Patent Application
20170209409
Generally speaking, formulations and devices for metered dose inhalers have historically been optimized and or improved for the ability to deliver a maximal amount of a formulation with specific characteristics.
The present application relates to metered dose inhaler related products, formulations, and methods of manufacturing.
In some embodiments, a formulation for metered dose inhalation is provided. The formulation can comprise an amount of at least one cannabinoid, an amount of a propellant suitable for metered dose inhalation application to a human subject, a polar solvent miscible with the propellant; the cannabinoid(s), and an amount of a wax and/or terpene.
In some embodiments, a formulation for metered dose inhalation is provided. The formulation can comprise an amount of an activated cannabinoid, wherein the activated cannabinoid comprises at least Tetrahydrocannabinol (THC) and Cannabidiol (CBD), and an amount of ethanol sufficient to serve as a solvent, an amount of a propellant, wherein the propellant is at least one of 1,1,1,2-Tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-Heptafluoropropane (HFA 227). The formulation can further comprise at least one of: a) an amount of a wax, wherein the amount of wax is at least sufficient to provide a higher level of comfort to a subject receiving a dose from a metered dose inhaler that is administering the formulation, and wherein the wax comprises a wax that naturally occurs in a cannabis plant, or b) an amount of a natural terpene, wherein the natural terpene is one that is present in a cannabis plant. The amount of the natural terpene is at least sufficient to provide a higher level of comfort to a subject receiving a dose from a metered dose inhaler that is administering the formulation.
In some embodiments, the formulation can comprise an amount of an activated cannabinoid, wherein the activated cannabinoid comprises at least Tetrahydrocannabinol (THC), tetrahydrocannabivarin (THCV), and Cannabidiol (CBD), and an amount of ethanol sufficient to serve as a solvent, an amount of a propellant, wherein the propellant is at least one of 1,1,1,2-Tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-Heptafluoropropane (HFA 227). The formulation can further comprise at least one of: a) an amount of a wax, wherein the amount of wax is at least sufficient to provide a higher level of comfort to a subject receiving a dose from a metered dose inhaler that is administering the formulation, and wherein the wax comprises a wax that naturally occurs in a cannabis plant, or b) an amount of a natural terpene, wherein the natural terpene is one that is present in a cannabis plant. The amount of the natural terpene is at least sufficient to provide a higher level of comfort to a subject receiving a dose from a metered dose inhaler that is administering the formulation.
In some embodiments, a method for preparing a formulation is provided. The method can comprise providing a source of a cannabinoid, obtaining an active ingredient from the source by carbon dioxide extraction, combining the active ingredient with a polar solvent to obtain a mixture, heating the mixture to solubilize into a solvent, cooling the solvent to thereby obtain a gel or viscous liquid, and solubilizing the gel or viscous liquid with HFA.
In some embodiments, a method for preparing a formulation is provided. The method can comprise providing a source of a cannabinoid, obtaining an active ingredient from the source by butane and/or organic solvent extraction, combining the active ingredient with a polar solvent to obtain a mixture, heating the mixture to solubilize into a solvent, cooling the solvent to thereby obtain a gel or viscous liquid, and solubilizing the gel or viscous liquid with HFA.
In some embodiments, a metered dose inhaler canister is provided. The canister can comprise a formulation according to any of those provided herein, and a coating over an interior surface of the canister, wherein the coating comprises at least one of anodized aluminum or a fluoropolymer.
In some embodiments, a metered dose inhaler is provided. The MDI can comprise a formulation as provided herein and an actuator drug/propellant pathway. The actuator can comprise an actuator orifice cylinder configured to provide an appropriate mean mass aerosol diameter (MMAD) particulate size distribution (between 0.5 and 5.0 micron, in some embodiments this can be as determined by the guidance set forth in the United States Pharmacopeia in chapter <601>) of the formulation, and of sufficient surface area and heat sink properties to provide for single and rapid dispensing cycles of the formulation (including propellant) to maintain dose content uniformity, particle size distribution, and the comfort of the patient. The actuator orifice cylinder is configured by at least one of: a) an appropriate surface area, internal geometry jet length or shape, surface texture, or material of the actuator orifice cylinder; or b) an increased mass of the external geometry of the actuator orifice cylinder to act as a heat sink by at least 5% additional mass.
In some embodiments, an amount of an extract from a cannabinoid containing plant is provided. The extract can comprise a) an activated cannabinoid, wherein the activated cannabinoid comprises at least Tetrahydrocannabinol (THC) and Cannabidiol (CBD), and b) at least one of: i) an amount of a wax, wherein the amount of wax is at least sufficient to provide a higher level of comfort to a subject receiving a dose from a metered dose inhaler that is administering the formulation, and wherein the wax comprises a wax that naturally occurs in a cannabis plant, or ii) an amount of a natural terpene, wherein the natural terpene is one that is present in a cannabis plant, and wherein the amount of the natural terpene is at least sufficient to provide a higher level of comfort to a subject receiving a dose from a metered dose inhaler that is administering the formulation. The extract can further include an amount of a polar solvent, and an amount of a HFA propellant. The propellant is at least one of 1,1,1,2-Tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-Heptafluoropropane (HFA 227). The extract:polar solvent:HFA propellent is in a ratio ranging from 0.5:0.5:99 to 30:30:40.
In some embodiments, an amount of an extract from a cannabinoid containing plant is provided. The extract can comprise a) an activated cannabinoid, wherein the activated cannabinoid comprises at least Tetrahydrocannabinol (THC), tetrahydrocannabivarin (THCV), and Cannabidiol (CBD), and b) at least one of: i) an amount of a wax, wherein the amount of wax is at least sufficient to provide a higher level of comfort to a subject receiving a dose from a metered dose inhaler that is administering the formulation, and wherein the wax comprises a wax that naturally occurs in a cannabis plant, or ii) an amount of a natural terpene, wherein the natural terpene is one that is present in a cannabis plant, and wherein the amount of the natural terpene is at least sufficient to provide a higher level of comfort to a subject receiving a dose from a metered dose inhaler that is administering the formulation. The extract can further include an amount of a polar solvent, and an amount of a HFA propellant. The propellant is at least one of 1,1,1,2-Tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-Heptafluoropropane (HFA 227). The extract:polar solvent:HFA propellent is in a ratio ranging from 0.5:0.5:99 to 30:30:40.
Provided herein are devices and formulations that provide or result in a more comfortable subject experience when a metered dose inhaler is used to administer a formulation. In some embodiments, the formulation and/or device and/or method delivers more than 1 mg of extract per actuation with the ratio of extract to ethanol greater than 15% for superior subject comfort.
In some embodiments, a formulation for metered dose inhalation is provided. The formulation can comprise an amount of at least one cannabinoid, an amount of a propellant suitable for metered dose inhalation application to a human subject, a polar solvent miscible with the propellant, a cannabinoid(s), and an amount of a wax. It has been discovered that the addition of a wax and/or a terpene to the formulation can result in a greater level of comfort for a subject receiving the formulation.
In some embodiments, the wax can be any type of wax. In some embodiments, the wax is a natural wax. The wax can comprise a plant based natural wax. The plant based natural wax can comprise a cannabis wax. In some embodiments, the plant based natural wax can comprise a non-cannabis wax. In some embodiments, the cannabis wax can include one or more of a straight chain paraffins such as nonacosane (C29), heptacosane (C27) or hentriacontane (C31), or branched chained parafins such as isononacosane, isoheptacosane or isohentriacontane.
In some embodiments, the formulation can further (or instead) comprise at least one terpene. In some embodiments, any type of terpene can be employed. In some embodiments, the amount of the terpene is at least 3 mcg/mL and less than 100 mg/mL. In some embodiments, the terpene is selected from the group of at least one of: Pinene, Limonene, Myrcene, Phellandrene, Carene, Terpinene, Linalool, Fenchol, Borneol, Terpineol, Geraniol, Humulene, Caryophyllene, Bisabolol or Phytol. In some embodiments, the terpene is selected from the group of at least one of: Pinene, Limonene, Myrcene, Phellandrene, Carene, Terpinene, Linalool, Fenchol, Borneol, Terpineol, Geraniol, Humulene, Caryophyllene, Caryophyllene Oxide, Bisabolol, Citronellol, Menthol, Ocimene, Camphene or Phytol.
In some embodiments, the amount of the at least one cannabinoid is sufficient for the desired purpose (for example achieving great subject comfort). In some embodiments, the amount of the at least one cannabinoid is at least 0.2 mg/mL and less than 350 mg/mL, for example 0.5 to 300 mg/mL, 1 to 200 mg/mL, 10 to 100, or 30 to 60 mg/mL.
In some embodiments, the cannabinoid employed can be 100% activated. In some embodiments, less than 100% of the cannabinoid present is activated, for example, less than 100%, 99, 98, 95, 90, 80, 70, 50, 40, 30, 20, 10, or 5% or less of the cannabinoid present can be activated. In some embodiments, at least 50% of the cannabinoid is activated, for example, at least 50, 60, 70, 80, 90, 95, 96, 97, 98, or 99 percent of the cannabinoid is activated. In some embodiments, none of the cannabinoid is activated. In some embodiments the at least one cannabinoid comprises at least one activated cannabinoid, such as 2, or more different cannabinoids are activated and/or at least partially activated.
The term “cannabinoid” as used herein denotes a class of diverse chemical compounds that act on cannabinoid receptors on cells that repress neurotransmitter release in the brain. The class includes endocannabinoids, phytocannabinoids, and synthetic cannabinoids. Examples include cannabis-derived cannabindoids, delta-nine-tetrahydrocannabinol (THC) and cannabidiol (CBD), Cannabigerol-type, Cannabichromene-type, Tetrahydrocannabinol- and Cannabinol-type, Cannabielsoin-type, iso-Tetrahydrocannabinol-type, Cannabicyclol-type, and Cannabicitran-type. In some embodiments, cannabinoid includes: CBG (Cannabigerol), CBC (Cannabichromene), CBL (Cannabicyclol), CBV (Cannabivarin), THCV (Tetrahydrocannabivarin), CBDV (Cannabidivarin), CBCV (Cannabichromevarin), CBGV (Cannabigerovarin), and/or CBGM (Cannabigerol Monomethyl Ether).
In some embodiments, the at least one cannabinoid can be at least one of tetrahydrocannabinol (THC), cannabidiol (CBD), and tetrahydrocannabivarin (THCV). In some embodiments, the at least one cannabinoid comprises both THC and CBD.
In some embodiments, the formulation further comprises at least one terpene. In some embodiments, in addition to the at least one terpene noted above, the formulation comprises at least one activated cannabinoid. In some embodiments, the at least one terpene comprises at least caryophyllene. In some embodiments, the at least one terpene is present in an amount of at least about 3 mcg/mL, for example, at least 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50 or more mcg/mL.
In some embodiments, the amount of wax present in the formulation is greater than 10 micrograms/mL and less than 50 mg/mL. In some embodiments, the wax is present in at least 0.03 mg/mL in the final formulation.
In some embodiments, the natural carbon dioxide cannabis extract has <10 ppm of residual solvent. In some embodiments, the solvent comprises an amount of ethanol, methanol, butane, acetone, propane, hexane, heptane, pentane, chloroform, octane, benzene, toluene, methyl tert-butyl ether, ethyl tert-butyl ether, methylene chloride chloromethane and/or isopropanol. In some embodiments, the ethanol is present in an amount of up to 30% w/w, for example, up to 5, 10, 15, 20, 25, or 30% w/w.
A variety of propellants can be employed in various embodiments. In some embodiments, the propellant comprises at least a HFA. In some embodiments, the HFA is at least one of 1,1,1,2-Tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-Heptafluoropropane (HFA 227). In other embodiments, alternative solvents can be employed.
In some embodiments, the formulation further comprises a surfactant. In some embodiments, the surfactant is present in an amount adequate for improving solubility. In some embodiments, the surfactant is present in an amount of up to 10% w/w. In some embodiments, the surfactant comprises oleic acid. In some embodiments, additional or alternative surfactants can be applied if confirmed for the uses as provided herein.
In some embodiments, a formulation for a metered dose inhalation is provided. The formulation can comprise an amount of an activated cannabinoid, wherein the activated cannabinoid comprises at least Tetrahydrocannabinol (THC) and Cannabidiol (CBD), an amount of ethanol sufficient to serve as a solvent, and an amount of a propellant, wherein the propellant is at least one of 1,1,1,2-Tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-Heptafluoropropane (HFA 227). The formulation can also include at least one of: a) an amount of a wax, wherein the amount of wax is at least sufficient to provide a higher level of comfort to a subject receiving a dose from a metered dose inhaler that is administering the formulation, and wherein the wax comprises a wax that naturally occurs in a cannabis plant, or b) an amount of a natural terpene. The natural terpene is one that is present in a cannabis plant, and wherein the amount of the natural terpene is at least sufficient to provide a higher level of comfort to a subject receiving a dose from a metered dose inhaler that is administering the formulation. In some embodiments, the wax is one that is natural to a cannabis plant, but is not removed fully during the processing of the cannabis plant.
In some embodiments, a formulation for metered dose inhalation is provided. In some embodiments, the formulation can comprise 1) an amount of an extract from a cannabinoid containing plant. The extract can comprise an activated cannabinoid, wherein the activated cannabinoid comprises at least Tetrahydrocannabinol (THC) and Cannabidiol (CBD). The formulation can further include at least one of: i) an amount of a wax, wherein the amount of wax is at least sufficient to provide a higher level of comfort to a subject receiving a dose from a metered dose inhaler that is administering the formulation, and wherein the wax comprises a wax that naturally occurs in a cannabis plant, or ii) an amount of a natural terpene. The natural terpene can be one that is present in a cannabis plant. The amount of the natural terpene and/or the natural wax is at least sufficient to provide a higher level of comfort to a subject receiving a dose from a metered dose inhaler that is administering the formulation. The formulation can further include 2) an amount of a polar solvent; and 3) an amount of a HFA propellant, wherein the propellant is at least one of 1,1,1,2-Tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-Heptafluoropropane (HFA 227). In some embodiments, the extract:polar solvent:HFA propellent is in a ratio ranging from about 0.5:0.5:99 to about 30:30:40. In some embodiments, the formulation further includes a surfactant at up to 10% w/w.
In some embodiments, the formulation further comprises Cannabidiol (CBD) and further comprises nicotine. In some embodiments, the formulation comprises nicotine.
In some embodiments, any one of the formulations provided herein can be configured for nasal delivery. In some embodiments, a satisfactory amount of the desired ingredients is effectively administered through the nose by such a formulation.
In some embodiments, a metered dose inhaler 80 is provided for the delivery of any of the formulations provided herein, or for the delivery of other metered dose inhaler formulations. The MDI 80 can include any standard component for a MDI. In some embodiments, it will include a chamber 50, configured for receiving the canister that contains the formulation, an actuator 70, which can include a valve mating boss 75 for the canister, a channel 12 which allows the formulation from the canister to pass through it, through the jet 11, out an orifice 21 of the actuator (or actuator orifice), through the opening for the mouth piece 30, to pass out of the mouth piece itself (not shown). The outer wall 40 of the MDI can form the mouthpiece and the chamber 50.
In some embodiments, altering the jet length 10 and/or the actuator orifice diameter 20 can result in a more desirable experience for the user for receiving the formulation. In some embodiments, any of the formulations provided herein can be applied in the device of
In some embodiments, the metered dose inhaler comprises a formulation as provided herein and an actuator drug/propellant pathway, that includes an actuator orifice 21 configured to provide an appropriate mean mass aerosol diameter (MMAD) particulate size distribution (between 0.5 and 5.0 micron) of the cannabis formulation, and of sufficient surface area and heat sink properties to provide for single and rapid dispensing cycles of the formulation (including propellant) to maintain dose content uniformity, particle size distribution, and the comfort of the subject. In some embodiments, the actuator orifice 21 is configured by at least one of an appropriate surface area (Pi×Jet Length×Orifice diameter), internal geometry “jet length,” shape, surface texture, or material, of the actuator orifice.
In some embodiments, the configuration denotes an increased mass of the external geometry of the actuator structure to act as a heat sink. In some embodiments, this is at least 5% additional mass beyond a traditional device. In some embodiments, this is at least 5, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000% more mass. Some embodiments of the areas and shapes of the additional mass are shown as item 22a-22c in
In some embodiments, the checkerboard pattern on
In some embodiments, the increased surface area is achieved by increasing the jet length 10 of the cylinder or a shape of the actuator orifice outlet 21.
In some embodiments, the increased surface area is achieved by increasing the texture of the cylinder area by using cuts, grooves, ridges, or by using a mold etched texture such as Mold-Tech MT-11200 of the path through which the formulation passes (from the valve mating boss 75 through to the orifice 21. Thus, in some embodiments, the channel 12 and/or jet 11 can include any additional structural feature so as to increase the surface area of the flow path of the formulation. In some embodiments, the flow path (the path between the valve mating boss and the orifice diameter, is not smooth. In some embodiments, the flow path from the orifice to the exit in the mouth piece is also configured so as to provide an increase in surface area interaction of the formulation with the device. As such, the increased surface area achieved by increasing the texture by using cuts, grooves, ridges, or by using a mold etched texture can also be applied to the interior surface of the outer walls of the MDI 40, in the area of the opening for the mouth piece 30.
In some embodiments, the orifice diameter 20 of the orifice 21 is about 0.15 mm to 0.65 mm, for example 0.2, 0.3, 0.4, 0.5. 0.6, or 0.65 mm, including any range defined between any two of the previous values. In some embodiments, the orifice diameter is greater than 0.3 mm. In some embodiments, the orifice diameter is between 0.3 and 0.7 mm, for example, 0.31, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, or 0.7, including any range defined between any two of the preceding values.
In some embodiments, the actuator jet length has a length of 0.15 to 2.50 mm, for example, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, or 2.5 mm, including any range defined between any two of the previous values.
In some embodiments, a MDI valve is located between the MDI canister and the valve mating boss 75, wherein the MDI valve is configured to dispense between 25 and 125 microliters of formulation per actuation, and wherein the MDI valve is made of at least one of polyoxymethalate (POM), polybutylterephalate (PBT), ABS, acrylic, polycarbonate, ethylene propylene diene monomer (EPDM), or silicon. In some embodiments, a MDI valve is located between the MDI canister and the valve mating boss 75, wherein the MDI valve is configured to dispense between 20 and 125 microliters of formulation per actuation, and wherein the MDI valve is made of at least one of polyoxymethalate (POM), polybutylterephalate (PBT), ABS, acrylic, polycarbonate, ethylene propylene diene monomer (EPDM), or silicon.
In some embodiments, a MDI canister is provided that can include any of the formulations provided herein and a coating over an interior surface of the canister. The coating can be one to increase the level of comfort to a subject to which the formulation is administered. In some embodiments, the coating can alter the taste and/or prevent the taste of the formulation from being altered from storage/exposure to the interior of the canister. In some embodiments, the coating comprises at least one of anodized aluminum or a fluoropolymer. In some embodiments, the fluoropolymer has either been sprayed on the interior surface or deposited via plasma deposition. In some embodiments, the canister further comprises a MDI valve that is configured to dispense between 25 and 125 microliters of formulation per actuation. In some embodiments, the MDI valve comprises at least one of polyoxymethalate (POM), polybutylterephalate (PBT), ABS, acrylic, polycarbonate, ethylene propylene diene monomer (EPDM), and silicon.
By increased “comfort” what is denoted is that the subject feels less discomfort from the inhalation of the formulation, in comparison to when the aspect is absent. In some embodiments, this indicates that the level of comfort is closer to the sensation of normal breathing. In some embodiments, this indicates that the inhaled formulation feels warmer or is less cold, bright or sharp when inhaled. In some embodiments, comfort will be increased due to a less cold spray. In some embodiments, this will be more evident with more rapid dosing as subsequent doses will not get as progressively colder as an unmodified system.
In some embodiments, the extract containing the cannabinoid can be decarboxylated by immersion in an oil bath. In some embodiments, this occurs at above 100 degrees centigrade for an adequate amount of time. In some embodiments, this occurs for 155 degrees centigrade for 80 minutes.
In some embodiments, the extract can then be mixed an organic solvent. In some embodiments, this can be alcohol. In some embodiments, it is 200 Proof USP grade ethanol. In some embodiments, this can be at a ratio of 37:63 extract to ethanol. Dissolution of the extract can be achieved by agitation and heating. In some embodiments, this can be heated to as much as 78 degrees Centigrade (boiling point of ethanol) to fully dissolve the extract. The sample is then cooled. In some embodiments, it is cooled to 5 degrees centigrade to form a gel phase. In some embodiments, this can be employed in a suitable MDI canister. The canister is crimped with a suitable valve and charged with 134a (or 227ea) by over pressure through the valvestem. The canister is agitated by hand for no less than 10 seconds.
In some embodiments, a method for preparing a formulation is provided. The method can include providing a source of a cannabinoid. The method can further include obtaining an active ingredient from the source by carbon dioxide extraction. The method can further include combining the active ingredient with a polar solvent to obtain a mixture. The method can further include heating the mixture to solubilize it into a solvent. The method can further include cooling the solvent to thereby obtain a gel or viscous liquid and solubilizing the gel or viscous liquid with HFA.
In some embodiments, the formulation is prepared by preparing the extract in separate fractions. In some embodiments, heating comprises extracting at least one of THC or CBD via an oil bath.
An extract containing a cannabinoid is obtained by CO2 extraction. The extract containing the cannabinoid will then be decarboxylated by immersion in an oil bath for 155 degrees centigrade for 80 minutes. The extract will then be mixed with 200 Proof USP grade ethanol in a ratio of 37:63 extract to ethanol. Dissolution of the extract will be achieved by agitation and heating to as much as 78 degrees centigrade (boiling point of ethanol) to fully dissolve the extract.
Upon to cooling to 5 C a gel phase will be formed.
The gel phase from example 1 will be filled into a suitable MDI canister that has an anodized interior coating over it. The canister will then be crimped with a suitable valve and charged with 134a (or 227ea) by over pressure through the valvestem. The canister will then be agitated by hand for no less than 10 seconds.
The canister from Example 2 is inserted into the MDI of
An extract containing a cannabinoid is obtained by CO2 extraction. The extract containing the cannabinoid will then be decarboxylated by immersion in an oil bath for 155 degrees centigrade for 80 minutes. The extract will then be mixed with 200 Proof USP grade ethanol in a mass ratio of 50:50 extract to ethanol. Dissolution of the extract will be achieved by agitation and heating to as much as 78 degrees centigrade (boiling point of ethanol) to fully dissolve the extract.
Upon to cooling to 5 C a gel phase will be formed.
Although the present application has been described in detail above, it will be understood by one of ordinary skill in the art that various modifications can be made without departing from the spirit of the invention. Accordingly, the present application is limited only by the following claims. All cited patents, patent applications and publications referred to in this application are herein incorporated by reference in their entirety. In this application, the use of the singular can include the plural unless specifically stated otherwise or unless, as will be understood by one of skill in the art in light of the present disclosure, the singular is the only functional embodiment. Thus, for example, “a” can mean more than one, and “one embodiment” can mean that the description applies to multiple embodiments. Additionally, in this application, “and/or” denotes that both the inclusive meaning of “and” and, alternatively, the exclusive meaning of “or” applies to the list. Thus, the listing should be read to include all possible combinations of the items of the list and to also include each item, exclusively, from the other items. The addition of this term is not meant to denote any particular meaning to the use of the terms “and” or “or” alone. The meaning of such terms will be evident to one of skill in the art upon reading the particular disclosure. All references cited herein, including patents, patent applications, papers, text books, and the like, and the references cited therein, to the extent that they are not already, are hereby incorporated by reference in their entirety. In the event that one or more of the incorporated literature and similar materials differs from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or the like, this application controls. The foregoing description and Examples detail certain preferred embodiments of the invention and describes the best mode contemplated by the inventors. It will be appreciated, however, that no matter how detailed the foregoing may appear in text, the invention may be practiced in many ways and the invention should be construed in accordance with the appended claims and any equivalents thereof. As will be appreciated by one of skill in the art, while the present specification may simply use one of the terms “comprise,” “consists,” or “consists essentially of,” this is simply a shorthand way of describing all three possibilities, unless otherwise specified or unless the term is used in the claim (in which case the terms will have their normally accepted meanings under claim interpretation). Thus, as the terms are used above, they designate all three possibilities, unless explicitly noted otherwise.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2015/036033 | 6/16/2015 | WO | 00 |
| Number | Date | Country | |
|---|---|---|---|
| 62017762 | Jun 2014 | US | |
| 62173266 | Jun 2015 | US |
