AU2015201102A1

AU2015201102A1 - Nasal spray device

Info

Publication number: AU2015201102A1
Application number: AU2015201102A
Authority: AU
Inventors: Jade Ly; Armando Morales; Declan Walsh; Xian-Ming Zeng
Original assignee: Ivax Pharmaceuticals Ireland; Teva Branded Pharmaceutical Products R&D Inc
Current assignee: Ivax Pharmaceuticals Ireland; Teva Branded Pharmaceutical Products R&D Inc
Priority date: 2010-10-12
Filing date: 2015-03-03
Publication date: 2015-03-19
Anticipated expiration: 2031-10-12
Also published as: AU2015201102B2

Abstract

A nasal spray device for the delivery of a pharmaceutical formulation to a nasal cavity in metered doses. The device comprises a pressurised aerosol canister 5 including a vial containing a pharmaceutical formulation comprising an active ingredient, a propellant and optionally a co-solvent. The aerosol canister further includes a metering valve having a valve stem. The device also comprises an actuator for the aerosol canister. The actuator includes a stem block having a receptacle into which the valve stem of metering valve of the aerosol canister is 10 received and axially located and being displaceable relative to the vial of the aerosol canister to actuate the metering valve of the aerosol canister, and a sump extending below the receptacle. The stem block further defines a discharge orifice for the pharmaceutical formulation and a transfer channel through which a dispensed dose of the pharmaceutical formulation is able to 15 pass from the sump to the discharge orifice. The actuator further comprises a delivery outlet for an aerosol plume. The discharge orifice is arranged to direct the aerosol plume through the delivery outlet. The device is adapted to produce an aerosol plume for a dispensed dose having a spray force value no greater than 40 mN measured at a distance of 30 mm from the discharge orifice. The 20 transfer channel has a first part in fluid communication with the sump of the stem block and a second part in fluid communication with the discharge orifice. The second part and the discharge orifice is defined by a separate insert received into an opening formed in the stem block of the actuator. An end of the insert is provided with a radial flange from which a resilient sleeve extends in a 25 coaxial relationship with the second part of the transfer channel and the discharge orifice. The resilient sleeve is received into the opening. 6261117_1 (GHMatters) P92922.AU.1 DENISET / -19 Fig.1I

Description

- 1 Nasal Spray Device Technical Field 5 This disclosure relates to a nasal spray device and particularly to a nasal spray device for the delivery of a pharmaceutical formulation to the nasal cavity in metered doses. Background Art 10 Nasal spray devices for the delivery of medicament to the nasal cavity, particularly the nasal mucosa, can be useful for the prophylaxis and/or treatment of certain diseases and disorders of the nasal cavity. Such devices are also capable of delivering medicament to the systemic circulation via the 15 turbinates and lymphoid tissues located at the back of the nasal cavity and to the central nervous system via the olfactory region at the top of the nasal cavity. Nasal spray devices include unit-dose (single use) devices having syringe-like mechanisms and metered-dose devices intended for multiple usage 20 cycles. Unit dose devices are appropriate for delivering certain medicaments such as vaccines, whereas metered-dose devices are more suited to long-term dosage regimes, for example for the treatment of rhinitis. A known metered dose device comprises a vial containing an aqueous suspension of a suitable medicament. The vial is provided with a manually operated pump adapted to 25 atomise metered doses of the medicament formulation for delivery to the nasal cavity. Examples of this type of nasal spray device include Flixonase@ (fluticasone propionate, GSK), Nasacort AQ@ (triamcinolone acetoinide, Sanofi Aventis) and Nasonex@ (momethasone furoate monohydrate, Schering Plough). 30 Although nasal spray devices having manually operated pumps have achieved some success in the marketplace, they have a number of drawbacks. For example, manually operated pumps have a relatively large actuation force 6261117_1 (GHMatters) P92922.AU.1 DENISET - 2 which may, for some users, such as the very young and the elderly, be difficult to achieve on a repeatable basis. Moreover, variations in the applied actuation force can lead to some users receiving medicament doses with less than optimal spray characteristics. 5 To address the problems associated with these known metered-dose nasal spray devices, it may be contemplated to replace the manually operated pump with a pressurised aerosol canister. A typical aerosol canister comprises a cylindrical vial containing the medicament. The medicament is typically an 10 active ingredient together with a suitable propellant. The medicament may be in the form of a solution or a suspension in the propellant and excipients may be added to facilitate dissolution of the active ingredient (e.g. co-solvents) or to stabilise the suspension (e.g. surfactants). The vial is provided with a metering valve having an axially extending valve stem. Displacement of the valve stem 15 relative to the vial causes the dispensation of a metered dose of the medicament formulation as an aerosol. Compared to manually operated pumps, pressurised aerosol canisters require low actuation forces and provide consistent aerosol characteristics. 20 However, whereas pressurised metered dose inhalers (MDIs) have found broad market acceptance in devices intended for the pulmonary administration of medicaments by inhalation via the mouth into the lungs, MDIs have not found applications in nasal spray devices. It has generally been considered that nasal spray formulations cannot tolerate the excipients found in 25 pMDI formulations. In particular, the high levels of co-solvents, such as ethanol, found in solution formulations are poorly tolerated by patients on account of the unpleasant sensation which they produce in the nasal cavity on administration. By way of an example, WO 92/06675 describes a medicament formulation for a pMDI comprising beclomethasone dipropionate, a co-solvent and an HFA 30 propellant. The disclosure is principally directed to administration of the formulation by inhalation into the lungs via the mouth. There is a mention that the formulation may be administered nasally; however, there is no disclosure of 6261117_1 (GHMatters) P92922.AU.1 DENISET - 3 how this method of administration can be achieved and there is no consideration of the problem of poor patient tolerability for nasal applications. The above references to the background art do not constitute an 5 admission that the art forms a part of the common general knowledge of a person of ordinary skill in the art. The above references are also not intended to limit the application of the method and system as disclosed herein. Summary of the Disclosure 10 Accordingly, the present disclosure provides a nasal spray device for the delivery of a pharmaceutical formulation to the nasal cavity in metered doses, the device comprising: a pressurised aerosol canister including a vial containing a pharmaceutical formulation comprising an active ingredient, a 15 propellant and, a co-solvent, the aerosol canister further including a metering valve having a valve stem; and an actuator for the aerosol canister, the actuator including a stem block having a receptacle into which the valve stem of the metering valve of the aerosol canister is received and axially located and the valve stem being displaceable relative to the vial of the aerosol canister to 20 actuate the metering valve of the aerosol canister, a sump extending below the receptacle, the stem block further defining a discharge orifice for the pharmaceutical formulation and a transfer channel through which a dispensed dose of the pharmaceutical formulation is able to pass from the sump to the discharge orifice, wherein the actuator further comprises a delivery outlet for the 25 aerosol plume, the discharge orifice being arranged to direct the aerosol plume through the delivery outlet, and wherein the device is adapted to produce an aerosol plume for a dispensed dose having a spray force value no greater than 40 mN measured at a distance of 30 mm from the discharge orifice, wherein the transfer channel has a first part in fluid communication with the sump of the 30 stem block and a second part in fluid communication with the discharge orifice, the second part and the discharge orifice being defined by a separate insert received into an opening formed in the stem block of the actuator; and wherein an end of the insert is provided with a radial flange from which a resilient sleeve 6261117_1 (GHMatters) P92922.AU.1 DENISET extends in a coaxial relationship with the second part of the transfer channel and the discharge orifice, wherein the resilient sleeve is received into the opening . In an embodiment, the resilient sleeve can provide an interference fit in 5 the opening. In an embodiment, the insert can be provided with a mechanical locking means for engagement with a corresponding means formed in the stem block. For example, the mechanical locking means can comprise an annular flange and the corresponding means can comprise a corresponding annular groove 10 formed in a side wall of the opening. In addition, the annular flange of the mechanical locking means may extend from the resilient sleeve. In an embodiment, the formulation is a solution formulation. In an alternative embodiment, the formulation is a suspension formulation. 15 Accordingly, use of the term formulation encompasses both solution and suspension formulations. The present disclosure also provides the use of the nasal spray device for the delivery of a pharmaceutical formulation (solution or suspension) to the 20 nasal cavity in metered doses. It has now surprisingly been found that even formulations containing high levels of co-solvent are well tolerated in a nasal spray formulation, provided the nasal spray device used to deliver the formulation to the nasal 25 cavity is adapted to provide a so-called "soft spray". The nasal spray device having the propellant-based formulation described hereinbelow may provide the advantages of a metered dose pressurised aerosol canister without suffering from the disadvantage of poor patient tolerability. 30 Brief Description of the Drawings 6261117_1 (GHMatters) P92922.AU.1 DENISET - 5 Embodiments of the present disclosure will now be described, by way of example only, with reference to the accompanying non-limiting drawings, in which: Fig. 1 shows a cut-away perspective schematic view of an embodiment 5 of a nasal spray device; Fig. 2 shows a conventional valve for a pMDI; Fig. 3 shows another cut-away view showing a portion of the nasal spray device of Fig. 1 in greater detail; Fig. 4 is a cross-sectional view showing a component for the nasal 10 spray device shown in Figs. 1 and 3; and Fig. 5 is a chart showing the effect of actuation variables on the spray force values for four different nasal spray devices. Detailed Description 15 The nasal spray device of the present disclosure contains an active ingredient. The pharmaceutical formulation of the present disclosure comprises an active ingredient and a propellant. In principle, any pharmaceutically active ingredient which is soluble or suspended in the formulation and acts via the 20 cavity, such as the nasal mucosa, may be used. The active ingredient is generally present in the formulation of the disclosure in a therapeutically effective amount, i.e. an amount such that metered volumes of the medicament administered to the patient contains an amount of drug effective to exert the intended therapeutic action. Non-limiting examples of the active ingredient 25 which may be used in the formulation of the present disclosure are as follows: (i) Steroids, such as alcometasone, beclomethasone, betamethasone, budesonide, ciclesonide, clobetasol, deflazacort, diflucortolone, desoxymethasone, dexamethasone, fludrocortisone, flunisolide, fluocinolone, 30 fluometholone, fluticasone, hydrocortisone, mometasone furoate, nandrolone 6261117_1 (GHMatters) P92922.AU.1 DENISET - 6 decanoate, neomycin sulfate, rimexolone, methylprednisolone, prednisolone and triamcinolone acetonide. The steroid is preferably beclomethasone dipropionate, budesonide, fluticasone propionate or mometasone furoate. Beclomethasone dipropionate (also termed beclometasone dipropionate (INN) 5 or (8S,9R, 1 OS, 11S,1 3S,1 4S,1 6S,1 7R)-9-chloro-I I-hydroxy-1 0,13,16-trirnethyl 3-oxo-17-[propionyloxy)acetyl]-6,7,8,9,10,11,12,13,14,15,16, 17-dodecahydro 3H-cyclopenta[a]phenanthren-17-yl propionate (IUPAC)) is particularly preferred. 10 (ii) Short- and long-acting p 2 -adrenergic agonists. Long-acting p2 agonists (LABAs) include formoterol, salmeterol and salts thereof, such as formoterol fumarate and salmeterol xinafoate. Short-acting p 2 -agonists include salbutamol, terbutaline and salts thereof such as salbutamol sulfate. 15 (iii) Anticholinergics, such as muscarinic receptor antagonists, e.g. dexpyrronium bromide, glycopyrronium bromide, ipratropium bromide, oxitropium bromide and tiotropium bromide. (iv) Other drugs, such as ACE inhibitors, acetylcholinesterase inhibitors, 20 alpha-blockers, analgesics, e.g. opioids, angiotensin II receptor blockers, antiarrhythmics, antibiotics, anti-cancer agents, anti-clotting agents, antidepressants, anti-emetics, antihistamines, anti-fungal drugs, anti inflammatory agents, antipsychotics, anti-viral agents, bisphosphonates, calcium channel blockers, diuretics, dopamine agonists, hormonal drugs, 25 hypoglycaemics, immunoglobulins, leukotriene receptor antagonists, local anaesthetics, mucolytic agents, narcotic agonists and opiate antidotes, nitrates, NMDA receptor antagonists, nucleic acids, phosphodiesterase 4 (PDE4) inhibitors, polypeptides, potassium channel modulators, serotonin agonists, serotonin antagonists, smoking cessation drugs and sympathomimetic drugs. 30 A therapeutically effective amount of the active ingredient needs to be delivered and this amount will vary depending on the nature of the active ingredient. A typical range is 1 pg to 1 mg. In a preferred embodiment, the nasal 6261117_1 (GHMatters) P92922.AU.1 DENISET - 7 aerosol device of the present disclosure provides a delivered dose of the active ingredient of at least 50 pg, more preferably at least 60 pg and most preferably at least 70 pg, while at the same time providing the desirable "soft spray". 5 The propellant of the pharmaceutical formulation of the present disclosure is preferably a hydrofluoroalkane (HFA) propellant, more preferably P134a (1,1,1,2-tetrafluoroethane), P227 (1,1,1,2,3,3,3-heptafluoropropane) or mixtures thereof. Other hydrofluorocarbons, hydrocarbons or aliphatic gases (e.g. butane or dimethylether) may be added to modify the propellant 10 characteristics as required. However, it is preferred that P134a and/or P227 are the sole propellants present. The propellant preferably constitutes 80% to 99% w/w, more preferably 90 to 98% w/w, based on the total weight of the formulation. 15 The present disclosure is applicable to nasal spray devices for delivering all types of pharmaceutical formulations, but is particularly effective for delivering pharmaceutical formulations which include a co-solvent for the active ingredient. The co-solvent is generally present in order to solubilise the active ingredient and the precise nature of the co-solvent will therefore depend 20 on the nature of the active ingredient. However, the co-solvent is preferably a C2-6 aliphatic alcohol, such as ethanol or propylene glycol, and preferably ethanol. When required, the co-solvent is present in an amount sufficient to dissolve substantially all of the medicament present in the formulation and to maintain the medicament dissolved over the time period and conditions 25 experienced by commercial aerosol products. Preferably the solvent is present in an amount to prevent precipitation of the active ingredient even at temperatures down to -200C. The solvent is preferably anhydrous, although trace amounts of water absorbed by the ingredients, for example during manufacture of the medicament, may be tolerated. Anhydrous ethanol is 30 particularly preferred. The co-solvent, preferably ethanol, is typically present at 1 -20% w/w, more preferably 6-15% w/w and most preferably about 8% w/w, based on the total weight of the formulation. 6261117_1 (GHMatters) P92922.AU.1 DENISET - 8 In a specific embodiment of the present disclosure, the pharmaceutical formulation comprises beclomethasone dipropionate, ethanol and a propellant selected from 1,1,1,2-tetrafluoroethane (P134a), 1,1,1,2,3,3,3 heptafluoropropane (P227) and a mixture thereof. This formulation is typically 5 used for the prophylaxis and/or treatment of seasonal allergic rhinitis (including hay fever) and perennial rhinitis. The active ingredient beclomethasone dipropionate is generally present in a formulation of the present disclosure in a therapeutically effective amount, i.e. an amount such that metered volumes of the medicament administered to the patient contains an amount of drug 10 effective to exert the intended therapeutic action. The aerosol formulation preferably contains 0.02% to 0.6% w/w, more preferably 0.05% to 0.5% w/w of beclomethasone dipropionate, based on the total weight of the formulation. A preferred formulation according to the present disclosure comprises 15 0.02% to 0.6% w/w beclomethasone dipropionate, 1 % to 20% w/w ethanol and 80 to 99% w/w of propellant, wherein the percentages by weight are based on the total weight of the aerosol. A particularly preferred formulation consists essentially of beclomethasone dipropionate, ethanol and a propellant selected from 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane and a mixture 20 thereof; more preferably the formulation consists of these components. The pharmaceutical formulation of the present disclosure is preferably substantially free of surfactant. Surfactants are often added to suspensions to stabilise the suspension. However, when the formulation of the present 25 disclosure is a solution, a surfactant is not required. Nevertheless, small quantities can be tolerated without adversely affecting the formulation. Preferably the formulation contains no more than 0.0005% w/w of a surfactant based on the total weight of the formulation. Preferred formulations contain no surfactant. The presence of a significant amount of a surfactant is believed to 30 be undesirable for solution formulations of beclomethasone dipropionate because surfactants such as oleic acid and lecithin are believed to promote chemical degradation of the active ingredient when the latter is dissolved in the mixture of the propellant and ethanol. 6261117_1 (GHMatters) P92922.AU.1 DENISET - 9 The pharmaceutical formulation of the present disclosure may be prepared by dissolving the desired amount of active ingredient in the desired amount of co-solvent accompanied by stirring or sonication. The aerosol 5 canister may then be filled using conventional cold-fill or pressure-fill methods. The present disclosure provides a nasal spray device for the delivery of a pharmaceutical formulation to the nasal cavity in metered doses. The device comprises a pressurised aerosol canister. Such canisters are known in the art 10 and are commercially available. The aerosol canister 3 is typically composed of aluminium or an aluminium alloy. The internal surfaces of the aerosol canister 3 may be coated with a fluorocarbon polymer, such as PTFE or FEP, optionally together with non-fluorinated polymer to promote adhesion, such as PES. The canister includes a vial containing a pharmaceutical formulation comprising an 15 active ingredient and a propellant. The aerosol canister further includes a metering valve having a valve stem axially displaceable relative to the vial to cause the dispensation of a metered dose of the pharmaceutical formulation through the valve stem. The device also comprises an actuator for the aerosol canister including a stem block having a receptacle into which the valve stem of 20 the aerosol canister is received and axially located, and being displaceable relative to the vial of the aerosol canister to actuate the metering valve of the aerosol canister. The stem block further defines a discharge nozzle for the pharmaceutical formulation and a transfer channel through which a dispensed dose of the pharmaceutical formulation is able to pass from the valve stem to 25 the discharge orifice. The actuator further comprises a delivery outlet, such as a nose piece, for the aerosol plume, the discharge orifice being arranged to direct the aerosol plume through the delivery outlet. According to the present disclosure, the device is adapted to produce 30 an aerosol plume for a dispensed dose of a formulation composition preferably having a spray force value no greater than 40 mN measured at a distance of 30 mm from the discharge orifice. 6261117_1 (GHMatters) P92922.AU.1 DENISET - 10 With reference to Fig. 1, a nasal spray device 1 according to the present disclosure is based on a conventional pressurised metered dose inhaler (pMDI), but modified for nasal use rather than for inhalation via the mouth. Accordingly, the device 1 comprises an actuator 2 accommodating an aerosol 5 canister 3 containing a pharmaceutical formulation for delivery to the nasal cavity of a user. The aerosol canister 3 is constructed to a standard design and specification and comprises a substantially cylindrical vial body 4 which 10 contains the pharmaceutical formulation. The aerosol canister 3 is charged with a pharmaceutical formulation as described hereinabove. The vial body 4 is provided with a ferrule 5 which is crimped over a lip of the body to hermetically seal the pharmaceutical formulation under pressure. 15 The ferrule 5 of the aerosol canister 3 is provided with a metering valve 6 designed to deliver a metered amount of the pharmaceutical formulation to the user for each actuation of the valve 6. The metering valve 6 is of a known type available from manufacturers such as Consort Medical pic and 3M Drug Delivery Systems. See WO 99/47195 for further details of the metering valve 20 suitable for use in the device of the present disclosure. The valve 6 generally comprises a metering chamber 7 (not visible in Fig. 1, but shown in Fig. 2 reproduced from WO 99/47195) and a valve stem 8 in the form of a narrow tube protruding outwardly from ferrule 5. The metering valve 6 is actuated by displacing the valve stem 8 into the valve body against the action of a valve 25 spring 9 to allow the metered amount of the pharmaceutical formulation to vent from the metering chamber through the stem 8. The propellant component of the pharmaceutical formulation causes atomisation of the active ingredient by vaporising on release to the atmosphere. The metering chamber 7 is then recharged with the pharmaceutical formulation as the valve stem 8 is allowed to 30 return to its starting position under the action of the valve spring 9. With further reference to Fig. 1 , the aerosol canister 3 is received into the open end of a body 10 of the actuator 2, with the valve stem 8 being 6261117_1 (GHMatters) P92922.AU.1 DENISET - 11 received into and axially located by a stem block 1 1 of the actuator 2. The actuator body 10 is a moulded plastics component and the stem block 11 is formed as a protrusion which stands from the closed end of the actuator body 10. The stem block 11 includes a cylindrical receptacle configured for an 5 interference fit with the valve stem 8 of the aerosol canister 3. The actuator body 10 generally defines a sleeve-like portion having a substantially circular cross-section, within which sleeve-like portion the aerosol canister 3 is axially displaceable relative to the stem block 11 and valve stem 8 to actuate the metering valve 6. A portion of the aerosol canister 3 at its non-valve end 10 remains exposed in use so that the user is able to apply a manual pressure to displace the aerosol canister relative to the valve stem. Although similar in the above-described respects, the nasal spray device 1 according to the present disclosure differs from conventional pMDIs in 15 two important respects. Firstly, the actuator body 10 defines a delivery outlet in the form of a nose piece 12 (rather than a mouth piece) for delivering the atomised pharmaceutical formulation to the nasal cavity. The delivery outlet may be a 20 tubular nose piece adapted for insertion into the nostril, and a circular end of the nose piece may have an inner diameter of 5 to 7.5 mm, preferably about 7.2 mm. The delivery outlet, the delivery orifice and the transfer channel may be aligned with each other, that is to say they may have substantially identical axes. The axis of the delivery outlet may be substantially perpendicular, or at an 25 angle of up to 200 to the perpendicular, to the aerosol canister and the receptacle of the stem block. Preferably an axis of the nose piece 12 defines an angle of about 800 with the sleeve-like portion of the actuator body 10. The nose piece 12 directly faces the stem block 1 1 so that an aerosol plume produced at the valve stem can be delivered through the nose piece 12 into the 30 nasal cavity. Secondly, the nasal spray device 1 according to the present disclosure differs from conventional pMDIs in relation to the design of the stem block 1 1. 6261117_1 (GHMatters) P92922.AU.1 DENISET - 12 A stem block of a conventional pMDI is moulded with a discharge orifice facing the delivery outlet, and the discharge orifice is fluidly connected to the receptacle of the stem block so that the pharmaceutical formulation is able to pass from the aerosol canister out through the delivery outlet. By comparison, 5 the nasal spray device 1 according to the present disclosure has a stem block 11 that is provided with a transfer channel 13 (not shown fully in Fig. 1 ) through which the pharmaceutical formulation is able to pass from the aerosol canister 3, through the nose piece 12, and into the nasal cavity of a user. In Fig. 1 , the stem block 11 is shown having a first part 14 of the transfer channel 13 10 extending from a sump 15 underneath the receptacle of the stem block 1 1 into an opening defining a socket 16. The sump 15 is preferably rounded to help to prevent blockages. The socket 16 is adapted to receive a moulded plastic insert 17 which defines a second part 18 of the transfer channel 13 and the discharge orifice 19, as described hereinbelow in more detail (note that the insert 17 is not 15 cut-away in Fig. 1). The first 14 and second 18 (in Fig. 3) parts together define a transfer channel 13 through which the pharmaceutical formulation is able to pass from the aerosol canister 3, through the nose piece 12, and into the nasal cavity of a user. That is, the transfer channel 13 has a first part 14 in fluid communication with the sump 15 of the stem block 11 and a second part 18 in 20 fluid communication with the discharge orifice 19, the second part 18 and the discharge orifice 19 being defined by a separate insert received into an opening formed in the stem block of the actuator. Fig. 3 is a view similar to that of Fig. 1, but with the insert 17 cut-away 25 to show the second part 18 of the transfer channel and the discharge orifice 19. It will also be seen more clearly that the sump 15 is narrower than the receptacle of the stem block 1 1 in order to locate axially the valve stem 8 of the aerosol canister (not shown in Fig. 3). An end of the insert 17 is provided with a radial flange from which a resilient sleeve 20 extends in a coaxial relationship 30 with the second part 18 of the transfer channel 13 and discharge orifice 19. The resilient sleeve 20 provides an interference fit in the socket 16. Alternatively, or additionally, the insert 1 7 may be provided with a mechanical locking means for engagement with a corresponding means formed in the stem block, such as an 6261117_1 (GHMatters) P92922.AU.1 DENISET - 13 annular flange (see flange 21 in Fig. 4) arranged to lock into a corresponding annular groove formed in the side wall of the socket 16. The second part 18 of the transfer channel 13 and the discharge orifice 5 19 are shown as defined by a separate insert 17 received into an opening formed in the stem block 11 of the actuator 2. Such a configuration may provide a number of benefits. For example, a nasal spray device can then be configured simply by altering the design of the insert. Furthermore, the insert may be manufactured with smaller tolerances than those of other components of the 10 nasal spray device. In this way, it may be possible to reduce unit-to-unit variation in the delivered dose and spray force value of the device. However, the device of the present disclosure is not limited to a separate insert and the first 14 and second parts 18 of the transfer channel 13 may be integrally formed into a unitary structure. Such a unitary structure may be produced by injection 15 moulding. The transfer channel 13 preferably has circular cross-section. It also preferably tapers down towards the discharge orifice 19. The transfer channel 13 may taper down towards the discharge orifice end, for example such that a 20 side wall of the chamber defines an angle of 0.5 to 30, preferably about 1 0. It is believed that the risk of blockages may be reduced by tapering the chamber in this way. The risk of blockages may also be reduced by avoiding sharp comers in the fluid path. A further preferred feature is a maximum transverse dimension of 1.0 to 3.0 mm, preferably from 1.2 to 2 mm and most preferably about 1.5 25 mm. The transfer channel 13 has a length of 3 to 20 mm, more preferably 4 mm to 15 mm, more preferably 4 to 10 mm and most preferably about 7 mm. The transfer channel 13 serves as an expansion chamber for modifying the spray characteristics of the aerosol plume, in particular by reducing the spray force value for the plume, as compared to the plume generated using a device with 30 no expansion chamber. The discharge orifice 19 has a diameter of 0.15 to 0.65 mm, preferably 0.20 to 0.50 mm and most preferably about 0.4 mm. It is believed that 6261117_1 (GHMatters) P92922.AU.1 DENISET - 14 discharge orifices smaller than 0.15 mm may be prone to blockages. A length of the outlet orifice, measured between the outlet end of the transfer channel 13 and the opening of the outlet orifice, (also known as the "land length") is 0.5 to 1 .0 mm, preferably 0.6 to 0.9 mm and most preferably about 0.65 mm. The 5 length of the outlet orifice is believed to be significant because it may strongly influence the shape (spread) of the aerosol plume. A focused plume is important in ensuring that a large proportion of the dose is delivered to the nasal cavity of the user and not retained on the surfaces of the actuator 2. 10 Fig. 4 is a cross-sectional view showing an insert 17 suitable for use with the nasal spray device shown in Figs. 1 and 3. Like reference numerals indicate the same or corresponding elements. The length of the insert 17 not only affects the volume of the transfer channel 13, but also modifies the distance of the delivery outlet 12 from the discharge orifice 19. It is believed that 15 a greater proportion of the dose is delivered to the nasal cavity of the user when this distance is reduced (for example, by employing a longer insert). Before use of the nasal spray device 1 described hereinabove, the user shakes the device 1 several times, as is normal practice for pMDIs. To use the 20 device 1, the user inserts the nose piece 12 into a nostril and depresses the exposed end of the aerosol canister 3. Displacement of the canister 3 relative to the valve stem 8 causes actuation of the metering valve 6 and a metered amount of the pharmaceutical formulation is vented from the metering chamber in the aerosol canister 3. The formulation passes through the sump 15 and into 25 the transfer channel 13 where it undergoes controlled expansion, before finally being discharged through the discharge orifice 19 and the nose piece 12. As described hereinabove, the present disclosure provides a nasal spray device in which the conventionally unpleasant effects of using a 30 propellant-based formulations are avoided by providing the device with soft spray characteristics; by which is meant a spray force value of no greater than 40 mN measured at 30 mm from the discharge orifice 19. The minimum spray force is less critical and may be any positive non-zero value. Preferably the 6261117_1 (GHMatters) P92922.AU.1 DENISET - 15 spray force is 10 to 40 mN measured at 30 mm from the discharge orifice 19. It has been found that such soft sprays are well tolerated by users and allows pMDI technology to be applied to the nasal delivery of medicaments, thereby avoiding the disadvantages associated with pump-action devices. 5 The desired spray force value may be achieved by appropriate combination of the orifice diameter, land length and the geometry of the transfer channel as described hereinabove. In particular, a lower spray force value is favoured by a smaller orifice diameter. However, a longer land length and a 10 geometry of the transfer channel such that the transverse dimension tapers down towards the discharge orifice is also preferred. Moreover, a balance must be obtained in order to prevent deposition of the active ingredient on the internal surfaces of the device which in turn can lead to reduced dose uniformity and even clogging of the device. In a preferred embodiment, the discharge 15 orifice has a diameter of 0.15 to 0.65 mm and a length of 0.5 to 1 .0 mm, and the transfer channel has a transverse dimension which tapers down towards the discharge orifice end. It has further been found that the proportion of the dose of active 20 ingredient that is retained by the device described herein may be no greater than 40%, preferably no greater than 30% and more preferably no greater than 20%. It has been found that the delivered dose uniformity of the device may be acceptable, with a relative standard deviation (RSD) no greater than 20%, preferably no greater than 10%. 25 The spray force value is given as the value measured at a predetermined distance, typically 30 mm, from the discharge orifice 19. Spray force values may be measured using conventional techniques, such as with an impaction plate coupled to a digital load cell, e.g. a Copley SFT 1000 spray 30 force tester available from Copley Scientific Limited, Nottingham, United Kingdom. This device comprises a circular impaction plate coupled to a digital load cell for measuring forces acting on the impaction plate. The device includes a movable carriage to which a spray device is mounted so that its 6261117_1 (GHMatters) P92922.AU.1 DENISET - 16 spray outlet is centred on and faces the impaction plate. The spray device is then actuated and the load cell measures the spray force value of the spray. Spray force values are measured under controlled conditions of 5 temperature of 250C, pressure of 101 kPa and relative humidity of 50%. The impaction plate is mounted in a vertical orientation. The spray device is mounted in the movable carriage so that the discharge orifice of the device is positioned 30 mm from the impaction plate. The spray device is then actuated and the maximum compression force of the impaction plate recorded. Six 10 actuations are measured for each device to be tested. The mean of these six values is recorded as the spray force value for the device. The measurements are preferably taken using an actuation velocity of 70 mm/s and an acceleration of 7,000 mm/s 2 , although this is not critical as the spray force is not significantly affected by these variables. 15 Examples Embodiments of the disclosure will now be described with reference to the accompanying non-limiting examples. Example 1 20 Spray force values for a nasal spray device according to the present disclosure were measured using a variety of actuation velocities and accelerations. The device tested was of the type shown in Figs. 1 and 3 and configured with a nose piece having an inner diameter of 8.2 mm. The stem block insert had the shape generally shown in Fig. 4. The orifice size is 0.4 mm 25 and insert length is 10 mm. The device was loaded with HFA aerosol canister configured to provide an 80 pg dose (ex-valve) of beclomethasone dipropionate. The solution formulation consisted of the beclomethasone dipropionate as the active ingredient, together with ethanol 4.8 mg per actuation as a co-solvent and P134a 55.1 mg per actuation as a propellant. 30 Spray force values for three commercially available manual pump-type nasal spray devices were also measured using the same variety of actuation 6261117_1 (GHMatters) P92922.AU.1 DENISET - 17 velocities and accelerations for comparison purposes. Details of the devices tested are summarised in Table 1. Table 1. Devices hvie tsi s a Ous API the present iscour (Examle1)wa aate o h et sn Example I SpaVEe Atatio Sys ava m P 5 -------------- __ __ ___ The testing was carried out using a Copley SFT 1000 spray force tester available from Copley Scientific Limited, Nottingham, United Kingdom following the test procedure described hereinabove. The nasal spray device according to the present disclosure (Example 1) was actuated for the tests using a 10 SprayViEW Vereo MDx Automated Actuation System available from Proveris Scientific Corporation, Marlborough, MA, USA. The manual pump- type nasal spray devices (Comparative Examples 1 to 3) were actuated using a SprayViEW® Vereo NSx Automated Actuation System available from Proveris Scientific Corporation, Marlborough, MA, USA. 15 The actuation velocities and accelerations used for the testing, together with the results of the testing, are set out in Table 2. The results are also illustrated in Figure 5, which is a chart plotting spray force values (vertical axis) against actuation settings. It will be seen from the chart that spray force values 20 for the manual pump-type nasal spray devices vary significantly with the actuation parameters, but this is not the case for the nasal spray device according to the disclosure (NQVAR 80 pg in Fig. 5). 6261117_1 (GHMatters) P92922.AU.1 DENISET - 18 Table 2. Spray force values vaIocdty amceafif Example 1. M aa'~ COMP~takw Qc pwr*~vo eape2 Exml 70 4000 4 3 A 7 X9 39 70o 7000 3111 X224b9S 70 60WO 29.3 I07$.a3 Statistical analysis was performed on the results for all four devices 5 tested to look for significant sources of variation in the spray force value data. The following equation was used to conduct ANOVA (Analysis of Variance): yijk - + + vi + + (va)k + (Tv)i + (Ta-i- + (Tva.i.k + Sijk (equation 1) where p is the overall mean, 10 yijk is the spray force value for the ith device, jth velocity and kth acceleration, Ti is the ith device, vi is the jth level of velocity, ak is the kth level of acceleration, yalk is the interaction of velocity and acceleration, 15 Tv0 is the interaction of device and velocity, Taik is the interaction of device and acceleration, Tvaij k is the interaction of device, velocity and acceleration, and s is the error term. 6261117_1 (GHMatters) P92922.AU.1 DENISET - 19 The ANOVA yielded values of F for each source of possible variation. The F values and associated p-values are recorded in Table 3. Table 3. Statistical analysis for all devices tested 5- ----- ---- Sourc F Significant? ------------------------------- --. 75.9 00.3 Yea Acceleaton 2 1 074 NO 128' ' *A0O1 Ye&_ iroAWw ii:I fl4 0.40~32 No* 5--- - -------- --------------- 7 - It will be seen from Table 3 that the spray force value data is significantly affected by the particular device being used, the velocity of actuation, and the interaction of the device and the velocity of actuation. Subsequently, reduced ANOVA for the manual pump-type nasal spray devices 10 only (Comparative Examples 1 to 3) was conducted. The following equation was used: yijk = [1 + Ti+ vj + ak+ (vc~jk + 8 ijk (equation 2) where p is the overall mean, 15 Tj is the ith device, vj is the jth level of velocity, 0 k is the k th level of acceleration, vc(Jk is the interaction of velocity and acceleration, and E is the error term. 20 The F values and associated p-values are recorded in Table 4. 6261117_1 (GHMatters) P92922.AU.1 DENISET - 20 Table 4. Statistical analysis for manual pump-type nasal spray devices cdiy*Acceraion 010 0$811 It will be seen from Table 4 that velocity of actuation is a significant 5 source of variation for spray force values of manual pump-type nasal spray devices. Reduced ANOVA was also conducted for the nasal spray device according to the present disclosure (Example 1 ). The following equation was used: yijk = p + vj + ak + (va)k + 8 ijk (equation 3) 10 where p is the overall mean, vj is the jth level of velocity, ak is the kth level of acceleration, vaik is the interaction of velocity and acceleration, and E is the error term. 15 The F values and associated p-values are recorded in Table 5. Table 5. Statistical analysis for nasal spray device according to the present disclosure Veh~t11 43 OASC_ ___ VelcayAcaert o 1 t 2500 No' 20 6261117_1 (GHMatters) P92922.AU.1 DENISET - 21 It will be seen from Table 5 that none of velocity of actuation, acceleration of actuation and the interaction between velocity and acceleration of actuation are considered to be significant sources of variation for spray force values. Accordingly, the nasal spray device according to the present disclosure 5 provides the advantage of consistent spray force values, regardless of the velocity and/or acceleration of actuation. This advantage is particularly important in relation to use by the very young and the elderly, who may find it difficult to actuate the device repeatedly with a consistent velocity. 10 Examples 2-5 Further testing was carried out on the test devices of the type shown in Figs. 1 and 3 having different stem block inserts. The devices were each configured with a nose piece having an inner diameter of 7.2 mm. The stem block insert of each device had the shape generally shown in Fig. 4, with the 15 dimensions provided in Table 6. The orifice size is 0.4 mm, the insert length of 10 mm, a land length of 0.65 mm, and a tip diameter of 6.4 mm. The device was loaded with an HFA aerosol canister configured to provide a 100 pg dose (ex-valve) of beclomethasone dipropionate. The solution formulation consisted of the beclomethasone dipropionate as the active ingredient, together with 20 ethanol 4.8 mg per actuation as a co- solvent and P134a 55.1 mg per actuation as a propellant. Table 6. Devices diamedor Imm) ___ 0,22 ---- __ _ _ - --- 205 6261117_1 (GHMatters) P92922.AU.1 DENISET - 22 The nasal spray devices were tested for spray force values using the test procedure set out hereinabove. The results of the testing are set out in Table 7. 5 Table 7. Spray force values and RSD. It will be seen that all four examples provided spray force values no greater than 40 mN. The two comparative examples provided spray force 10 values in excess of this figure, and are therefore outside the scope of the present disclosure. In all cases the relative standard deviation (RSD) was less than 20%. It will be appreciated that the spray force value for a nasal spray device according to the present disclosure depends to a large degree on the size and shape of the stem block insert. In general, for any given dose size, 15 lower spray force values may be obtained with smaller orifice diameters and with shorter insert lengths. The nasal spray devices were also tested for spray content uniformity (SCU) to measure variation in delivered doses of the active ingredient. The 20 results of this testing are set out in Table 8. Table 8. Delivered doses 6261117_1 (GHMatters) P92922.AU.1 DENISET - 23 Ese t a t tEs 3 Ex 4 Comp, pa {0, - 06 1101. --------- --- - ------ ~i i~ tprovided a delivered dose through the actuator of at least 70 pg, with an 5 acceptable relative standard deviation (RSD). Furthermore, in all cases, less that 40% of the dose delivered through the valve was retained on the surfaces of the actuator. Examples 2 and 4, for which the insert length was 10 mm, exhibited markedly reduced retention of the dose in the actuator. In the claims which follow and in the preceding description, except 10 where the context requires otherwise due to express language or necessary implication, the word "comprise" or variations such as "comprises" or "comprising" is used in an inclusive sense, i.e., to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the method and apparatus. 15 6261117_1 (GHMatters) P92922.AU.1 DENISET

Claims

1. A nasal spray device for the delivery of a pharmaceutical formulation to a nasal cavity in metered doses, the device comprising: a pressurised aerosol 5 canister including a vial containing a pharmaceutical formulation comprising an active ingredient, a propellant and optionally a co-solvent, the aerosol canister further including a metering valve having a valve stem; and an actuator for the aerosol canister, the actuator including a stem block having a receptacle into which the valve stem of metering valve of the aerosol canister is received and 10 axially located and being displaceable relative to the vial of the aerosol canister to actuate the metering valve of the aerosol canister, a sump extending below the receptacle, the stem block further defining a discharge orifice for the pharmaceutical formulation and a transfer channel through which a dispensed dose of the pharmaceutical formulation is able to pass from the sump to the 15 discharge orifice, wherein the actuator further comprises a delivery outlet for an aerosol plume, the discharge orifice being arranged to direct the aerosol plume through the delivery outlet, and wherein the device is adapted to produce an aerosol plume for a dispensed dose having a spray force value no greater than 40 mN measured at a distance of 30 mm from the discharge orifice, 20 wherein the transfer channel has a first part in fluid communication with the sump of the stem block and a second part in fluid communication with the discharge orifice, the second part and the discharge orifice being defined by a separate insert received into an opening formed in the stem block of the actuator; and 25 wherein an end of the insert is provided with a radial flange from which a resilient sleeve extends in a coaxial relationship with the second part of the transfer channel and the discharge orifice, wherein the resilient sleeve is received into the opening. 30

2. A nasal spray device as claimed in claim 1, wherein the resilient sleeve provides an interference fit in the opening. 6261117_1 (GHMatters) P92922.AU.1 DENISET - 25

3. A nasal spray device as claimed in any preceding claim, wherein the insert is provided with a mechanical locking means for engagement with a corresponding means formed in the stem block. 5

4. A nasal spray device as claimed in claim 3, wherein the mechanical locking means comprises an annular flange and the corresponding means comprises a corresponding annular groove formed in a side wall of the opening.

5. A nasal spray device as claimed in claim 4, wherein the annular flange of the 10 mechanical locking means extends from the resilient sleeve.

6. A nasal spray device as claimed in any preceding claim, wherein the discharge orifice has a diameter of 0.15 to 0.65 mm. 15

7. A nasal spray device as claimed in any preceding claim, wherein the maximum transverse dimension of the transfer channel is greater than the diameter of the discharge orifice.

8. A nasal spray device as claimed in any preceding claim, wherein the 20 maximum transverse dimension of the transfer channel is from 1.0 to 3.0 mm.

9. A nasal spray device as claimed in any preceding claim, wherein the transfer channel has a circular cross-section. 25

10. A nasal spray device as claimed in any preceding claim, wherein the transfer channel has a transverse dimension which tapers down towards an end of the discharge orifice.

11. A nasal spray device as claimed in any preceding claim, wherein the 30 transfer channel has a length of 3 to 20 mm.

12. A nasal spray device as claimed in in any preceding claim, wherein the discharge orifice has a length of 0.5 to 1.0 mm. 6261117_1 (GHMatters) P92922.AU.1 DENISET - 26

13. A nasal spray device as claimed in any preceding claim, wherein the discharge orifice has a diameter of 0.15 to 0.65 mm and a length of 0.5 to 1.0 mm, and wherein the transfer channel has a transverse dimension which tapers 5 down towards an end of the discharge orifice.

14. A nasal spray device as claimed in any preceding claim, wherein the co solvent is present at 0.5 to 20% w/w, based on a total weight of the pharmaceutical formulation. 10

15. A nasal spray device as claimed in any preceding claim, wherein the active ingredient is beclomethasone dipropionate, the propellant is selected from P134a, P227 or mixtures thereof, or other pressurised gases, and the co solvent is present and is anhydrous ethanol. 15

16. Use of a nasal spray device according in any one of the preceding claims for the delivery of a pharmaceutical formulation to the nasal cavity in metered doses. 20

17. A nasal spray device as claimed in any of claims claim 1 to 7, wherein the pharmaceutical formulation is a solution formulation.

18. A nasal spray device as claimed in claim 1, wherein the pharmaceutical formulation is a suspension formulation. 6261117_1 (GHMatters) P92922.AU.1 DENISET