Patent Application
20080259519
Not applicable.
1. Field of the Invention
The present invention relates to the field of non-respirable aerosols, particularly non-respirable aerosols produced from very low-resistivity liquid compositions, particularly very low-resistivity aqueous liquid compositions, using electrohydrodynamic (EHD) means, including an improved nozzle, for generating small, uniform, non-respirable aerosol particles comprising biologically-active agents, as well as to methods of using such liquid formulations to deliver biologically-active agents to a target surface.
2. Description of Related Art
Creating non-respirable particles of highly-aqueous liquid formulations using EHD presents some unique problems. To effect the Taylor cone, which is the hallmark of EHD, the liquid must be subjected to a charge sufficient to overcome the surface tension of the liquid and the liquid breaks apart (a process called comminution). In a highly-aqueous formulation, the surface tension which must be overcome is generally very high. In addition, the resistivity of the formulation is very low which inhibits formation of a charge on the liquid and the formation of the Taylor cone. To overcome the surface tension in a highly-aqueous, high-resistivity formulation, a high charge is required. This, in turn, creates particles of very small size, at very low delivery rates, and generally non-uniform dispersions. Thus, there is a need to create larger, non-respirable particles of highly-aqueous, high-resistivity formulations that can be utilized in situations where respiration would be harmful.
Handheld electrohydrodynamic aerosolization/spraying means are known in the art. U.S. Pat. No. 6,397,838 to Zimlich et al. describes a handheld, EHD pulmonary aerosol delivery device that produces a cloud of aerosolized liquid particles having a mono-disperse, respirable particle size and mean zero velocity. As described in Zimlich, the aerosol particles are such that at least about 80 percent have a diameter of less than or equal to about 5 microns.
U.S. Pat. No. 4,381,533 to Coffee describes an EHD spray device, principally for use in crop spraying. A stated essential component of the Coffee spray device is a circular field intensifying electrode, sited annularly adjacent to the circular sprayhead. In use, it is stated to reduce the incidence of corona discharge which interferes with spray production and thereby allows lower electric field strengths to be used during spray generation.
U.S. Pat. No. 6,503,481 to Thurston et al. teaches a method for delivering a biologically-active material to the respiratory tract of a patient in need of treatment comprising the steps of producing a respirable aerosol of a liquid composition using an EHD spraying means and administering the aerosol to the pulmonary tract of a patient via inhalation of the aerosol. The aerosol comprises a pharmaceutically-effective amount of an active agent in a carrier liquid in which the active agent is dissolved, emulsified, or suspended. Specific liquid medicament formulations are described which are useful in the methods of the invention.
Various liquid medicament formulations suitable for aerosolization using an EHD device and administration to a patient by pulmonary delivery are described in the following U.S. Pat. Pub. Nos. 2002/0102218 to Cowan and 2002/0110524 and 2003/0185762 to Cowan et al. None of these publications disclose the particular non-respirable aerosols described and claimed herein.
Finally, especially with multiple-nozzle arrays, and particularly with multiple-nozzle arrays that are substantially linear, the field intensity at each nozzle, or spray site, varies from site to site due to the effect each nozzle has on adjacent nozzles. Such uneven field intensity results in uneven aerosolization and uneven particle size, which, in turn, results in a much greater particle size distribution. This interferes with the spraying of aqueous formulations using multiple nozzle arrays, and particle size variability can also be undesirable when spraying biologically-active materials.
There is, therefore, a need for improved highly-aqueous non-respirable aerosols, methods of making same, and devices therefor.
The invention is directed to non-respirable aerosols useful for delivery of a biologically-active agent to a target surface, as well as to methods of treating a target surface using such biologically-active aerosols, and further to highly-aqueous liquid carrier vehicles for biologically-active agents which are suitable for aerosolization using an EHD spraying means. An improved sprayhead assembly for generating such aerosols is also disclosed.
One object of the present invention is to provide an aqueous liquid carrier vehicle for direct delivery of an aerosol having a particle size of between about 60 μm and about 800 μm and containing a dissolved or suspended optionally biologically-active agent, comprising about 60 weight percent to about 100 weight percent water, about zero weight percent to about 40 weight percent co-solvent, about 0.05 weight percent to about 10 weight percent of an acceptable surfactant, and about zero weight percent to about 10 weight percent of an optionally biologically-acceptable excipient, wherein the liquid carrier vehicle has a resistivity of about 0.05 ohm-m to about 20 ohm-m, a surface tension of about 20 dynes/cm to about 100 dynes/cm, and a viscosity of about 0.1 cPs to about 100 cPs.
It is a further object of the present invention to provide an aqueous liquid carrier vehicle for direct delivery of an aerosol having particles having a GSD of about 1.10 to about 1.65.
It is a further object of the present invention to provide an aqueous liquid carrier vehicle comprising a surfactant having a surface tension of about 30 dynes/cm or less.
Another object of the present invention is to provide an aerosol, using EHD means, having a particle size between about 60 μm and about 800 μm and comprising a biologically-effective amount of a biologically-active agent dissolved, suspended, or emulsified in the aqueous liquid carrier vehicle described herein above.
Yet another object of the present invention is to provide a method for delivering a biologically-active agent to a target surface in need of treatment, comprising the steps of preparing an aqueous liquid carrier vehicle as described herein above, dissolving, suspending, or emulsifying a biologically-effective amount of the biologically-active agent in the liquid carrier vehicle, producing an aerosol of the solution or suspension using EHD means, wherein the aerosol particle size in about 60 μm to about 800 μm and applying the aerosol to the target surface.
Yet another object of the present invention is to provide a sprayhead assembly for EHD spraying, comprising a nozzle array, the nozzle array comprising a plurality of nozzles, preferably configured in a substantially linear arrangement, and comprising at least one, preferably a plurality or array, of inner nozzles and preferably at least one first and at least one second nozzle (also referred to herein as a first array and a second array of outer nozzles, respectively), at least one field-equalizing counter electrode, the counter electrode in charge communication with the nozzle array and comprising a first end portion, a second end portion, and a central portion therebetween, wherein the central portion is positioned closer to the array of inner nozzles than the first end portion is positioned to the first array of outer nozzles and than the second end portion is positioned to the second array of outer nozzles.
It is yet another object of the present invention to provide a method of substantially equalizing the fields about a plurality of nozzles, the method comprising the steps of providing a plurality of nozzles, charging at least two of the plurality of nozzles, wherein the charge on the at least two nozzles in unequal, providing at least one counter electrode, and applying a charge or ground to the at least one counter electrode, whereby the field on the at least two nozzles becomes substantially equal.
In EHD practice, as described hereinabove, the liquid is subject to a charge which causes it to form a Taylor cone and, subsequently, to comminute. It is the charge on the liquid at the Taylor cone that, in part, controls the comminution. An electrical charger is placed in electrical communication with the liquid, either directly via the fluid itself, or indirectly via the nozzle. It is well within the ability of EHD spraying to provide a substantially monodisperse aerosol when using one spray site. In practice, however, a higher flowrate is often desired than is practically achievable with a single site. In a multi-site nozzle array, especially one that is substantially linear, the charge experienced by the liquid in the Taylor cone may be affected by the charge on nearby sites. Thus, not all sites (Taylor cones) will produce the same aerosol distribution.
The present invention introduces a counter electrode design that can alter the charge at each site by affecting the field at the spray site in the vicinity of the Taylor cone in a manner which alters, influences, and can make more equal or substantially equal, the charge at each spray site, cause the collective aerosol to be more monodisperse, and provide control of droplet size. This ability of the counter electrode to effect the charge at the spray sites without being in electrical contact with the spray site is referred to herein as “charge communication”.
It may be understood that not only may varying the shape and charge of the counter electrode one may effect charge communication with a series of spray sites, but also that such charge communication can be adjusted on a given spray head mechanically or electrically. Mechanical adjustment is possible by placing the counter electrode of the present invention (whether a curved filament or a series of individual counter electrodes) on adjustable or movable supports which permit adjustment in the three dimensions of height relative to the spray sites, distance of the electrode to the spray sites, or curvature of the counter electrode. Where a series of individual electrodes comprise the counter electrode in accordance with the present invention, each of the individual electrodes of the counter electrode may be separately adjustable.
As well, electrical adjustment of the counter electrode of the present invention alone or in combination with mechanical adjustment features, permits controlled application of charge communication to tune an apparatus as needed for spraying a particular material, and to create desired dispersion characteristics. To this end, the voltage on the counter electrode can be changed as desired. Alternatively, the charge on ones of a series of counter electrodes arranged in accordance with the present invention can be separately controlled and thus dynamically adjusted to vary the charge communication and influence spray site performance. Electronic controllers may be useful in this regard to provide dynamic adjustment during use.
The following detailed description of the embodiments of the invention will be more readily understood when taken in conjunction with the following drawing, wherein:
In one embodiment of the present invention, an aqueous
As used herein, the term “electrohydrodynamic” or “EHD” may also be referred to as “electric field effect technology” or “EFET” and these terms are used interchangeably. Dispensing devices are known which produce a finely divided spray of liquid particles EFET (EHD) means. These sprayers have found use in many areas, including, without limitation, medicine for the administration of medicaments and biologicals by topical application or inhalation, in agriculture for crop spraying, in consumer markets for consumer products, and in industry for spraying coatings, paints, and other materials used in manufacturing processes.
The EHD spraying means described herein may be stationary or handheld. Such devices are “stationary” in the respect that their size prevents them from being easily held and carried by the user. Stationary EHD devices may be portable if moved on a cart, dolly, or vehicle such as a truck or an airplane. In many of the applications described herein, it is advantageous that the EHD device be small, portable, and handheld. As an example, an EHD device about the size of a cell phone would enable the user/applicator to use apply the biologically active aerosols in a variety of locations where it would be inconvenient to move a larger device. For example, a portable, handheld EHD device is ideal for treating one's clothing in a wooded or field environment where there may be deer ticks infected with the bacterium Borrelia burgdorferi, which causes Lyme Disease and which is transmitted to humans by the bite of an infected deer tick.
In a typical EHD device, a fluid delivery means delivers fluid to be aerosolized to a nozzle and the fluid or the nozzle is maintained at high electric potential. One type of nozzle used in EHD devices is a capillary tube capable of conducting electricity. An electric potential is placed on the capillary tube which charges the fluid contents or upon the fluid itself such that, as the fluid emerges from the tip or end of the capillary tube, a so-called Taylor cone is formed. This cone shape results from a balance of the forces of electric charge on the fluid and the surface tension of the fluid Desirably, the charge on the fluid overcomes the surface tension and at the tip of the Taylor cone, a thin jet of fluid forms and subsequently and rapidly separates a short distance beyond the tip into an aerosol. Studies have shown that the aerosol from a single capillary nozzle can have a substantially uniform particle size and a high velocity leaving the tip but that it quickly decelerates to a very low velocity a short distance beyond the tip.
EHD sprayers produce charged particles at the tip of the nozzle. Depending upon the use, these charged particles can be partially- or fully-neutralized (with, for example, a discharge electrode in the sprayer device). When the EFET device is used to deliver therapeutic, respirable aerosols, it is preferred that the aerosol be completely electrically neutralized prior to inhalation by the user to permit the aerosol to reach the pulmonary areas where the particular therapeutic formulation is most effective. In the case of a non-therapeutic, non-respirable aerosol such as the subject of the present invention, typically the aerosol is intended to be deposited on a target surface, and an EFET sprayer without means for discharging or with means for only partially discharging an aerosol might be preferred since the aerosol would have a residual electric charge as it leaves the sprayer so that the particles would be attracted to and tightly adhere to the target surface.
The nozzle assembly of an EHD spray device may include one or more, preferably two for a linear nozzle array, so-called “dummy” electrodes. In practice, a dummy electrode is placed at each end of the nozzle array. While the dummy electrodes are charged similarly to the active spray sites, no fluid is supplied to them. They serve only to help balance the electric charges, especially at the outermost spray sites in a linear array. See, e.g., U.S. Pat. No. 6,302,331 to Dvorsky et aL. cited above.
Int'l App. No. PCT/US2004/000556, to which the instant application claims priority, the contents of which are included herein by reference as if fully rewritten herein, discloses a spray-shaping mechanism comprising parallel counter electrodes. These counter electrodes may be employed in “localizing” the electric field that is produced at the spray site. The counter electrodes may effectively boost the velocity of the EHD spray forward, as well as shape or split the spray toward a desired target. This feature is capable of presenting a more uniform field to each spray site. Alternatively, a counter electrode may be referred to as a “reference” electrode. What is intended, however, is that the electrode has a potential relative to the spray site. As will be appreciated by those skilled in the art, no implication is intended as to any specific polarity or relativity to earth ground or other external reference for the counter electrode. The key is that the counter electrode has a potential relative to the spray site. As described in more detail herein below, counter electrodes have been developed which are particularly suitable to effecting a more uniform field about each spray site in a substantially linear nozzle array.
Various EHD devices are known in the art, for example, U.S. Pat. Nos. 6,302,331 to Dvorsky et al., 6,105,877, 6,457,470, 6,386,195, and 6,252,129 to Coffee, and 6,595,208 to Coffee et al. Although, the various patents disclose different methods for obtaining aerosols having an aerosol particle size of in the range of from 0.1 um to 50 um, very little direction is provided regarding suitable carrier liquids or improving spray site field uniformity.
The term “aqueous liquid carrier vehicles” as used herein refers to the liquid carrier vehicle in which the biologically-active agent to be applied to a target surface is dissolved or suspended. The aqueous liquid carrier vehicle is required to contain at least about 60 weight percent to about 100 weight percent water, preferably from about 85 weight percent to about 100 weight percent water, and more preferably from about 90 weight percent to about 100 weight percent water. The term “highly aqueous” is used herein to describe aqueous liquid carrier vehicles of the invention containing from about 90 weight percent to about 99 weight percent water and more preferably from about 95 weight percent to about 100 weight percent water.
The aerosols of the invention can be used to deliver a “biologically-active agent” to a target surface. The term “target surface” as used herein may be any surface that benefits from treatment of a biologically-active agent with a soft cloud of a non-respirable aerosol according to the invention. As used herein, the term “target surface” does not refer to an interior tissue surface in a human or animal body such as the lungs or oral, vaginal, or rectal cavities. The target surface may be for example, plants, the soil (ground) around plants, the leaves and stems of plants, the eyes, skin, coat, hide, or hide of animals such as cats, dogs, and horses, the skin, eyes, and hair of humans, the clothing of humans, and hard surfaces such as walls, floors, tables, desks, beds, and other furnishings, manufacturing and building infrastructure, and the like found in hospitals, nursing homes, schools, and restaurants.
As used herein, the term “biologically-active agent” refers to an agent or combination of agents that may be used in agriculture, horticulture, veterinary medicine, personal animal, or human care, disinfecting, and other applications where it is desirable to deliver a biologically-active agent to a target surface. The biologically-active agents contemplated for use in the aerosols and methods of the invention include but are not limited to herbicides, plant growth regulators, insecticides, fungicides, miticides, biocides, antibacterials, antivirals, anti-inflammatories, disinfectants, ocular decongestants, skin and eye treatments, and the like.
Illustrative, but non-limiting examples of the aerosols prepared as described herein are aerosols useful to deliver insecticides and fungicides to trees and shrubs, plants such as roses, orchids, violets, and other valuable flowering plants, as well as to deliver herbicides to bed plantings and home gardens, especially when handheld, battery powered, portable EHD devices are used to produce the aerosol. The aerosols and methods of the invention can be used to apply anti-tick, flea, and mite active agents to the coat of mammals such as dogs, cats, and horses, the skin and hair of humans, and the outer clothing of humans to protect against fleas, ticks, and mites. The aerosols of the invention can be used to apply disinfectant agents to hard surfaces in schools, restaurants, hospitals, businesses, stores, manufacturing facilities, and the home. In schools, for example, the aerosols may be use to treat desks and cafeteria tables to prevent the spread of viruses and bacterial, especially in influenza season.
Illustrative, but non-limiting examples of specific biologically-active agents useful in the aerosols and methods of the invention include: herbicides e.g., (2,4,5-trichlorophenoxy)acetic acid, (4-chloro-2-methylphenoxy)acetic acid, (2,4-dichlorophenoxy)acetic acid, 4-(4-chloro-o-tolyloxy)butyric acid, fluazifop-p-butyl (Ornamec®, Gordon Corp, Kansas City, Mo.), pelargonic acid (Scythe®, Mycogen Corp., San Diego, Calif.), and isopropylamine salt of N-(phosphonomethyl)glycine (Roundup®, Scotts, Marysville, Ohio or Glyphomax®, Dow Agrosciences, Indianapolis, Ind. ); fungicides e.g., manganese ethylene bisdithiocarbamate (Maneb), 1-(4-chlorophenoxy)-3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl)-2-butanone (Strike®, Olympic Horticultural Products, Mainland, Pa.), azoxystrobin (Amistar®, Syngenta, Basel, CH), andtrifloxystrobin (Compass™, Bayer CropScience, Research Triangle Park, N.C.); insecticides, e.g., Bacillus thuringiensis (B.t.) (sold under the trade names Dipel® (Valent Corp, Dublin, Calif.), Thuricide® (Bonide Products, Oriskany, N.Y.), Bactospeine® (PBI/Gordon, Kansas City, Mo.), Leptox, Novabac, and Bug Time); synthetic pyrethroids, e.g., permethrin, cypermethrin, fenvalerate/esfenvalerate, tralomethrin, bifenthrin, cyfluthrin, and lambda-cyhalothrin, O,O-Diethyl 0-(2-isopropyl-6-methyl-4-pyrimidinyl) phosphorothioate (diazinon); treatments for fleas, ticks, and lice, e.g., lindane and malathion (headlice, pubic lice), permethrin (ticks), N,N-diethyl-meta-toluamide (DEET) (mosquitoes), fenthion, and cythioate (fleas); and disinfectants, e.g., 3,4′,5 tribromosalicylanilide (tribromsalan).
The biologically-active agents described herein are present in the aerosols of the invention at a “biologically-effective amount”. As would be recognized by one skilled in the art, by “biologically-effective amount” is meant an amount of a biologically-active agent that is sufficient to provide the result sought. In general, from about 0.01 weight percent to about 50 weight percent of the biologically-active agent will be present in the liquid carrier vehicle. Specific details of the effective dosage or concentration of a particular active agent may be found in its product labeling, e.g., the package insert if the active agent is regulated by the United States Food and Drug Administration (FDA) (see, 21 CFR § 201.56 & 201.57) or the labeling approved by the United States Environmental Protection Agency (EPA) if the active agent is, e.g., a herbicide, insecticide, miticide, and the like, which is covered by the rules and regulations of the EPA.
When a biologically-active agent is added to the aqueous liquid carrier vehicle, a solution is produced if the active agent is soluble in the liquid carrier vehicle and a suspension is produced if the active agent is insoluble. The term “suspension” as used herein is given its ordinary meaning and refers to particles of active agent or aggregates of particles of active agent suspended in the liquid carrier vehicle. When the active agent is present as a suspension the particles of active agent will preferably be in the nano or micron range.
Among the advantages of the present invention is the ability to use a highly-aqueous carrier liquid that is more “bio-friendly” than conventional EHD carriers such as oil-based or solvent-based carriers. The multi-nozzle configuration further enables higher flowrates, while the counter electrodes of the present invention enable design and control over particle size for a given application. A further advantage in many applications is the elimination of slippery or undesired oil or solvent residue from other carrier liquids.
Depending on the biologically-active agent used in the aerosols and methods of the invention, it may be advantageous to include a co-solvent in the aqueous liquid carrier vehicle. The co-solvent may be selected from such groups as alcohols, ethers, alkyl sulfoxides, and propylene oxides. Examples of specific co-solvents include ethanol, 2-ethylhexanol, diacetone alcohol, diisobutyl ketone, isobutanol, isophorone, methyl isobutyl ketone, n-butanol, n-pentanol, n-propanol, and combinations thereof. Ethanol is a particularly preferred solvent because it is soluble in water, is relatively inexpensive, and is safe for the environment, animals, and humans.
The choice of a particular co-solvent or mixture of co-solvents is within the skill of the art and will be made by the skilled artisan taking into account such factors as how an aerosol of the invention will be used, the particular active agent, and if the target surface is a plant, animal, or hard surface. The co-solvent should be soluble in or miscible with water, have a viscosity in the range of 0.1 cPs to 100 cPs, and should not raise the surface tension of the liquid carrier vehicle or aerosol above 60 dynes/cm. The co-solvent will be present in the liquid carrier vehicle of the invention at from about zero weight percent to about 40 weight percent, preferably from about 1 weight percent to about 40 weight percent, and more preferably from about 5 weight percent to about 15 weight percent.
An essential component of the highly-aqueous liquid carrier vehicle of the invention and the aerosols produced therefrom is the surfactant. It important that the surfactant selected be capable of quickly lowering surface tension at the interface between air and liquid as the liquid is exiting the EHD spray nozzle and the electric charge is being applied to the liquid to form the aerosol droplets.
While not being bound by theory, the choice of surfactant or mixtures of surfactants used in the liquid carrier vehicles described herein, it is important to control the surface tension as the aerosol droplet is formed coming from the EHD spray nozzle. It is desirable to keep the surface tension as low as possible at this point in order to produced good aerosolization of the aqueous liquid.
The surfactant, or mixtures of surfactants, used in the aqueous liquid carrier vehicles of the invention should be non-corrosive to the EHD device, should be environmentally safe at the concentrations used, should be non-toxic to humans and animals at the concentrations used, and should have no adverse effect on the activity of the biologically-active agent being delivered in the aerosols of he invention.
Examples of surfactants found to be useful in the aerosols and liquid carrier vehicles of the invention are non-ionics such as alkoxypoly(ethyleneoxy) alcohols such as Rhodasurf® BC 720 (Brenntag, Antwerp, BE), a water-soluble alkoxypoly(ethyleneoxy) ethanol surfactant having an HLB (Hydrophile-Liphophile Balance) of 13.8, alkyl polyglycosides sold under the tradenames Agnique® PG 8107-U (HLB 13.6) and Agnique® PG 9116 (HLB 13.1) (both from Cognis Corp., Cincinnati, Ohio); polyoxyethylene ethers, e.g., polyoxyethylene(10) tridecyl ether (ANAPOE®-C12E10, Anatrace, Maumee, Ohio); alkyl-β-D-glucopyranosides, e.g., hexyl-, heptyl-, octyl-, decyl-, and dodecyl-β-D-glucopyranoside; and alkyl-β-D-maltoglucopyranosides, e.g., hexyl-, octyl-, nonyl-, decyl-, undecyl-, dodecyl-, and tetradecyl-β-D-maltoglucopyranoside (Anatrace).
The choice of a particular surfactant for use in a particular liquid carrier vehicle will be made considering the physical and chemical properties of the active agent to be aerosolized, e.g. whether the active agent is soluble in water or very insoluble, the amount of co-solvent in the liquid carrier vehicle, the nature and amount of any excipient in the liquid carrier vehicle, the desired particle size of the resulting aerosol and the desired spray flow rate. The surfactant will be present in the liquid carrier vehicle of the invention at from about 0.05 weight percent to about 10 weight percent, preferably from about 0.05 weight percent to about 5 weight percent, and more preferably from about 0.1 weight percent to about 2.5 weight percent.
Other optionally-present components in the aerosols and aqueous liquid carrier vehicles of the invention are “biologically-acceptable excipients”. A used herein, the term “biologically-acceptable excipients” include those compounds and additives listed by the FDA as being generally recognized as safe (GRAS) for use in humans (see, 21 CFR § 182). The term also includes those additives that are exempted from the requirement of a tolerance when used in accordance with good agricultural practices. See Federal Insecticide, Fungicide and Rodenticide Act (FIFRA), 7 U.S.C. §136 et seq. (1996) and 40 C.F.R. § 180.1001.
Illustrative of such excipients include but not limited to polyols e.g., propylene glycol, glycerol, polyvinyl alcohol (PVA), and polyethylene glycol (PEG) having an average molecular weight between about 200 and 4000, antioxidants, e.g., Vitamin E, Vitamin E TPGS (alpha-tocopferol polyethylene glycol 1000 succinate), ascorbic acid, anti-microbials, e.g., parabens, pH-adjusting agents, e.g., sodium hydroxide and hydrochloric acid, viscosity-adjusting agents, e.g., polyvinylpyrrolidone, and ionic materials to add charge to the liquid carrier formulation are contemplated for use herein.
The aerosols and aqueous liquid carrier vehicles of the invention may include minor amounts, that is, up to 10 weight percent, preferably from about 0.05 weight percent to about 5 weight percent, and more preferably from about 0.1 weight percent to about 2.5 weight percent of a “biologically-acceptable excipient”. As used herein, the term “biologically-acceptable excipient” refers not only to a single excipient but also to mixtures of two or more excipients; e.g., an aerosol or aqueous liquid carrier vehicle of the invention might contain an antioxidant, a viscosity-adjusting agent, and an ionic material.
While the selection of any particular biologically-acceptable excipient or mixture of excipients is within the skill of the art, the decision regarding whether to add an excipient, and if so which one, will be made taking into account the purpose of the excipient in a specific aqueous liquid carrier vehicle. Any excipient used in the aerosols or liquid carrier vehicles described herein should have no effect or minimal effect on the sprayability of the aqueous liquid containing the biologically-active agent.
The particle size of the aerosol droplets of the invention should be sufficiently large to ensure that the aerosol particles will not be inhaled by an animal or human. The particle size of the aerosol droplets should average from about 60 μm to about 800 μm, preferably from about 80 μm to about 500 μm, and more preferably about 150 μm to about 350 μm in diameter. The average particle size of the droplets is usually referred to as “mass median diameter” (MMD). It is also important that the corresponding geometric standard deviation (GSD) be low, indicating a monodisperse or nearly monodisperse aerosol. A polydisperse aerosol will contain many aerosol particles that are smaller than the target range and many that are larger. Aerosol particles smaller than about 50 μm might be inhaled or “respired” by animals or humans as the aerosol is being applied to the target surface. On the other hand, if the aerosol particles are larger than about 800 μm the aerosol droplets can coalesce and drip off the target surface wasting the biologically-active agent. It is thus highly desirable that the aerosol be as nearly monodisperse as possible.
The highly-aqueous liquid carrier vehicles and compositions prepared according to the invention have a resistivity of from about 0.05 ohm-m to about 100 ohm-m, preferably from about 0.1 ohm-m to about 10 ohm-m, and more preferably from about 0.25 ohm-m to about 5 ohm-m. The highly-aqueous liquid carrier vehicles and compositions prepared according to the invention have a viscosity of from about 0.1 cPs to about 100 cPs, and a surface tension of from about 20 dynes/cm to about 60 dynes/cm.
Unlike the prior art aqueous liquid carrier vehicles, which are generally aerosolized/ sprayed at relatively low flow rates (on the order of μl/sec), the highly-aqueous liquid carrier vehicle of the invention maybe sprayed at commercially-acceptable flow rates. As an example, if a multiple site nozzle having ten sites is used to produce an aerosol according to the invention, and the flowrate at each site is on the order of 0.5 μl/sec/site to 2.0 μl/sec/site, an overall flow rate of 5 μl/sec to 20 μl/sec would result.
The following examples illustrate the method and various compositions and carrier vehicles described herein. The examples were aerosolized using a linear nozzle assembly (4 metallic nozzle ports plus a “dummy” nozzle at each end) with curvilinear-shaped grounded counter electrodes. The nozzles were constructed of stainless steel tubing, had an outside diameter of 0.8 mm, an inside diameter of approximately 0.5 mm and were on 3.5 mm centers. The counter electrodes were constructed of 0.8 mm tubing and, when installed, measured 12.7 mm from top-of-arc to top-of-arc. Each arc was 15.9 mm start-of-bend to end-of-bend. Each arc was orthogonal to the nozzles and was positioned at various points behind, even with, or in front of the tops of the nozzles.
In the examples below, the term “kV” indicates the voltage applied to each spray site of the nozzle of the EHD device to place a charge on the composition. A high voltage source ranging from 0 to +20 kV and 0 to −20 kV was used. The particle size analysis was performed using a Malvern MasterSizer® X particle size analyzer (Malvern Instruments, Inc., Southborough, Mass.). It has been discovered, furthermore, that a charge of negative polarity may work best for spraying highly aqueous formulations, due, it is thought to the bipolar nature of the water molecule.
In general, the formulations of the invention are prepared by adding the components together and mixing to give a liquid solution, an emulsion, or solid in liquid suspension. If the active agent is soluble in water, the active agent is mixed with the aqueous liquid and the co-solvent, surfactant, and excipient (if any) are added to the aqueous solution and the mixture is shaken or stirred to produce a homogenous solution. Where the active agent is substantially insoluble in the aqueous liquid component of the carrier vehicle and is soluble in the co-solvent, the active agent is added to the co-solvent, mixed, and the mixture is added to the aqueous component of the aqueous carrier vehicle. Where the active agent is only slightly soluble in water and/or the co-solvent, it may be advantageous to disperse fine particles of the active agent in the liquid carrier vehicle in order to achieve the desired concentration of the active in the carrier vehicle.
As shown by Ex. 1 and accompanying
As shown by Ex. 2 and accompanying
Although satisfactory sprays were obtained, they were less satisfactory than those observed when a surfactant was added.
As shown by Ex. 4 and accompanying
As shown by Ex. 5 and accompanying
Ex. 6 seems to indicate a surfactant is needed to spray PBS.
At flowrates of 0.42 and 1.04 μl/sec/site, a reasonably good spray was produced.
As shown by Ex. 8 and accompanying
As shown by Ex. 9 and accompanying
As shown by Ex. 10 and accompanying
Ex. 11 demonstrates the feasibility of using a combination of two different surfactants for spraying aqueous formulations using EHD. Good sprays were also observed at 0.42 and 0.84 μl/sec/site. As shown in
EXAMPLE 12
As shown by Ex. 12 and accompanying
Referring now to
As well, a curvilinear array of nozzles may be combined with curvilinear counter electrodes or a curvilinear arrangement of counter electrode elements to achieve more uniform spraying in a desired spray pattern.
As will be appreciated by those skilled in the art, a myriad of configurations are possible within the spirit of the invention. By adjusting the field of the spray sites with one or more counter electrodes, spray site uniformity may be improved with commensurate improvement in particle size uniformity at increased fluid flow and increased rates of aerosol delivery.
Turning now to
Table 1, below, summarizes the cases.
In Table 1, the sites noted are active sites. In all cases, the active sites were flanked by one dummy electrode at each end. The Center-to-Edge dimension is the distance from the center of the port (spray site) to the edge of the counter electrode.
In each case, the nozzle ports 14, have an outside diameter (O.D.) of 2 mm which is a median size for many practical ports. Also in each case, because it can be difficult to accurately examine the field directly at the surface of the spray port, an arbitrary circle 0.5 mm beyond the periphery of the port was established to measure and plot the field about each port. Finally, in addition to the sites noted, there is an additional dummy port 20 at each end. (See, e.g.,
In the detail shown in each case (e.g.,
Seen in
Case 2, shown in
Case 3, shown in
Case 4, shown in
Case 5, shown in
Case 6, shown in
Case 7, shown in
Case 8, shown in
Case 9, shown in
Case 10, shown in
Case 11, shown in
Case 12, shown in
Case 13, shown in
Case 14, shown in
Case 15, shown in
One skilled in the art will readily appreciate that the present invention is well adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those objects, ends, and advantages inherent herein. The present examples, along with the methods, procedures, treatments, specific active agents, and devices described herein, are presently representative of preferred embodiments, are exemplary, and are not intended as limitations on the scope of the invention. Changes therein and other uses will occur to those skilled in the art which are encompassed within the spirit of the invention as defined by the scope of the claims.
| Number | Date | Country | Kind |
|---|---|---|---|
| 10/541681 | Jul 2005 | US | national |
This Application claims priority to i) Provisional U.S. Pat. App. No. 60/609,791, filed Sep. 14, 2004, and ii) Int'l App. No. PCT/US2004/000556, U.S. patent application Ser. No. 10/541,681, now U.S. Pat. No. ______, which claims priority to Provisional U.S. Pat. App. Nos. i) 60/439,254, filed Jan. 10, 2003, now abandoned, ii) 60/439,257, filed Jan. 10, 2003, now abandoned, and iii) 60/439,606, filed Jan. 11, 2003, now abandoned, the contents of which are incorporated herein by reference as if fully rewritten herein.
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/US05/33108 | 9/14/2005 | WO | 00 | 2/7/2008 |
| Number | Date | Country | |
|---|---|---|---|
| 60609791 | Sep 2004 | US |
