Animal intranasal administration device, systems, and associated methods

A veterinary subject intranasal administration device includes a first support member portion including a septum interface portion sized for insertion into a nasal passage of the veterinary subject; an actuation mechanism connected to the first support member portion; and a fluid conduit having a distal end opposite a supported end, the distal end sized for insertion into the nasal passage of the veterinary subject, the fluid conduit being flexible and configured to receive fluid from a fluid source and discharge the fluid through the distal end into the nasal passage, the distal end of the fluid conduit being unsupported and movable relative to the septum interface portion.

BACKGROUND OF THE DISCLOSURE

Nitric oxide gas has an antimicrobial effect and when safely administered can be used as a therapeutic treatment of microbial infection in a subject. While many systems have been described for the use of nitric oxide in clinical settings, these systems are designed for the delivery of nitric oxide gas to the subject in a way that requires the subject to remain stationary for an extended period of time. Unfortunately, many instances where treatment of nitric oxide would be particularly beneficial do not allow for the subject to be stationary or immobilized for the length of time needed to receive an effective dosage of nitric oxide gas.

For example, one such instance is in the cattle industry, where Bovine Respiratory Disease Complex (BRDc) continues to be the most common disease in feeder beef cattle in North America, affecting 20-40% of receiver calves annually. Production losses from BRDc include respiratory morbidity and mortality as well as increased treatment and processing cost. Its pathogenicity has been linked to a primary viral infection followed by a secondary bacterial infection.

While the incidence of BRDc has been shown to be reduced in animals treated with a suitable dosage of nitric oxide gas, effective commercialization of such therapy remains infeasible due to administration time constraints. Accordingly, there exists a need for a device, system, and method to quickly and efficiently deliver an effective dose of a nitric oxide gas.

The background of the disclosure is described herein to explain the context of the present invention. This is not to be taken as an admission or a suggestion that any of the material referred to was published, known or part of the common general knowledge in the art to which the present invention pertains, in the United States or in any other country, as at the priority date of any of the claims.

SUMMARY OF THE DISCLOSURE

In one aspect, devices for intranasal administration of fluids are provided. In some embodiments, an intranasal administration device for a veterinary subject comprises a first support member portion including a septum interface portion sized for insertion into a nasal passage of the veterinary subject; an actuation mechanism connected to the first support member portion; and a fluid conduit having a distal end opposite a supported end, the distal end sized for insertion into the nasal passage of the veterinary subject, the fluid conduit being flexible and configured to receive fluid from a fluid source and discharge the fluid through the distal end into the nasal passage, the distal end of the fluid conduit being unsupported and movable relative to the septum interface portion.

In some embodiments, an intranasal administration device for a veterinary subject comprises a first member pivotally coupled to a second member, each of the first member and the second member including an arm, wherein the arm of the first member is pivotally coupled to the arm of the second member; a handle portion coupled to and extending proximally from the arm; and a jaw coupled to and extending distally from the arm and having a distal end, wherein the distal end of the jaw of the first member and the distal end of the jaw of the second member are configured to clamp the nasal septum of a veterinary subject; a fluid conduit supported by the first member and having a distal end detached from the distal end of the jaw of the first member; and a second fluid conduit supported by the second member and having a distal end detached from the distal end of the jaw of the second member. When the intranasal administration device is clamped to the nasal septum the first fluid conduit and the second fluid conduit extend past a flow constriction formed by the alar folds and the basal folds of the veterinary subject to deliver a fluid into the veterinary subject.

In another aspect, a method to deliver a fluid intranasally to a veterinary subject is provided. In some embodiments, the method comprises opening jaws of an intranasal administration device, the intranasal administration device comprising fluid conduits; inserting the jaws and the fluid conduits into the nostrils of the veterinary subject; clamping the nasal septum of the veterinary subject with the jaws to retain the fluid conduits in the nose of the veterinary subject; and discharging a fluid through the fluid conduits. The animal intranasal administration device can include a first support member pivotally coupled to a second support member, each of the first support member and the second support member including an arm, wherein the arm of the first support member is pivotally coupled to the arm of the second support member; a handle portion coupled to and extending proximally from the arm; a jaw coupled to and extending distally from the arm, wherein the jaw of the first support member and the jaw of the second support member are configured to clamp the nasal septum of an animal; a first fluid conduit supported by the first support member and having a distal end; and a second fluid conduit supported by the second support member and having a distal end, wherein when the animal intranasal administration device is clamped to the nasal septum the first fluid conduit and the second fluid extend past a flow constriction formed by the alar fold and the basal fold of the animal to deliver a fluid into the nasopharynx of the animal.

There has thus been outlined, rather broadly, various features of the invention so that the detailed description thereof that follows may be better understood, and so that the present contribution to the art may be better appreciated. Other features of the present invention will become clearer from the following detailed description taken with the accompanying claims.

Corresponding reference characters indicate corresponding parts throughout the several views. Although the drawings represent embodiments of various features and components according to the present disclosure, the drawings are not necessarily to scale and certain features may be exaggerated in order to better illustrate and explain the present disclosure. The exemplifications set out herein are not to be construed as limiting the scope of the invention in any manner.

DETAILED DESCRIPTION

Each of the following terms has the meaning associated with it in this section.

“About” as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±20%, ±10%, ±5%, ±1%, and ±0.1% from the specified value, as such variations are appropriate. It is to be understood that in the present specification, the use of the term “about” in connection with a numerical value also affords support for the exact numerical value as though it had been recited without the term “about”.

The terms “comprises,” “comprising,” “containing,” and “having” and the like can have the meaning ascribed to them in U.S. Patent law and can mean “includes,” “including,” and the like, and are generally interpreted to be open ended terms. The terms “consisting of” or “consists of” are closed terms, and include only the components, structures, steps, or the like specifically listed in conjunction with such terms, as well as that which is in accordance with U.S. Patent law.

Except where a contrary intent is expressly stated, terms are used in their singular form for clarity and are intended to include their plural form.

“NORS” as used herein may refer to a nitric oxide releasing solution or substance. In one aspect, NO released from NORS may be a gas.

As used herein, “gaseous nitric oxide,” or “gNO” refers to exogenous nitric oxide. gNO can be delivered to a veterinary subject per se, or can be delivered via NORS.

The term “veterinary subject” refers to a non-human animal or individual. Some non-limiting examples of veterinary subjects can include a bovine, goat, swine, foul, canine, feline, horse, bison, alpaca, llama, sheep, and the like. In one embodiment, the veterinary subject can be a bovine. In another embodiment, the veterinary subject can be a chicken, rooster, duck, goose, pheasant, or other fowl. In another embodiment, the veterinary subject can be a pig or other swine. In another embodiment, the veterinary subject can be a dog or a cat. In another embodiment, the veterinary subject can be a ferret or a mink. In yet another embodiment, the veterinary subject can be a commercially salable animal.

Occurrences of the phrase “in one embodiment,” or “in one aspect,” herein do not necessarily all refer to the same embodiment or aspect.

As used herein a “therapeutic agent” refers to an agent that can have a beneficial or positive effect on a veterinary subject when administered to the veterinary subject in an appropriate or effective amount. In one aspect, NO can be a therapeutic agent.

As used herein, an “effective amount” of an agent is an amount sufficient to accomplish a specified task or function desired of the agent. The phrase “therapeutically effective amount,” as used herein, refers to an amount that is sufficient or effective to prevent or treat (delay or prevent the onset of, prevent the progression of, inhibit, decrease or reverse) a disease or disorder in a subject. It is understood that various biological factors may affect the ability of a substance to perform its intended task. Therefore, a “therapeutically effective amount” may be dependent in some instances on such biological factors. Further, while the achievement of therapeutic effects may be measured by veterinarian, or other qualified veterinary personnel using evaluations known in the art, it is recognized that individual variation and response to treatments may make the achievement of therapeutic effects a somewhat subjective decision. The determination of an effective amount or therapeutically effective amount is well within the ordinary skill in the art of pharmaceutical sciences and medicine.

In one aspect, the present disclosure provides an animal intranasal administration device, and associated systems and methods related to a nitric oxide releasing solution (NORS) capable of reducing the presence of a bacteria, virus, or other pathogen in a veterinary subject. In one aspect, the present disclosure provides a method and apparatus for treating a subject animal with the delivery of a nitric oxide releasing solution to a treatment site of the veterinary subject, such as at least a portion of an upper respiratory tract of the animal.

The present disclosure allows for delivery of nitric oxide to an ambulatory veterinary subject, or to an assembly line of veterinary subjects where the administration protocol for delivery of the nitric oxide releasing solution is accomplished in a short time period. For example, the extended release and delivery of nitric oxide to the treatment site by way of the administered nitric oxide releasing solution allows for the treated subject to remain ambulatory during treatment, or stationary for a very short period of time. Thus, the veterinary subject is not constrained to a nitric oxide delivery device during the entire duration of nitric oxide delivery. Rather, the nitric oxide releasing solution can be administered to the subject over a short duration of treatment, and following administration the nitric oxide releasing solution will continue to deliver an extended release of a therapeutically effective amount of nitric oxide to the subject. The ability for the subject to remain ambulatory during treatment is particularly important in cattle, because cattle or other veterinary subjects can become stressed when they are restrained, such as in a squeeze chute, and stress can exacerbate and increase the incidence of BRDc. In some embodiments, for example in connection with companion animals, it may be desirable to guide the fluid conduits without the animal fully supporting the intranasal administration device. Instead, the animal's head may be held while the fluid conduits are inserted until the depth stop surface contacts the nose of the animal and the fluid is discharged, at which time the device can be removed.

In certain embodiments, the nitric oxide releasing solution is prepared just prior to administration to the subject through the administration of an acidifying or activation agent (e.g., citric acid) to a dormant NORS solution. Alternatively, a sodium nitrite can be administered to a dormant acidified solution. Either mechanism can be selected and used based on a number of performance factors such as most stable shelf life, etc. For example, administration of the acidifying agent to the dormant solution results in the lowering of the pH of the dormant solution, thereby activating the nitric oxide releasing solution to be administered to the treatment site. Importantly, the nitric oxide releasing solution can provide for extended production of nitric oxide, for example, beyond the time required to administer the nitric oxide releasing solution. In one embodiment, the nitric oxide releasing solution produces nitric oxide for a period of between 1 minute and 24 hours. In one embodiment, the nitric oxide releasing solution produces nitric oxide for a period of between 10 and 45 minutes. In one embodiment, the nitric oxide releasing solution produces nitric oxide for at least 15 minutes. In one embodiment, the nitric oxide releasing solution produces nitric oxide for at least 30 minutes. In another embodiment, the nitric oxide releasing solution produces nitric oxide for at least 1 hour. In another embodiment, the nitric oxide releasing solution produces nitric oxide for at least 4 hours. In another embodiment, the nitric oxide releasing solution produces nitric oxide for at least 8 hours. In another embodiment, the nitric oxide releasing solution produces nitric oxide for at least 12 hours. In another embodiment, the nitric oxide releasing solution produces nitric oxide for at least 24 hours. Thus, the administered nitric oxide releasing solution provides for continuous delivery of nitric oxide to the treatment site of the subject. It should be noted that in some embodiments, the treatment site can be at or near the location of NORS administration, for example, the upper respiratory tract. However, in some embodiments, the treatment site (i.e. the location where nitric oxide therapy is desired) can be distal from the location of NORS administration (e.g. the lower respiratory tract).

The nitric oxide releasing solution may be administered to the subject in a variety of forms. The nitric oxide releasing solution may be administered as a liquid, a spray, a vapor, micro-droplets, mist, or any form which provides the release of nitric oxide from the solution, as would be understood by one skilled in the art. In one embodiment, the nitric oxide releasing solution is administered as a spray. In another embodiment, the nitric oxide releasing solution is administered as a vapor. In another embodiment, the nitric oxide is administered as a gas. The amount or dosing volume of administered nitric oxide releasing solution may be varied in order to optimize the duration of nitric oxide production and delivery. In one embodiment, the amount of nitric oxide releasing solution administered to a subject is between about 0.1 mL and 5000 mL. In another embodiment, the amount of nitric oxide releasing solution administered to a subject is between about 10 mL and 1000 mL. In one embodiment, the amount of nitric oxide releasing solution administered to a subject is about 2 mL. In one embodiment, the amount of nitric oxide releasing solution administered to a subject is about 10 mL. In one embodiment, the amount of nitric oxide releasing solution administered to a subject is about 32 mL. In another embodiment, the amount of nitric oxide releasing solution administered to a subject is about 160 mL. These amounts or others may be administered in a single spray or in multiple sprays (e.g. 2, 3, 4, 5, 6, or 8-10 sprays) within a given dosage time, for example within 1 minute, 30 seconds, 10 seconds, 5 seconds, 2 seconds, or any other window deemed suitable or beneficial for administering single or multiple sprays. The nitric oxide releasing solution may be readministered one or more times, as necessary to effectively treat the subject. In one embodiment, the nitric oxide releasing solution is administered once to a subject. In another embodiment, the nitric oxide releasing solution is administered multiple times to a subject, where the nitric oxide releasing solution is readministered substantiantially after completion of the extended release of nitric oxide gas from the prior dosage administered.

In certain embodiments, nitric oxide releasing solution is directly administered into the upper respiratory tract of the subject. For example, in one embodiment, the nitric oxide releasing solution is sprayed into the upper respiratory tract of the subject. The solution may be administered into the upper respiratory tract of the subject once an hour, once a day, once a week, once every two weeks, once a month, once every two months, once a year, and any and all ranges therebetween as required to treat the subject. In one embodiment, the solution is sprayed once a week. In another embodiment, the solution is sprayed once a week for four consecutive weeks. The nitric oxide releasing solution provides for extended nitric oxide production, thereby providing continuous delivery of therapeutic nitric oxide to the respiratory system of the subject.

The duration of administering the nitric oxide releasing solution to the subject may be varied in order to obtain a desired delivery. In one embodiment, the nitric oxide releasing solution is administered to the subject over a time period of less than 5 seconds. In another embodiment, the nitric oxide releasing solution is administered to the subject over a time period of about 5 seconds. In another embodiment, the nitric oxide releasing solution is administered to the subject over a time period of about 30 seconds. In another embodiment, the nitric oxide releasing solution is administered to the subject over a time period of about 1 minute. In another embodiment, the nitric oxide releasing solution is administered to the subject over a time period of about 2 minutes. In another embodiment, the nitric oxide releasing solution is administered to the subject over a time period of about 10 minutes. In another embodiment, the nitric oxide releasing solution is administered to the subject over a time period of about 30 minutes.

In one aspect, the principles disclosed herein provide for the treatment, prevention, or reduction of incidence of a respiratory disease or disorder in a subject. Exemplary respiratory diseases or disorders that can be treated include, but are not limited to BRDc, porcine respiratory disease complex (PRDc), and the like. In some cases, the respiratory disease or disorder may be caused by a bacterium (e.g.,M. haemolytica, H. somni, mycobacteria), fungus, a virus (e.g., Infectious Bovine Rhinotracheitis (IBR), Bovine Parainfluenza-3 (PI-3), and Bovine Respiratory Syncytial Virus (BRSV)), a protozoan, a parasite, and/or an arthropod, including a bacterium that has developed resistance to one or more antibiotics. Treatment of a respiratory disease by way of the present disclosure comprises the delivery of a nitric oxide releasing solution into the upper respiratory tract of the subject to be treated. For example, in certain embodiments, the nitric oxide releasing solution may be sprayed, inhaled, or instilled into the respiratory tract of the subject. The nitric oxide releasing solution may be administered to the respiratory tract of the subject via the nasal cavity or oral cavity of the subject. In one embodiment, the nitric oxide releasing solution is sprayed into the upper respiratory tract of the subject. In one embodiment, the solution is administered to the subject intranasally. In one embodiment, the solution is administered to the sinuses. The nitric oxide releasing solution provides for extended nitric oxide production, thereby providing continuous delivery of therapeutic nitric oxide to the respiratory tract of the subject.

With reference toFIG. 1, illustrated is an animal intranasal administration system100in accordance with an example of the present disclosure. The system100can include an animal intranasal administration device101that can be used for administering a fluid (e.g., nitric oxide releasing solution) to a nostril103of an animal104. The system100can also include a fluid source102to provide the fluid to the intranasal administration device101. In one aspect, the fluid provided by the fluid source102and/or administered by the device101to the animal104can be in a liquid or gas state. In some embodiments, the liquid may be prepared to have a desired viscosity.

The intranasal administration device101can include a nasal passage nozzle110for each nostril configured to receive fluid from the fluid source102fluidly coupled to the nasal passage nozzles, such as via a fluid conduit120. The intranasal administration device101can also include a biasing mechanism to bias the nasal passage nozzles toward a septum105of the animal104, such that the device is secured in place about the septum during administration of the fluid into nasal passages of the animal. The biasing action of each nozzle toward the septum allows the nasal passage nozzles or other parts of the device to effectively pinch the septum as they are on opposite sides thereof. The device can then be held in place as it pinches the septum. The animal intranasal administration system100can also include a pump121operable to deliver fluid from the fluid source102to the nasal passage nozzles110. The pump121can be a motorized pump powered by electricity and/or a hand-operated pump. Any pump that is sufficient to deliver NORS in a volume and at a velocity that provides effective NO treatment can be used. In one example, NORS can be delivered at a velocity sufficient to ensure delivery of NORS liquid to the pharyngeal tonsillar material in the upper airway. Other deliver parameters and characteristics, such as volume, delivery time and variation can be selected and controlled in order to achieve a specific result, such as placing a specific volume of NORS at a specific physical location within a subject can be used, for example a set volume can be delivered with varying pressure, or a set time with a fixed pressure can be used to achieve a desired volume.

In one example, a hand-operated pump (e.g., a trigger operated vacuum hand pump) can be coupled to the fluid conduit120“inline” to deliver the fluid to the device101without the use of electricity. In one aspect, the fluid source can be portable by a user while in use. In some embodiments, the system100can include one or more carrying straps126coupleable to the fluid source102(e.g., directly coupled or coupled via a backpack or other carrying case) to facilitate portability by the user. Thus, in certain embodiments, the system100can be portable and powered entirely by the user. In alternative embodiments, the fluid source can be substantially stationary and in some cases can be attached to a post or other fixture. This embodiment can be advantageous when treating a large number of subjects as it allows a large volume of nitric oxide releasing solution to be utilized (i.e. from a large container).

The system100can include one or more valves associated with the fluid source102, fluid conduit120, and/or the device101to control the flow of fluid to the nasal passage nozzles110, such as to control a fluid dosage to the animal104. For example, a valve106can be located at or near the fluid source102and a valve107can be located at or near the device101, although a valve may be disposed in any suitable location. In one aspect, a valve can be associated with one or both of the nasal passage nozzles110to control the flow of fluid to a specific nozzle. Any other mechanism for metering out a specific volume or dose of nitric oxide releasing solution for administration to the subject can also be used, including simply the amount of time over which the solution is administered (i.e. administration period) in combination with flow rate, etc.

In some embodiments, the fluid source102can comprise inactivated nitric oxide releasing solution123, an activation agent124, activated nitric oxide releasing solution, and/or nitric oxide gas. The activation agent124can be configured to activate the inactivated nitric oxide releasing solution123upon mixing. In one aspect, the activation agent124can be maintained separate from the inactivated nitric oxide releasing solution123. The activation agent124can be in any suitable form, such as a solid (e.g., a powder, a tablet, and a capsule), a liquid (e.g., a solution), a gas, etc. The fluid source102can also comprise one or more containers122or reservoirs for the inactivated nitric oxide releasing solution123, the activation agent124, activated nitric oxide releasing solution, and/or nitric oxide gas. In general, the activation agent124and the inactivated nitric oxide releasing solution123can be at least partially mixed in a mixing chamber125, which can be within the container122. Thus, in one aspect, the inactivated nitric oxide releasing solution123can be activated within the container122and dispensed or delivered to the device101to be administered to the animal104. The pump121can convey activated nitric oxide releasing solution from the fluid source102to the device101. Alternatively, activated nitric oxide releasing solution can be conveyed from the fluid source102to the device101by pressure in the container122due to the production of nitric oxide gas resulting from activation of the nitric oxide releasing solution. In other words, an increase in gas pressure in the container122, due to the formation of nitric oxide, can cause activated nitric oxide releasing solution to move from the container122to the device101via the fluid conduit120for delivery to the animal. In such embodiments, pump121may not be needed, or can be utilized if the pressure inside the container122, becomes insufficient to continue dispensing the nitric oxide releasing solution at the desired rate/volume. In an alternative embodiment as described more fully below, a pump, either electric or manually operated, can be used to create pressure within the container and facilitate administration of the nitric oxide releasing solution.

In another aspect, illustrated inFIGS. 2A-2C, an activation agent and inactivated nitric oxide releasing solution can be at least partially mixed in a mixing chamber external to a container, such as the container122ofFIG. 1. For example, as shown inFIG. 2A, an intranasal administration system200can include a fluid source202fluidly coupled to an intranasal administration device201(e.g., to nasal passage nozzles210) via a conduit220, which includes a conduit220aassociated with inactivated nitric oxide releasing solution223and a conduit220bassociated with an activation agent224, each of which can be disposed in separate containers. The conduits220a,220bcan combine prior to the nasal passage nozzles210, such as in a mixing chamber225within the intranasal administration device201, such that mixing of the inactivated nitric oxide releasing solution223and the activation agent224occurs between the fluid source202and the nasal passage nozzles210. Thus the nitric oxide releasing solution can be activated, or in other words, the activated solution can be formed, during delivery or administration of the nitric oxide releasing solution to a subject.

In another example, shown inFIG. 2B, an intranasal administration system300can include a fluid source302fluidly coupled to an intranasal administration device301(e.g., to nasal passage nozzles310) via a conduit320, which includes a conduit320aassociated with inactivated nitric oxide releasing solution323and a conduit320bassociated with an activation agent324, each of which can be disposed in separate containers. The conduits320a,320bcan combine prior to the nasal passage nozzles310, such as in a mixing chamber325external to the fluid source302and the intranasal administration device301, such that mixing of the inactivated nitric oxide releasing solution323and the activation agent324occurs between the fluid source302and the nasal passage nozzles310. In one aspect, the mixing chamber325can comprise at least a portion of the conduit320such that mixing of the inactivated nitric oxide releasing solution323and the activation agent324takes place “in-line” to the intranasal administration device301. Accordingly, the mixing chamber325can comprise any suitable structure, such as tubing, that can be disposed between the fluid source302and the intranasal administration device301and serve to mix the inactivated nitric oxide releasing solution323and the activation agent324. The mixing chamber325can form an integral part of tubing that forms the conduit320or the mixing chamber325can be a separate component coupled to tubing to form a portion of the conduit320. Activated nitric oxide releasing solution can be conveyed to the intranasal administration device301from the mixing chamber325via conduit320c.

In yet another example, shown inFIG. 2C, an intranasal administration system400can include a fluid source402fluidly coupled to an intranasal administration device401(e.g., to nasal passage nozzles410) via a conduit420, which includes a conduit420aassociated with inactivated nitric oxide releasing solution423and a conduit420bassociated with activation agent424, each of which can be disposed in separate containers. The conduits420a,420bcan combine at the nasal passage nozzles410, which can form a mixing chamber, such that mixing of the inactivated nitric oxide releasing solution423and the activation agent424occurs at the nasal passage nozzles410. Accordingly, the nasal passage nozzles410can comprise any suitable structure that can serve to accommodate the introduction of solution from multiple conduits and mix the inactivated nitric oxide releasing solution423and the activation agent424. Thus, the conduits420a,420bcan remain separate from the fluid source402to the nasal passage nozzles410such that mixing of the inactivated nitric oxide releasing solution and the activation agent occurs at an animal engaged by the intranasal administration device401. In other words, the nitric oxide releasing solution is activated or formed in-vivo at the administration site, or after being dispensed from the nozzle.

In one aspect, each nasal passage nozzle can receive either an activation solution or inactivated nitric oxide releasing solution, such that each is administered to the animal separately. Thus, the activation solution and the inactivated nitric oxide releasing solution can mix after being dispensed from the intranasal administration device at or inside the animal, such as inside a nasal passage, to activate the nitric oxide releasing solution. In some embodiments, each nozzle may have separate openings and supporting fluidic connections to the respective sources of activation agent and nitrite solution (i.e. inactivated NORS). In this way, solution from each source can be brought to the nozzle separately, yet simultaneously for delivery to a subject concurrently. A nozzle can have a single opening and the solutions can be alternately administered, for example, a spray of inactivated NORS (i.e. nitrite solution, citric acid) followed by a spray of activator solution (e.g. citric acid, ascorbic acid, nitrite solution, etc.).

FIGS. 3A-3Cillustrate an animal intranasal administration device501in accordance with an example of the present disclosure. The intranasal administration device501can include a nasal passage nozzle510a,510bfor each nostril503(FIG. 3C) configured to receive fluid from a fluid source, as described hereinabove. The intranasal administration device501can also include a biasing mechanism530to bias the nasal passage nozzles510a,510btoward a septum505(FIGS. 3B and 3C) of an animal, such that the device501is secured in place about the septum505during administration of the fluid into nasal passages of the animal.

In one aspect, the intranasal administration device501can include a support member540having support member portions541a,541bcoupled to, and in support of, the nasal passage nozzles510a,510b, respectively. The support member portions541a,541bcan be movable relative to one another (i.e., pivotally coupled to one another at pivot coupling543) to secure the nasal passage nozzles510a,510bat least partially within the nostrils503of the animal about the septum505and such that fluid is directed into nasal passages of the animal. Thus, the nasal passage nozzles510a,510bcan be oriented to align nozzle openings511a,511bwith nasal passages when the device501is engaged with the septum505of the animal to provide for delivery of fluid to deep nasal passages.

In one aspect, the nasal passage nozzles510a,510bcan be configured to direct fluid into the nasal passages past nasal folds508a,508bwhich may exist in the animal, as represented inFIG. 3B. For example, a bovine may have an alar fold, a basal fold, and a straight fold. Thus, the nasal passage nozzles510a,510bcan be configured to direct fluid into the nasal passages past one or more of such folds to deliver the fluid to deep nasal passages. In one example, the nasal passage nozzles510a,510bcan be configured to extend or penetrate into the nostrils beyond one or more nasal folds508a,508b, as illustrated inFIG. 3Bto reach as far as the nasopharyngeal tonsillar material of the nasopharynx. In another example, the nasal passage nozzles510a,510bcan be located and oriented to direct the fluid past one or more nasal folds without extending or penetrating into the nostrils beyond one or more of the nasal folds. In short, any configuration required to effectively administer nitric oxide releasing solution into the nasal passages, or any other desired or specified location in the respiratory tract of any subject in a manner sufficient to allow the subject to receive effective nitric oxide therapy, given the subject's specific anatomy, can be used.

In one aspect, the support member portions541a,541bcan be movable relative to one another by the biasing mechanism530to bias the nasal passage nozzles510a,510btoward a secured position about the septum50in direction531a,531b. For example, the biasing mechanism530can comprise a spring acting on the support member portions541a,541bto bias the support member portions541a,541btoward the secured position about the septum505. The biasing mechanism530can therefore cause the nasal passage nozzles510a,510bto pinch the septum505therebetween so that the nozzles510a,510bare held in place in the nostrils503. While illustrated as a spring, it is to be understood that the biasing mechanism530can be any device, part, or mechanism that is sufficient to provide the desired biasing action. Moreover, the biasing mechanism530can be located anywhere on the device501that is adequate to provide the desired biasing action. In one aspect, biasing or spring strength can be adjustable as desired to secure the device501to the animal without causing undue pain to the animal. In one aspect, the support member540can be configured to provide clearance about a tip506of the septum505. For example, the support member portions541a,541bcan comprise arcuate configurations to provide clearance about the tip506of the septum505, as illustrated inFIG. 3B.

The intranasal administration device501can include a septum interface portion512a,512bassociated with the nasal passage nozzles510a,510b, respectively, to interface with the septum505and position the nasal passage nozzles to facilitate directing fluid deep into the nasal passages of the animal. For example, the septum interface portion512a,512bcan serve to space or position the nasal passage nozzles510a,510band openings511a,511bat a sufficient distance from the septum505to facilitate and maintain dispersal or spray pattern coverage into the nasal passages without interference from the septum505.

The intranasal administration device501can also include a positioning member550configured to contact the tip506of the septum505to facilitate and maintain proper positioning and/or orientation of the nasal passage nozzles510a,510bwithin the nostrils503of the subject so that the nasal passage nozzles510a,510bdirect fluid in a direction substantially aligned with the nasal passage openings of the animal. In this way, positioning member550may act as a depth stop for maintaining proper positioning and/or orientation of the nasal passage nozzles510a,510bwithin the nostrils503of the subject. For example, the positioning member550can be configured to position the nasal passage nozzles510a,510bsuch that the openings511a,511bare at a depth554from the tip506of the septum505to properly position the nasal passage nozzles510a,510bat a suitable distance relative to the nasal passage openings. In one aspect, the positioning member550can comprise an elongated portion551having a longitudinal axis552that is substantially parallel to an axis542of rotation for movement of the support member portions541a,541brelative to one another. For example, the positioning member550can have a “T” configuration where a base portion553supports the elongated portion551. The base portion553can be coupled to the support member540, such as to one or both of the support member portions541a,541b, at the pivot coupling543of the support member portions541a,541b. The elongated portion551can be configured to contact a muzzle507of the animal to prevent or minimize sagging or downward rotation of the device501during use, thereby facilitating proper alignment of the nasal passage nozzles510a,510b.

The intranasal administration device501can include a user interface560coupled to the support member540to facilitate movement of the support member portions541a,541brelative to one another by a user. For example, the user interface560can include user interface portions561a,561b, such as handles, coupled to the support member portions541a,541b, respectively, to facilitate movement of the nasal passage nozzles510a,510bby a user in a direction opposite the biasing direction531a,531b, such as by squeezing the user interface portions561a,561btoward one another.

In one aspect, the intranasal administration device501can include one or more nostril nozzles513a,513bconfigured to direct fluid onto the nostrils503of the subject. In a particular aspect, the nostril nozzles513a,513bcan be configured to direct fluid onto the anterior nostrils. The nostril nozzles513a,513bcan be coupled to the support member540. For example, the support member540can comprise lateral extension portions544a,544bto position the nostril nozzles513a,513b, respectively. In one aspect, the lateral extension portions544a,544bcan be coupled to, and extend from, the support member portions541a,541b, respectively. In another aspect, the intranasal administration device501can include one or more muzzle nozzles (not shown in these figures) configured to direct fluid onto the muzzle507of the animal. A muzzle nozzle can be supported by one or more of the support member portions541a,541band/or the lateral extension portions544a,544b. As such, delivery of the nitric oxide releasing solution can be made to both the nasal passages and the nares simultaneously, or at the very least, using a single device.

Although the intranasal administration device501is shown with four total nozzles, it should be recognized that an intranasal administration device in accordance with the present disclosure can include any suitable number of nozzles, which can have an appropriate dispersal or spray pattern directed at an appropriate angle to any suitable area of an animal's muzzle, nares, nostrils, nasal passage, etc. In other words, nozzle dispersal or spray patterns can be specifically suited for a particular area (i.e., the nasal passages, nostrils, muzzle, etc.) and can be oriented at any suitable angle to direct fluid onto or into the area. In one aspect, one nozzle can be configured to direct fluid onto multiple areas. For example, the nostril nozzles513a,513bcan be configured to disperse or spray fluid on the nares and the muzzle. Thus, the nozzles of an intranasal administration device in accordance with the present disclosure can be configured to have various dispersal or spray patterns to cover nasal passages and entry surfaces into the nasal passages. Nozzles used with the device501may therefore initiate any spray pattern known in the art suitable for a given purpose or dispersing target region.

In one aspect, the intranasal administration device501can include a fluid distribution manifold532fluidly coupled to the nozzles of the device501. For clarity, external fluid couplings or conduits, such as tubing or hoses, have been omitted inFIGS. 3A-3C. The fluid distribution manifold532can have an inlet port533to receive fluid from a fluid source and outlet ports534a,534b,535a,535bto distribute fluid to the various nozzles of the device501. For example, outlet ports534a,534bcan be fluidly coupled to the nasal passage nozzles510a,510b, respectively, and outlet ports535a,535bcan be fluidly coupled to the nostril nozzles513a,513b, respectively. Thus, each of the nasal passage nozzles510a,510band the nostril nozzles513a,513bcan be configured to couple with a conduit to receive fluid from a fluid source. Although the fluid distribution manifold532is shown separate from other structural components of the device501, such as the support member540or the positioning member550, it should be recognized that a fluid distribution manifold can be coupled to or integrally formed with any structural portion of the device501, such as one or more portions of the support member540and/or the positioning member550. In one aspect, the fluid manifold532can include at least two inlet ports and a mixing chamber, as discussed above, such that mixing of inactivated nitric oxide releasing solution and activation agent occurs between a fluid source and the nasal passage nozzles510a,510b. In another aspect, the fluid distribution manifold532can include one or more valves to control fluid flow one or more nozzles of the device501.

In one aspect, the support member540can have internal fluid conduits defined by one or more openings or passageways through the support member540. For example, one or more of the support member portions541a,541bcan include at least a portion of a fluid conduit to direct fluid to the respective nasal passage nozzle510a,510bfrom the fluid source. Similarly, one or more of the lateral extension portions544a,544bcan include at least a portion of a fluid conduit to direct fluid to the respective nostril nozzle513a,513bfrom the fluid source. Thus, such internal fluid conduits can receive fluid directly from the fluid source or after distribution from the fluid distribution manifold532.

In one aspect, the intranasal administration device501can be constructed to facilitate interchangeability of parts. For example, the support member portions541a,541bcan be configured to removably couple with nozzle or spray heads514a,514b, such as with fasteners515. Similarly, the lateral extension portions544a,544bcan be configured to removably couple with nozzle or spray heads516a,516b, such as with fasteners515. In addition, the support member portions541a,541bcan be configured to removably couple with the user interface portions561a,561b. Furthermore, the biasing member or spring530can be removably coupled to the support member540. Thus, nozzles, springs, handles, positioning members, etc. can be interchangeable and replaced as desired to accommodate different animal species and/or animals of a different size. Thus, the device501can be configured and customized for the anatomy of a cow of a given age. In one aspect, the intranasal administration device501can be disassembled to facilitate cleaning and/or servicing of the various parts or components of the device.

In one aspect, the nozzle or spray heads514a,514bcan include or incorporate the nasal passage nozzles510a,510bas well and the septum interface portions512a,512b, respectively. As illustrated inFIGS. 3A-3C, the spray heads514a,514bcan have a spherical or ball configuration that provides a curved interface surface for the septum interface portions512a,512bfor contacting the septum505. Such a spherically curved surface can accommodate various septum thicknesses and maintain a consistent interface with the septum505. The spherical surface can have a diameter configured to provide adequate surface area for effective “clamping” (i.e. pinching) contact with the septum without providing excessive pressure to the contact area of the septum such that the device501is uncomfortable for the animal. The diameter of the spherical surface can also contribute to providing adequate space for the nasal passage nozzles510a,510bfrom the septum to provide and maintain a suitable dispersal or spray pattern.

FIG. 4illustrates nozzle or spray heads614a,614bin accordance with another example of the present disclosure. As with the spray heads514a,514bofFIGS. 3A-3Cdiscussed above, the spray heads614a,614bcan include or incorporate nasal passage nozzles610a,610bas well as septum interface portions612a,612b, respectively. In this case, the spray heads614a,614bhave a fan configuration with an arcuate surface for the septum interface portions612a,612bfor contacting a septum. Such an arcuate curved surface can accommodate various septum thicknesses and may be useful when a higher contact pressure is desired, due to the relatively small contact area that can be provided by this configuration. The size of the arcuate surface can also contribute to providing adequate space for the nasal passage nozzles610a,610bfrom a septum to provide and maintain a suitable dispersal or spray pattern.

FIG. 5illustrates an animal intranasal administration device701in accordance with another example of the present disclosure. The intranasal administration device701can include a nasal passage nozzle710a,710bfor each nostril configured to receive fluid from a fluid source, as described hereinabove. In one aspect, the intranasal administration device701can include a support member740having support member portions741a,741bcoupled to, and in support of, the nasal passage nozzles710a,710b, respectively. In one aspect, the support member740can be resiliently flexible or include resiliently flexible components. Thus, in a particular aspect, one or both of the support member portions741a,741bcan be resiliently flexible and therefore movable relative to one another to secure the nasal passage nozzles710a,710bat least partially within the nostrils of an animal about a septum and such that fluid is directed into nasal passages of the animal. The resilient flexibility of the support member portions741a,741bcan provide a biasing mechanism to bias the nozzles710a,710btoward a septum of an animal, such that the device701is secured in place about the septum during administration of the fluid into nasal passages of the animal. Thus, the resilient flexibility of the support member portions741a,741bcan bias the nasal passage nozzles710a,710btoward a secured position about the septum70in direction731a,731b. The nasal passage nozzles710a,710bcan be oriented to align nozzle openings711a,711bwith nasal passages when the device701is engaged with the septum of the animal to provide for delivery of fluid to deep nasal passages.

The intranasal administration device701can also include a septum interface portion712a,712bassociated with the nasal passage nozzles710a,710b, respectively, to interface with the septum and position the nasal passage nozzles to facilitate directing fluid deep into the nasal passages of the animal. For example, the septum interface portion712a,712bcan serve to space or position the nasal passage nozzles710a,710band openings711a,711baway from the septum to facilitate and maintain dispersal or spray pattern coverage into the nasal passages without interference from the septum. The septum interface portions712a,712bare illustrated with a spherical configuration, although any suitable configuration may be utilized.

The intranasal administration device701can further include a positioning member750configured to contact a tip of the septum to facilitate and maintain proper positioning and/or orientation of the nasal passage nozzles710a,710bwithin the nostrils of the animal so that the nasal passage nozzles710a,710bdirect fluid in a direction substantially aligned with the nasal passage openings of the animal. For example, the positioning member750can be configured to position the nasal passage nozzles710a,710bsuch that the openings711a,711bare at a distance from the tip of the septum to properly position the nasal passage nozzles710a,710bat a suitable distance relative to the nasal passage openings. In one aspect, the positioning member750can be coupled to the support member740, such as between the support member portions741a,741b. The positioning member750can be configured to contact a muzzle of the animal when the device701is engaged with the animal to prevent or minimize sagging or downward rotation of the device701during use, thereby facilitating proper alignment of the nasal passage nozzles710a,710b.

In one aspect, the intranasal administration device701can include one or more nostril nozzles713a,713bconfigured to direct fluid onto the nostrils of the animal. In particular, the nostril nozzles713a,713bcan be configured to direct fluid onto the anterior nostrils. In one aspect, the nostril nozzles713a,713bcan be coupled to the support member740. For example, the support member740can comprise lateral extension portions744a,744bto position the nostril nozzles713a,713b, respectively. In another aspect, the intranasal administration device701can include one or more muzzle nozzles717configured to direct fluid onto a muzzle of the animal. The muzzle nozzle717can be coupled to the support member740at any suitable location.

FIGS. 6A-6Cillustrate aspects of an animal intranasal administration system800in accordance with another example of the present disclosure. The system800can include an animal intranasal administration device801of any suitable configuration described hereinabove for administering a fluid to a nostril of an animal. The system800can also include a fluid source802to provide the fluid to the intranasal administration device801, such as via a fluid conduit820. The fluid source802can comprise inactivated nitric oxide releasing solution, an activation agent, activated nitric oxide releasing solution, and/or nitric oxide gas.

In one aspect, the fluid source802can comprise a container822or a reservoir with inactivated nitric oxide releasing solution disposed therein. The container822may be of any desired size and shape. In one aspect, the container822can be suitable for holding multiple doses or application volumes of nitric oxide releasing solution without requiring a refill. The fluid source802can also have a fluid outlet port870, which can be configured to couple with the fluid conduit820for delivering the fluid to the device801. The fluid outlet port870can be associated with a cap871(as shown) or with the container822. A sump conduit872can be fluidly coupled to the fluid outlet port870to deliver fluid to the fluid outlet port870. The sump conduit872will typically extend to a bottom of the container822to facilitate evacuating substantially all the fluid from the container822. The sump conduit872can be associated with the cap871(as shown) and/or with the container822(e.g., molded into a side of the container822). The fluid source802can also include a gas port873to allow a gas into the container822during use of the system800. For example, a pump821can be a gas pump and can be fluidly coupled to the gas port873by a conduit to provide pressurized gas (e.g., air or other suitable gas) to the container822such that “head space pressure” in the container822causes the fluid to exit the container822via the sump conduit872and fluid outlet port870for delivery to the device801through the fluid conduit820. The gas port873can be associated with the cap871(as shown) or with the container822. The gas port873will typically be located above a level of the inactivated nitric oxide releasing solution in the container822. In one aspect, the container822can be pressurized to about 50 psig during operation (with about 30 psig being typical), although the system can be configured to operate at any suitable pressure. In one aspect, the pump821can provide a pressure to deliver a specific spray volume onto the muzzle and into the nares and nasal passages of an animal. In one aspect, a pressure gage or sensor (i.e., as part of the pump821) can monitor pressure in the container822and/or the fluid conduit820to determine whether a nozzle has been clogged.

In one aspect, the pump821can be a liquid pump and can operate to pump liquid fluid out of the container822without creating head space pressure in the container822. The pump821can be a gas pump and/or a liquid pump of any suitable configuration. In one aspect, the pump821can be a motorized pump powered by electricity and/or a hand-operated pump. A cover874can be provided for the cap871to protect the fluid outlet port870and the gas port873when not in use. Components of the system can be constructed with metals, plastics, and other polymers compatible with the activation agent (e.g., citric acid, sodium nitrite), nitric oxide releasing solution, and nitric oxide.

In one aspect, the fluid source802can include an activation agent maintained separate from the inactivated nitric oxide releasing solution. The activation agent can be configured to activate the inactivated nitric oxide releasing solution upon mixing. Once mixed, the production of nitric oxide in the solution can create a head space pressure sufficient to deliver fluid from the container822to the device801. Thus, fluid can dispense automatically from the device801upon mixing the activation agent and the inactivated nitric oxide releasing solution utilizing a gas pressure resulting from the activation of the nitric oxide releasing solution.

The activation agent can be in any suitable form, such as a solid (e.g., a powder, a tablet, a capsule, etc.), a liquid (e.g., a solution), a gas, etc. In one aspect, an activation agent in solid form can be in a dissolvable pouch and/or supported by a cage875, which can be configured to be disposed within the container822below the level of the inactivated nitric oxide releasing solution to ensure contact or mixing with the inactivated nitric oxide releasing solution. The cage875can include one or more openings to facilitate mixing of the activation agent and the inactivated nitric oxide releasing solution. Thus, when the activation agent is submerged in the inactivated nitric oxide releasing solution the activation agent will dissolve producing nitric oxide in the solution. The cage875can be coupled to the sump conduit872(as shown) and supported within the container above a bottom of the container822or simply dropped into the container822. In one aspect, the cage875can be coupled to a rod or tube having an end that is located proximate an opening of the container822. Coupling the cage875to the sump conduit872or a rod or tube can simplify retrieval of the cage875.

In one aspect, the animal intranasal administration system800can be provided as a kit. For example, the container822can have a device coupling feature880to couple with and support the device801. The container822can also have a handle881. The handle881can have a free end826that can couple to a body of the container822via coupling features882,883. The coupling features882,883can be configured to further capture and secure the device801to the container822. A fluid conduit coupling feature884can extend from the free end826of the handle881to capture and secure the fluid conduit820to the container822. In addition, the pump821can be configured to removably couple with a bottom of the container822. If the pump821includes electrical components, a battery pack may be included. The cover874can cover the cap871and/or an opening of the container822when not in use.

In use of the system800, an animal can arrive in a holding chute and a user can engage the intranasal administration device801with the animal's nostril, as described hereinabove or further below. Because the device801is secured to the animal, the user can administer fluid to the animal “hands free.” The fluid source802can be supported by a post of the holding chute and can hold a volume (e.g., 5 gallons) of premixed nitric oxide releasing solution in its dormant state. Once the activation agent and the inactive nitric oxide releasing solution are mixed, nitric oxide gas is produced in the solution in the container822. The activated nitric oxide releasing solution is then conveyed from the fluid source to the device801and dispensed or sprayed onto the treatment site or area, such as into the animal's nasal passages. For example, the activated solution may be sprayed into the nasal passages of the cattle in brief, measured bursts. In one aspect, the animal can receive one spray of about 8 mL into each nasal passage, twice, for a total of about 32 mL before being released. The duration of treatment administration can be between about 3-5 seconds. At the user's convenience the device801can be released or disengaged from the animal. The activated solution now lining the nasal passages of the animal can continue to release nitric oxide gas for up to 30 minutes or longer.

Furthermore, animal intranasal administration systems100,800may be used in conjunction with any intranasal administration device according with the invention. Additional examples of intranasal administration devices are described below with reference toFIGS. 7 to 16. Generally, embodiments of the intranasal administration devices described below comprise fluid conduits including at the distal ends thereof nasal passage nozzles. The distal ends of the fluid conduits are detached from the septum interface portions, such that as the first and second support member portions, or jaws, are closed the nasal passage nozzles can move relative to the jaws. Movement may be laterally and/or in the anterior/posterior direction. The nasal passage nozzles may move to align with, and enter into, the ventral meatus. As used herein, the terms “open” and “close” mean, respectively, to separate the jaws or to bring them closer together. Thus, the jaws are opened to enable insertion thereof into the nostrils and are closed to clamp the nasal septum of the animal. The fluid conduits are secured to the intranasal administration device such that the angle formed by the centerlines of the fluid conduits at their distal ends is smaller when the jaws are open and increases as the jaws close.

In some embodiments, the fluid conduits are formed of a flexible material. The fluid conduits have lengths between their distal ends and areas where the fluid conduits are supported by the intranasal administration device which are sufficient to allow the flexible fluid conduits to bend due to contact with the tissue of the veterinary subject as the jaws are closed. Example flexible materials include PVC and vinyl. The combination of the self-alignment of the fluid conduits to the nasal septum and/or the ventral meatus and the insertion depth of the nasal passage nozzles into the nostrils enhances delivery of the fluid into the nasopharynx. In some instances it is desirable to substantially coat the nasal turbinates, the pharyngeal tonsillar material, and the nasopharynx of the animal. As used herein, the nasopharynx is substantially coated when at least 50% of its surface is coated by the fluid. Of course, to the extent possible the nasopharynx should be substantially coated without disturbing or causing trauma to the animal. In some embodiments, the jaws are sized and configured to minimally impede breathing of the animal during the intervention, and the jaws are blunted to reduce the likelihood of tissue damage. The distal ends of the jaws may comprise septum interference members which are twice as wide as they are thick, to enable clamping while permitting substantially unimpeded breathing by the animal.

Referring now toFIGS. 7 to 17,FIG. 7is a perspective view of the head of an animal104with an intranasal administration device900including two fluid conduits918,919extending into the nostrils of its nose902. An intervention is performed by administering a fluid through at least one of fluid conduits918,919into the nasopharynx1164of animal104. An example intervention comprises delivery of nitric oxide, in various embodiments and variations thereof described hereinabove, including liquid, gas, gas releasing solution, and combinations thereof, to the nasopharynx to prevent, control, and/or treat bovine respiratory disease in bovine animals. Although the present invention may be described with reference to a particular animal species and disease, the invention is suitable to effect any other treatments intranasally with subjects of any other animal species.

A schematic illustration of a sectioned head of a bovine animal is depicted inFIG. 17illustrating the alar fold1150and the basal fold1152at the nose of animal104. The folds form a nasal constriction at the nasal vestibule1154which inhibits passage into the ventral meatus1166of the nasal passage.FIG. 17further illustrates the locations of the dorsal nasal concha1156, the middle nasal concha1158, the nasal septum1160, and the soft palate1162of the bovine animal. Intranasal administration devices in accordance with the disclosure include fluid conduits, e.g. tubes, which extend through the nasal constriction into ventral meatus1166of the nasal passage to facilitate discharge of fluid along a direction parallel to nasal septum1160, which enables the fluid to reach nasopharynx1164. Intranasal administration devices900,1000are structured such that fluid conduits918,919and nasal passage nozzles920,921are inserted medially and posteriorly into ventral meatus1166to effectively reach into the cavities of interest.

Referring now toFIGS. 8 to 12, intranasal administration device900comprises fluid conduits918,919, nasal passage nozzles920,921(best shown inFIGS. 10 and 11) inserted at the distal ends of fluid conduits918,919, an actuation mechanism928, and first and second support member portions, or jaws,980,981. Actuation mechanism928comprises a first member930pivotally coupled by a joint mechanism964to a second member931. Jaws980,981extend distally from first and second members930,931, respectively. First member930comprises a first arm932having an opening at one end thereof (not shown) and a protrusion934at the opposite end. Protrusion934includes an elongate fluid conduit support opening938through which fluid conduit918passes. The portion of fluid conduit918in contact with elongate fluid conduit support opening938may be referred to as the “supported portion” of fluid conduit918, which is opposite its distal end, in which nasal passage nozzles920is positioned. The distal end is thus unsupported and movable relative to the septum interface portion. The distance between the supported portion of the fluid conduit, and the flexibility of the fluid conduit, affect the amount of potential movement of the distal end relative to the distal ends of the septum interface portions. In some embodiments, a distance of about 2 or more inches provides sufficient flexibility. In some embodiments, a distance of about 3 or more inches provides sufficient flexibility. The force to cause such movement of the distal end is a result of insertion into the nasal passage and contact with the nasal septum during the insertion, thus the amount of force should be sufficiently small to avoid distressing the animal.

A first handle member942extends from first arm932and includes a first handle portion944and a second handle portion946. Second member931comprises a second arm933having an opening at one end thereof (not shown) and a protrusion935at the opposite end. Protrusion935includes an elongate fluid conduit support opening939through which fluid conduit919passes. A second handle member943extends from second arm933and includes a first handle portion945and a second handle portion947. First and second handle members942,943form a handle948, also referred to as a user interface. In use, the user compresses handle948against the tension provided by a biasing mechanism954to cause jaws980,981to open, thereby allowing their insertion into the nostrils of the animal, and upon release of the compressive force by the user biasing mechanism954causes jaws980,981to close, clamping nasal septum1160. First handle portions944,945are provided to extend second handle portions946,947proximally from the pivot point of joint mechanism964to enhance actuation leverage. Second handle portions946,947have larger contact surfaces than first handle portions944,945to increase the user's comfort when compressing them to open jaws980,981. Second handle portions946,947may have spherical contact surfaces, may comprise spherical shapes, and may further comprise any shape with curves radiused to correspond to the fingers of the user to distribute the force applied by the user. Alternatively, or additionally, second handle portions946,947may have elongated shapes to distribute the force along their length.

An angle929(shown inFIG. 9) formed by the centerlines940,941of elongate fluid conduit support openings938,939is larger when jaws980,981are closed than when they are open. First and second securement members950,951are provided in first handle portions944,945to secure biasing mechanism954. An example biasing mechanism954comprises a spring, as shown. Arms932,933have decreased thickness portions936,937at their ends and openings (not shown) in decreased thickness portions936,937through which a bolt978passes. Bolt978is secured by a nut974. Joint mechanism964is formed by decreased thickness portions936,937, nut974, and bolt978.

In the present embodiment, a depth adjuster958, or positioning member, is provided which can be secured to first and second members930,931by bolt978at any of a plurality of positions. Depth adjuster958includes two slots962traversed by bolt978and a depth stop surface960. Depth adjuster958can be moved proximally or distally to set a desired insertion depth of jaws980,981, and thereby fluid conduits918,919, into the nostrils of the animal. Depth stop surface960contacts the nose of the animal at the desired insertion depth to stop forward, or distal, movement of intranasal administration device900.

First and second jaws980,981extend distally from actuation mechanism928and include, at the distal ends thereof, septum interference members990,991configured to form a pinch point996when first and second jaws980,981are closed. Jaws980,981, in the present embodiment, comprise straight jaw portions988,989coupled to first and second arms932,933and curved jaw portions984,985; and septum interference members990,991. In the present embodiment, curved jaw portions984,985curve outwardly and then inwardly, thus extend on both sides of the centerline of straight portions988,989. Septum interference members990,991have blunted edges to prevent tissue trauma and are curved and substantially flat perpendicularly to the curvature. As shown, septum interference members990,991are about twice as wide as they are thick, to enable clamping while permitting substantially unimpeded breathing by the animal. The flat profile increases the ability of the animal to breathe. The thickness of septum interference members990,991(across the flat profile) is sufficient to prevent tissue trauma at pinch point996. These characteristics may depend on the age and weight of the animal, and the weight of intranasal administration device900, which collectively determine the minimum biasing force necessary to clamp intranasal administration device900onto the nasal septum.

As illustrated inFIG. 9, fluid conduits918,919are supported by first and second members930and931via elongate fluid conduit support openings938,939. The distal ends of fluid conduits918,919extend past pinch point996, and thereby nasal passage nozzles920,921are also positioned distally of septum interference members990,991The insertion depth of the fluid conduits may be adjusted by sliding fluid conduits918,919within elongate fluid conduit support openings938,939or by cutting fluid conduits918,919to achieve an appropriate insertion depth. A distance A is defined by the longitudinal distance between depth stop surface960and pinch point996. A transverse line994passing through pinch point996is shown to better illustrate distance A. A longitudinal distance B is defined by depth stop surface960and the distal ends of fluid conduits918,919. A transverse line998passing through nasal passage nozzles920,921is shown to better illustrate distance B. In some embodiments, distance A is between 1 and 3 inches, more preferably between 1½ and 2½ inches, for a bovine animal weighing between 400 and 700 pounds, and distance B is between 2 and 6 inches, more preferably between 3 and 5 inches, and even more preferably between 3½ and 4½ inches. Elongate fluid conduit support openings938and939are disposed at least partially below jaws980,981to facilitate alignment of the fluid conduits with the ventral meatus. In addition to providing support, elongate fluid conduit support openings938and939establish an angle between the fluid conduits, which changes as the device is opened or closed. In some embodiments, the angle comprises between 35 and 60 degrees when the jaws are in contact with each other, as shown inFIG. 9. In some embodiments, the angle comprises between about 40 and 50 degrees when the jaws are in contact with each other. Fluid conduits918,919and nasal passage nozzles920,921are designed for insertion into the right and left ventral meatus of the nasal passages at an angle/orientation that is substantially aligned with a longitudinal direction of the ventral meatus. This orientation reduces tissue trauma and aids in insertion depth and animal acceptance.

FIGS. 10 and 11are perspective and side views of an embodiment of nasal passage nozzle920, which is identical to nasal passage nozzle921. Nasal passage nozzle920comprises a head922connected to a body924having a plurality of ribs925configured to secure body924within the distal end of fluid conduit918. Head922has an external diameter perpendicular to its longitudinal axis which is substantially equal to the diameter of fluid conduit918. Head922may be semi-spherically shaped. In various examples, the diameter of head922is between about 0.300 and 0.450 inches, more preferably between about 0.350 and 0.400 inches, and even more preferably between about 0.370 and 0.380 inches. In some embodiments, body924has a diameter between about 0.220 and 0.280 inches, and more preferably between about 0.240 and 0.260 inches. As shown inFIG. 11, nasal passage nozzle920further comprises a distal cavity926with an orifice923at its distal end and a medial cavity927having a diameter larger than the diameter of distal cavity926with conical transition portion therebetween configured to constrict and stabilize the fluid prior to discharge. As shown, distal cavity926is cylindrical. It is estimated that fluid discharged through distal cavity926exhibits a full cone spray pattern with a round impact area and uniform distribution, and a spray angle of 55 degrees at 29 pounds per square inch (PSI) of pressure, discharging at said pressure 0.13 gallons per minute (GPM) of fluid with a mean drop diameter of 270 microns. As shown, distal cavity926has a cylindrical shape. In other embodiments other shapes may be used to produce spray patterns with different impact areas. For example, an elliptical pattern may be desired. The diameter of distal cavity926may be changed to increase the discharge capacity above or below 0.13 GPM. In some embodiments, the discharge capacity is between about 0.12 and 0.26 GPM. In some embodiments, the discharge pressure is between about 20 and 25 PSI at the nozzle opening of the nasal passage nozzle. In some embodiments, the mean drop diameter is between about 260 and 300 microns. The nasal passage nozzle may be fitted with a whirler. Exemplary whirlers comprise X shaped, disc-shaped and spiral-shaped whirlers, which are configured to distribute the fluid evenly to produce the full cone spray shape.

A pump is fluidly coupled between a reservoir for the fluid and the intranasal administration device. The pump may be controlled to change the pressure and discharge time, which may be configured to generate a dosing volume of between about 30 and 35 milliliters of fluid at nozzle pressure of between about 20 to 25 PSI with a fluid having a density similar to the density of water. Larger or smaller dosing volumes would be appropriate for differently sized animals. A density similar to the density of water may range between 0.8 and 1.2 g/cm3.

FIG. 13is a perspective view of the head of animal104illustrating another embodiment of an intranasal administration device, denoted by numeral1000, which is illustrated inFIGS. 14 to 16. Intranasal administration device1000differs from intranasal administration devices101,201,301,401,501,701,801, and900in that the jaws and the handle have different characteristics. Intranasal administration device1000comprises an actuation mechanism928including a handle1004, and jaws1020,1021. Handle1004comprises first and second handle members1012,1013. First handle member1012extends from first arm932and includes first handle portion944and a second handle portion1016. Second handle member1013extends from second arm933and includes a first handle portion945and a second handle portion1017. Second handle portions1016,1017are transverse bars that extend from first handle portions944,945and which may have any desirable length sufficient to enable operation of handle1004by permitting the user to grip second portions1016,1017without interference from fluid conduits918,919. Second handle portions1016,1017may face upward or downward, depending on the relative position of the pump system, so as to limit interference with the fluid conduits. Handle1004is also referred to as a user interface. Jaws1020,1021include straight jaw portions1022,1023and curved jaw portions1024,1025. By contrast with intranasal administration device900, jaws1020,1021curve inwardly and no part thereof extends outside the longitudinal axis of straight jaw portions1022,1023. The curvature of the jaws can interfere with the nostrils of the animal and can also prevent or interfere with breathing of the animal.

In one embodiment, a dosing volume of between about 30 and 35 milliliters of fluid at a nozzle tip discharge pressure of between about 20 to 25 PSI was delivered with intranasal delivery device900to a bovine animal weighing between 400 and 700 lbs. The fluid contained a colored dye and had a density similar to the density of water. Upon dissection of the head of the animal it was observed that the nasopharynx of the animal was substantially coated.

In some embodiments, a method to deliver a fluid intranasally to a veterinary subject, the method comprises opening the jaws of an intranasal administration device900,1000; inserting the jaws into the nostrils of the veterinary subject while inserting the distal ends of fluid conduits medially and posteriorly into the ventral meatus; clamping the nasal septum of the veterinary subject with the jaws; and discharging a fluid through the fluid conduits.

Inserting the jaws and the fluid conduits into the nostrils of the veterinary subject comprises inserting the fluid conduits through flow constrictions formed by the alar folds and the basal folds of the veterinary subject. Inserting the jaws and the fluid conduits into the nostrils of the veterinary subject may comprise moving the intranasal administration device toward the veterinary subject until a depth stop surface of the intranasal administration device contacts the nose of the veterinary subject.

The fluid may comprise a nitric oxide releasing solution or a nitric oxide gas or a combination of the nitric oxide releasing solution and the nitric oxide gas. After delivery of the fluid, the jaws are unclamped and the intranasal administration device is removed.

Embodiments of the invention have been described including an actuation mechanism, two jaws, and two fluid conduits. In various embodiments, the actuation mechanism may comprise a ratchet mechanism including a gear and a pawl mounted on a base, and a release lever to release the pawl from the gear, whereby the first and second members are brought together by the user to clamp the device and movement of the release lever enables separation of the first and second members to release the device. Other actuation mechanisms known in the art may also be used.

The following examples pertain to further embodiments:

In one example, an animal intranasal administration device can comprise a nasal passage nozzle for a nostril configured to receive fluid from a fluid source; a support structure opposing the nasal passage nozzle; and a biasing mechanism to bias the nasal passage nozzle and the support structure toward a septum such that the device is secured in place about the septum during administration of the fluid into a nasal passage.

In on example, the support structure comprises a second nasal passage nozzle.

In one example, the biasing mechanism comprises a spring to bias the nasal passage nozzles toward the septum.

In one example, the animal intranasal administration device can further comprise a support member having a first support member portion and a second support member portion each in support of a nozzle, wherein the first support member portion and the second support member portion are movable relative to one another by the biasing mechanism.

In one example, the biasing mechanism comprises resilient flexibility of at least one of the first support member portion and the second support member portion.

In one example, the first and second support member portions are pivotally coupled to one another.

In one example, the animal intranasal administration device can further comprise a positioning member configured to contact a tip of the septum to facilitate and maintain proper positioning of nasal passage nozzles.

In one example, the nasal passage nozzles are oriented to align nozzle openings with nasal passages when the device is engaged with the septum.

In one example, the nasal passage nozzles are configured to direct fluid into the nasal passages past nasal folds.

In one example, the nasal passage nozzles are configured to extend into the nostrils beyond the nasal folds.

In one example, the nasal folds comprise at least one of an alar fold, a basal fold, and a straight fold.

In one example, the animal intranasal administration device can further comprise a fluid distribution manifold fluidly coupled to the nasal passage nozzles, the fluid distribution manifold having an inlet port to receive fluid from the fluid source and outlet ports to distribute fluid to the nasal passage nozzles.

In one example, the animal intranasal administration device can further comprise a septum interface portion associated with each of the nasal passage nozzles to interface with the septum and position the nasal passage nozzles to facilitate directing fluid into the nasal passages.

In one example, the animal intranasal administration device can further comprise a user interface to facilitate movement of the nasal passage nozzles by a user in a direction opposite a biasing direction.

In one example, the fluid is selected from the group consisting of: a liquid, a gas, a gel, or a combination thereof.

In one example, an animal intranasal administration device can comprise a support member having a first support member portion and a second support member portion, a first nasal passage nozzle, and a second nasal passage nozzle, wherein the first support member portion and the second support member portion are movable relative to one another to position the first and second nasal passage nozzles at least partially within nostrils of an animal about a septum and such that fluid is directed into nasal passages of the animal.

In one example, the first and second support member portions are biased toward a secured position about the septum.

In one example, the animal intranasal administration device can further comprise a spring to bias the first and second support member portions toward the secured position.

In one example, at least one of the first and second support member portions is resiliently flexible to bias the at least one of the first and second support member portions toward the secured position.

In one example, the support member is configured to provide clearance about a tip of the septum.

In one example, the first and second support member portions comprise arcuate configurations to provide clearance about the tip of the septum.

In one example, the first and second nasal passage nozzles are oriented to align nozzle openings with the nasal passages of the animal when the device is engaged with the animal.

In one example, the fluid conduits are external to the support member.

In one example, at least one of the first and second support member portions comprises at least a portion of the conduit. The distal ends of the conduits thus protrude from the first and second support member portions and are not supported therewith.

In one example, the user interface comprises a first user interface portion coupled to the first support member portion, and a second user interface portion coupled to the second support member portion, and wherein the first and second user interface portions are movable relative to one another to facilitate movement of the first and second support member portions relative to one another.

In one example, an animal intranasal administration system can comprise any of the animal intranasal administration devices described herein. The animal intranasal administration system can further comprise a pump operable to deliver fluid from the fluid source to the first and second nasal passage nozzles. The pump is configured to pump at least one of a liquid and a gas.

In one example, a pump of an animal intranasal administration system comprises a motorized pump, a hand pump, or a combination thereof.

In one example, the fluid source comprises activated nitric oxide releasing solution.

In one example, the fluid source comprises inactivated nitric oxide releasing solution.

In one example, the fluid source comprises a container with the inactivated nitric oxide releasing solution disposed therein, and wherein the inactivated nitric oxide releasing solution is activatable within the container.

In one example, fluid is configured to dispense from the fluid source to the first and second nasal passage nozzles following activation of the nitric oxide releasing solution due to a pressure in the container resulting from the activation of the nitric oxide releasing solution.

In one example, the animal intranasal administration system can further comprise a cage for containing an activation agent prior to mixing the activation agent with the inactivated nitric oxide releasing solution, wherein the cage is configured to facilitate mixing of the activation agent and the inactivated nitric oxide releasing solution.

In one example, the cage is supported within the container above a bottom of the container.

In one example, the fluid source further comprises an activation agent maintained separate from the inactivated nitric oxide releasing solution and configured to activate the inactivated nitric oxide releasing solution upon mixing.

In one example, the fluid source is fluidly coupled to the first and second nasal passage nozzles via a first conduit associated with the inactivated nitric oxide releasing solution and a second conduit associated with the activation agent.

In one example, the first and second conduits combine prior to the first and second nasal passage nozzles such that mixing of the inactivated nitric oxide releasing solution and the activation agent occurs between the fluid source and the first and second nasal passage nozzles.

In one example, the first and second conduits combine at the first and second nasal passage nozzles such that mixing of the inactivated nitric oxide releasing solution and the activation agent occurs at the first and second nasal passage nozzles.

In one example, the first and second conduits remain separate from the fluid source to the first and second nasal passage nozzles such that mixing of the inactivated nitric oxide releasing solution and the activation agent occurs at the animal.

In one example, the fluid source comprises nitric oxide gas.

In one example, the animal comprises a domesticated animal.

In one example, the domesticated animal comprises a bovine, a swine, an equine, an ovine, or a goat.

In one example, a method of administering a fluid to an animal's nostril can comprise providing an animal intranasal administration device including a support member having a first support member portion and a second support member portion, a first nasal passage nozzle coupled to the first support member portion, and a second nasal passage nozzle coupled to the second support member portion, wherein the first support member portion and the second support member portion are movable relative to one another to secure the first and second nasal passage nozzles at least partially within nostrils of an animal about a septum and such that fluid is directed into nasal passages of the animal, engaging the device with the animal's nostril, and dispensing the fluid from the device and into the animal's nostrils.

In one example, an amount of nitric oxide releasing solution dispensed to the animal is between about 0.1 mL and about 5000 mL.

In one example, the amount of nitric oxide releasing solution dispensed to the animal is between about 10 mL and 1000 mL.

In one example, an amount of nitric oxide releasing solution dispensed to the animal is about 2 mL.

In one example, an amount of nitric oxide releasing solution dispensed to the animal is about 10 mL.

In one example, an amount of nitric oxide releasing solution dispensed to the animal is about 32 mL.

In one example, an amount of nitric oxide releasing solution dispensed to the animal is 160 mL.

In one example, the fluid source comprises inactivated nitric oxide releasing solution.

In one example, the method can further comprise activating the inactivated nitric oxide releasing solution.

In one example, the fluid is dispensed utilizing a gas pressure resulting from the activation of the nitric oxide releasing solution.

In one example, activating the inactivated nitric oxide releasing solution occurs prior to dispensing the fluid from the device and into the animal's nostril.

In one example, activating the inactivated nitric oxide releasing solution occurs when dispensing the fluid from the device and into the animal's nostril.

In one example, activating the inactivated nitric oxide releasing solution occurs after dispensing the fluid from the device and into the animal's nostril.

It is noted that no specific order is required in the methods disclosed herein, though generally in some embodiments, the method steps can be carried out sequentially.