This invention relates to an equine intranasal delivery system for the delivery of cold-adapted equine viruses. The invention also includes both apparatus and methods for the intranasal delivery of various materials, compositions or medicaments to both humans and animals. Generally, the invention provides basic technology for the delivery of various compositions to target locations.
There are many advantages to intranasal administration of medications and other compositions which include, among others, a direct route to the blood stream, avoidance of hepatic first pass metabolism, bioavailability, ease and convenience, and proximity to the central nervous system. See Y. W. Chien et al., Anatomy and Physiology of the Nose, Nasal Systemic Drug Delivery, Chapter 1, 1-26, 1989. Various types of compositions, therapeutics, prophylactics or otherwise, may be delivered intranasally including, but not limited to, topical anesthetics, sedatives, hypnotics, analgesics, ketamines, opiates, glucagons, vaccines, anti-nausea and motion sickness medications, antihistamines, antihypertensive drugs, psychoactive medications, antibiotics, and hormones. See, as examples, M. R. Nott et al., Topical Anaesthesia for the Insertion of Nasogastric Tubes, European Journal of Anaesthesiology, 12(3), May 1995; R. J. Henry et al, A pharmacokinetic Study of Midazolam in Dogs: Nasal Drop Versus Atomizer Administration, Journal of the American Academy of Pediatric Dentistry, 20(5), 321-326, 1998; J. Lithander et al., Sedation with nasal Ketamine and Midazolam for Cryotherapy in Retinopathy of Prematurity, British Journal of Ophthalmology, 77(8), 529-530, 1993; F. E. Ralley, Intranasal Opiates: Old Route For New Drugs, Canadian Journal of Anesthesiology, 36(5) 491-493, 1989; B. Haneberg et al, Intranasal Administration of Mengiococcal outer membrane vesicle vaccine induces persistent local Mucosal Antibodies and Serum Antibodies with Strong Bactericidal Activity in Humans, Infection and Immunity, 66(4), 1334-1341, 1998; B. K. Wager et al, A Double Blind Placebo-Controlled Evaluation of Intranasal Metoclopramide in the Prevention of Postoperative nausea and Vomiting, Pharmacotherapy, 16(6), 1063-1069 1996; and J. Q. Wang, et al., An Experimental Study on Nasal Absorption of Gentamycin in Dogs, Chinese Medical Journal, 107(3), 219-221, 1994.
Specifically with respect to live virus vaccines, it has been shown that they are often too pathogenic for use as immunogens for either humans or animals as described in U.S. Pat. No. 3,953,592. Attempts to vaccinate against viral infection With inactivated virus, however, may not offer effective protection and can produce undesirable side effects as indicated in U.S. Pat. No. 3,953,592; R. Belshe et al, Immunization of Infants and Young Children with Live Attenuated Trivalent Cold-Recombinant Influenza A H1N1, H3N2, and B Vaccine, The Journal of Infectious Disease, Volume 165, 727-732, 1992; K. M. Nelson et al., Local and Systemic Isotype-specific Antibody Responses to Equine Influenza Virus Infection Versus Conventional Vaccination, Vaccine, Volume 16, Number 13, 1998. Injection of equids with inactivated viruses may cause, for example, inflammatory reactions at the site of injection. See Mumford et al., Serological Methods for Identification of Slowly-Groweing Herpesviruses Isolated from the Respiratory Tract of Horses, Equine Infectious Disease IV, 49-52, 1978; Mumford et al., Consultation on Newly Emerging Strains of equine Influenza,Vaccine 11, 1172-1174, 1993. It has also been shown that protective responses to viral infection are not limited to the production of antibodies but that a local antibody system and an interferon production mechanism operate at the primary site of infection in the nasal passage membranes as disclosed by U.S. Pat. No. 4,132,775; T. Tomoda et al., Prevention of influenza by the Intranasal Administration of Cold-Recombinant, Live-attenuated Influenza Virus Vaccine: Importance of Interferon-xcex3 Production and Local IgA Response, Vaccine, Volume 13, Number 2, 185-190, 1995; and Holmes, Lamb, Coggins, et al, Live Temperature Sensitive Equine-2 Influenza A Virus Vaccine: Production and Eficacy in Experimental Ponies, Equine infectious disease VI, 253-258, 1992.
As such, intranasal delivery of the above mentioned compositions has become a preferred route of administration for both inactivated viruses as described by U.S. Pat. No. 3,953,592, and cold-adapted live virus vaccines which are inhibited from replication in the range of the normal body temperature but do replicate at lower temperatures, such as perhaps, associated with the mucosae of the upper respiratory tract as disclosed by U.S. Pat. No. 3,927, 208; Maassab, et al., Biologic and Immunologic Characteristics of Cold-Adapted Influenza Virus, Journal of Immunology. 102, 728-732, 1969; and Keitel et al., Trivalent Attenuated Cold-Adapted Virus Vaccine: Reduced Viral Shedding and Serum Antibody Responses in Susceptible Adults, The Journal of Infectious Disease, Volume 167, 305-311, 1993. Intranasal delivery of compositions has also been effective for certain reassortant cold-adapted viruses which may also possess a dominant interference phenotype which may inhibit the growth of the corresponding wild-type strains and other heterologous viruses as disclosed by U.S. Pat. Nos. 4,683,137 and 4,693,893.
Due to the increased use of intranasal delivery of various compositions, including inactivated and cold-adapted live viruses, in both humans and animals, there is corresponding demand in the marketplace for intranasal apparatus and methods of intranasal delivery which address existing problems, and which are especially acute with respect to equids including, for example, horses, ponies, or exotic equids such as zebra which may be part of a zoological collection, or otherwise.
A significant problem with intranasal delivery of compositions is interspecies and intraspecies anatomical variation. With regard to one aspect of these differences, it is evident from casual observation that the gross morphology of bovine species present a shorter nasal passage then, for example, equid species. An inflexible intranasal administrator, for example, may be adequate for intranasal delivery of a composition or dose to a bovine where the intranasal administrator need only tranverse a short distance in the bovine nasal passage, however, such an inflexible device may not be suitable for equids where the intranasal administrator may have to traverse several inches within the nasal passages of an equid.
A related problem with intranasal delivery of compositions in equids as opposed to bovine, for example, is the presence of a false nostril (nasal diverticulum) as described by Klaus, Dieter, Budras, Anatomy of the Horse an Illustrated Text, 2nd edition, Mosby-Wolfe, London, 1994. The nasal diverticulum presents two problems with regard to intranasal delivery in equids although other species may have anatomical structures which present equivalent difficulties. First, an intranasal probe for equids must be designed such that the user has an immediate means of determining if the delivery aperture of the intranasal probe has properly entered the nasal passage or if the intranasal probe has inadvertently entered the nasal diverticulum. The second problem associated with the nasal diverticulum is that the type of cells which line the nasal diverticulum are not the same type of cells which line the nasal passage of the upper respiratory tract. Delivery of compositions, including the delivery of cold-adapted live viruses, to the type of cells which line the nasal diverticulum may not provide therapy because such cells may not be susceptible to such compositions, or cold adapted live viruses. While the nasal diverticulum provides a remarkable example of the necessity of coordinating therapeutic compositions with an anatomical location having cells susceptible to a particular composition or dose, dose-location coordination may be an important aspect of intranasal delivery in many other species.
Another significant problem with intranasal delivery is the movement and regional distribution of the composition or dose subsequent to administration. The deposition of a composition or dose after intranasal delivery depends upon particle inertia, sedimentation due to gravity, and diffusion due to Brownian motion. M. Dolovich, Principles Underlying Aerosol Therapy, Journal of Aerosol Medicine, Vol. 2, No. 2, 1989; see also A. Brown and J. Slusser, Propellent-driven Aerosols of Function Proteins as Potential Therapeutic Agents in the Respiratory Tract, Immmunopharmacology 28, 241-257, 1994. Each of these mechanisms can be dependent upon the particle size of the dose or composition delivered. As disclosed by M. Dolovich, particles having a diameter of less than about 1 micrometer can remain suspended as the time required for the particle to diffuse to an airway wall tends to be greater than the time to complete the inspiratory phase of a normal breath. Optimum deposition in the lung may be achieved with particles having a diameter of about 3 micrometers. Larger particles having a diameter of greater than about 5 micrometers are often deposited in the upper airways. M. Dolovich, at pages 173-174. As such the proper particle size should be selected depending on where in the airway or lung compartment deposition is to occur. With respect to cold-adapted viruses delivered intranasally from devices designed to provide a fine aerosol or heterodisperse aerosol, a portion of the dose may remain suspended in the respired air and subsequently exhaled without deposition. This may be particularly true when treating animals which may not be instructed to hold their breath. Alternately, the cold-adapted virus having a somewhat larger particle size may remain suspended and then deposited in the lung compartment. Once in the lung compartment the virus may be prohibited from replication by exposure to the normal body temperature of the animal. In either event, a portion of the dose may be rendered ineffective because the dose was delivered as a particle of non-optimal size.
To the extent that xe2x80x9cmultiple studies show that atomized pump is the best nasal delivery system because it gives a constant dose and a very good mucosal distributionxe2x80x9d and that research has demonstrated xe2x80x9cclearance of spray is much slower than clearance of dropsxe2x80x9d, these studies, research and marketing descriptions, teach away from a non-aerosol-location coordinated intranasal delivery system. See T. Wolfe, Intranasal Medication Administration: Literature Review, Wolf Tory Medical, Incorporated, http://www. wolfetory.com/intr.html,1, 1-17, at page 3, 1999.
A related problem is coordinating the delivery of a particular type of composition with a particular location of delivery. Often the location to which the dose is to be administered is hidden from view. As such, there may be little assurance that the composition has actually been delivered to the proper location or target. This may be particularly problematic for those individuals that have little or no formal medical training.
Yet another problem with existing devices for intranasal administration of compounds is generation of excess physical stimulation of the nasal passage as the intranasal probe or dose administrator is guided along the intranasal passage. This physical stimulation may be more acute when the force used to move the intranasal probe along the intranasal passage is translated to a tip of the dose administrator having a small surface area which contacts the nasal mucosae. As can be understood, an intranasal administrator comprising a relatively small diameter tube with a thin sidewall may be more likely to irritate, cut, score or pierce the intranasal surface causing the human or animal to move unpredictably. After the intranasal passage has been injured it may also subsequently become infected and require additional medical attention. Moreover, when attempting to administer a composition or dose intranasally to a human or an animal, unpredicted movement caused by such physical stimulation may force the intranasal dose administrator into contact with the eye or perhaps into contact with the person attempting to administer the composition or dose. This inadvertant movement may also transfer biological fluids between the patient and the practitioner or cause the loss of a portion or all of the composition or dose. As such, reducing physical stimulation of the spot contacted by the intranasal probe may be preferred.
Another problem related to intranasal administrators which have a small diameter or thin wall construction is that axial deflection of the intranasal administrator may be excessive under the typical forces encountered during use. Axial collapse of the administrator may result in a failure to deliver the dose properly, additional physical stimulation of the intranasal passage, or cause injury.
Still another significant problem is the amount of composition or dose that may remain in devices upon delivery of the composition or dose to the patient. This xe2x80x9cdead volumexe2x80x9d within the device represents an amount of the dose or composition that is unavailable to the patient. With regard to some types ofjet nebulizers, this may amount to as much as 0.5-1.0 milliliters of concentrated solution, as disclosed by M. Dolovich, Physical Principles Underlying Aerosol Therapy, Journal of Aerosol Medicine, Volume 2, Number 2, 1989. The dead volume associated with intranasal devices having administrators or intranasal probes designed for equids, for example, which are quite long may have a similarly large dead volume. Even if devices with a smaller dead volume were designed, even such smaller volume of a composition or a dose made unavailable to the patient may be significant where the cost of the dose is high. An intranasal delivery system which reduces dead volume by design of the intranasal device or by the method of use may provide substantial benefit.
Another problem with some delivery systems may be a lack of unitized construction. Components which may have been produced as a single unit may comprise several component parts which are compression fit together, or bonded together with use of a solvent, as can be understood from the Misty device. These several component parts may disassemble during intranasal administration or subsequently become lodged in the intranasal passage of the human or animal. These component parts may cause immediate injury or remain in the intranasal passages undiscovered to cause subsequent injury. Removal of these component parts from the intranasal passages may also require additional medical procedures.
From the consumer""s point of view there are several problems which have not been adequately addressed by existing systems for the administration of compositions. The first is the fear of needles. Many people are needle phobic and as a result many people are not inoculated. S. Hoffert, Biotech Innovations Aim to Conquer Influenza Virus, The Scientist, 1 and 6, Mar. 2, 1998. A second problem for the consumer is the potential for inadvertent needle sticks which may transfer either the composition or physiological fluids from the patient to the person administering the composition or dose. A third problem for the consumer is proper disposal of needles. A delivery device which eliminates injection of the composition with a needle may induce the needle phobic to obtain inoculation and may also address the problems of inadvertent needle sticks and needle disposal. A fourth problem for the consumer untrained in medical or veterinary fields is the fear of self administration of compositions to themselves, or other humans or animals. A part of this fear may be the use of needles, or other devices, which the consumer believes may cause injury to the patient due to the consumer""s lack of training. However, even with respect to delivery devices which may be designed for use without a needle, the consumer may have concerns that the composition or dose may be delivered in a manner that is not therapeutic for the patient. A properly engineered intranasal device may address these consumer concerns by providing features which assure proper measurement of a dose and delivery of the dose to an intranasal location in a manner which will be therapeutically effective.
As to each of these problems regarding devices for the delivery of compositions and the methods of delivering compositions, the present invention discloses technology which overcomes every one of the problems disclosed in a practical fashion.
Accordingly, the broad goal of the invention is to provide a delivery system for various compositions including medicaments which safely and effectively delivers the entire amount of a composition or a dose to the proper target. Specifically, the broad goal of the invention also addresses the particular requirements of intranasal delivery of such compositions and medicaments in the equine field which is particularly difficult due to the size, mobility and deposition of equids. The composition or dose delivery features disclosed are varied and may be incorporated into a variety of devices or used in numerous applications. Naturally, as a result of these several different and potentially independent aspects of the invention, the objects of the invention are quite varied.
One of the broad objects of the invention is to provide basic technology to improve the delivery of a wide variety of compositions, including medicaments, across a broad range of commercial, research, medical and veterinary applications.
Another object of the invention, is to provide specific apparatus and methods for the intranasal delivery of prophylactic and therapeutic compositions to both humans and animals incorporating the above mentioned basic technological aspects of the invention.
Another object of the invention is to define the scope of existing technology that may be improved by using such technology with specific strains of cold-adapted equine influenza virus.
Another object of the invention is to provide an intranasal delivery device for equids which specifically incorporates certain aspects of the invention so as to accommodate the longer or more complicated nasal passages of the equine anatomy.
Related to this object are certain embodiments of the invention which provide for the effective delivery of compositions or doses, including particular cold-adapted influenza or coldadapted equine influenza viruses, to specific dose-location coordinates which may be hidden from visual observation. A particular goal is to provide apparatus and methods for assuring that specific strains of equine cold-adapted equine influenza viruses may be delivered to a location on the nasal mucosa of an equid having a temperature range suitable for replication of these specific equine influenza strains.
Another object of the invention is to provide an element which prevents the axial collapse of the dose administrator due to incidental contact as it is brought into position for delivery of the composition or dose to the target.
Another object of the invention is to provide delivery of the composition or dose in a manner which assures that a substantial portion of such composition or dose will remain in the proximity of the desired dose-location coordinate or target.
Another object of the invention is to minimize the cutting, scoring or other injuries and physical stimulation from the incidental contact of various surfaces, including intranasal passages, with the dose administrator as it is positioned for delivery of the composition or dose.
Another object of the invention is to minimize the amount of the dose which is retained by the dose delivery administrator after delivery of the composition or dose to the dose-location coordinate or target. Specifically, with respect to devices which have larger dead volumes or larger minimum dose delivery volumes, such as those which have longer dose administrators, this aspect of the invention allows the dose to be sequestered proximate to the dose delivery aperture. A sequestered dose comes into contact with less surface area of the delivery system and is expelled from the dose administrator with a lower minimum delivery volume.
Another object of the invention is to make an uncomplicated delivery device which may be used by individuals that have little or no formal training. A goal related to this object is elimination of parts which may inadvertently become disassembled during the use of the device.
Naturally further objects of the invention are disclosed throughout other areas of the specification and claims.