Patent Application
20190328660
The present disclosure relates in general to the application of gas nanobubbles, and in particular, to therapeutic applications utilizing such gas nanobubbles in a liquid absorbed within an absorbent material.
This section is intended to introduce various aspects of the art, which may be associated with exemplary embodiments of the present disclosure. This discussion is believed to assist in providing a framework to facilitate a better understanding of particular aspects of the present disclosure. Accordingly, it should be understood that this section should be read in this light, and not necessarily as admissions of prior art.
The human skin is a protective organ, but also one that is filled with blood vessels and nerve endings, all of which can be adversely affected by disease. For example, an inherent problem with peripheral neuropathy is the narrowing of blood vessels that supply oxygen and nutrients to the nerves in the extremities, and as a result, oxygen and nutrients are not delivered to the peripheral nerves, which eventually die. Thus, a good solution would be able to alter the situation of a patient such that the blood vessels that supply the nerves in the extremities are enlarged, allowing greater flow of blood, and additionally increasing the concentration of oxygen at these locations.
It is known that carbonated springs, which are typically hot springs with a high concentration of carbon dioxide (“CO2”), contribute to create beautiful and healthy skin. The effect of the CO2 is the expanding of blood vessels, and as a result naturally improving the blood flow (see, e.g., H. Hayashi et al., “Immersing Feet in Carbon Dioxide-enriched Water Prevents Expansion and Formation of Ischemic Ulcers after Surgical Revascularization in Diabetic Patients with Critical Limb Ischemia,” Ann Vasc Dis., 1(2), pp. 111-117, Oct. 24, 2008; M Hashimoto et al., “Decrease in heart rates by artificial CO2 hot spring bathing is inhibited by β1-adrenoceptor blockade in anesthetized rats,” J Appl Physiol, 96, pp. 226-232, Aug. 29, 2003; and M. Maeda et al., “The Effects of High Concentration Artificial CO2 Warm Water Bathing for Arteriosclerotic Obstruction (ASO),” The Journal of The Japanese Society of Balneology, Climatology and Physical Medicine, Volume 66, Issue 3, pp. 156-164, Apr. 30, 2010, which are all hereby incorporated by reference herein). The CO2 penetrates through the skin into the capillaries, causing the blood vessels to dilate, and frees up more oxygen that has been bound to the hemogoblin (also referred to as the Bohr Effect) (e.g., see, N. Nishimura et al., “Effects of repeated carbon dioxide-rich water bathing on core temperature, cutaneous blood flow and thermal sensation,” Eur. J. Appl. Physiol. 87, pp. 337-342, Jun. 7, 2002, which is hereby incorporated by reference herein).
Referring to the diagram of the dermis and epidermis in
In U.S. patent application Ser. No. 15/850,362, there is disclosed the utilization of gas nanobubbles coming in contact with human skin for therapeutic reasons. Further described is how nanobubbles can come in contact with skin using a nanobubbler to produce or generate gas nanobubbles (e.g., oxygen, CO2, etc.), in a liquid (e.g., water) and then the liquid containing the gas nanobubbles is put in contact with the skin.
Though this approach can be utilized in many applications, such as to treat peripheral neuropathy, wound irrigation, hypoxia, etc., there may be applications that require a different way to bring gas nanobubbles in contact with skin.
Referring to
Each bubble is surrounded by an interface with different properties than the bulk liquid. Bubbles with a diameter less than 1 micron may be referred to herein as “ultra-fine bubbles” (“UFB”), which include the family of nanobubbles as defined above.
The surface area of a bubble is inversely proportional to the bubble diameter. As an example, for 100 nm diameter bubbles, a 1 ml liquid can contain about 2×1015 such bubbles, with a surface area that is 1,000 times (240 m2) more than the surface area of 1 mm diameter bubbles in the same volume of liquid (e.g., 2×106 bubbles with a total surface area of 0.24 m2). “Fine bubbles” have inflexible surfaces (for example, as in high pressure balloons) that limit distortions, while larger bubbles have flexible surfaces (for example, as in low pressure balloons) and can break up relatively easily.
The buoyancy of larger bubbles causes them to rise to the surface of the liquid. Although the behavior of bubbles in liquids is complex, the rising rate of bubbles can be approximated using Stokes's equation:
R=μgd
2/18μ
where R represents the rise rate, p represents the density, g represents gravity, d represents the bubble diameter, and μ represents the dynamic viscosity (Pa×s). Accordingly, a 25 μm diameter bubble will rise at a rate of ˜2.3 cm/min, while nanobubbles will rise much more slowly than their Brownian motion. Since nanobubbles are dominated by Brownian motion rather than behaving according to Stoke's equation, they diffuse into the liquid with minimal or no buoyancy effects.
The generation of nanobubbles can be accomplished by vigorously mixing a combination of gas and a liquid, which will generally produce bubbles with a wide range of diameters. Referring to
The degree of saturation next to a bubble depends on the gas pressure within the bubble. The energy cost of bubble formation depends on the interfacial area and is governed by the bubble's surface tension. Smaller bubbles have higher internal pressure and release gas to dissolve under pressure into an under-saturated liquid. Larger bubbles grow by taking up gas from a super-saturated liquid. As a result, smaller bubbles shrink and larger bubbles grow. As bubbles rise, the pressure on them drops, and consequently they enlarge and rise faster. Nanobubbles rise much slower due to low buoyancy and their random Brownian motion. The overall behavior of nanobubbles is complex due to the shrinking effects that are in competition to the effect of buoyancy. Consequently nanobubbles have a tendency to diffuse into the liquid; they do not rise and they never accumulate in the upper part of the liquid.
Additionally, the electrostatic interaction between nanobubbles can be large enough to avoid coalescence. Electrostatic interaction will slow any rise even more. The zeta potential is generally negative and mostly independent of the bubble diameter. The zeta potential depends strongly on the pH and the dissolved salt concentrations whereby increased ionic strength reduces zeta potential. As all the bubbles are similarly charged, their coalescence is discouraged. The zeta potential of a bubble can be determined from its horizontal velocity in a horizontal electric field:
v=ζϵ/μ
where ζ represents the zeta potential, ϵ represents the permittivity, and μ represents the dynamic viscosity.
According to the Laplace equation, the following is the pressure inside a gas bubble for soluble gases:
P
in
=P
out+4γ/d
where Pin represents internal pressure, Pout represents external pressure, γ represents surface tension, and d represents bubble diameter. The expression 4γ/d is defined as the excess pressure.
The controversy over nanobubbles' existence is based on the fact that as the diameter of the bubble is in the range of nanometers, the internal pressure will be very high, significantly reducing their lifespan. By reducing the surface tension utilizing a surface-active agent (e.g., a surfactant), which coats the surfaces of the nanobubbles, the excess pressure can be lowered in order to stabilize the bubbles, which has the effect of lengthening the lifetime of the nanobubbles in the liquid. The concentration of surface-active agents (e.g., surfactant) may also be used to stabilize/regulate the bubble size (e.g., see M Chaplin, previously cited herein), such as limiting the growth or shrinkage of the nanobubbles.
However, the Laplace equation may not hold at small diameters such as nanobubbles. For nanobubbles, the calculated internal gas pressure should cause an almost instantaneously dissolution, but as nanobubbles are now known to exist for long periods, the existing basic theories may be insufficient.
Although nanobubbles are smaller than the wavelength of light and therefore too small to be visible to the naked eye or standard microscope, they can be visualized by backscattering of the light from a laser. Nanobubbles can be also observed by dynamic light scattering (“DLS”). The fluctuation of the scattering of laser light travelling through the sample liquid is due to the Brownian motion whereby larger bubbles are showing greater scattering but lower fluctuations. Analysis of the total signal gives both the concentration and size distribution of the nanobubbles. Other detection methods include cryoelectron microscopy (“cryo-EM”) and resonant mass measurement.
Referring to
Surface charge can counter the surface tension preventing high pressure within the nanobubbles. It may be expected that as the nanobubble shrinks, the charge density will increase. The effect of charges at the liquid/gas interface is that the surface negative charges repelling each other are stretching out the surface of the bubble. Thus, the effect of the charges is to reduce the effect of the surface tension. The surface tension tends to reduce the surface, whereas the surface charge tends to expand it. Equilibrium will be reached when these opposing forces are equal meaning that Pin=Pout.
Pout can be found to be:
P
out=Φ2/2Dϵ0)
where Φ represents the surface charge density on the inner surface of the bubble, D represents the relative dielectric constant of the gas bubble, and ϵ0 represents the permittivity of vacuum.
The inward pressure, Pin, due to the surface pressure is given from the Laplace equation:
P
in=4γ/d
where γ represents the surface tension, and d represents the diameter of the bubble. Equalizing these two pressures, one can determine the charge density at different bubble diameters. For example, for nanobubble diameters of 10 nm, 20 nm, 50 nm, 100 nm, and 200 nm, the charge density is 0.14, 0.1, 0.06, 0.04, and 0.03 e−/nm2, respectively. The surface tension reduction contributes to the stability of nanobubbles.
The charge similarity, together with the lack of van der Waals attraction, tends to prevent coalescence of the nanobubbles.
Furthermore, the nanobubbles protect each other from diffusive loss by a shielding effect, effectively producing a back pressure of gas from neighboring bubbles, which may be separated by approximately the thickness of the unstirred layer, which slows the dissolution. The slow dissolution will be even slower than expected due to higher osmotic pressure at the gas/liquid interface, which is also driving the dissolved gas near the interface back to the nanobubble.
In accordance with embodiments of the present disclosure, nanobubbles of a desired type of gas, or multiple gas types, (e.g., oxygen (O2), nitrogen (N2), carbon monoxide (CO), carbon dioxide (CO2), ozone (O3), air, nitric oxide (NO), nitrous oxide (N2O), helium, hydrogen, nitrogen, methane, noxious gases, pure gases, mixed gases, etc., or any gas as listed at https://en.wikipedia.org/wiki/List_of_gases) are generated in a liquid, and the liquid is infused or otherwise absorbed into a matching or corresponding suitable absorbent material. Pure gases can take several different forms. They might be made up of individual atoms, such as atomic gases. For example, oxygen is a pure gas because it is made of one type of elemental molecule. Pure gases may also be compound molecules, which are composed of a bunch of different atoms. For example, carbon dioxide would be considered a pure gas, but it is also a compound molecule. Mixed gases, on the other hand, are composed of more than one kind of pure gas (e.g., NO, N2O, etc.).
Generation of nanobubbles in a liquid may be performed utilizing any well-known nanobubble generating device, apparatus, or system (such as the nanobubbler utilizing a nozzle made of a porous carbon-based material commercially available from Anzai Kantetsu Co., LTD (e.g., see, anzaimcs.com/en/main/examplenanobubble.html, which is hereby incorporated by reference herein), which may be referred to herein as the “Anzai Device,” or as disclosed in U.S. published patent application no. 2018/0177737), or by utilizing one of the nanobubble generating systems disclosed herein with respect to
The liquid may be of any composition in which gas nanobubbles can be generated including, but not limited to, water, solutions containing water, solvents, saline, gels, foams, lotions, ointments, alcohols, oils, etc.
The absorbent material may be of any specified viscosity (including those previously listed), a hydrogel as described herein, or any material or matrix of material(s) that are absorbent of a liquid in which gas nanobubbles have been generated. Types of suitable liquid absorbent materials, include, but are not limited to, ointments, creams, sponge-type materials (e.g., cellulose sponge, etc.), all types of gels (e.g., hydrogels, silica gels, etc.), absorbent foams (e.g., Flexan, which is commercially available from Dow Hickam Pharmaceuticals, Inc.), synthetic fibers (e.g., polyester, rayon, Aquacel, which is commercially available from ConvaTech, Inc., etc.), natural fibers (e.g., cotton, wool, silk, etc.), hydrofibers that absorb water, hydrocolloids (e.g., Nu-Derm, which is commercially available from Johnson & Johnson, Inc., or RepliCare, which is commercially available from Smith & Nephew, Inc.), nano-porous materials (e.g., see Vladimir M Gun'ko et al., “Properties of Water Bound in Hydrogels,” Gels, 3, 37, Oct. 19, 2017, which is hereby incorporated by reference herein), and any other materials containing liquid absorbent molecules. For example, in the case of water, any materials having hydrophilic properties may be utilized. In addition to foams, gels, ointments, and creams, any absorbent material with a similar viscosity as these may also be utilized.
Hydrogels are gels that are composed of an aqueous dispersion medium that is gelled with a suitable hydrophilic gelling agent. Hydrogels are polar hydrophilic polymers (natural or synthetic) physically or chemically cross-linked into a three-dimensional network that can bond large amounts of water (up to 100 g per g or higher). The hydrogel hydrophilicity is due to groups such as —OH, —COOH, —COO−, >C═O, >CHNH2, —CONH2, SO3H, etc. in the polymer network. Water plays an important role in hydrogels by supporting their integrity, solubility, and diffusion of substances, which can have importance for biomedical and biotechnological applications. For example, see R. Jayakumar et al., “Biomedical applications of chitin and chitosan based nanomaterials—A short review,” Carbohydr. Polym., 82, pp. 227-232, May 2, 2010; R. Jayakumar et al., “Novel chitin and chitosan nanofibers in biomedical applications,” Biotechnol. Adv., 28, pp. 142-150, January 2010; Y. F. Zhang et al., “O-Carboxymethyl-chitosan/organosilica hybrid nanoparticles as non-viral vectors for gene delivery,” Mater. Sci. Eng., 29, pp. 2045-2049, Apr. 8, 2009; Y.-Z. Long et al., “Recent advances in synthesis, physical properties and applications of conducting polymer nanotubes and nanofibers,” Prog. Polym. Sci., 36, pp. 1415-1442, Apr. 17, 2011; A. H. Karoyo et al., “Physicochemical properties and the gelation process of supramolecular hydrogels: A review,” Gels, 3, 1, Jan. 1, 2017, 18 pages; A. Sgambato et al., “Bioresponsive hydrogels: Chemical strategies and perspectives in tissue engineering,” Gels, 2, 28, Oct. 14, 2016, 14 pages; M Casolaro et al., “Polyelectrolyte hydrogel platforms for the delivery of antidepressant drugs,” Gels, 2, 24, Sep. 27, 2016, 15 pages; and Vladimir M Gun'ko et al., “Properties of Water Bound in Hydrogels,” Gels, 3, 37, Oct. 19, 2017, all of which are hereby incorporated by reference herein.
The water content in a hydrogel can change the hydrogel volume by swelling and shrinking, which can be purposefully influenced by external conditions. Furthermore, the water bounded in the hydrogel pores can be in a different state, strong and weak bound to the polymer network, and some of the water can be free (non-bounded).
Some hydrogels (called “smart hydrogels”) have the quality of changing their properties of absorption of water as a function of a change in an internal or external condition or parameter. This property can be utilized to accelerate and improve the release of the absorbed water including the gas nanobubbles that is in contact with the skin. For example, there are hydrogels that can change their hydrophilic properties to hydrophobic properties, as a function of a change in internal or external conditions, such as pH value (e.g., of the water), temperature, pressure, and others. This can be beneficial in applications where initially one wants the hydrogel to be hydrophilic and absorb large quantities of gas nanobubbled water, but then eventually change to hydrophobic so the water is expelled from the hydrogel, increasing the quantity of gas nanobubbled water in contact with the skin. For example, one can start by absorbing water with gas nanobubbles when the hydrogel material is very hydrophilic, but when it is desired for the gas nanobubbles to be closer to the skin, the hydrogel material can be caused to change to hydrophobic, for example by changing the pH, which will “propel” the water containing the gas nanobubbles toward the skin.
A similar principle can be utilized for storing a liquid with gas nanobubbles and then extracting the gas from the liquid absorbing material for different applications and not necessarily for bringing the material in contact with the skin. For example, see
Additionally, embodiments of the present disclosure include other types of liquid absorbent materials that are configured to be chemically stimulated in response to external cues like pH and temperature or by enzymatic action to effectively cause the liquid absorbent material to release the gas nanobubbles from the liquid absorbent material.
There are two types of hydrogels: anionic and cationic. Due to the fact that gas nanobubbles in water (liquids) are negatively charged, a question arises about the possibility, depending on the nature of the hydrogel, that the gas nanobubbles could be pinned to the walls of the pores of the hydrogel and affect their release. In such cases, anionic hydrogels may be implemented for use because the positive pole of the water molecule will be attracted to the anions of the hydrogel structure, leaving the negative pole of the water toward the water that is free. When this occurs, the negatively charged nanobubbles will primarily remain in the free water.
As will be further disclosed herein, certain embodiments of the present disclosure supply CO2 and/or oxygen directly to areas in the skin, and more specifically CO2 and/or oxygen nanobubbles, which can easily penetrate into the skin pores and deep into the dermis to dilate the blood vessels that supply the peripheral nerves, while also supplying additional oxygen directly to the nerves. It is known that while oxygen has antibacterial and antimicrobial properties, ozone (O3) is even more effective; thus, nanobubbles containing ozone can also be supplied to the skin as disclosed herein. Furthermore, embodiments of the present disclosure can also be utilized in a similar approach for wound irrigation, and even for cosmetic reasons, such as beautification of the skin.
It is important to note that when gas nanobubbles are absorbed/infused in water or in any other material, the partial pressure of the gas dissolved in the water/material will increase by a factor of between 2 and more than 10 times, and as a result, a strong force will be applied between the water/material in contact with the skin toward the inside of the skin such that the gas penetrates through the skin, and in addition will “drive” the gas nanobubbles through the pores of the skin.
Note that the apparatus 600 may include a plurality of nanobubblers 100, each configured to generate nanobubbles in the liquid containing a different type of gas (e.g., oxygen (O2), nitrogen (N2), CO2, O3, ambient air, and/or any other desired gas). The liquid may be pumped through a combination (e.g., arranged in parallel or in series) of such plurality of nanobubblers 100, and then the liquid combined as it exits from each nanobubbler 401. Alternatively, a single nanobubbler 100 may be configured to generate nanobubbles in the liquid with a plurality of different gases (e.g., oxygen (O2), nitrogen (N2), CO2, O3, ambient air, and/or any other desired gas), whereby either the different plurality of gases are simultaneously passed through the diffuser 101, or in an intermittent basis, one after the other.
Exemplary Non-Limiting Nanobubbler Apparatus Specifications:
Note that such specifications for a nanobubbler may be dependent upon the particular gas, or gases, to be contained within the generated nanobubbles, and also dependent upon the viscosity of the liquid within which the nanobubbles are generated/infused.
As shown in the illustrated cross-section of the nanobubbler 100, the gas is injected, via the inlet 103, into the porous ceramic material 101, while the liquid is injected, via the inlet 104, into the adjoining chamber 105 so that is passes across the surface 102, which is emitting the nanobubbles into the liquid. The nanobubble-infused liquid (i.e., gas nanobubbled liquid) then exits via the outlet 106.
In accordance with embodiments of the present disclosure, high quality ceramics are acquired from vendors, and then using a process described herein, the sizes of the emitting pores can be tuned as desired. In such a case, between 100 nm to 600 nm pores can be obtained that are adequate for creating nanobubbles (diameter less than 100 nm) and “minibubbles” (diameter less than or equal to 1 μm).
In accordance with certain embodiments of the present disclosure, the nanobubbler 100 may be configured with a film 102 on the top of the emitting ceramic pores that provides an external control of the diameters of the emitting pores achieving both narrower pores and a much narrower distribution of the pore diameters.
Referring to
Other similar materials polymeric in nature may alternatively be utilized with UV curing (or any other curing method that can achieve the desired solution as explained above).
Furthermore, the apparatus 600 may be utilized to form the pores in the UV curable epoxy film.
The nanobubbler 100 may be configured to produce a combination of microbubbles and nanobubbles with a larger proportion of nanobubbles with respect to the microbubbles. The nanobubbler 100 may be made of a high-density porous ceramic (without added carbon) with pores less than 1 μm, including many around 0.5 μm. The nanobubbler 100 may have a substantially rectangular shape whereby the liquid flow through the chamber 105 is laminar and parallel to the nanobubbles, emitting surface.
In accordance with embodiments of the present disclosure, any well-known technique for manufacturing, or otherwise creating, an absorbent material in which a liquid is absorbed, or otherwise infused, into the absorbent material may be utilized. As described herein, such a liquid will contain nanobubbles generated/infused therein.
In the process block 803, the absorbent material may then be packaged in accordance with any well-known technique for sale and/or transfer. For example, this could be water and/or gas impermeable materials in the shape of booties, socks, bags, sacks, or any suitably-shaped container, as shown in
In accordance with certain embodiments of the present disclosure, by combining hydrogels and gas nanobubbles one can create a dressing, film, mask, or gel that contains hydrogels absorbed/infused with gas nanobubbled water (e.g., see
Nanocomposites of hydrogel and nanobubbles can be produced (e.g., see Vladimir M Gun′ko et al., previously cited) in which changing internal or external (e.g., environmental) conditions, such as temperature, hydration, pH, ionic strength, salinity, pressure, etc., can cause such nanocomposites to exhibit a complex hierarchy of dynamic processes (e.g., hydrophilic, hydrophobic) that can be very fast and local conformational rearrangements. As a whole, the behavior of bounded and non-bounded water molecules in the micro-pores and polymers at the interfaces may depend on many factors such as topology, porosity, surface chemistry, etc., such that many structures with different water bonding qualities and configurations can be obtained.
A number of products exist for wound dressings that are infused with hydrogels. For example, the commercially available McKesson Hydrogel Impregnated Dressing is a primary dressing for wounds with light or no exudate that add or maintain moisture. The dressing helps maintain a moist wound healing environment to assist in autolytic debridement. Additionally, embodiments of the present disclosure may be incorporated with commercially available Hydrofiber technology or wound dressings.
In the case of peripheral neuropathy, special dressings can be made that are applied directly to the skin areas affected by the peripheral neuropathy and may be more comfortable and effective. Similar embodiments could be used in other applications such as cosmetics, skin treatment, gas infusion through the skin, etc.
Other applications related to hydrophilic materials that are very strong water absorbents (for example, hydrogels) are discussed in George Paleos, “What are Hydrogels?”, Pittsburgh Plastics Manufacturing Inc., 2012, 4 pages, and Enas M Ahmed, “Hydrogel: Preparation, characterization, and applications: A review,” Journal of Advanced Research, Volume 6, Issue 2, pp 105-121, Jul. 18, 2013, which are both incorporated by reference herein. There are many types of water absorbent materials and molecules (F. Dehghani et al., “Engineering porous scaffolds using gas-based techniques,” Current Opinion in Biotechnology, 22, pp. 661-666, May 3, 2011, which is incorporated by reference herein), and all of these materials can be produced as described herein to absorb water with nanobubbled gas or gases for many medical, agricultural, industrial, and hygienic materials.
The applications of water absorbent materials infused with nanobubbled gas or gases in water or other liquids are numerous: for example, cosmetics, hygienic products, wound care products, diapers, water-absorbent socks, and so on.
In addition to the foregoing disclosure, it should be noted that the human skin acts as a protective barrier to keep noxious substances out of the body and prevent excessive loss of water from the internal organs. Strategies have been developed to deliver drugs to the skin and surpass the skin's barrier properties. Consequently, there are many applications related to transdermal and topical drug delivery (e.g., see D. I. J Morrow et al., “Innovative Strategies for Enhancing Topical and Transdermal Drug Delivery,” The Open Drug Delivery Journal, 2007, vol. 1, pp. 36-59, which is incorporated by reference herein).
Based on the examples previously disclosed herein, cutaneous external applications of gases (such as oxygen, carbon dioxide, ozone, etc.) may have very positive effects on the health of human beings in the same way as transdermal drug delivery. A critical factor in drug delivery, for example, is the permeability through the skin (e.g., see R. J. Scheuplein, “Permeability of the Skin: A Review of Major Concepts and Some New Developments,” The Journal of Investigative Dermatology, vol. 67, issue 5, part 2, pp. 619-681, November 1976, which is incorporated by reference herein), and lately, penetration enhances were developed in particular for drug delivery systems.
In accordance with embodiments of the present disclosure, methods and devices utilizing a cutaneous external application of gases may implement skin penetration enhancer materials (also referred to herein as skin penetration agents) for the specific gases utilized such that an improved transdermal delivery can be achieved. Such skin penetration enhancers may be combined with the absorbent material that contains a gas nanobubbled liquid. For example, in the process of
As previously noted, human skin has the unique property of functioning as a physiochemical barrier; however, especially small molecules can surpass this barrier by being able to pass through the corneal layer, which is considered to form the main deterrent. In the publication J. D. Bos et al., “The 500 Dalton rule for the skin penetration of chemical compounds and drugs,” Exp. Dermatol., vol. 9, pp. 165-169, July 2000, which is incorporated by reference herein, it was asserted that the molecular weight of a compound must be under 500 Dalton to allow skin absorption. Larger molecules cannot pass the corneal layer. As a result, the most commonly used pharmacological agents applied in topical dermatological therapy drug delivery systems are under 500 Dalton (the 500 Dalton rule). For example, nanobubbles of oxygen and carbon dioxide easily fulfill this rule (oxygen having 32 Dalton and CO2 having 44 Dalton).
As previously disclosed, gas nanobubbles can be supplied externally to the skin in a number of ways, such as when they are contained in liquids, gels, ointments, creams, etc. In accordance with certain embodiments of the present disclosure, their effectivity may be improved with implementation of a skin penetration enhancement material, be it physical or chemical (e.g., see H. Trommer et al., “Overcoming the Stratum Corneum: The Modulation of Skin Penetration,” Skin Pharmacol. Physiol., vol. 19, pp. 106-121, May 9, 2006, which is incorporated by reference herein). The main lipids in the stratum corneum are ceramides such as fatty acids and cholesterol. Gas nanobubbles supplied to the human skin, as stated above, can have an important function if, in addition to their small sizes on the order of magnitude smaller than that of the skin pores, they are embedded in formulations that also contain a skin penetration enhancer material.
The nanobubbles permeation options include sweat ducts and hair follicles, which can function as diffusion shunts with relatively easy pathways to the stratum corneum. However, other options for nanobubbles permeation are through the transepidermal route and the route via pores. The transepidermal route can be divided into the transcellular and intercellular route, whereby the more direct route is the transcellular, but the more common route for nanobubbles to penetrate the skin is the intercellular route (e.g., see J. Hadgraft, “Skin deep,” Int. J. Pharm. Investig., vol. 1, issue 1, pp. 291-299, April, 15, 2004, which is incorporated by reference herein).
There are many substances that can improve the nanobubbles gas permeation, for example dimethylsuphoxide, pyrolidones, etc. (e.g., see J. Hadgraft et al., “Transdermal Drug Delivery: Developmental Issues and Research Initiatives,” Marcel Dekker, 1989, which is incorporated by reference herein), but at least some of the properties of a penetration enhancer are that it should be non-toxic, non-irritant, and non-allergenic; it should not illicit any pharmacological activity within the body; it should be compatible and stable with the other components in the formulation, such as the vehicle for transporting the nanobubbles; it should not enhance the loss of substances from the body; the skin barrier integrity should recover rapidly; it should not be expensive; and it should be acceptable in terms of odor, color, and texture.
For example, hydration fatty acids fulfill the properties above (as long they are not used in concentrations that may irritate the skin). Fatty acids are carboxylic acids often with long unbranched aliphatic tails. Examples are lauric acid, linoleic acid, and oleic acid. Generally, unsaturated fatty acids possess a configuration that is more effective as a skin penetrator. In this configuration, a “kink” into the alkyl tail is introduced, and as a result, this configuration causes a greater disruption to the lipid layers. Furthermore, the length of the tail is also significant whereby C10 and C12 carbon chain lengths provide the greatest permeation enhancement (e.g., see B. J. Aungst et al., “Enhancement of naloxone penetration through human skin in vitro using fatty acids, fatty alcohols, and caffeine,” J. Pharmaceut, 1986; 33: pp. 255-34, which is incorporated by reference herein).
For example, oleic acid is a “kinked” fatty acid, and has a long C18 tail. It was proven by thermal analysis that the action of oleic acids disrupts the intercellular lipid packing, which was also proved using electron microscopy.
As a result, and as an example, a formulation that includes the gas nanobubbles absorbent material (e.g., a liquid, such as water, oil, saline, a film, a gel, a cream, a lotion, an aerosol, or an ointment), combined with hydration agents and oleic acids, can be a suitable formulation to optimize the nanobubble gas permeation through the stratum corneum. Other agents that can be very helpful to enhance the skin permeability are alcohols among the polyvalent alcohols; propylene glycol has co-solvent properties and may have a synergetic action in a mixture with oleic acids. These agents can be combined together, used individually, or in partial mixtures (e.g., see H. Trommer et al., previously referenced herein).
The skin can be considered to be a composite diffusion media corresponding to stratum corneum, epidermis, and a thin layer of dermis, each with its corresponding diffusion coefficient and thickness. This overlays the blood stream, which has a flow that can also affect the diffusional resistance (e.g., see R. J. Scheuplein, previously referenced herein).
Some of the gases available for creating nanobubbles in a vehicle can have a strong action against bacteria, viruses, and fungi, and can exercise significant antimicrobial activity. As previously disclosed, application of ozone nanobubbles has a therapeutic window; if the ozone nanobubbles are applied in a low concentration, they have little therapeutic effect, while higher concentrations can be toxic and irritating. In practice, the ozone nanobubbles may be applied together with oxygen nanobubbles reducing the respiratory exposure to ozone. Ozone has a relatively short lifetime, and when administered, must be produced at the point of use. In particular, ozone, due to its actions on wound pathogens, is very helpful when due to poor blood circulation and neuropathy, diabetic foot lesions result (e.g., see G. V. Sunnen, “Diabetic Wound Management: A Key Ingredient is Missing,” March 2007, 10 pages, which is incorporated by reference herein).
Within other embodiments of the present disclosure, administration of gas nanobubbles that include a contained medication (pharmacological agent can be performed (e.g., by incorporating them into capsules, a spray, ointments, gels, pills, lotions, etc.). Or, a pharmacological agent may be included in the liquid that also contains the absorbed gas nanobubbles. For example, in the process of
For example, administration of gas nanobubbles with a contained medication in gaseous form can be performed by incorporating them with the absorbent material into capsules/pills/tablets, which are then taken by mouth through the GI system so that there is an uptake through the kidney and/or liver to be absorbed into the blood stream. Other more rapid administration of such medication contained within gas nanobubbles, for example, can be by sublingual and buccal methods. Sublingual administration involves placing a drug, a pill, a capsule, etc. under the tongue to be absorbed into the blood through the tissue there. Buccal administration involves a drug, a pill, a capsule, etc. administered between the gums and cheek where it dissolves and is absorbed into the blood stream. Both methods may come in the form of capsules, tablets, films, sprays, lozenges, etc. Gas nanobubbles can also be supplied by these methods with therapeutic effects. For example, direct delivery of oxygen, CO2, and others into the blood stream. Other drug delivery methods can be adjusted to deliver gas nanobubbles including for example administration through the skin.
In accordance with embodiments of the present disclosure, a gas nanobubbled liquid may be produced in accordance with the process of
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which the presently disclosed subject matter belongs. Although any methods, devices, and materials similar or equivalent to those described herein can be used in the practice or testing of the presently disclosed subject matter, representative methods, devices, and materials are now described.
Following long-standing patent law convention, the terms “a” and “an” mean “one or more” when used in this application, including the claims. Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by the presently disclosed subject matter.
As used herein, the term “about,” when referring to a value or to an amount of mass, weight, time, volume, concentration or percentage is meant to encompass variations of in some embodiments ±20%, in some embodiments ±10%, in some embodiments ±5%, in some embodiments ±1%, in some embodiments ±0.5%, and in some embodiments ±0.1% from the specified amount, as such variations are appropriate to perform the disclosed method.
As used herein, the term “and/or” when used in the context of a listing of entities, refers to the entities being present singly or in combination. Thus, for example, the phrase “A, B, C, and/or D” includes A, B, C, and D individually, but also includes any and all combinations and subcombinations of A, B, C, and D. The use of “/” between words means “and/or.”
It will be understood that particular embodiments described herein are shown by way of illustration and not as limitations of the disclosure. The principal features of this disclosure can be employed in various embodiments without departing from the scope of the disclosure.
All publications and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.
Any steps recited in any method or process claims may be executed in any order and are not limited to the order presented in the claims.
As used herein with respect to an identified property or circumstance, “substantially” refers to a degree of deviation that is sufficiently small so as to not measurably detract from the identified property or circumstance. The exact degree of deviation allowable may in some cases depend on the specific context.
The terms “or combinations thereof” and “and combinations thereof” as used herein refer to all permutations and combinations of the listed items preceding the term. For example, “A, B, C, or combinations thereof” is intended to include at least one of: A, B, C, AB, AC, BC, or ABC, and if order is important in a particular context, also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB. Continuing with this example, expressly included are combinations that contain repeats of one or more item or term, such as BB, AAA, MB, BBC, AAABCCCC, CBBAAA, CABABB, and so forth. The skilled artisan will understand that typically there is no limit on the number of items or terms in any combination, unless otherwise apparent from the context.
The use of the term “or” is used to mean “and/or” unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and “and/or.”
This application claims priority to U.S. provisional patent application Ser. No. 62/662,832. This application incorporates by reference U.S. provisional patent applications Ser. Nos. 62/437,920, 62/490,800, 62/662,832, and 62/551,356, and U.S. patent application Ser. No. 15/850,362.
| Number | Date | Country | |
|---|---|---|---|
| 62662832 | Apr 2018 | US |
