular system, especially arteries and veins leading to and from the heart. Diabetic heart conditions, arteritis, phlebitis, vascular inflammations such as vasculitis, arterial obstructive diseases such as arteriosclerosis and stenosis, peripheral arterial disease, aneurysms, embolism, detachment, pseudoaneurysms, angioplasty, angioplasty, thrombosis, thrombophlebitis, varicose veins, There are more than 60 types of cardiovascular disorders including but not limited to stroke. Signs of cardiovascular disorders affecting the heart include chest pain or chest discomfort (angina), pain in one or both forearms, left shoulders, neck, jaw or back, shortness of breath, dizziness, faster heart rate, nausea, abnormal heartbeat, severe tiredness Includes sense without limitation. Signs of cardiovascular disorders affecting the brain include: sudden numbness or weakness in the face, forearms or legs, especially on one side of the body, sudden confusion or difficulty in speech or language, sudden vision difficulties in one or both eyes, sudden dizziness, It includes, but is not limited to, difficulty walking, loss of balance or coordination, and sudden severe headache of unknown origin. Signs of cardiovascular disorders affecting the legs, pelvis, and / or forearms include, but are not limited to, muscle pain, limping, pain or cramping, and especially cold or numbness of the feet or toes at night. The treatments disclosed herein can improve blood circulation and delivery of oxygen enriched blood to the body, thereby treating cardiovascular disorders.

In an aspect of this embodiment, a method of treating a cardiovascular disorder comprises administering to a subject suffering from a cardiovascular disorder a composition comprising a substance comprising a therapeutically effective amount of dissolved molecular carbon dioxide using the transdermal delivery device disclosed herein. Wherein the administration of the composition reduces signs associated with cardiovascular disorders.

In another embodiment, a method of treating a diabetic disorder comprises administering a composition comprising a substance comprising a therapeutically effective amount of dissolved gas to an individual suffering from a diabetic disorder using a transdermal delivery device as disclosed herein. Wherein the administration of the composition reduces signs associated with a diabetic disorder. Diabetes disorders are a group of metabolic diseases in which a person has high blood sugar because the body does not produce enough insulin or because cells do not respond to the insulin produced. Diabetes disorders include, but are not limited to, type 1 diabetes, type 2 diabetes, and gestational diabetes. Signs of diabetes disorders include, but are not limited to, increased hunger, unexplained weight loss, frequent urination, high blood sugar, lethargy, slow wound healing, and persistent wounds. The treatments disclosed herein can improve blood circulation and delivery of oxygen enriched blood to the body, thereby treating diabetic disorders.

In an aspect of this embodiment, a method of treating a diabetic disorder comprises administering to a subject suffering from a diabetic disorder a composition comprising a substance comprising a therapeutically effective amount of dissolved molecular carbon dioxide using a transdermal delivery device disclosed herein. Wherein the administration of the composition reduces signs associated with a diabetic disorder.

In another embodiment, a method of treating a wound comprises administering a composition comprising a material comprising a therapeutically effective amount of dissolved gas to an individual suffering from a wound using a transdermal delivery device as disclosed herein. Administration of the composition reduces signs associated with the wound. The delivery of oxygen, nutrients and other substances is essential for setting essential physiological functions in the area and for promoting wound healing. The treatments disclosed herein can enhance blood circulation and delivery of oxygen enriched blood to the area of the wound to facilitate healing, thereby treating the wound.

In an aspect of this embodiment, a method of treating a wound comprises administering to a subject suffering a wound a composition comprising a material comprising a therapeutically effective amount of dissolved molecular carbon dioxide using the transdermal delivery device disclosed herein. Administration of the composition reduces signs associated with the wound.

In another embodiment, a method of treating chronic inflammation comprises administering a composition comprising a substance comprising a therapeutically effective amount of dissolved gas to an individual suffering from chronic inflammation using a transdermal delivery device as disclosed herein. Wherein the administration of the composition reduces signs associated with chronic inflammation. In general, inflammation not only eliminates noxious stimuli but also serves as a protective mechanism by the organism to initiate a healing process for damaged tissue. This acute neurological inflammation forms a first defensive line by maintaining tissue integrity and contributing to tissue repair. Indeed, in the absence of acute neurological inflammation, wounds and infections never heal and progressive destruction of tissues can impair the survival of the organism. However, a serious or prolonged noxious stimulus causes a chronic inflammatory response that causes injury rather than mediating restoration. This infection has been involved in the pathophysiology of a wide range of unrelated disorders that underlie a wide range of human diseases. Non-limiting examples of disorders that indicate infection as a symptom include acne, acid reflux / heartburn, Alzheimer's disease, appendicitis, arteritis, arthritis, asthma, allergies, allergic rhinitis, atherosclerosis, autoimmune disorders, glansitis, eyelids , Bronchiolitis, bronchitis, bullous swelling, mucous cyst, cancer, heart disease, celiac disease, soft tissue, cervicitis, cholangitis, cholecystitis, chorioamnitis, chronic obstructive pulmonary disease (COPD), cirrhosis, colitis, conjunctivitis, cystitis, Colds, lacrimitis, dementia, dermatitis, dermatitis, eczema, emphysema, encephalitis, endocarditis, endometritis, enteritis, small intestinal colitis, gastroarthritis, epididymitis, fasciitis, fibritis, gastritis, gastroenteritis, gingivitis, glomerulonephritis, Pericarditis, heart disease, hepatitis, purulent glanditis, hypertension, calculitis, inflammatory skin disease, inflammatory neuropathy, insulin resistance, interstitial cystitis, iris infection, ischemic heart disease, keratitis, cornea conjunctivitis, laryngitis, mastitis, lactation Dendrite, meningitis, metabolic syndrome (syndrome X), migraine, myelitis, cardiomyelitis, myositis, nephritis, obesity, navelitis, ovarian infection, testicles, osteopenia, osteochondritis, osteoarthritis, otitis, pancreatitis, Parkinson's disease, mumps, pelvic inflammation Diseases, measles, pericarditis, peritonitis, pharyngitis, phlebitis, pleurisy, pneumonia, proctitis, prostatitis, psoriasis, pulpitis, pyelonephritis, portal inflammation, rheumatoid fever, rhinitis, uterine arthritis, salivary pneumonia, sinusitis, intestinal spasms, stomatitis Include, but are not limited to, synovialitis, tendinitis, tendinitis, hay salt, thrombophlebitis, tonsillitis, bladder trigonitis, tumors, urethritis, uveitis, vaginitis, vasculitis and vulvitis. Common signs of chronic inflammation include, but are not limited to fatigue, pain, asthma, swelling of tissue, while other signs are specific for certain types of chronic inflammation and are known to those skilled in the art. The treatments disclosed herein can enhance the delivery of oxygen-rich blood to the blood circulation and inflammation-prone areas, thereby treating chronic inflammation.

In an aspect of this embodiment, a method of treating chronic inflammation comprises administering a composition comprising a substance comprising a therapeutically effective amount of dissolved molecular carbon dioxide to an individual suffering from chronic inflammation using the transdermal delivery device disclosed herein. Wherein the administration of the composition reduces signs associated with chronic inflammation.

In another embodiment, a method of treating arthritis comprises administering to a subject suffering from arthritis a composition comprising a material comprising a therapeutically effective amount of dissolved gas using a transdermal delivery device as disclosed herein. And administration of the composition reduces the signs associated with arthritis. Osteoarthritis includes osteoarthritis, rheumatoid arthritis, ankylosing spondylitis such as juvenile idiopathic arthritis, ankylosing spondylitis, reactive arthritis (lighter syndrome), psoriatic arthritis, inflammatory bowel disease, enteric arthritis such as whiff and Behcet's disease, septic arthritis, gout (gout) 100, accompanied by damage to the joints of the body due to inflammation of the synovial membrane, including but not limited to arthritis, crystalline synovial inflammation, metabolic arthritis), pseudogout (calcium pyrophosphate deposition) and Still's disease Group of excess conditions. Arthritis can affect a single joint (single arthritis), two to four joints (oligo-arthritis), or five or more arthritis (polyarthritis), and an autoimmune disease or visa may be an immune disease. Signs of arthritis include, but are not limited to, joint pain, joint swelling, joint stiffness, chills, fever, joint tenderness, joint redness and anorexia. The treatments disclosed herein can improve the delivery of oxygen rich blood to the blood circulation and arthritis areas, thereby treating arthritis.

In an aspect of this embodiment, a method of treating arthritis comprises administering to a subject suffering from arthritis a composition comprising a substance comprising a therapeutically effective amount of dissolved molecular carbon dioxide using the transdermal delivery device disclosed herein. Administration of the composition reduces signs associated with arthritis.

In another embodiment, a method of treating migraine headaches comprises administering a composition comprising a substance comprising a therapeutically effective amount of dissolved gas to an individual suffering from migraine using a percutaneous delivery device as disclosed herein. And administration of the composition reduces the signs associated with migraine headaches. Migraine headache is a chronic nervous system disorder characterized by alleviating severe headaches and nausea. Migraine headaches include, without exception, migraine headaches, migraine headaches, menstrual migraine headaches, migraine equivalents, migraine headaches, retinal migraine headaches, abdominal migraine headaches or mixed tension migraine headaches. Signs of migraine headaches include, but are not limited to, pulsating pain, nausea, vomiting, diarrhea, facial paleness, water hydration, foot colds, sensitivity to light and sensitivity to sound on one side of the head. The treatments disclosed herein can improve blood circulation and delivery of oxygen enriched blood to brain regions, thereby treating migraine headaches.

In an aspect of this embodiment, a method of treating migraine comprises administering to a subject suffering from migraine a composition comprising a substance comprising a therapeutically effective amount of dissolved molecular carbon dioxide using the transdermal delivery device disclosed herein. And administration of the composition reduces the signs associated with migraine headaches.

In another embodiment, a method of treating a cellulite disorder is administered to an individual suffering from a cellulite disorder using a percutaneous delivery device as disclosed herein comprising a composition comprising a material comprising a therapeutically effective amount of dissolved gas. And administering the composition reduces signs associated with cellulite disorders. Cellulite is a surface fat located just below the top layer of skin. Cellulite occurs when fat cells become too large for the natural fiber compartments that hold the skin, causing them to swell and form a non-uniform layer under fat. The treatments disclosed herein can improve blood circulation and improve the delivery of oxygen enriched blood to the cellulite region, thereby destroying fat cells and treating cellulite disorders.

In an aspect of this embodiment, a method of treating a cellulite disorder comprises administering a composition comprising a substance comprising a therapeutically effective amount of dissolved molecular carbon dioxide to an individual suffering from a cellulite disorder using the transdermal delivery device disclosed herein. And administering the composition reduces signs associated with cellulite disorders.

In another embodiment, a method of treating a pale skin disorder is disclosed to an individual suffering from a pale skin disorder using a transdermal delivery device as disclosed herein comprising a composition comprising a material comprising a therapeutically effective amount of dissolved gas. Administering, the administration of the composition reduces the signs associated with pale skin disorders. Pale skin occurs when there is a reduced amount of oxygen hemoglobin in the skin or mucous membranes. This can happen suddenly or gradually, depending on the cause. Pale color can be caused by illness, emotional shock or stress, use of stimulants, lack of exposure to sunlight, anemia or heredity. Pale skin is more apparent on the face and palms. The treatments disclosed herein can improve blood circulation and delivery of oxygen-rich blood to the skin, thereby treating pale skin.

In an aspect of this embodiment, a method of treating a pale skin disorder is administered to an individual suffering from a pale skin disorder using a transdermal delivery device disclosed herein comprising a composition comprising a material comprising a therapeutically effective amount of dissolved molecular carbon dioxide. And administering the composition reduces signs associated with pale skin disorders.

In another embodiment, a method of treating a cosmetic disorder comprises administering to a subject suffering from a cosmetic disorder a composition comprising a substance comprising a therapeutically effective amount of dissolved gas using a transdermal delivery device disclosed herein. And administration of the composition reduces the signs associated with cosmetic disorders. Beauty is the preservation, restoration or award of body beauty. As used herein, the term “beauty disorder” refers to a skin condition having unwanted or undesirable features that interfere with body beauty. Skin is the largest organ of the body and is the first line of defense for diseases, chemicals, sunlight and other environmental agents. Increasing oxygenation and blood flow within the entire skin surface create a stronger and more resilient barrier to combat these environmental invaders. Cosmetic disorders include, but are not limited to, diseases, defects or incompleteness of the skin. The location is non-limiting to the face, neck, upper arm, lower arm, hands, shoulders, back, torso including abdomen, buttocks, upper and lower legs including calf, foot, genital area or any other body part, zone or area. It may include any part of the body where the skin containing the present. Non-limiting examples of cosmetic disorders include skin wrinkles, skin lines, skin wrinkles, skin marks or other size, shape or contour incompleteness or defects of the skin. Facial wrinkles, lines, and / or wrinkles include, but are not limited to, glacial lines, nasolabial lines, lines around the mouth, and / or cheek lines. The treatments disclosed herein can enhance the delivery of oxygen enriched blood to areas including blood circulation and cosmetic disorders, thereby treating cosmetic disorders.

In an aspect of this embodiment, a method of treating a cosmetic disorder comprises administering to a subject suffering from a cosmetic disorder a composition comprising a substance comprising a therapeutically effective amount of dissolved molecular carbon dioxide using the transdermal delivery device disclosed herein. Wherein the administration of the composition reduces signs associated with cosmetic disorders.

In another embodiment, a method of treating fungi comprises administering a composition comprising a substance comprising a therapeutically effective amount of dissolved gas to an individual suffering from a fungus using a transdermal delivery device as disclosed herein. And administration of the composition reduces the signs associated with the fungus. In one embodiment, carbon dioxide may be used as the treatment gas. Fungi can be located in or on the body. Locations such as nails, toes, fingers, pubis, and the like can be treated using the delivery device described herein. The fungus may be an anaerobic bacterium that may only survive in a low oxygen environment. Thus, treatment with a therapeutic gas can result in increased oxygen enriched microcirculation enhancement that can kill and / or treat fungi and diseases and signs associated with them. In one embodiment, the treatments disclosed herein can improve blood circulation and delivery of oxygen enriched blood to the skin, thereby treating fungi.

Yes

The following non-limiting examples are provided for illustrative purposes only to facilitate a more complete understanding of the presently contemplated exemplary embodiments. These examples should not be construed to limit any of the embodiments described herein, including those belonging to the device, composition or method and the use of treating the conditions disclosed herein.

Example 1

Measurement of blood flow

Studies have been conducted to demonstrate that the use of the devices disclosed herein can improve blood flow in an individual. Treatment was administered by allowing an individual to insert a left thumb into the open end delivery outlet of the device disclosed herein to create a seal. The fingers will be “bathed” for 5 minutes with a vapor containing supersaturated dissolved molecular carbon dioxide from a canister that provides pure medical grade carbon dioxide. Nine individuals were tested.

Tissue perfusion in the distal artery was accessed using a SensiLase System (FDA-approved instrument) and skin perfusion pressure (SPP) and pulse volume recording (PVR) were measured. SPP is a pressure measurement in mmHg that assesses local blood perfusion in capillaries using a laser Doppler to measure reactive hyperemia. PVR is a measure of hemometry to assess changes in arterial blood volume. The change in capillary blood flow (CBF) is calculated by determining the change in SPP value over time. For this study, the CBF values of all post-treatment measurements were calculated by dividing the post-treatment SPP value by the post-treatment SPP value. The SPP was measured at 6 points, 1) 5 minutes before treatment (before treatment), 2) 5 minutes after treatment, 3) 30 minutes after treatment, 4) 60 minutes after treatment, 5) 120 minutes after treatment, and 6) treatment. After 240 minutes it was performed on the right toe of the individual.

The results indicate that administration of molecular carbon dioxide increases blood flow in all individuals examined at some point during the measured time period (Table 1). Seven of the nine individuals studied showed an increase of about 25% of capillary blood flow above baseline, and four of them showed an increase of at least about 35% of capillary blood flow (Table 1). In addition, six of the nine patients showed a continuous increase in capillary blood flow over the course of the entire 240 minute study.

Example 2

Measurement of blood pressure

The study was conducted to demonstrate that the use of the devices disclosed herein can reduce hypertension in an individual. To carry out this study, an individual from the study described in Example 1 had a blood pressure taken there. Measurements of both brachial diastolic and systolic blood pressure were made at 6 points, 1) 5 minutes before treatment (before treatment), 2) 5 minutes after treatment, 3) 30 minutes after treatment, 4) 60 minutes after treatment, 5) treatment. After 120 minutes and 6) 240 minutes after treatment in the right upper arm of the individual.

The results indicate that administration of molecular carbon dioxide reduces the blood pressure of all individuals examined at some point during the measured time period (Table 2). Seven of the nine individuals studied had diminished diastolic and systolic blood pressure over the course of the entire 240 minute study.

Finally, although aspects of the present application are highlighted with reference to specific embodiments, those skilled in the art should understand that these disclosed embodiments merely illustrate the principles of the subject matter disclosed herein. Thus, it should be understood that the disclosed subject matter is in no way limited to the specific methodologies, protocols, and / or reagents described herein. As such, various modifications, changes, or alternative configurations of the disclosed subject matter may be made in accordance with the teachings herein without departing from the spirit of the disclosure. Finally, the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the invention as defined only by the claims. Accordingly, the present invention is not limited to what is exactly shown and described.

Certain embodiments of the invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations of these described embodiments will be apparent to those skilled in the art upon reading the above description. The inventors expect those skilled in the art to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, the present invention includes all modifications and equivalents of the subject matter referred to in the claims appended hereto as permitted by applicable law. Moreover, any combination of the foregoing embodiments of all possible variations thereof is encompassed by the present invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Groupings of alternative embodiments, elements or steps of the invention should not be construed as limiting. Each group member may refer to or claim an individual or any combination with other group members disclosed herein. It is anticipated that one or more members of a group may be included in or deleted from the group for reasons of convenience and / or patentability. When any such inclusion or deletion occurs, the specification is deemed to meet the written description of all Markush groups used in the appended claims, thus including the group as modified.

Unless otherwise indicated, all numbers expressing features, items, quantities, parameters, properties, durations, etc., as used in this specification and claims, are to be understood as being modified in all instances by the term "about." As used herein, the term “about” means a plus or minus ten percent greater than the value of a characteristic, item, amount, parameter, characteristic or duration in which such modified characteristic, item, quantity, parameter, characteristic or duration is mentioned and It means to include the range below. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the description and appended claims are approximations that may change. At the very least, and not as an attempt to limit the application of the principles of equivalents to the scope of the claims, each numerical indication should be construed at least in terms of the number of significant digits recorded and by applying ordinary approximation techniques. Notwithstanding that the numerical ranges and numerical values describing the broad scope of the invention are approximations, the numerical ranges and numerical values set forth in the specific examples are recorded as precisely as possible. However, any numerical range or numerical value inherently includes certain errors that arise essentially from the standard deviation found in their respective test measurements. Reference to a numerical range of values herein is intended to serve only as a shorthand for individually referring to each individual numerical value within the range. Unless otherwise indicated herein, each individual value of a numerical range is incorporated herein as individually referred to herein.

The terms used in the singular and the like used in the context of the present invention should be construed to cover both the singular and the plural unless the context clearly dictates otherwise or otherwise clearly contradicts the context. All methods described herein may be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (eg, "such as") provided herein, is intended merely to better illustrate the invention and is within the scope of the invention as otherwise claimed. It is not intended to impose a limitation. No language in this specification should be construed as indicating any non-claimed element essential to the practice of the invention.

Certain embodiments disclosed herein may be further defined in the claims, which may be in language or consisting essentially of language. When used in the claims, whether in the filed state or as added in accordance with the amendment, the phrase “consisting of” excludes any element, step or component not specified in the claims. The phrase “consisting essentially of” defines the scope of the claims to those that do not substantially affect a particular material or step and the basic novel property (s). Embodiments of the invention so claimed are inherently or expressly described and enabled herein.

All patents, patent publications, and other publications referenced and identified herein are, for example, individually and separately herein for the purpose of describing and disclosing the compositions and methodologies described in such publications that may be used in connection with the present invention. And expressly incorporated by reference. These publications are provided only for their disclosure prior to the filing date of the present application. Nothing in this regard should be construed as an admission that the inventors acknowledge the prior disclosure of this prior art or for any other reason as preceding this invention. All references or representations to the contents of these documents are based on information available to the applicant and do not constitute any acceptance of the accuracy of the dates or contents of these documents.

102: compression cylinder 104: permeation valve
106: fluid chamber 108: processing chamber
200: housing 202: outer body shell
206: open end delivery outlet 208: steam generating assembly compartment
212: cartridge holding container 214: outer cover shell
216: internal cartridge compartment 302: fluid chamber assembly
304: permeation valve 306: tube
308: thread attachment point 314: male thread
316: internal thread 318: steam generating assembly
320: control switch assembly 322: first connection device

Claims (35)

As a percutaneous delivery device,
a) housing,
i) an outer body shell comprising a fluid chamber assembly access cover movably coupled with the outer body shell,
ii) an interior compartment comprising an open end delivery outlet and a vapor generation assembly compartment, and
iii) a cartridge holding container comprising an outer lid shell and an inner cartridge compartment capable of holding a compressed gas cartridge, said cartridge holding container being detachably coupled with said outer body shell,
The outer shell forms an inner compartment,
The vapor generation assembly compartment is located between the open end delivery outlet and the cartridge holding vessel;
b) a steam generating assembly,
i) a fluid chamber assembly comprising a fluid container and a removable fluid container cap, and
ii) a permeation valve configured to reduce the pressure of the gas removed from the compressed gas cartridge and delivered to the fluid chamber assembly,
The steam generating assembly is substantially contained within a steam generating assembly compartment.
Percutaneous delivery device comprising a. The transdermal delivery device of claim 1, further comprising a control switch assembly. The transdermal delivery device of claim 2, wherein the control switch assembly is a mechanical switch or an electronic switch. The percutaneous delivery device according to claim 1, further comprising a compressed gas cartridge. The transdermal delivery device of claim 4, wherein the compressed gas cartridge is a 16 g compressed gas cartridge. 6. The percutaneous delivery device of claim 4 or 5, wherein the compressed gas cartridge comprises carbon dioxide. 7. The percutaneous delivery device of claim 1, wherein the permeate valve is set to reduce the pressure of the gas to 40 psi (275.789 kPa) or less. 8. The percutaneous delivery device of claim 1, wherein the permeation valve comprises a permeable member selected from rubber, cork, fabric, porous polymer, high density sintered metal, and combinations thereof. As a percutaneous delivery device,
A cylinder for receiving the compressed carbon dioxide,
A permeation valve configured to reduce the pressure of the compressed carbon dioxide;
A chamber configured to form a therapeutic vapor by supersaturating the liquid with carbon dioxide in the chamber,
A treatment chamber configured to deliver the treatment vapor to an individual
Percutaneous delivery device comprising a. A method of transdermally administering a therapeutically effective amount of dissolved molecular carbon dioxide to an individual,
A method comprising administering to an individual a composition comprising a vapor comprising a supersaturated amount of dissolved molecular carbon dioxide using a transdermal delivery device according to claim 1. A method of transdermally administering a therapeutically effective amount of a therapeutic agent to an individual,
A method comprising administering to an individual a composition comprising a therapeutic agent and a vapor comprising a supersaturated amount of dissolved molecular carbon dioxide using the percutaneous delivery device according to claim 1. 12. The method of claim 10 or 11, wherein the amount of dissolved molecular carbon dioxide is at least 600 ppm. The method of claim 10, wherein the administering increases blood flow. The method of claim 13, wherein said administering increases blood flow by at least 10%. The method of claim 13, wherein said administering increases blood flow by about 10% to about 100%. 16. The method of any one of claims 13-15, wherein the increased blood flow is for at least 5 minutes. 16. The method of any one of claims 13-15, wherein the increased blood flow is for about 5 minutes to about 240 minutes. 18. The method of any one of claims 9-17, wherein the administering reduces blood pressure. The method of claim 18, wherein said administering reduces blood pressure by at least 10%. The method of claim 18, wherein said administering reduces blood pressure by about 10% to about 100%. 21. The method of any one of claims 18-20, wherein the reduced blood pressure is for at least 5 minutes. 22. The method of any one of claims 18-21, wherein the reduced blood pressure is for about 4 hours to about 24 hours. As a method of treating an individual's condition,
A method comprising administering a composition comprising a substance comprising a therapeutically effective amount of dissolved molecular carbon dioxide to an individual suffering from a condition using a transdermal delivery device according to any one of claims 1 to 9,
Administering the composition is such as to reduce signs associated with the condition. The method of claim 23, wherein the condition is ischemia, hypertension, cardiovascular disorder, diabetes disorder, wound, chronic inflammation, arthritis, migraine, cellulite disorder, pale skin disorder and cosmetic disorder. The method of claim 23 or 24, wherein the amount of dissolved molecular carbon dioxide is at least 600 ppm. 27. The method of any one of claims 23-25, wherein the administration increases blood flow. The method of claim 26, wherein said administering increases blood flow by at least 10%. The method of claim 26, wherein said administering increases blood flow by about 10% to about 100%. 29. The method of any one of claims 26-28, wherein the increased blood flow is for at least 5 minutes. 29. The method of any one of claims 26-28, wherein the increased blood flow is for about 5 minutes to about 240 minutes. 31. The method of any one of claims 23-30, wherein the administration reduces blood pressure. The method of claim 31, wherein said administering reduces blood pressure by at least 10%. The method of claim 31, wherein said administering reduces blood pressure by about 10% to about 100%. 34. The method of any one of claims 31-33, wherein the reduced blood pressure is for at least 5 minutes. 34. The method of any one of claims 31-33, wherein the reduced blood pressure is for about 4 hours to about 24 hours.

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