Patent Grant
11998681
A portion of the disclosure of this patent document contains material that is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or the patent disclosure as it appears in the Patent and Trademark Office patent file or records, but otherwise reserves all copyright rights whatsoever.
The respiratory tract may be an available pathway for the rapid contacting of pharmaceutical compounds or pharmaceutical compositions with the blood stream of a subject (e.g., a patient). Drugs may be delivered to a subject via vapors or aerosols comprising pharmaceutical compounds or pharmaceutical compositions. The drugs delivered to respiratory tissues may include drugs with specific respiratory effects, or drugs that create medical responses in other tissues within a subject.
Recognized herein is the need for an effective method of drug delivery via the respiratory tract utilizing a device that advantageously generates vapors or aerosols containing pharmaceutical compounds or pharmaceutical compositions. The drug delivery device of the present disclosure may be especially effective in situations where rapid pharmacokinetics are needed or gastrointestinal (GI) tract uptake issues need to be avoided. Drug delivery via the respiratory tract using provided devices may also avoid the cost and complexity of intravenous drug delivery when possible.
Some drug delivery devices may advantageously deliver particles comprising a pharmaceutical compound or pharmaceutical composition deep into the respiratory tract with a small enough particle size to permit rapid pharmacokinetics (e.g., aerosol size optimized to be in the 1-3 micrometer range Mass Median Aerodynamic Diameter (MMAD) range). A respiratory drug delivery device may also accurately meter dosages of delivered pharmaceutical compounds and minimize the degradation or decomposition of the pharmaceutical compounds.
In an aspect, the present disclosure provides a vaporizer device comprising: a reservoir configured to contain a medicament; a dispenser having an outer surface, wherein the outer surface comprises a regular array of apertures arranged thereabout, and wherein the dispenser is configured to receive the medicament pumped from the reservoir; and a heater, wherein the heater at least partially surrounds at least a portion of the dispenser, wherein the heater is configured to heat the medicament received by the dispenser.
In some embodiments, the regular array of apertures comprises a radial array of apertures. In some embodiments, the apertures in the regular array of apertures are congruent. In some embodiments, the dispenser is formed of a thermally stable material comprising metal, glass, ceramic, plastic, or any combination thereof. In some embodiments, the dispenser comprises: a first dispenser portion having a surface comprising an array of first slots; and a second dispenser portion having a surface comprising an array of second slots. In some embodiments, the array of first slots and the array of second slots interdigitate. In some embodiments, the first dispenser and the second dispenser form an open cavity therebetween. In some embodiments, the reservoir comprises a seal configured to contain the medicament within the reservoir. In some embodiments, the heater comprises a helical heater. In some embodiments, the helical heater comprises two or more helical coils. In some embodiments, the helical heater has: a diameter of about 0.006 inches to about 0.008 inches; a length of about 25 inches to about 75 inches; a working voltage of about 3 volts to about 9 volts; a working power of about 5 watts to about 50 watts; two or more helical revolutions; or any combination thereof. In some embodiments, the heater is configured to vaporize the medicament received by the dispenser. In some embodiments, the vaporizer device further comprises a housing comprising a first inlet and an outlet, wherein the housing is configured to direct a fluid from the inlet, through the heater, and to the outlet. In some embodiments, the housing further comprises a second inlet configured to isolate at most a portion of the fluid from the heater. In some embodiments, the first inlet and the second inlet, individually or in combination, have a cross sectional area of at least about 50 mm2. In some embodiments, the vapor device further comprises a valve coupled to an outlet of the reservoir. In some embodiments, at least a portion of the valve is surrounded by the heater, the dispenser, or both. In some embodiments, the valve comprises a pressure release valve in a direction from the reservoir to the outlet. In some embodiments, the vaporizer device further comprises a preheater configured to heat the medicament in the reservoir, the medicament in the dispenser, or both. In some embodiments, at least a portion of the preheater is at least partially surrounded by the dispenser. In some embodiments, the vaporizer device is capable of emitting at least about 5 mg/second of the medicament. In some embodiments, the vaporizer device is capable of forming an aerosol particle of the medicament having a size of greater than about 1 μm. In some embodiments, the vaporizer device does not comprise a wick. In some embodiments, the vaporizer device further comprises an actuator configured to pump the medicament from the reservoir
In another aspect, the present disclosure provides a vaporizer assembly comprising: the vaporizer device herein and a vaporizing base device comprising an actuator configured to pump the medicament from the reservoir. In some embodiments, the actuator comprises a motor, a spring, a compressed fluid container, a chemical expander, or any combination thereof.
In another aspect, the present disclosure provides an aerosolizing device for substance delivery to a user. The device may comprise a rotational pump configured to receive a formulation from a source. The formulation may comprise a target substance that is designed to effect a physiological change in the user. The rotational pump can be further configured to transport the formulation from the source and deliver the formulation in a vapor form with aid of a vaporization element for inhalation by the user.
In some embodiments, the rotational pump may comprise at least one rotatable element configured to rotate about one or more axes. The rotational pump can be configured to transport the formulation via rotational movement of the at least one rotatable element. The formulation can be flown over a surface of the rotatable element as the formulation is being transported by the rotational pump.
In some embodiments, the rotational pump may comprise an actuator configured to drive the at least one rotatable element. The actuator may comprise a magnet and/or an electromagnet. The at least one rotatable element may comprise a blade or a vane.
In some embodiments, the vaporization element may comprise a heater. The heater may comprise a resistive heating element or an induction heating element. The rotational pump can be configured to transport the formulation to the vaporization element. The vaporization element can be configured to cause the formulation to be transformed from a liquid state into the vapor form. In some embodiments, the formulation may be in a liquid state when held in the source. The formulation may be in a liquid state as it is being transported through the rotational pump.
In some embodiments, the rotational pump and the vaporization element may be provided as separate discrete components. The vaporization element may be operably coupled to the rotational pump. The vaporization element may be integrated with or on the rotational pump. The pump can be further configured to measure a viscosity of the formulation as the formulation is being transported by the pump.
In another aspect, the present disclosure provides an aerosolizing device for substance delivery to a user. The device may comprise a chamber configured to store a formulation. An internal volume of the chamber may be adjustable. The formulation may comprise a target substance that is designed to effect a physiological change in the user. The device may further comprise an actuator operably coupled to the chamber. The actuator can be configured to effect changes in the internal volume of the chamber so as to transport the formulation out of the chamber. The formulation may be delivered in a vapor form with aid of a vaporization element for inhalation by the user.
In some embodiments, the actuator may comprise a pump. The pump may be, for example, a peristaltic pump. In some embodiments, the actuator can be configured to generate a rotational motion to effect the changes in the internal volume of the chamber. In some embodiments, the actuator may comprise a plunger or piston. The actuator can be configured to generate a linear motion to effect the changes in the internal volume of the chamber.
In some embodiments, the chamber may comprise a hollow cavity for storing the formulation. The chamber may comprise a wall that is made of a flexible material. A wall of the chamber may be collapsible as the changes in the internal volume of the chamber are being affected.
In another aspect, the present disclosure provides an aerosolizing device for substance delivery to a user. The device may comprise a viscosity sensor provided in proximity to (1) a source configured to hold a formulation, wherein the formulation may comprise a target substance that is designed to effect a physiological change in the user, and/or (2) a vaporization element configured to transform the formulation to a vapor state, wherein the viscosity sensor may comprise at least one rotational element and is configured to measure a viscosity of the formulation.
In some embodiments, the device may further comprise a pump configured to transport the formulation to the vaporization element. The pump may be a rotational pump. The rotational pump can be further configured to function as the viscosity sensor. In some embodiments, the source may comprise a collapsible chamber configured to store the formulation.
In some embodiments, the device may further comprise a pump operably coupled to the chamber. The pump can be configured to effect changes in an internal volume of the chamber to transport the formulation out of the chamber. The pump can be further configured to function as the viscosity sensor. The viscosity sensor can be configured to measure the viscosity of the formulation based in part on a torque exerted on the at least one rotational element. The viscosity sensor can be configured to measure the viscosity of the formulation based in part on a response time when driving the at least one rotational element.
In some embodiments, the pump may comprise a stepped motor. The response time of the pump may be based at least in part on a measurement of a time interval that the stepped motor takes to move from one step to a next step. In some embodiments, the device may further comprise a heater configured to heat the formulation if the viscosity of the formulation is higher than a selected viscosity threshold.
In some embodiments, the device may further comprise a heater configured to modulate a temperature of the formulation to maintain the viscosity of the formulation within a selected viscosity range. The heater can be configured to modulate the temperature of the formulation substantially in real time as the formulation is being transported within the device. The heater can be configured to modulate the temperature of the formulation based at least in part on an ambient temperature in an environment in which the device is operated. The heater can be located on at least one of the pump and the source.
In some embodiments, the viscosity of the formulation is capable of being measured using the rotational pump, without using any other viscosity measurement or flowrate sensors. The viscosity of the formulation is capable of being measured using the pump, without using any other viscosity measurement or flowrate sensors.
In another aspect, the present disclosure provides an aerosolizing device for substance delivery to a user. The device may comprise: a distribution element provided adjacent to a heater. The heater can be configured to heat and transform a formulation into a vapor form. The formulation may comprise a target substance that is designed to effect a physiological change in the user. The distribution element can be configured to uniformly and consistently spread the formulation over the heater to promote the heating and transformation of the formulation into the vapor form.
In some embodiments, the distribution element may comprise an elastomeric material. The elastomeric material may be selected from the group consisting of silicone, polyisoprene, polyurethane, nitrile, natural rubber, styrene butadiene rubber, and any combination thereof. In some embodiments, the distribution element may comprise one or more channels. The formulation may be distributed over the heater along the one or more channels. The one or more channels may comprise at least one open-faced channel. In some embodiments, the distribution element may be flexible and can be configured to conform to different types and shapes of surfaces.
In some embodiments, the formulation can be uniformly and consistently spread over the heater, without being affected by an ambient environment in which the device is operated. The formulation can be uniformly and consistently spread over the heater, without being affected by a number of operations of the device and/or an age of the device. The formulation can be uniformly and consistently spread over the heater, without being affected by a viscosity of the formulation.
In some embodiments, the distribution element can be configured to be used with a plurality of formulations of different viscosities. The heating and transformation of the formulation into the vapor form can be improved using the distribution element compared to using a wick. Accordingly, the distribution element may not be subject to changes in wicking properties. In some embodiments, the distribution element does not envelope an interior surface or an outer surface of the heater.
In some embodiments, the source may comprise a collapsible reservoir or chamber.
In some embodiments, the target substance may be an active chemical or pharmaceutical ingredient. The active chemical or pharmaceutical ingredient may be selected from the group consisting of nicotine, tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), cannabielsoin (CBE), cannabicitran (CBT), and any combinations thereof.
The formulation may be a solution, suspension, or an emulsion. In some embodiments, the formulation may comprise a carrier for holding the target substance. The carrier may comprise ethanol, propylene glycol, vegetable glycerin, water, or any combination thereof.
In some embodiments, the formulation in the vapor form may be delivered to a dispenser. The dispenser is configured to be placed in proximity to a respiratory tract of the user. The dispenser may comprise a plurality of openings permitting the formulation in the vapor form to pass through.
In some embodiments, the device may further comprise a flow channel, and the heater may be located in the flow channel. A porous layer may be provided on a surface of the heater. The porous layer may comprise a metal mesh. The porous layer may comprise glass fiber, glass frit, or ceramic frit.
In some embodiments, the device can be configured to dispense the formulation in the vapor form at a rate ranging from about 0.001 μL to about 5 μL per pump cycle. The pump can be configured to operate at a cycle frequency of less than about 50 Hz. The pump can be configured to operate at a pump rate that is dependent based in part on a rate of inhalation of the user.
In some embodiments, the formulation may further comprise a compound that is selected from the group consisting of acebutolol, acetaminophen, alprazolam, amantadine, amitriptyline, apomorphine diacetate, apomorphine hydrochloride, atropine, azatadine, betahistine, brompheniramine, bumetanide, buprenorphine, bupropion hydrochloride, butalbital, butorphanol, carbinoxamine maleate, celecoxib, chlordiazepoxide, chlorpheniramine, chlorzoxazone, ciclesonide, citalopram, clomipramine, clonazepam, clozapine, codeine, cyclobenzaprine, cyproheptadine, dapsone, diazepam, diclofenac ethyl ester, diflunisal, disopyramide, doxepin, estradiol, ephedrine, estazolam, ethacrynic acid, fenfluramine, fenoprofen, flecainide, flunitrazepam, galanthamine, granisetron, haloperidol, hydromorphone, hydroxychloroquine, ibuprofen, imipramine, indomethacin ethyl ester, indomethacin methyl ester, isocarboxazid, ketamine, ketoprofen, ketoprofen ethyl ester, ketoprofen methyl ester, ketorolac ethyl ester, ketorolac methyl ester, ketotifen, lamotrigine, lidocaine, loperamide, loratadine, loxapine, maprotiline, memantine, meperidine, metaproterenol, methoxsalen, metoprolol, mexiletine HCl, midazolam, mirtazapine, morphine, nalbuphine, naloxone, naproxen, naratriptan, nortriptyline, olanzapine, orphenadrine, oxycodone, paroxetine, pergolide, phenytoin, pindolol, piribedil, pramipexole, procainamide, prochloperazine, propafenone, propranolol, pyrilamine, quetiapine, quinidine, rizatriptan, ropinirole, sertraline, selegiline, sildenafil, spironolactone, tacrine, tadalafil, terbutaline, testosterone, thalidomide, theophylline, tocainide, toremifene, trazodone, triazolam, trifluoperazine, vaiproic acid, venlafaxine, vitamin E, zaleplon, zotepine, amoxapine, atenolol, benztropine, caffeine, doxylamine, estradiol 17-acetate, flurazepam, flurbiprofen, hydroxyzine, ibutilide, indomethacin norcholine ester, ketorolac norcholine ester, melatonin, metoclopramide, nabumetone, perphenazine, protriptyline HCl, quinine, triamterene, trimipramine, zonisamide, bergapten, chlorpromazine, colchicine, diltiazem, donepezil, eletriptan, estradiol-3,17-diacetate, efavirenz, esmolol, fentanyl, flunisolide, fluoxetine, hyoscyamine, indomethacin, isotretinoin, linezolid, meclizine, paracoxib, pioglitazone, rofecoxib, sumatriptan, tolterodine, tramadol, tranylcypromine, trimipramine maleate, valdecoxib, vardenafil, verapamil, zolmitriptan, zolpidem, zopiclone, bromazepam, buspirone, cinnarizine, dipyridamole, naltrexone, sotalol, telmisartan, temazepam, albuterol, apomorphine hydrochloride diacetate, carbinoxamine, clonidine, diphenhydramine, thambutol, fluticasone proprionate, fluconazole, lovastatin, lorazepam N,O-diacetyl, methadone, nefazodone, oxybutynin, promazine, promethazine, sibutramine, tamoxifen, tolfenamic acid, aripiprazole, astemizole, benazepril, clemastine, estradiol 17-heptanoate, fluphenazine, protriptyline, ethambutal, frovatriptan, pyrilamine maleate, scopolamine, and triamcinolene acetonide.
Another aspect of the present disclosure provides a non-transitory computer readable medium comprising machine executable code that, upon execution by one or more computer processors, implements any of the methods above or elsewhere herein.
Another aspect of the present disclosure provides a system comprising one or more computer processors and computer memory coupled thereto. The computer memory comprises machine executable code that, upon execution by the one or more computer processors, implements any of the methods above or elsewhere herein.
Additional aspects and advantages of the present disclosure will become readily apparent to those skilled in this art from the following detailed description, wherein only illustrative embodiments of the present disclosure are shown and described. As will be realized, the present disclosure is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, all without departing from the disclosure. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive.
All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and/or take precedence over any such contradictory material.
The novel features of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings (also “Figure” and “FIG.” herein), of which:
While preferable embodiments of the invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention.
Various terms used throughout the present description may be read and understood as follows, unless the context indicates otherwise: “or” as used throughout is inclusive, as though written “and/or”; singular articles and pronouns as used throughout include their plural forms, and vice versa; similarly, gendered pronouns include their counterpart pronouns so that pronouns should not be understood as limiting anything described herein to use, implementation, performance, etc. by a single gender; “exemplary” should be understood as “illustrative” or “exemplifying” and not necessarily as “preferred” over other embodiments. Further definitions for terms may be set out herein; these may apply to prior and subsequent instances of those terms, as will be understood from a reading of the present description.
Provided herein are aerosol drug delivery devices for effectively delivering pharmaceutical compounds to the respiratory tract. Devices of the present disclosure may be utilized for delivering any type of pharmaceutical compound, including cannabinoids, nicotine, and steroids. The aerosol drug delivery devices may offer more accurate dosing of pharmaceutical compounds and more effective control of aerosol particle size to permit more effective drug delivery further into the respiratory tract. The aerosol drug delivery devices may also minimize the degradation of delivered pharmaceuticals before and during drug delivery.
Pharmaceutical Compositions
The present disclosure provides devices for the aerosol delivery of pharmaceutical compounds and pharmaceutical compositions. A pharmaceutical compound may include any chemical species that is intended to produce a biological response in a treated subject. A pharmaceutical compound may include a small molecule drug, a peptide, a nucleic acids, or a salt. A pharmaceutical compound may comprise an active pharmaceutical ingredient (API). A pharmaceutical composition may include one or more pharmaceutical compounds. A pharmaceutical composition may comprise additional components for non-biological purposes. Additional components in a pharmaceutical composition may include cations, anions, stabilizers, antioxidants, solubilizers, viscosity enhancers, and buffers. A pharmaceutical composition may comprise one or more carrier liquids. Carrier liquids may include water, ethanol, propylene glycol, glycerin, and oils. A pharmaceutical composition may comprise a solution, mixture, or suspension. A pharmaceutical composition may comprise an emulsion. A pharmaceutical composition may comprise one or more non-volatile components.
In some instances, pharmaceutical compounds and pharmaceutical compositions of the present disclosure may be provided to a subject as a vapor or aerosol. In some instances, vapors or aerosols comprising a pharmaceutical compound or pharmaceutical composition may be generated by vaporizing or boiling of a liquid-phase component. In other instances, a vapor or aerosol may be generated by the removal of a carrier liquid followed by vaporization or the sublimation of a solid-phase pharmaceutical compound or pharmaceutical composition.
A pharmaceutical compound or pharmaceutical composition of the present disclosure may be characterized by a particular boiling temperature or sublimation point/range. A pharmaceutical compound or pharmaceutical composition may have a boiling temperature or sublimation point/range of at least about 40 degrees Celsius (° C.), 60° C., 80° C., 100° C., 120° C., 140° C., 160° C., 180° C., 200° C., 250° C., 300° C., or at least about 350° C. or more. A pharmaceutical compound or pharmaceutical composition may have a boiling temperature or sublimation point/range of no more than about 350° C., 300° C., 250° C., 200° C., 180° C., 160° C., 140° C., 120° C., 100° C., 80° C., 60° C., or no more than about 40° C. or less. A pharmaceutical compound or pharmaceutical composition may have a boiling temperature or sublimation point/range in a range from about 40° C. to about 60° C., about 40° C. to about 100° C., about 40° C. to about 200° C., about 40° C. to about 350° C., about 60° C. to about 100° C., about 60° C. to about 200° C., about 60° C. to about 350° C., about 100° C. to about 200° C., about 100° C. to about 350° C., or about 200° C. to about 350° C.
A pharmaceutical compound or composition may experience degradation during any portion of its lifecycle, including synthesis, formulation, storage, and delivery. A pharmaceutical compound or composition may experience degradation due to any mechanism, including without limitation, reduction, oxidation, isomerization, reaction, defunctionalization, precipitation, or other mechanisms of chemical loss. A pharmaceutical compound or pharmaceutical composition may be characterized by an extent of degradation at the time of delivery to a subject. An extent of degradation may be defined as the percentage, on a mass or molar basis, of pharmaceutical compound or pharmaceutical composition remaining at the time of delivery when compared to the original formulation. For example, a particular pharmaceutical compound with an original formulation concentration of about 10 mg/ml and about a 20% extent of degradation may have a concentration of about 8 mg/ml at the time of drug delivery. An extent of degradation may be measured for a specific process during drug delivery. For example, an extent of degradation may be measured during vaporization or aerosolization of a pharmaceutical compound or pharmaceutical composition to characterize the amount of degradation occurring during the process.
A pharmaceutical compound or pharmaceutical composition may have an extent of degradation of about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 1, 1%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or about 95%. A pharmaceutical compound or pharmaceutical composition may have an extent of degradation of at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10, 1%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more. A pharmaceutical compound or pharmaceutical composition may have an extent of degradation of no more than about 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11, 1%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less.
An extent of degradation may be measured at a particular temperature. An extent of degradation may be measured at a temperature of at least about −40° C., −30° C., −20° C., −10° C., 0° C., 10° C., 20° C., 30° C., 40° C., 50° C., 100° C., 150° C., 200° C., 250° C., 300° C., 350° C., 400° C., or more. An extent of degradation may be measured at a temperature of no more than about 400° C., 350° C., 300° C., 250° C., 200° C., 150° C., 100° C., 50° C., 40° C., 30° C., 20° C., 10° C., 0° C., −10° C., −20° C., −30° C., −40° C., or less. An extent of degradation may be measured over a particular time period. An extent of degradation may be measured over a period of about 1 millisecond (ms), 10 ms, 100 ms, 1 second (s), 10 s, 30 s, 1 minute (min), 5 min, 10 min, 30 min, 1 hour (hr), 3 hrs, 6 hrs, 12 hrs, 1 day, 1 week, 1 month, or 1 year. An extent of degradation may be measured over a period of at least about 1 millisecond (ms), 10 ms, 100 ms, 1 second (s), 10 s, 30 s, 1 minute (min), 5 min, 10 min, 30 min, 1 hour (hr), 3 hrs, 6 hrs, 12 hrs, 1 day, 1 week, 1 month, 1 year or more. An extent of degradation may be measured over a period of no more than about 1 year, 1 month, 1 week, 1 day, 12 hrs, 6 hrs, 3 hrs, 1 hr, 30 min, 10 min, 5 min, 1 min, 30 s, 10 s, 1 s, 100 ms, 10 ms, 1 ms, or less.
A pharmaceutical composition of the present disclosure may comprise a liquid with particular rheological properties. A pharmaceutical composition may comprise a Newtonian fluid or non-Newtonian fluid. A pharmaceutical composition may be shear-thickening or shear-thinning. A pharmaceutical composition may be thixotropic, pseudoplastic, or rheopectic. A pharmaceutical composition of the present disclosure may comprise a fluid with a temperature-dependent viscosity. In some instances, increasing temperature may decrease the viscosity of a fluid comprising a pharmaceutical compound (e.g., a liquid formulation). In other instances, increasing temperature may increase the viscosity of a fluid comprising a pharmaceutical compound (e.g., a vapor formulation). A liquid formulation of a pharmaceutical composition may have a viscosity of about 1 centipoise (cP), 10 cP, 100 cP, 1000 cP, 10000 cP, 100000 cP, or 1000000 cP at a given temperature. A liquid formulation of a pharmaceutical composition may have a viscosity of at least about 1 centipoise (cP), 10 cP, 100 cP, 1000 cP, 10000 cP, 100000 cP, or 1000000 cP or more at a given temperature. A liquid formulation of a pharmaceutical composition may have a viscosity of no more than 1000000 cP, 100000 cP, 10000 cP, 1000 cP, 100 cP, 10 cP, or about 1 cP or less at a given temperature.
A pharmaceutical compound or pharmaceutical composition of the present disclosure may be selected for any purpose that is disposed to aerosol or vapor delivery to the respiratory tract. In some instances, a pharmaceutical compound or pharmaceutical composition may be selected for aerosol or vapor delivery due to the need for rapid pharmacokinetic uptake of the compound or composition. In other instances, a pharmaceutical compound or pharmaceutical composition may be selected for aerosol or vapor delivery due to the need to avoid uptake issues in the gastrointestinal tract (e.g., acid reactivity) or to avoid the cost and intrusiveness of intravenous drug delivery.
A pharmaceutical compound or pharmaceutical composition of the present disclosure may be selected from any class of pharmaceuticals that is disposed to aerosol or vapor delivery to the respiratory tract. A pharmaceutical compound or pharmaceutical composition may include, but is not limited to, an antacid, reflux suppressant, antidopaminergic, cytoprotectant, antispasmodic, opioid, cannabinoid, alpha blocker, beta blocker, calcium channel blocker, diuretic, antiarrhythmic, nitrate, antianginal, vasoconstrictor, vasodilator, antihypertensive, coagulant, anti-coagulant, haemostatic, statin, hypolipidaemic, anti-depressant, anti-psychotic, stimulant, depressant, anti-anxiety, anti-inflammatory, anesthetic, muscle relaxant, anticholinesterase, antibiotic, antiviral, antifungal, steroid, bronchodilator, antitussive, mucolytic, decongestant, antitoxin, antivenom, antihistamine, anabolic, catabolic, therapeutic peptide, therapeutic nucleic acid, vitamin, mineral, cofactor, or supplement.
Specific pharmaceutical compounds of the present disclosure may include nicotine, acebutolol, acetaminophen, alprazolam, amantadine, amitriptyline, apomorphine diacetate, apomorphine hydrochloride, atropine, azatadine, betahistine, brompheniramine, bumetanide, buprenorphine, bupropion hydrochloride, butalbital, butorphanol, carbinoxamine maleate, celecoxib, chlordiazepoxide, chlorpheniramine, chlorzoxazone, ciclesonide, citalopram, clomipramine, clonazepam, clozapine, codeine, cyclobenzaprine, cyproheptadine, dapsone, diazepam, diclofenac ethyl ester, diflunisal, disopyramide, doxepin, estradiol, ephedrine, estazolam, ethacrynic acid, fenfluramine, fenoprofen, flecainide, flunitrazepam, galanthamine, granisetron, haloperidol, hydromorphone, hydroxychloroquine, ibuprofen, imipramine, indomethacin ethyl ester, indomethacin methyl ester, isocarboxazid, ketamine, ketoprofen, ketoprofen ethyl ester, ketoprofen methyl ester, ketorolac ethyl ester, ketorolac methyl ester, ketotifen, lamotrigine, lidocaine, loperamide, loratadine, loxapine, maprotiline, memantine, meperidine, metaproterenol, methoxsalen, metoprolol, mexiletine HCl, midazolam, mirtazapine, morphine, nalbuphine, naloxone, naproxen, naratriptan, nortriptyline, olanzapine, orphenadrine, oxycodone, paroxetine, pergolide, phenytoin, pindolol, piribedil, pramipexole, procainamide, prochloperazine, propafenone, propranolol, pyrilamine, quetiapine, quinidine, rizatriptan, ropinirole, sertraline, selegiline, sildenafil, spironolactone, tacrine, tadalafil, terbutaline, testosterone, thalidomide, theophylline, tocainide, toremifene, trazodone, triazolam, trifluoperazine, vaiproic acid, venlafaxine, vitamin E, zaleplon, zotepine, amoxapine, atenolol, benztropine, caffeine, doxylamine, estradiol 17-acetate, flurazepam, flurbiprofen, hydroxyzine, ibutilide, indomethacin norcholine ester, ketorolac norcholine ester, melatonin, metoclopramide, nabumetone, perphenazine, protriptyline HCl, quinine, triamterene, trimipramine, zonisamide, bergapten, chlorpromazine, colchicine, diltiazem, donepezil, eletriptan, estradiol-3,17-diacetate, efavirenz, esmolol, fentanyl, flunisolide, fluoxetine, hyoscyamine, indomethacin, isotretinoin, linezolid, meclizine, paracoxib, pioglitazone, rofecoxib, sumatriptan, tolterodine, tramadol, tranylcypromine, trimipramine maleate, valdecoxib, vardenafil, verapamil, zolmitriptan, zolpidem, zopiclone, bromazepam, buspirone, cinnarizine, dipyridamole, naltrexone, sotalol, telmisartan, temazepam, albuterol, apomorphine hydrochloride diacetate, carbinoxamine, clonidine, diphenhydramine, thambutol, fluticasone proprionate, fluconazole, lovastatin, lorazepam N,O-diacetyl, methadone, nefazodone, oxybutynin, promazine, promethazine, sibutramine, tamoxifen, tolfenamic acid, aripiprazole, astemizole, benazepril, clemastine, estradiol 17-heptanoate, fluphenazine, protriptyline, ethambutal, frovatriptan, pyrilamine maleate, scopolamine, and triamcinolene acetonide.
A pharmaceutical compound or pharmaceutical composition may be delivered in a particular dosage to a subject. A pharmaceutical compound or pharmaceutical composition may be delivered in an amount of at least about 1 microgram (μg), 10 μg, 50 μg, 100 μg, 250 μg, 500 μg, 750 μg, 1 milligram (mg), 5 mg, 10 mg, 50 mg, or at least about 100 mg or more. A pharmaceutical compound or pharmaceutical composition may be delivered in an amount of no more than about 100 mg, 50 mg, 10 mg, 5 mg, 1 mg, 750 μg, 500 μg, 250 μg, 100 μg, 50 μg, 10 μg, or no more than about 1 μg or less.
Pharmaceutical compositions of the present disclosure may comprise one or more cannabinoid compounds. Cannabinoids comprise a class of chemical compounds that bind to the cannabinoid receptor system of many animals, including humans. Cannabinoids may be broadly grouped into categories such as endocannabinoids that are naturally produced by animals for internal signaling, phytocannabinoids that are produced by plants, and synthetic cannabinoids that are manufactured. Cannabinoids may produce a broad range of pharmacological effects, making them an active target for pharmaceutical research. Most commercially available cannabinoids are derived from plants of the Cannabis genus. At least 100 cannabinoid compounds have been derived from cannabis plants, including such common compounds as tetrahydrocannabinol (THC), cannabinol (CBN), and cannabidiol (CBD).
Cannabinoids disclosed herein include but are not limited to cannabigerol-type (CBG), cannabigerolic acid (CBGA), cannabigerolic acid monomethylether (CBGAM), cannabigerol monomethyl ether (CBGM), cannabichromene-type (CBC), cannabichromanon (CBCN), cannabichromenic acid (CBCA), cannabichromevarin-type (CBCV), cannabichromevarinic acid (CBCVA), cannabidiol-type (CBD), tetrahydrocannabinol-type (THC), iso-tetrahydrocannabinol-type (iso-THC), cannabinol-type (CBN), cannabinolic acid (CBNA), cannabinol methylether (CBNM), cannabinol-C4 (CBN-C4), cannabinol-C2 (CBN-C2), cannabiorcol (CBN-C1), cannabinodiol (CBND), cannabielsoin-type (CBE), cannabielsoic acid A (CBEA-A), cannabielsoic acid B (CBEA-B), cannabicyclol-type (CBL), cannabicyclolic acid (CBLA), cannabicyclovarin (CBLV), cannabicitran-type (CBT), cannabitriol, cannabitriolvarin (CBTV), ethoxy-cannabitiolvarin (CBTVE), cannabivarin-type (CBV), cannabinodivarin (CBVD), tetrahydrocannabivarin-type (THCV), cannabidivarin-type (CBDV), cannabigerovarin-type (CBGV), cannabigerovarinic acid (CBGVA), cannabifuran (CBF), dehydrocannabifuran (DCBF), and cannabiripsol (CBR) cannabinoids.
The cannabinoids of the subject compositions disclosed herein can comprise cannabidiol-class compounds, including but not limited to cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidiol monomethylether (CBDM), cannabidiol-C4 (CBD-C4), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), cannabidiorcol (CBD-C1), and combinations thereof. CBD can comprise delta-1-cannabidiol, delta-2-cannabidiol, delta-3-cannabidiol, delta-3,7-cannabidiol, delta-4-cannabidiol, delta-5-cannabidiol, delta-6-cannabidiol, and combinations thereof.
The compositions of the present disclosure can comprise tetrahydrocannabinol (THC) as a type of cannabinoids. THC can comprise delta-9-THC, delta-8-THC, and combinations thereof. THC can comprise delta-6a,7-tetrahydrocannabinol, delta-7-tetrahydrocannabinol, delta-8-tetrahydrocannabinol, delta-9,11-tetrahydrocannabinol, delta-9-tetrahydrocannabinol, delta-10-tetrahydrocannabinol, delta-6a,10a-tetrahydrocannabinol, and combinations thereof. Delta-9-tetrahydrocannabinol can comprise stereoisomers including (6aR,10aR)-delta-9-tetrahydrocannabinol, (6aS,10aR)-delta-9-tetrahydrocannabinol, (6aS,10aS)-delta-9-tetrahydrocannabinol, (6aR,10aS)-delta-9-tetrahydrocannabinol, and combinations thereof.
The cannabinoid compositions described herein may also contain other ingredients, including terpenes. The cannabinoid compositions of the present disclosure can comprise one or more terpene compounds, including but not limited to terpenoids such as monoterpenoids, sesquiterpenoids, diterpenoids, and triterpenoids. Terpenes can be acyclic, monocyclic, or polycyclic. Terpenes can include but are not limited to myrcene, limonene, linalool, trans-ocimene, cis-ocimene, alpha-pinene, beta-pinene, alpha-humulene (alpha-caryophyllene), beta-caryophyllene, delta-3-carene, trans-gamma-bisabolene, cis-gamma-bisabolene, trans-alpha-farnesene, cis-beta-farnesene, beta-fenchol, beta-phellandrene, guajol, alpha-gualene, alpha-eudesmol, beta-eudesmol, gamma-eudesmol, terpinolene, alpha-selinene, beta-selinene, alpha-terpineol, fenchone, camphene, cis-sabinene hydrate, alpha-trans-bergamotene, alpha-cis-bergamotene, bomeol, gamma-curcumene, alpha-thujene, epi-alpha-bisabolol, ipsdienol, alpha-ylangene, beta-elemene, gamma-muurolene, alpha-cadinene, alpha-longipinene, caryophyllene oxide, and combinations thereof.
Cannabinoid compositions of the present disclosure can comprise one or more additional compounds or derivatives thereof, including but not limited to pregnenolone or other compounds that counteract THC intoxication, MSM, fulvic acid, L-Theanine, Fish Oil, and phenylethylamine (PEA).
The cannabinoid compositions of the present disclosure can comprise pregnenolone, including derivatives thereof. Pregnenolone can help protect a subject from cannabis intoxication, for example from THC. Pregnenolone or derivatives thereof can be formulated to be water soluble. A cannabinoid composition of the present disclosure can comprise between about 1 and 50 milligrams (mg) of pregnenolone or derivatives thereof. For example, a unit dosage of the present disclosure can comprise between about 1 and 50 milligrams (mg) of pregnenolone. Cannabinoid compositions of the present disclosure (e.g., unit dosages) can comprise about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, or 50 mg of pregnenolone. Cannabinoid compositions of the present disclosure (e.g., unit dosages) can comprise at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, or 50 mg of pregnenolone. Cannabinoid compositions of the present disclosure (e.g., unit dosages) can comprise at most about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, or 50 mg of pregnenolone.
Aerosol Drug Delivery Devices
Provided herein are devices for delivering a gas flow carrying an aerosol or vapor comprising a pharmaceutical compound or pharmaceutical composition. A device of the present disclosure may be designed for delivering a gas flow into the respiratory tract of a subject. Gas flow may be provided to a subject via any passage or orifice that provides access to the respiratory tract. In some instances, gas flows comprising a pharmaceutical compound or pharmaceutical composition may be provided to the oral cavity, nasal passage, or another opening such as a tracheotomy.
An aerosol or vapor drug delivery device may provide a pharmaceutical compound or pharmaceutical composition via a passive or active delivery mechanism. A passive aerosol or vapor delivery mechanism may include any mechanism where gas flow is provided by the input of momentum transfer from an external source. In some instances, passive delivery mechanisms may include inhalation by a subject or manual mechanical actuation of the device by a subject or administering individual. An active aerosol or vapor delivery mechanism may include any mechanism where gas flow is generated by the input of momentum transfer from an internal source. In some instances, active delivery mechanisms may include pumps, blowers, or fans that impart gas flow. In other instances, active delivery mechanisms may include gas flow generated by propellants or other pressurized gas sources.
An aerosol or vapor drug delivery device of the present disclosure may comprise a gas flow channel, a heating element, a liquid flow channel, a pump, and a reservoir.
An aerosol or vapor drug delivery device may comprise one or more reservoirs containing pharmaceutical compounds or pharmaceutical compositions. Reservoirs may be operatively connected to a pump that delivers a liquid comprising a pharmaceutical compound or a pharmaceutical composition through at least one liquid flow channel to one or more heating elements. The heating elements may provide sufficient thermal energy to convert a liquid comprising a pharmaceutical compound or pharmaceutical composition to an aerosol or vapor. The aerosol or vapor comprising a pharmaceutical compound or pharmaceutical composition may become entrained in a gas flow in the gas flow channel that carries the aerosol or vapor to a subject for administration of the pharmaceutical compound or composition. The drug delivery device of the present disclosure may comprise additional features such as housing, sensors, microprocessors, power sources (e.g., batteries) and control devices such as buttons and switches. In some instances, the drug delivery device of the present disclosure may not comprise a wicking material between the reservoir and the heating element.
An aerosol or vapor drug delivery device of the present disclosure may have several advantageous aspects that enhance the delivery of aerosols or vapors comprising pharmaceutical compounds or pharmaceutical compositions, or improve the control of the device. An aerosol or drug delivery device may have a minimized volume of the liquid flow path (e.g., small diameter needle), thereby making the response time from changes in the pumping speed rapid for the depositing of liquid onto the heating element. A non-heated or minimally heated liquid flow channel minimizes the heating of the liquid prior to vaporization. Reduced heating before vaporization may reduce the extent of degradation of a pharmaceutical compound or pharmaceutical composition during the drug delivery process. A heating element may have a large surface area in which to vaporize material from, and to reduce the thickness of the deposited liquid on the heated surface. A thinner liquid layer may increase the vaporization rate, thereby permitting less loss of pharmaceuticals by degradation, precipitation, and other loss mechanisms. The heating element may have a surface that can be wetted by liquid, or alternatively have a material (such as a fibrous material) that can hold the liquid against heater.
In some embodiments, the heating element may have a reasonable high and consistent temperature coefficient. The heating element may be designed to be in the 0.1 to 2.0-ohm range, or 0.4 to 1.5 ohm, allowing common resistive materials to be utilized. The heating element may be designed to minimize the air-path from the heated surface to the gas flow channel. Last, it may be advantageous to have a high temperature coefficient heating material to enable temperature measurement and control of the heater element. In some embodiments, the heating element comprises a plurality of heating coils (e.g., shaped as a single helix, a double helix, or a triple helix) (4321 and 4322) as demonstrated in
In some embodiments, the aerosol generating device as disclosed herein is powered by a battery, which provides about 3 to about 7 volt range. The amount of the electrical power that may be transferred into the heating element is about from 3 to about 10 watts. When the electrical current powering the heater element is passed through a single length of the coil wire, the resultant resistance (at room temperature) may be around 4.6 ohms. Further, as the heating element increases in temperature the resistance may increase to close to 10 Ohms (due to an increase in the electrical resistance due to the temperature coefficient of nickel being relatively high. Alpha=0.006 change in Ohms/C). When the heating element comprises more than one heating coils, connected to each other in parallel, the resistance of the resultant circuit may be reduced. As a result, the power available may be increased. The total resistance Rt is calculated as: 1/Rt=1/R1+1/R2+1/R3 . . . . Since R1=R2=R3 . . . this gives the expression Rt=N/RS, where N is the number of parallel heater elements and RS is the resistance of a single heating coil wire.
A reservoir of the present disclosure may comprise any chamber or vessel configured to hold a liquid comprising a pharmaceutical compound or pharmaceutical composition. A reservoir may be a rigid vessel or may be flexible, deformable, or collapsible. A reservoir may comprise a polymeric or metallic material. A reservoir may comprise a flexible or collapsible material such as multi-layer laminates made of plastic and metal layers. Plastic layers can comprise one, or many layers of Polyethylene (PE), Low density PE, Linear Low Density PE, Medium Density PE, High Density PE, Polypropylene, Polyethylene Terephthalate (PET), Polyester, or Nylon. Sealant additives may include coatings that can improve performance, and can include ethylene acrylic acid, metallocene, surlyn, vinyl alcohol, or vinylidene chlorine, or metal layers deposited onto the plastic layers, or laminated between plastic layers and may be made from various aluminum alloys. A reservoir may comprise a rigid vessel with a piston or syringe type actuation member that drives fluid from the reservoir. A reservoir may comprise one or more inlets ports or outlet ports. A reservoir may comprise one or more fittings that allow the reservoir to be operatively connected to other components of the drug delivery device. A reservoir may comprise a disposable cartridge. A reservoir may compose a fixed or refillable cartridge. A reservoir may connect to one or more ports external to the housing that permit fluids including liquids and gases to be injected into the reservoir.
A reservoir may comprise a permanent or non-permanent fixture of an aerosol or drug delivery device. A permanent reservoir may comprise a fixed chamber or compartment within the aerosol or drug delivery device that can be loaded with a fluid comprising a compound for aerosol delivery. A permanent reservoir may be loaded or charged with a fluid through one or more ports. In some cases, the fluid may be charged through a port other than the port used to deliver the fluid into the device's airflow stream. A non-permanent reservoir may comprise any suitable cartridge or bladder that may accommodate a fluid for the aerosol or drug delivery device. In some cases, a reservoir may comprise a syringe or piston-plunger device. The cartridge or bladder may be a sealed or non-sealed vessel that is held or placed within the device. A seal may be made of plastic, metal foil, or any other suitable material. Non-permanent reservoirs may be intended for single use or multiple uses (e.g., refillable cartridges).
A permanent or non-permanent reservoir may be sealed to prevent fluid loss during storage or transportation, or to ensure the stability or shelf life of a compound for the aerosol or drug delivery device. A permanent or non-permanent reservoir may be sealed at a fluid delivery port with a material that can be manually or non-manually removed. The reservoir may be unsealed by a mechanism inside the aerosol or drug delivery device. A seal on a reservoir may be unsealed by a method such as mechanical rupture, thermal thinning, thermal degradation, chemical reaction, or chemical dissolution. A sealed reservoir may have an intended shelf life for the compound to be delivered. The shelf life may be a minimum, maximum, or average shelf life. A sealed reservoir may have a shelf life of about 1 day, 1 week, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 9 months, 1 year, 1.5 years, 2 years, 3 years, 4 years, 5 years, or more than 5 years. A sealed reservoir may have a shelf life of at least about 1 day, 1 week, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 9 months, 1 year, 1.5 years, 2 years, 3 years, 4 years, 5 years, or more than 5 years. A sealed reservoir may have a shelf life of no more than about 5 years, 4 years, 3 years, 2 years, 1.5 years, 1 year, 9 months, 6 months, 5 months, 4 months, 3 months, 2 months, 1 month, 1 week, 1 day, or less than 1 day.
A reservoir may have a total volume. A reservoir may have a volume of at least about 100 microliters (μl), 500 μl, 1 milliliter (ml), 5 ml, 10 ml, 20 ml, 30 ml, 40 ml, 50 ml, or about 100 ml. A reservoir may have a volume of at least about 100 microliters (μl), 500 μl, 1 milliliter (ml), 5 ml, 10 ml, 20 ml, 30 ml, 40 ml, 50 ml, or at least about 100 ml or more. A reservoir may have a volume of no more than about 100 ml, 50 ml, 40 ml, 30 ml, 20 ml, 10 ml, 5 ml, 1 ml, 500 μl, or no more than about 100 μl or less. A reservoir may accommodate a particular number of doses of a pharmaceutical compound or pharmaceutical composition. A reservoir may accommodate about 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, or about 200 doses of a compound or composition. A reservoir may accommodate at least about 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, or at least about 200 doses or more of a compound or composition. A reservoir may accommodate no more than about 200, 150, 100, 90, 80, 70, 60, 50, 40, 30, 20, 10, 5, or no more than about 1 dose of a compound of composition.
An aerosol or vapor drug delivery device may comprise liquid flow channels or liquid flow paths for the transfer of liquids comprising pharmaceutical compounds or pharmaceutical compositions. A flow channel or flow path may comprise materials such as polymers, metals, glass fibers, glass frits, ceramic fibers, and ceramic frits. A flow channel or flow path may comprise a high temperature polymer such as PEEK or Kapton. A flow channel or flow path may comprise one or more sections of tubing or piping. A flow channel or flow path may comprise a molded or fabricated section of housing that operatively connects two other components, e.g., a reservoir and a pump. A flow channel or flow path may comprise additional components such as fittings that secure the flow channel or path and seal the fluid flow path from leaks or contamination. A flow channel may comprise embedded or inserted components such as heaters, flow sensors, temperature sensors, and pressure sensors.
An aerosol or vapor drug delivery device may comprise one or more pumps. A pump may comprise a positive displacement pump. A pump may comprise a rotary pump. In other cases, a pump may comprise a piston pump. A pump may comprise a mechanical actuator or element that pushes or squeezes fluid from a reservoir, thereby decreasing the volume of liquid within the reservoir. A pump may be a component placed in a flow channel or flow path between a reservoir and a heating element. A pump may comprise various materials, including polymers, metals, and magnetic materials. A pump may be operatively connected to an electrical source or an electromagnetic source. A pump may be operated electrically or electromagnetically.
An aerosol or vapor drug delivery device may comprise a rotary or rotational pump. A rotary or rotational pump may comprise a housing. The pump housing may be made of plastic (e.g., injection molded plastic) or stamped metal or a combination of materials having an optimal internal volume. A rotary or rotational pump may have one or more inlets for liquid to enter the pump and one or more outlets for liquid to exit the pump. A rotary or rotational pump may comprise one or more interior members that rotate or otherwise move within the interior chamber causing liquid to be moved from the inlets to the outlets. One or more of the interior members can include a magnet, or multiple magnets, that can be used, in part, to drive the pump. A rotary or rotational pump may be configured to drive, move, or rotate one or more of the interior members. For example, the rotary or rotational pump may comprise a rotating mechanical shaft that is attached to a member or can be a moveable magnetic field that acts on a magnet, or magnets, on the interior of the pump. In some instances, the moveable magnetic field may be generated by an electromagnet.
In some instances, it may be desirable to have a mechanical advantage on pumping (to minimize the torque required from the drive mechanism). It may be advantageous to have a pump that rotates about once/second. A 3-toothed gear pump may have a volume of about 0.1 to about 1 mm3 per tooth cavity (as there may be 2 gears). To keep the features of the pump relatively large to make manufacturing simple, the thickness of the gears may be kept to the minimum thickness that can be easily injection molded, e.g., 0.1 mm to about 0.5 mm. A cross-section area of each tooth cavity of about 0.1 to about 3.5 mm2. In some instances, the tooth cavity is roughly elliptical and the depth (inside to outside) is 0.5 mm, resulting in a length of about 0.5 mm to 5.0 mm). The resultant rough size of the pump may have a diameter between be 1 and 10 mm.
An aerosol or vapor drug delivery device may comprise a method of pumping that involves driving fluid directly from the reservoir. In some instances, the drug delivery device comprises one or more rigid reservoirs with a mechanical actuator, such as a piston or syringe-like device. In other instances a drug delivery device may comprise one or more collapsible or flexible reservoirs. A collapsible or flexible reservoir may be made from a foil, or thin membrane, that forms a chamber that houses a liquid. For rigid, collapsible, or flexible reservoirs, a mechanism, component, element, or actuator is driven along the reservoir, causing the liquid housed in the reservoir to be ejected from the reservoir. The mechanism, component, element, or actuator may be mechanically or electrically coupled to a shaft for controlling the rate and volume of liquid dispensed, e.g., an electrically driven shaft that rolls two barrels along a flexible reservoir.
In some instances, the fluid properties of a liquid comprising a pharmaceutical compound or pharmaceutical composition may be altered to maintain a constant pumping rate or to allow the pump to operate. With some liquids, e.g., some of the cannabinoids, the viscosity of the liquid may be high (100,000 to as high as 1,000,000 centipoise). In such cases, liquids may require a greater amount of pumping work. The viscosity of liquids also may become higher as the temperature of the liquid drops. In some instances, the viscosity of the liquid can be measured during pumping with a rotary or rotational pump by measuring the response time of the pump to the electrical drive circuit (measurement of the time interval that the pump takes to reach the next step in the stepped motor). This may be useful with rotational pump that do not have a large mechanical reduction in the drive, such as with worm drives, or with multiple gear reductions. If an undesirable high viscosity is measured then the liquid may be heated in the pump itself, in the reservoir, in a liquid flow channel or path, or in a combination thereof, to reach a desired viscosity of the liquid. In other instances, a drug delivery device may comprise a rotational element such as an impeller that independently measures liquid viscosity somewhere within the liquid reservoir or the liquid flow path.
In some cases, the aerosol or vapor drug delivery device comprises a display as showed in
A rotational element for viscosity sensing may be coupled to other components necessary for sensing. A rotational element may be coupled to mechanical shafts, gears, motors wiring, power sources, circuitry components, rotational sensors, torque sensors, or microprocessors. A combination of electrical and mechanical elements including a rotational element may comprise a viscosity sensing circuit. A viscosity sensing circuit may be operatively linked to one or more heaters or heat exchanging components that alter the liquid temperature to achieve a targeted viscosity or viscosity range. A viscosity sensing circuit may have a characteristic response time. A characteristic response time may comprise the time differential between measuring a viscosity and achieving a target viscosity by altering the liquid temperature. A viscosity sensing circuit may have a characteristic response time of about 1 microsecond (μs), 10 μs, 100 μs, 500 μs, 1 millisecond (ms), 10 ms, 50 ms, 100 ms, 250 ms, 500 ms, 1 second (s), 5 s, or about 10 s. A viscosity sensing circuit may have a characteristic response time of at least about 1 microsecond (μs), 10 μs, 100 μs, 500 μs, 1 millisecond (ms), 10 ms, 50 ms, 100 ms, 250 ms, 500 ms, 1 second (s), 5 s, or about 10 s or more. A viscosity sensing circuit may have a characteristic response time of no more than about 10 s, 5 s, 1 s, 500 ms, 250 ms, 100 ms, 50 ms, 10 ms, 1 ms, 500 μs, 100 μs, 10 μs, or no more than about 1 μs or less.
An aerosol or vapor drug delivery device may comprise one or more heating elements. In some instances, a heating element may be disposed in a gas flow channel to permit aerosol or vapor formation within the inhaled or injected gas flow. In other instances, a heating element may be disposed in proximity to a fluid flow path to permit direct thermal energy input to a liquid comprising a pharmaceutical compound or pharmaceutical composition. A heating element may comprise a resistive heater or an inductive heater.
In some embodiments, a heater element may be designed without a wicking material that passively transports fluid from a reservoir. In some instances, a liquid pharmaceutical compound or pharmaceutical composition may be pumped directly onto, or into, the heater element. It may be advantageous for the design of the heater element and the liquid flow channel to be designed so that the form factor is conducive to use in conventional vaping devices, such as having the heater element aligned across the gas flow channel, or to have a size that may fit into existing “pod” type vaping cartridges.
The heater element may be made of conventional steel alloys or from other metal elements and/or alloys. Titanium, copper, or tungsten, for example, may be used if it is desirable to have a heating element with a large thermal coefficient so that the temperature of the element can be determined and controlled. This temperature control may be important for the control of temperature in conjunction with pump speed (amount of formulation vaporized). A heating element may comprise in part a polymer or elastomeric material, such as Kapton or PEEK. The polymer or elastomeric material may be resistant to thermal degradation. In some instances, the polymer or elastomeric material may be stable at a temperature of 350° C. or higher. The polymer or elastomeric material may enhance or assist the even dispersion of a liquid over the surface of the heating element or may be used to support the heater element, or electrically insulate the heater element.
A heating element may be formed from wire or may be formed from sheet (foils) of a number of metal alloys. If the heating element is to be heated by passing an electrical current though it (as compared to using electrical induction) the heating element may have an optimal electrical resistance. The electrical resistance of a heating element may be about 0.1 ohms (Ω), 0.2Ω, 0.3Ω, 0.4Ω, 0.5Ω, 0.6Ω, 0.7Ω, 0.8Ω, 0.9Ω, 1.0Ω, 1.1Ω, 1.2Ω, 1.3Ω, 1.4Ω, 1.5Ω, 1.6Ω, 1.7Ω, 1.8Ω, 1.9Ω, 2.0Ω, 2.5Ω, or about 3.0Ω. The electrical resistance of a heating element may be at least about 0.1 ohms (Q), 0.2Ω, 0.3Ω, 0.4Ω, 0.5Ω, 0.6Ω, 0.7Ω, 0.8Ω, 0.9Ω, 1.0Ω, 1.1Ω, 1.2Ω, 1.3Ω, 1.4Ω, 1.5Ω, 1.6Ω, 1.7Ω, 1.8Ω, 1.9Ω, 2.0Ω, 2.5Ω, or at least about 3.0Ω or more. The electrical resistance of a heating element may be no more than about 3.0 ohms (Q), 2.5Ω, 2.0Ω, 1.9Ω, 1.8Ω, 1.7Ω, 1.6Ω, 1.5Ω, 1.4Ω, 1.3Ω, 1.2Ω, 1.1Ω, 1.0Ω, 0.9Ω, 0.8Ω, 0.7Ω, 0.6Ω, 0.5Ω, 0.4Ω, 0.3Ω, 0.2Ω, or at least about 0.1Ω or less. The electrical resistance of heating element may be in a range from about 0.1Ω to about 0.4Ω, about 0.1Ω to about 1.0Ω, about 0.1Ω to about 1.5Ω, about 0.1Ω to about 2.0Ω, about 0.1Ω to about 3.0Ω, about 0.4Ω to about 1.0Ω, about 0.4Ω to about 1.5Ω, about 0.4Ω to about 2.0Ω, about 0.4Ω to about 3.0Ω, about 1.0Ω to about 1.5Ω, about 1.0Ω to about 2.0Ω, about 1.0Ω to about 3.0Ω, about 1.5Ω to about 2.0Ω, about 1.5Ω to about 3.0Ω, or about 2.0Ω to about 3.0Ω.
A heating element may be electrically connected to an electrical source. An electrical source may comprise one or more primary or secondary batteries. A heating element may provide a particular heat output or have a particular power requirement. A heating element may provide a heat output or power requirement of about 5 watts (W), 10 W, 15 W, 20 W, 25 W, 30 W, 35 W, 40 W, or about 50 W. A heating element may provide a heat output or power requirement of at least about 5 watts (W), 10 W, 15 W, 20 W, 25 W, 30 W, 35 W, 40 W, or at least about 50 W or more. A heating element may provide a heat output or power requirement of no more than about 50 W, 40 W, 35 W, 30 W, 25 W, 20 W, 15 W, 10 W, or about 5 W or less. In some instances, a heating element may have a heat output or power requirement of about 6 W to about 22 W.
In some instances, the heating element comprises an inductive heater. If the heating element is to be heated by way of electrical induction then an electrical coil may be positioned around the element to be heated. The coil may be in close proximity to the element and can incorporate the use of ferrite material and other materials to direct the electromagnetic field (energy) to the element. The frequency of the alternating electrical current in the inductive coil may be chosen with the geometry of the element in mind. As the thickness of the element is increased, the frequency may be lowered. For example, if the “skin” of the element is for example 0.004 in. in thickness then a frequency may be around 200-400 khz.
In some instances, a heating element of the present disclosure may be in physical contact with a fibrous or fritted material that aids in dispersing a liquid compound or composition over the surface of the heating element. In other instances, a liquid flow channel or path may comprise a material (e.g., fritted metal) that is resistively or inductively heated at the outlet of the channel or path to create an aerosol or vapor from a flowing liquid.
An aerosol or vapor drug delivery device may comprise a gas flow channel that carries a pharmaceutical compound or pharmaceutical composition to a subject. A gas flow channel may comprise one or more inlets and one or more outlets. A gas flow channel may primarily transport air or other gases. A gas flow channel may be operatively connected to one or more sources of propellants or compressed gases that cause gas flow in the gas flow channel. A gas flow channel may comprise one or more sections of tubing or piping. A gas flow channel may comprise a molded or fabricated section of the device housing. A gas flow channel may comprise materials such as polymers, metals, ceramics, and glasses.
An aerosol or vapor drug delivery device may comprise a housing. A housing may comprise one or more pieces that serve to secure and enclose the components of the aerosol or vapor drug delivery device. A housing may comprise materials such as polymers, metals, ceramics, and glasses. A housing may contain one or more windows for viewing the liquid level in a reservoir. The housing may comprise one or more ports for establishing electrical or fluid connectivity with the drug delivery device. A housing may comprise one or more digital or analog displays, e.g., number of doses remaining. A housing may comprise various buttons and switches for control of the drug delivery device. A housing may be designed to be leakproof, waterproof, or resistant to breakage. A housing may be formed by injection molding.
Vaporizer Devices
In an aspect, the present disclosure provides, as illustrated in
In some embodiments, the dispenser 4360 is configured to receive the medicament pumped from the reservoir 4840. In some embodiments, as illustrated in
In some embodiments, the heater 4320 at least partially surrounds at least a portion of the dispenser 4360. In some embodiments, the heater 4320 completely surrounds the dispenser 4360. In some embodiments, the heater 4320 surrounds the first dispenser 4360, the second dispenser 4360, or both. In some embodiments, the heater 4320 is configured to heat the medicament received by the dispenser 4360. In some embodiments, the heater 4320 is formed of a conductive metal, wherein applying a voltage to the heater 4320 heats the medicament received by the dispenser 4360. In some embodiments, the heater 4320 is configured to vaporize the medicament received by the dispenser 4360. In some embodiments, the heater 4320 comprise a helical heater 4320, wherein the heater 4320 has a spiral shape. In some embodiments, the helical heater 4320 comprises two or more helical coils. In some embodiments, the two or more helical coils are interdigitated. In some embodiments, the two or more helical coils overlap. In some embodiments, the helical heater 4320 has a diameter of about 0.006 inches to about 0.008 inches. In some embodiments, the helical heater 4320 has a length of about 25 inches to about 75 inches. In some embodiments, the helical heater 4320 has a working voltage of about 3 volts to about 9 volts. In some embodiments, the helical heater 4320 has a working power of about 5 watts to about 50 watts. In some embodiments, the helical heater 4320 has two or more helical revolutions.
In some embodiments, the vaporizer device 4600 further comprises a housing comprising a first inlet and an outlet, wherein the housing is configured to direct a fluid from the inlet, through the heater 4320, and to the outlet. In some embodiments, the housing further comprises a second inlet configured to isolate at most a portion of the fluid from the heater 4320. In some embodiments, the first inlet and the second inlet, individually or in combination, have a cross sectional area of at least about 50 mm2.
In some embodiments, the vapor device 4600 further comprises a valve coupled to an outlet of the reservoir 4840. In some embodiments, at least a portion of the valve is surrounded by the heater 4320, the dispenser 4360, or both. In some embodiments, the valve comprises a pressure release valve in a direction from the reservoir 4840 to the outlet. In some embodiments, the pressure relieve valve is resealable.
In some embodiments, the vaporizer device 4600 further comprises a preheater configured to heat the medicament in the reservoir 4840, the medicament in the dispenser 4360, or both. In some embodiments, at least a portion of the preheater is at least partially surrounds the reservoir 4380. In some embodiments, the vaporizer device 4600 further comprises a mouthpiece 4330.
In some embodiments, the vaporizer device 4600 is capable of emitting at least about 5 mg/second of the medicament. In some embodiments, the vaporizer device 4600 is capable of forming an aerosol particle of the medicament having a size of greater than about 1 μm. In some embodiments, the vaporizer device 4600 does not comprise a wick. In some embodiments, the vaporizer device 4600 further comprises an actuator configured to pump the medicament from the reservoir 4840.
As shown in
Vaporizing Base Device
In another aspect, the present disclosure provides, as illustrated in
As illustrated in
Computing Systems
The present disclosure provides computer systems that are programmed to implement methods of the disclosure.
The computer system 3601 includes a central processing unit (CPU, also “processor” and “computer processor” herein) 3605, which can be a single core or multi core processor, or a plurality of processors for parallel processing. The computer system 3601 also includes memory or memory location 3610 (e.g., random-access memory, read-only memory, flash memory), electronic storage unit 3615 (e.g., hard disk), communication interface 3620 (e.g., network adapter) for communicating with one or more other systems, and peripheral devices 3625, such as cache, other memory, data storage and/or electronic display adapters. The memory 3610, storage unit 3615, interface 3620 and peripheral devices 3625 are in communication with the CPU 3605 through a communication bus (solid lines), such as a motherboard. The storage unit 3615 can be a data storage unit (or data repository) for storing data. The computer system 3601 can be operatively coupled to a computer network (“network”) 3630 with the aid of the communication interface 3620. The network 3630 can be the Internet, an internet and/or extranet, or an intranet and/or extranet that is in communication with the Internet. The network 3630 in some cases is a telecommunication and/or data network. The network 3630 can include one or more computer servers, which can enable distributed computing, such as cloud computing. The network 3630, in some cases with the aid of the computer system 3601, can implement a peer-to-peer network, which may enable devices coupled to the computer system 3601 to behave as a client or a server.
The CPU 3605 can execute a sequence of machine-readable instructions, which can be embodied in a program or software. The instructions may be stored in a memory location, such as the memory 3610. The instructions can be directed to the CPU 3605, which can subsequently program or otherwise configure the CPU 3605 to implement methods of the present disclosure. Examples of operations performed by the CPU 3605 can include fetch, decode, execute, and writeback.
The CPU 3605 can be part of a circuit, such as an integrated circuit. One or more other components of the system 3601 can be included in the circuit. In some cases, the circuit is an application specific integrated circuit (ASIC).
The storage unit 3615 can store files, such as drivers, libraries, and saved programs. The storage unit 3615 can store user data, e.g., user preferences and user programs. The computer system 3601 in some cases can include one or more additional data storage units that are external to the computer system 3601, such as located on a remote server that is in communication with the computer system 3601 through an intranet or the Internet.
The computer system 3601 can communicate with one or more remote computer systems through the network 3630. For instance, the computer system 3601 can communicate with a remote computer system of a user (e.g., the subject for a drug delivery device). Examples of remote computer systems include personal computers (e.g., portable PC), slate or tablet PC's (e.g., Apple® iPad, Samsung® Galaxy Tab), telephones, Smart phones (e.g., Apple® iPhone, Android-enabled device, Blackberry®), or personal digital assistants. The user can access the computer system 3601 via the network 3630.
Methods as described herein can be implemented by way of machine (e.g., computer processor) executable code stored on an electronic storage location of the computer system 3601, such as, for example, on the memory 3610 or electronic storage unit 3615. The machine executable or machine readable code can be provided in the form of software. During use, the code can be executed by the processor 3605. In some cases, the code can be retrieved from the storage unit 3615 and stored on the memory 3610 for ready access by the processor 3605. In some situations, the electronic storage unit 3615 can be precluded, and machine-executable instructions are stored on memory 3610.
The code can be pre-compiled and configured for use with a machine having a processer adapted to execute the code, or can be compiled during runtime. The code can be supplied in a programming language that can be selected to enable the code to execute in a pre-compiled or as-compiled fashion.
Aspects of the systems and methods provided herein, such as the computer system 3601, can be embodied in programming. Various aspects of the technology may be thought of as “products” or “articles of manufacture” typically in the form of machine (or processor) executable code and/or associated data that is carried on or embodied in a type of machine readable medium. Machine-executable code can be stored on an electronic storage unit, such as memory (e.g., read-only memory, random-access memory, flash memory) or a hard disk. “Storage” type media can include any or all of the tangible memory of the computers, processors or the like, or associated modules thereof, such as various semiconductor memories, tape drives, disk drives and the like, which may provide non-transitory storage at any time for the software programming. All or portions of the software may at times be communicated through the Internet or various other telecommunication networks. Such communications, for example, may enable loading of the software from one computer or processor into another, for example, from a management server or host computer into the computer platform of an application server. Thus, another type of media that may bear the software elements includes optical, electrical, and electromagnetic waves, such as used across physical interfaces between local devices, through wired and optical landline networks and over various air-links. The physical elements that carry such waves, such as wired or wireless links, optical links, or the like, also may be considered as media bearing the software. As used herein, unless restricted to non-transitory, tangible “storage” media, terms such as computer or machine “readable medium” refer to any medium that participates in providing instructions to a processor for execution.
Hence, a machine readable medium, such as computer-executable code, may take many forms, including but not limited to, a tangible storage medium, a carrier wave medium or physical transmission medium. Non-volatile storage media include, for example, optical or magnetic disks, such as any of the storage devices in any computer(s) or the like, such as may be used to implement the databases, etc. shown in the drawings. Volatile storage media include dynamic memory, such as main memory of such a computer platform. Tangible transmission media include coaxial cables; copper wire and fiber optics, including the wires that comprise a bus within a computer system. Carrier-wave transmission media may take the form of electric or electromagnetic signals, or acoustic or light waves such as those generated during radio frequency (RF) and infrared (IR) data communications. Common forms of computer-readable media therefore include for example: a floppy disk, a flexible disk, hard disk, magnetic tape, any other magnetic medium, a CD-ROM, DVD or DVD-ROM, any other optical medium, punch cards paper tape, any other physical storage medium with patterns of holes, a RAM, a ROM, a PROM and EPROM, a FLASH-EPROM, any other memory chip or cartridge, a carrier wave transporting data or instructions, cables or links transporting such a carrier wave, or any other medium from which a computer may read programming code and/or data. Many of these forms of computer readable media may be involved in carrying one or more sequences of one or more instructions to a processor for execution.
The computer system 3601 can include or be in communication with an electronic display 3635 that comprises a user interface (UI) 3640 for providing, for example, drug delivery and device control options. Examples of UI's include, without limitation, a graphical user interface (GUI) and web-based user interface.
Methods and systems of the present disclosure can be implemented by way of one or more algorithms. An algorithm can be implemented by way of software upon execution by the central processing unit 3605. The algorithm can, for example, determine the fluid viscosity and modulate the output of heating elements to adjust the fluid properties.
Aerosols for respiratory drug delivery can be generated using a handheld device. The device may be intended for medical use, medicinal use, recreational use, or combinations thereof. The device contains a user interface intended for permitting control and display of dosing history and dose control. The device comprises a body with an integrated screen, control buttons, a mouthpiece with an inhalation port, and a cap. The screen may be curved or flat, with backlighting, data display, and security measures. The device further comprises a cartridge containing a fluid compound. The device also comprises an aerosol generation mechanism and a power source. The power source may be a rechargeable battery or replaceable battery. An aerosol delivery device with a rechargeable battery may also have a charge port such as a Micro USB port. The charge port may also permit external connections to the user interface, for example for uploading dosage controls.
An aerosol delivery device, such as those described herein, may contain a syringe-type reservoir. For the product to be able to be shipped and to have a reasonable shelf life, the reservoir, in this case the interior of the syringe, needs to be able to be sealed upon loading of the formulation. To do this the syringe is manufactured with the outlet of the syringe sealed with a breakable seal that ruptures upon the syringe pump drive exerting sufficient pressure on the seal. This seal may be a section of plastic witch has been relieved or weakened by a thinning, or narrowing, of the seal (such that it ruptures with sufficient force). To fill the syringe with formulation, vacuum may be applied to the interior of the syringe, removing the majority of the air from the interior. Formulation may then be pumped into the reservoir. Subsequently, the entry point may be sealed by a method such as heat sealing or any other suitable methods.
The aerosol delivery device containing a dose cartridge comprises a syringe reservoir and a plunger. The element of the syringe pump that drives the plunger may be located in the reusable part of the product. The plunger of the syringe may be mated to a drive element in case at the end of an inhalation the syringe pump drive needs to pull back on the plunger to preclude unwanted formulation to be expressed. The plunger may be connected to a drive element with a mating clasp (ball and socket) or other suitable component between the plunger and the drive element. Alternatively, a magnet may be located on the drive element and a metal component may be located on the plunger.
An aerosol delivery device may contain a position sensing apparatus to accurately determine when the drive element has mated to the syringe plunger. Upon a dose cartridge being inserted into the reusable part of the product, the drive may locate the syringe plunger and properly mate to it. The aerosol delivery device may contain a position sensing apparatus that determines the position of the lead screw.
An aerosol delivery device may contain a dispensing system that transfers fluid from a reservoir to a heating element to permit aerosol formation.
An aerosol delivery device may contain a dispensing system that transfers fluid from a reservoir to a heating element to permit aerosol formation.
In the current market, devices that are used to generate an aerosol for inhalation may have a drawback in that they product an aerosol that has a particle size where a large proportion of the aerosol does not deposit in the respiratory tract and is exhaled making the exhaled aerosol visible. Aerosols from some vaping devices have particle sized in the 0.4-0.9-micron range (see data below, Table #1) and are too light to gravitationally settle or impact in the lung and are subsequently exhaled. As such, the devices and systems herein form aerosols with a particle size of greater than about 1 micron. When a proportion of the aerosol is exhaled it is both seen and smelt by others. This is often not optimal as the vape user may wish to not draw attention to themselves. Some vaping devises vaporize around 1.0-1.5 mg/sec (see data below) and because of the small cross section on their airway (e.g., 10 to 15 mm2) mix the vaporized compound into the entirety of the inhaled air.
In some embodiment, the device disclosed herein comprises a housing (4314) as showing in
The current example provides an embodiment of the device disclosed herein that provides a larger cross-sectional area of the airway to increase aerosol particle size. In one embodiment, the device disclosed herein can produce 10 mg/sec of vapor of the pharmaceutical composition disclosed herein. The cross sectional area of the airway in
As shown in
Further, in some embodiments as illustrated in
Certain cannabinoid extracts such as those called “Budder, Badder, Sugar, THCa Powder, Distillate, Rosin, Thick sauces” may have a high viscosity at room temperature. As such these extracts are difficult to pump from the syringe pump. In some embodiments, the device disclosed herein is used to preheat these compounds to a temperature wherein the viscosity is lowered to a point where pumping can occur. The preheating temperature ranges from about 35 to about 45 C.
While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. It is not intended that the invention be limited by the specific examples provided within the specification. While the invention has been described with reference to the aforementioned specification, the descriptions and illustrations of the embodiments herein are not meant to be construed in a limiting sense. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. Furthermore, it shall be understood that all aspects of the invention are not limited to the specific depictions, configurations or relative proportions set forth herein which depend upon a variety of conditions and variables. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is therefore contemplated that the invention shall also cover any such alternatives, modifications, variations, or equivalents. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.
This application is a continuation-in-part of U.S. application Ser. No. 17/564,085, filed Dec. 28, 2021, which is a continuation of International Application No. PCT/US2020/040765, filed Jul. 2, 2020, which claims the benefit of U.S. Provisional Patent Application No. 62/870,612, filed Jul. 3, 2019, each of which is incorporated by reference herein in its entirety.
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| Number | Date | Country | |
|---|---|---|---|
| Parent | PCT/US2020/040765 | Jul 2020 | WO |
| Child | 17564085 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 17564085 | Dec 2021 | US |
| Child | 17746785 | US |
