Nasal delivery devices

Abstract

A nasal delivery device for and method of delivering substance to a nasal airway of a subject, the delivery device comprising: a nosepiece (117) for fitting to a nasal cavity of a subject; a mouthpiece (119) into which the subject in use exhales; a delivery unit, which comprises an actuation part which is manually displaceable to actuate the delivery unit to deliver substance from the nosepiece; and a valve assembly (127) which is fluidly connected to the nosepiece and the mouthpiece, wherein the valve assembly comprises a body element (128) and a valve element (131) which is movably disposed to the body element between closed and open configurations by manual displacement of the actuation part of the delivery unit to provide for an air flow through the nosepiece simultaneously with delivery of substance.

Description

Nasal delivery devices The present invention relates to a nasal delivery device for administering a substance, in particular a liquid, such as a suspension or solution, or a powder, for example containing a drug, especially systemic or topical pharmaceutical products, or a vaccine, to the nasal airways of a subject. Referring to Figure 10, nasal passage 1 comprises the two nasal cavities separated by the nasal septum. Nasal passage 1 includes numerous ostia, such as the paranasal sinus ostia 3 and the tubal ostia 5, and olfactory cells, and is lined by nasal mucosa. Nasal passage 1 can communicate with the nasopharynx 7, the oral cavity 9, and the lower respiratory tract 11. Nasal passage 1 is in selective communication with the anterior region of the nasopharynx 7 and the oral cavity 9 by opening and closing the oropharyngeal velum 13. The velum 13, often called the soft palate, is illustrated with a solid line in the closed position, achieved by providing a certain positive pressure in the oral cavity 9, such as that achieved during exhalation through the oral cavity 9, and with a dashed line in the open position. There are many nasal conditions that require treatment. One such condition is nasal inflammation, specifically rhinitis, which can be allergic or non-allergic and is often associated with infection, impairing normal nasal function. For example, allergic and non-allergic inflammation of the nasal passages typically affects between 10% and 20% of the population. The most common symptoms include nasal congestion of the turbinate tissues, watery eyes, watery mucus discharge, sneezing, and itching. As you can imagine, nasal congestion impedes nasal breathing and promotes mouth breathing, leading to snoring and sleep disturbances. Other nasal conditions include nasal polyps arising from the sinuses, enlarged adenoids, secretory otitis media, sinus disease, and a reduced sense of smell. Topical administration of medications is preferred for the treatment of certain nasal conditions, particularly when the nasal mucosa is the primary affected area, such as in the treatment or relief of nasal congestion. Medications commonly administered topically include decongestants, antihistamines, cromolyn sodium, steroids, and antibiotics. Currently, among known anti-inflammatory drugs, topical steroids have demonstrated an effect on nasal congestion. The use of topical decongestants has also been suggested for relieving nasal congestion. Although somewhat controversial, the treatment of hypertrophic adenoids and chronic secretory otitis media with topical decongestants, steroids, and antimicrobials has also been proposed.In addition, topical administration of pharmaceutical products has been used to treat or at least relieve the symptoms of inflammation in the anterior region of the nasopharynx, the paranasal sinuses, and the ear canals. Drugs can also be administered systemically via the nasal route, the nasal route offering a good route of administration for the systemic administration of pharmaceuticals such as hormones, for example oxytocin and calcitonin, and analgesics such as antimigraine compositions, since the high blood flow and large surface area of ​​the nasal mucosa advantageously provide rapid systemic absorption. Nasal administration is also expected to be advantageous for administering drugs that require a rapid onset of action, such as analgesics, antiemetics, insulin, antiepileptics, sedatives, and hypnotics, as well as other pharmaceuticals, such as cardiovascular drugs. Nasal administration is anticipated to provide a rapid onset of action, at a rate similar to that of injection and much faster than that of oral administration. In fact, for the treatment of many acute conditions, nasal administration is advantageous over oral administration, as gastric stasis can further slow the onset of action following oral administration. Nasal administration is also expected to provide an efficient route for delivering proteins and peptides such as those produced using modern biotechnological techniques. For such substances, intestinal metabolism and the first-pass effect in the liver pose significant obstacles to reliable and cost-effective delivery. Furthermore, nasal administration using the nasal delivery technique of the present invention is expected to be effective in treating many common neurological diseases, such as Alzheimer's, Parkinson's, psychiatric disorders, and intracerebral infections, when existing techniques are not feasible. The nasal delivery technique of the present invention allows administration to the olfactory region, located in the upper part of the nasal cavity, which is the only region where it is possible to bypass the blood-brain barrier (BBB) ​​and allow communication with the cerebrospinal fluid (CSF) and the brain. Furthermore, the nasal delivery technique of the present invention is expected to allow for the efficient administration of vaccines. In addition to medication administration, nasal irrigation with fluids, particularly saline solutions, is commonly practiced to remove particles and secretions, as well as to improve mucociliary activity of the nasal mucosa. These solutions may be used in combination with active pharmaceutical ingredients. Accurate and reliable dosing is essential for any type of drug administration, but it is particularly important for potent drugs with a narrow therapeutic window, drugs with potentially serious adverse effects, and drugs for treating serious and life-threatening conditions. For some conditions, individualizing dosage based on the specific situation is crucial, for example, in the case of diabetes mellitus. For diabetes, and indeed for many other conditions, drug dosing is preferably based on real-time measurements. Currently, blood samples are most frequently used, but analyzing molecules in exhaled breath has been proposed as an alternative to blood tests for several conditions. Breath analysis is currently used to diagnose conditions such as Helicobacter pylori infections that cause gastric ulcers. WO-A-2000 / 051672 discloses a delivery device for administering a substance, particularly a drug, in a bidirectional airflow through the nostrils, i.e., an airflow that passes into one nostril, around the posterior margin of the nasal septum, and in the opposite direction out of the other nostril. This bidirectional airflow advantageously stimulates the sensory nerves in the nasal mucosa, thus preparing the subject for administration and providing a more comfortable administration experience. Document US-A-6648848, document US-A-2008 / 0163874, document US-A-2011 / 0088690 and document US-A-2011 / 0259329 disclose additional delivery devices for administering substances to a subject's nasal airways. It is an objective of the present invention to provide nasal delivery devices for administering substances to a subject's nasal cavity, and in particular relatively simple mechanically driven delivery devices. In one aspect, the present invention provides a nasal delivery device for administering a substance to a subject's nasal airway according to claim 1. The preferred embodiments of the present invention will be described herein and hereafter by way of example only with reference to the accompanying drawings, in which: Figures 1(a) and (b) illustrate a perspective view of a nasal delivery device according to a first embodiment of the present invention; Figure 2 illustrates an exploded perspective view of the administration device in Figure 1; Figure 3 illustrates a vertical cross-sectional view of the management device of Figure 1, in the non-actuated standby configuration; Figure 4 illustrates a vertical cross-sectional view of the management device of Figure 1, in the powered configuration; Figure 5 illustrates a detailed vertical cross-sectional fragmentary view of the administration device of Figure 1, in the powered configuration; Figures 6(a) to (c) illustrate the opening of the valve assembly sealing member by operating the delivery unit of the delivery device in Figure 1; Figure 7 illustrates graphs of the flow rates in the nosepiece and mouthpiece and the pressure in the mouthpiece for an exemplary device; Figures 8(a) and (b) illustrate fragmentary vertical section views in the non-actuated rest and actuated configurations of a nasal delivery device according to a second embodiment of the present invention; Figures 9(a) and (b) illustrate fragmentary vertical section views in the non-actuated rest and actuated configurations of a nasal delivery device according to a third embodiment of the present invention; and Figure 10 schematically illustrates the anatomy of the upper respiratory tract of a human subject. Figures 1 to 7 illustrate a manually operated nasal delivery device according to a first embodiment of the present invention. The delivery device comprises a housing 115, a nasal piece 117 to fit into a subject's nostril, a mouthpiece 119 into which the user exhales, to allow the delivery of an airflow to and through the subject's nasal passage when the subject exhales through the mouthpiece 119, and a delivery unit 120, which can be manually operated to deliver a substance to the subject's nostril. The housing 115 comprises a body element 121, in this embodiment having a substantially elongated tubular section that includes an opening 123 at one end thereof, through which a drive portion of the administration unit 120 protrudes, in this embodiment defined by the base of a substance chamber 173 of a substance supply unit 169. In this embodiment, body element 121 comprises two body sections 121a, b that are joined together. In this embodiment, the body sections 121a, b include mutually engaging tabs 124 and retainers 125, in this case of a press-fit type, and sealing elements 126, which act to close the airflow paths at the joining points of the body sections 121a, b. In this embodiment, the sealing elements 126 are joined by adhesive, but alternatively they could be mechanically joined, such as by welding. In an alternative embodiment, sealing elements 126 could be omitted. The housing 115 further comprises a valve assembly 127 that is in fluid communication with the nosepiece 117 and the mouthpiece 119, and which can be actuated between closed and open configurations, as illustrated in Figures 3 and 4, to provide airflow, in this embodiment in the form of an air burst, through the nosepiece 117 simultaneously with the actuation of the administration unit 120, as will be described in more detail later in this document. The valve assembly 127 comprises a main body element 128 that includes a valve seat 129 defining a valve opening 130, and a valve element 131 that is movably disposed with respect to the body element 128 between closed and open positions, as illustrated in Figures 3 and 4. As particularly illustrated in Figure 3, the body element 128 comprises a pivot 135, in this embodiment on a lower side of the valve seat 129, about which one end 145 of the valve element 131 pivots, and a sliding surface 137, in this embodiment on the other upper side of the valve seat 129, against which the other end 147 of the valve element 131 can slide. The valve element 131 comprises an elongated arm 141, in this embodiment a flexible arm, the end 145 of which, in this embodiment, is the lower end, pivots with respect to the pivot 135 of the body element 128, and the upper end 147 is slidably engaged with the sliding surface 137 of the body element 128, and a sealing member 149 that is supported by the arm 141. In this embodiment, the arm 141 comprises a first arm section, in this case lower, 151 which is deflected, in this case inwards, so that when the valve element 131 is in the closed rest position, the lower arm section 151 is inclined inwards with respect to the longitudinal axis of the housing 115 and can be engaged by the substance supply unit 169 when manually actuated to move the valve element 131 to the open position, as will be described in more detail later. In this embodiment, the arm 141 further comprises a second arm section 153, in this case upper, which engages the sliding surface 137 of the body element 128 and acts to deflect the valve element 131 to the closed position. In this embodiment, the sealing member 149 comprises a seal 161, in this embodiment a flexible or elastic element, which acts to close the valve opening 130 defined by the valve seat 129 when the valve element 131 is in the closed position, and a support 163 that supports a central area of ​​the seal 161. With this configuration, and referring to figures 6(a) to (c), in which the seal 161 is centrally supported, when the valve element 131 moves to the open position, the support 163 deflects the central area of ​​the seal 161, as illustrated in figure 6(b), causing the seal 161 to bulge outwards in this central area and thus allowing the seal 161 to engage the valve seat 129 only at the peripheral edge of the seal 161, until the point is reached where the seal 161 is suddenly and explosively released from the valve seat 129, as illustrated in figure 6(c). This release mode is believed to be particularly effective in the present application where a sudden initial burst of airflow is desired, in that substantially the entire sealing surface of seal 161 is released in an instant, compared to an alternative peel-type release mode, in which a smaller section of a sealing surface is released, followed by the remainder of the sealing surface, which tends to provide a lower initial burst pressure. In this embodiment, the administration unit 120 comprises an outlet unit 167 for administering a substance to the subject's nasal passage, and a substance delivery unit 169 for administering a substance to the outlet unit 167. In this embodiment, the valve assembly 127 provides a pre-actuation efficiency of less than 5 l / min when a user develops an exhalation pressure of 3 kPa, preferably less than 5 l / min when a user develops an exhalation pressure of 10 kPa, more preferably less than 1 l / min when a user develops an exhalation pressure of 3 kPa, even more preferably less than 1 l / min when a user develops an exhalation pressure of 10 kPa, even more preferably substantially no flow when a user develops an exhalation pressure of 3 kPa, and even more preferably no flow when a user develops an exhalation pressure of 10 kPa; the pre-actuation efficiency being a measure of the volume of air escaping from the device before actuation as a fraction of the volume of air delivered to the mouthpiece 119. In this embodiment, the delivery device is configured to provide a post-actuation efficiency of at least 80% at a flow rate of 50 l / min and an exhalation pressure of 3 kPa, preferably at least 85% at a flow rate of 50 l / min and an exhalation pressure of 3 kPa, more preferably at least 88% at a flow rate of 50 l / min and an exhalation pressure of 3 kPa, and even more preferably at least 90% at a flow rate of 50 l / min and an exhalation pressure of 3 kPa; the post-actuation efficiency being a measure of the volume of air delivered from the nosepiece 117 as a fraction of the volume of air delivered to the mouthpiece 119. Figure 7 illustrates, for an exemplary device, the graphs of the flow rates in the nasal piece 117 and the mouthpiece 119 and the pressure in the mouthpiece 119. In this embodiment, the pre-actuation efficiency is 1 l / min at a pre-actuation pressure of 5 kPa. In this embodiment, the post-activation efficiency is 88% at a flow rate of 57.1 l / min. In this embodiment, the valve element 131 provides a burst of airflow when opened, which has a first initial burst phase followed by a second prolonged burst phase, wherein the peak flow rate in the initial burst phase is higher than the average flow rate in the prolonged burst phase, and the prolonged burst phase has a substantially longer duration than the initial burst phase. In this embodiment, the maximum flow rate in the initial burst phase is at least 10%, preferably at least 15%, and more preferably at least 20%, higher than the average flow rate of the prolonged burst phase over a period corresponding to ten times the duration of the period in which the substance is administered from the nasal piece 117 by the delivery unit 120. In this embodiment, the administration unit 120 provides a spray that starts 54 ms after the opening of the sealing element 149 and ends 134 ms after the opening of the sealing element 149. In one embodiment, the administration unit 120 provides substance administration after the opening of the sealing element 149. In one embodiment, the delivery unit 120 provides the administration of substance in a period of less than approximately 250 ms from the opening of the sealing element 149, preferably less than approximately 200 ms from the opening of the sealing element 149, more preferably less than approximately 150 ms from the opening of the sealing element 149, and even more preferably less than approximately 100 ms from the opening of the sealing element 149. In one embodiment, the delivery unit 120 provides substance delivery starting less than approximately 150 ms after the opening of the sealing element 149, preferably less than approximately 100 ms after the opening of the sealing element 149, even more preferably less than approximately 50 ms after the opening of the sealing element 149, even more preferably less than approximately 25 ms after the opening of the sealing element 149, even more preferably less than approximately 15 ms after the opening of the sealing element 149. In this embodiment, the outlet unit 167 comprises a nozzle 171 for administering a substance to the subject's nasal passages. In this embodiment, the nozzle 171 is configured to deliver an aerosol spray. In an alternative embodiment, for administering a liquid, the nozzle 171 could be configured to deliver a liquid stream in the form of a column of liquid. In a preferred embodiment, the distal end of the outlet unit 167 is configured to extend at least approximately 2 cm, preferably at least approximately 3 cm, and more preferably from approximately 2 cm to approximately 3 cm, into the subject's nasal cavity. In this embodiment, the substance delivery unit 169 is a pumping unit, comprising a substance chamber 173 containing the substance and extending from the inlet 123 into the housing 115 as the drive part of the substance delivery unit 169, and a mechanical delivery pump 175 that can be actuated, in this case by pressing the substance chamber 173, usually by a finger or thumb of the subject, to deliver a measured dose of substance from the substance chamber 173 to the outlet unit 167 and from the nozzle 171 thereof, in this case in the form of an aerosol spray. In this embodiment, the substance chamber 173, when pressed to actuate the substance delivery unit 169, engages the lower arm section 151 of the arm 141 of the valve element 131, such as to simultaneously provide actuation of the substance delivery unit 169 and opening of the seal 161 of the valve element 131, thereby simultaneously administering the substance, in this case in the form of a spray, and an airflow, in this case in the form of a burst of air, to the subject's nostril. In this embodiment, the mechanical delivery pump 175 is a liquid delivery pump for administering a measured dose of substance, but in an alternative embodiment the mechanical delivery pump 175 could be a powder delivery pump, which administers measured doses of a powdered substance when actuated. In this embodiment, the substance delivery unit 169 is a multi-dose unit for administering a plurality of measured doses of substance in successive administration operations. In an alternative embodiment, the substance delivery unit 169 could be a single-dose unit for administering a single measured dose of substance or a double-dose unit for administering two measured doses of substance in two successive administration operations. In another alternative embodiment, the substance delivery unit 169 could comprise a dry powder administration unit that delivers measured doses of a substance, in the form of a dry powder, when actuated. In yet another alternative embodiment, the substance delivery unit 169 could comprise a nebulizer that delivers measured doses of a substance, in the form of an aerosol spray, when actuated. In yet another alternative embodiment, the substance delivery unit 169 could comprise an aerosol container for administering measured volumes of a propellant, preferably a hydrofluoroalkane (HFA) or similar propellant, containing the substance, in the form of a suspension or solution. In this embodiment, the housing 115 further comprises a sealing element 181, in this case an annular seal, in the form of an O-ring, which slides into the substance chamber 173 of the substance supply unit 169, to prevent the escape of the administered airflow from the inlet 123 in the housing 115. In one embodiment, sealing element 181 could be omitted. Figures 8(a) and (b) illustrate a nasal delivery device according to a second embodiment of the present invention. The administration device of this embodiment is substantially the same as the administration device of the first embodiment described, and therefore, to avoid unnecessary duplication of the description, only the differences will be described in detail, with similar parts being designated by similar reference signs. The actuating device of this embodiment differs from that of the first embodiment described primarily in that the sealing member 149 is configured such that the support 163 extends virtually the entire width of the valve opening 130. In this way, the seal 161 cannot bulge as in the previously described embodiment and is instead opened by a peeling action. Figure 8(a) illustrates the valve assembly 127 in the non-actuated rest configuration. Figure 8(b) illustrates the valve assembly 127 in the actuated configuration. Figures 9 (a) and (b) illustrate a nasal delivery device according to a third embodiment of the present invention. The administration device of this embodiment is very similar to the administration device of the first embodiment described and, therefore, to avoid unnecessary duplication of the description, only the differences will be described in detail, with similar parts being designated by similar reference signs. The dispensing device of this embodiment differs from that of the first embodiment described mainly in that the seal 161 is not supported by the arm 141, but is instead a separate element, which is displaced by the movement of the arm 141, such as that caused by the manual actuation of the substance delivery unit 169. Figure 9(a) illustrates the valve assembly 127 in the non-actuated rest configuration. Figure 9(b) illustrates the valve assembly 127 in the actuated configuration. In this embodiment, the seal 161 comprises a flexible element, in this case in the form of a flap, and in one embodiment an elastic element, which is hooked by a hooking element 185 on the arm 141. In this embodiment, the locking element 185 comprises a projection that acts to cause the seal 161 to bulge in the manner of the first embodiment described. In an alternative embodiment, the engagement element 185 could be substantially extended across the width of the valve opening 130, causing the seal 161 to move from the valve seat 129 with a peel-off action similar to the second embodiment described. Finally, it shall be understood that the present invention has been described in its preferred embodiments and that it may be modified in many different ways without departing from the scope of the invention as defined in the appended claims.

Claims

1. A nasal delivery device for administering a substance to the nasal airways of a subject, comprising: a nasal piece (117) for fitting into the nasal cavity of a subject; a mouthpiece (119) into which the subject exhales; a delivery unit (120), comprising an actuating portion (173) that can be manually moved to actuate the delivery unit (120) to deliver the substance from the nasal piece (117); and a valve assembly (127) that is fluidly connected to the nasal piece (117) and the mouthpiece (119),wherein the valve assembly (127) comprises a body element (128) and a valve element (131) that is movably disposed on the body element (128) between closed and open configurations by manual displacement of the actuating portion (173) of the delivery unit (120) to provide airflow through the nasal piece (117) simultaneously with the administration of the substance; characterized in that: the body element (128) of the valve assembly (127) includes a valve seat (129) defining a valve opening (130), the valve element (131) of the valve assembly (127) comprises a seal (161) acting to close the valve opening (130) of the valve seat (129) when the valve element (131) of the valve assembly (127) is in the closed position,and the delivery unit (120) is configured to provide delivery of the substance subsequent to the opening of the valve element (131) and within a period of less than approximately 250 ms from the opening of the valve element (131).

2. The delivery device of claim 1, further comprising: a housing (115) including an opening (123) through which the actuating portion (173) of the delivery unit (120) extends; optionally, the housing (115) further comprises a sealing member (181) that slideably receives the actuating portion (173) of the delivery unit (120) to prevent air from flowing from the opening (123) into the housing (115).

3. The delivery device of claim 1 or 2,wherein the delivery unit (120) is configured to provide delivery of the substance within a period of less than approximately 200 ms from the opening of the valve element (131), optionally within a period of less than approximately 150 ms from the opening of the valve element (131), optionally within a period of less than approximately 100 ms from the opening of the valve element (131).

4. The delivery device of any of claims 1 to 3, wherein the delivery unit (120) is configured to provide delivery of the substance beginning less than approximately 150 ms after the opening of the valve element (131), optionally less than approximately 100 ms after the opening of the valve element (131), optionally less than approximately 50 ms after the opening of the valve element (131),Optionally less than approximately 25 ms after the opening of the valve element (131), optionally less than approximately 15 ms after the opening of the valve element (131).

5. The delivery device of any of claims 1 to 4, wherein the delivery unit (120) comprises an outlet unit (167) from which the substance is delivered through the nasal piece (117) and a substance delivery unit (169) that can be actuated to deliver the substance to the outlet unit (167), optionally the outlet unit (167) of the delivery unit (120) comprises a spray nozzle (171).

6. The delivery device of claim 5, wherein the actuating portion (173) of the delivery unit (120) comprises a substance-containing chamber (173) of the substance delivery unit (169).

7. The administration device of claim 6,wherein the substance delivery unit (169) comprises a mechanical delivery pump (175) that can be actuated by pressing the substance-containing chamber (173) of the substance delivery unit (169).

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