Field of the Invention

The present invention relates to novel dry powder medicament delivery device and uses thereof.

More particularly, the invention relates to novel dry powder medicament delivery device which is suitable for use as, for example, a naso-pulmonary medicament delivery device for the delivery of medicaments, e.g. for the treatment of a respiratory disorder; especially for delivering a vaccine or a hormone, such as, glucagon, in dry powder form; or the treatment of pulmonary disorders, such as asthma, COPD, cystic fibrosis and lung cancers.

The naso-pulmonary delivery device is especially suitable for the delivery of small doses and is therefore useful for use with infants, including neonates, or small animals. The delivery device is therefore useful for use, inter alia, in animal models, e.g. in pre-clinical studies.

Background to the Invention

In recent years drug formulations have been developed in dry powder form, e.g. for delivery by inhalation, or by admixing in a solution for delivery by intravenous infusion. Such dry powder formulations include existing compounds reformulated into dry powder form and newly developed compounds, used in the treatment of many conditions and diseases. Drug formulations in the form of inhaled dry powders, dry powders passively delivered to the lung or nasal cavity, and the like; offer advantages over other forms such as liquids and tablets, particularly when considering storage, stability and bioavailability.

Oral (pulmonary) or nasal delivery of a medicament using a dry powder medicament delivery device is a particularly attractive method of drug administration as such devices can be relatively easy for an individual to use. As well as delivering medicament to treat local diseases of the airway and other respiratory disorders, dry powder medicament delivery devices have more recently also be used to deliver drugs to the bloodstream via the lungs or nasal passages, thereby avoiding, for example, the need for injections; and for delivery direct to the brain via the olfactory region.

Nasal drug delivery is well known for the treatment of common ailments such as cold, cough, hay fever, rhinitis, etc. A large number of problems are associated with oral, parenteral, rectal, injectable and other routes of drug administration. Therefore, there has been an increase in interest in intranasal delivery of various drugs for systemic use including peptides, proteins, vaccines and the like.

Nasal delivery offers many benefits over traditional approaches to vaccine administration. These include ease of administration without needles that reduces issues associated with needle injuries and disposal, reduces the need for advance training in administration and assists with self-administration. Furthermore, recently dry powder intranasal vaccines have been developed. There are a number of advantages to intranasal delivery of drugs, in particular in dry powder form. Intranasal drug delivery offers rapid uptake into the blood stream by absorption through the nasal mucus, the potential to reduce or eliminate cold chain management of vaccines during storage and transportation, and the elimination of needles and the potential for needle stick injuries.

Intranasal vaccination represents an attractive non-invasive alternative to needlebased injection and provides superior protection at mucosal surfaces. However, new formulations and delivery devices are needed to improve efficacy and reduce the refrigerated storage and distribution requirements associated with standard liquid vaccines.

Vaccines and other pharmaceutically active agents, formulated as liquids, can be subject to chemical degradation, e.g., aggregation, denaturation, hydrolysis, and oxidation that can result in their inactivation. Liquid vaccine formulations can also be sensitive to temperature: high temperatures can increase inactivation, and freezing temperatures can result in ice that can damage antigen in the vaccine. Thus, to prevent inactivation, liquid vaccines often must be stored at a temperature range of from 2-8°C.

The mode of administration of a vaccine can play a role in its efficacy. One mode of administration, non-parental administration (e.g., nasal), can induce and promote mucosal and systemic immune responses. In addition, nasal mucosa can help bind a virus or other pathogen at the mucosal surface, preventing access of the pathogen to deeper tissues and/or decreasing the likelihood of full-blown infection.

However, this interest presents a number of difficulties, including the delivery of small doses required when treating infants, including neonates.

Furthermore, the use of preclinical animal models is often a requirement for pharmaceutical and medical device development and approval by medicines regulator}' authorities.

Intranasal delivery on animal models, especially murinae, such as rats and mice, present particular difficulties. The volume of a mouse’s nasal cavity is only a quarter the size of that of a rat which itself presents several issues with delivery. With conventional intranasal devices the force and volume of air exiting the device can be potentially lethal for murinae. For example, when delivering air pulses to rats, air pulses should not exceed of 2ml per pulse.

Attempts have been made to address this problem. A dry powder insufflator device was made commercially available by Penn-Century Inc., the Penn-Century Dry Powder Insufflator™ -DP-4. The main application for this insufflator device was for delivery to the lungs, but it was also advertised as being suitable for intranasal delivery. However, the Penn-Century device was withdrawn from sale and has not been available for several years. In addition, a PADA (Powder Administration Device for Animals) starter kit is available from Aptar Pharma. The kit is designed to enable intra-tracheal administration of a powder directly to the lungs of mice.

International Patent application No. WO 2013/088112 describes a single dose disposable dry powder medicament delivery device comprising a medicament container containing a unit dose of dry powder medicament, a medicament dispensing assembly and an air source. However, for the delivery of low doses of dry powder medicaments, e.g. for use with infants, including neonates, or animal models, further improvements are required.

The present invention seeks to provide a dry powder medicament delivery device that overcomes or substantially alleviates the problems with conventional inhalation devices.

Summary of the Invention

We have now surprisingly found that the use of a holding chamber is capable of reducing the force and volume of air exiting a nasal inhalation device.

Therefore, according to a first aspect of the invention there is provided a dry powder medicament naso-pulmonary delivery device comprising: a medicament container, e.g. a cartridge, containing a unit dose of dry powder medicament; a main body, optionally provided with an air source; and a medicament dispensing assembly, said medicament dispensing assembly comprising: a dispensing nozzle; a holding chamber; and a naso-pulmonary adaptor.

Dispensing Nozzle

The dispensing nozzle will generally comprise an airway, e.g. with an inlet end and an outlet end. The inlet end of the dispensing nozzle is adapted to be attached to the main body of the naso-pulmonary delivery device. The outlet end of the dispensing nozzle is adapted to be attached to the holding chamber. Alternatively, the naso- pulmonary adaptor may be provided with an integral holding chamber, in which case the outlet end of the dispensing nozzle may be adapted to be attached to the naso- pulmonary adaptor. A naso-pulmonary adaptor provided with an integral holding chamber is a preferred embodiment of the present invention. According to one aspect of the invention the naso-pulmonary adaptor is a nasal adaptor. In another aspect of the invention the naso-pulmonary adaptor is a pulmonary adaptor.

Holding Chamber

The holding chamber is provided at one end with an inlet to receive a dispensed dry powder and an outlet to transmit the dry powder into the naso-pulmonary adaptor. In one embodiment of the invention the inlet end of the holding chamber is adapted to be attached to the outlet end of the dispensing nozzle and the outlet end of the holding chamber is adapted to be attached to the inlet end of the naso-pulmonary adaptor. In another embodiment of the invention the holding chamber is integral to the naso- pulmonary adaptor.

Naso-Pulmonary Adaptor

The naso-pulmonary adaptor is provided at one end with an inlet to receive a dispensed dry powder and an outlet to transmit the dry powder into the nasal cavity or the lungs of an individual upon administration. In one embodiment of the invention the inlet end of the naso-pulmonary adaptor is adapted to be attached to the outlet end of the holding chamber. In another embodiment the holding chamber is integral to the naso-pulmonary adaptor in which case the naso-pulmonary adaptor is adapted to be attached to the outlet end of the dispensing nozzle. It is preferred for the holding chamber to be integral to the naso-pulmonary adaptor.

Cartridge

The medicament container comprises a cartridge provided with a well cavity adapted to holding a medicament, usually in the form of a dry powder. The cartridge may be provided with a protective sleeve, said sleeve being adapted to be retracted. In a first position the protective sleeve covers and protects the dry powder medicament, but when the protective sleeve is retracted it renders the cartridge in an open position and exposes the well cavity and the dry powder medicament therein.

In a further embodiment the cartridge is provided with an abutment, e.g. an integral abutment or a pair of integral abutments. The use of a pair of abutments, e.g. in the form of “wings” around the cartridge creates a stop when the assembly is actuated and the cartridge moved to an open position. Furthermore, the use of a pair of abutments aids in providing a seal around the cartridge.

According to this aspect of the invention there is provided a dry powder medicament naso-pulmonary delivery device comprising: a medicament container, e.g. a cartridge, containing a unit dose of dry powder medicament; a main body, optionally provided with an air source; and a medicament dispensing assembly, said medicament dispensing assembly comprising: a dispensing nozzle; and a naso-pulmonary adaptor, wherein said naso-pulmonary adaptor includes an integral holding chamber.

According to one aspect of the invention the naso-pulmonary adaptor is a nasal adaptor. In another aspect of the invention the naso-pulmonary adaptor is a pulmonary adaptor. A pulmonary adaptor may optionally be provided with a cannula to facilitate delivery of a dry powder medicament to the lungs of an individual.

The outlet of the naso-pulmonary adaptor will generally comprise a conduit with an orifice at an outlet end. The shape and dimensions of the outlet orifice may vary depending upon, inter alia, the nature of the individual being treated and dry powder being delivered. For an intranasal insufflator, the outlet orifice is desirably sized and shaped to be suitable for placing inside the nostril of an individual (infant, murinae or other small animals, such as, rabbits, guinea pigs and the like). For administering dry powders to infants, including neonates, and/or murinae the outlet orifice may have an external diameter of from about 0.5mm to about 2mm. For example, for use with rats the outlet orifice external diameter may be about 1.6mm or with mice the external diameter may be about 0.5mm. Generally, for use with murinae the outlet will be about the size of a hypodermic needle, e.g. a Gauge (Birmingham Gauge) 10 to 25 hypodermic needle, for example, for use with rats the outlet orifice external diameter may be about 16 gauge or with mice about a 25 gauge. It will be understood by a person skilled in the art that for use with infants, including neonates, the outlet orifice may have a generally larger external diameter or be of a larger gauge.

In some instances, with the use of smaller diameter orifices the backpressure may reduce the pick-up of powder. Therefore, an air flow restrictor may optionally be included, dependent upon the, inter alia, the exit orifice diameter of the naso- pulmonary adaptor attached to the device. Such an air flow restrictor, when present, may be incorporated in the naso-pulmonary delivery device of the invention between the air source, e.g. a syringe, and the main body of the naso-pulmonary adaptor. The use of an air flow restrictor may be advantageous in that, inter alia, it improves performance of the naso-pulmonary delivery device, for example, by adjusting the ratio of the outlet nozzle of the tip to the diameter of the restrictor hole the pickup of powder from the medicament container can be significantly improved.

As an alternative to the use of an air flow restrictor, the medicament dispensing assembly may be provided with a valve situated between the air source and the medicament dispensing assembly, such that, if the valve is in the closed position upon actuation of the air source, a pocket of pressurised air will be created; and opening of the valve will provide a burst of pressurised air to medicament dispensing assembly. It will be understood that a variety of valves may suitably be used. One example of a valve is a stopcock, e.g. a two-way manual stopcock, which is adapted to be manually switched from a closed to an open position. However, although generally a valve may be utilised instead of an air flow restrictor, it is within the scope of the present invention for the medicament dispensing assembly to be provided with an air flow restrictor and a valve. Use of a valve, e.g. a stopcock, may be advantageous, since it assists in clearing the dry powder medicament from the dispensing assembly. It has been found that, with the use of a valve, about 25% w/w more of the dry powder medicament is cleared from the dispensing assembly and delivered to the nasal cavity or lungs of an individual.

The dry powder medicament delivery device may be mounted on a moveable plate. The moveable plate may desirably be provided with a releasable locking mechanism. One example of a locking mechanism comprises a retractable plate provided with a tongue adapted to fit a groove in the moveable plate on which the syringe sits. The moveable plate may be locked with the tongue sitting in the groove. By retracting the plate the tongue can be withdrawn from the groove, allowing the moveable plate to freely move and allowing the syringe plunger to prime the delivery device with air.

In the dry powder medicament naso-pulmonary delivery device of the invention, if backpressure is expected to occur, then the medicament container may optionally be clamped to the main body of the device. Any conventionally known clamping mechanism may be used, but in one aspect of the invention the clamp may comprise a thumb screw clamp. The size of the dose delivered may be varied, for example, by altering the size of the medicament container.

When the naso-pulmonary adaptor comprises an integral holding chamber, the holding chamber may comprise a conical, frusto conical or tapered chamber. The holding chamber may be provided with an inner conduit, e.g. a longitudinal conduit, which is an airway with a first end adjacent the connection with the dispensing nozzle and a second end which protrudes into the holding chamber. The inner conduit may have an external diameter of from about 0.1mm to about 2.0mm. The use of the holding chamber and the inner conduit is advantageous in that, inter alia, the force of the air flow is reduced. In a preferred aspect of the invention the naso-pulmonary adaptor comprises a frusto conical or tapered holding chamber. The use of a frusto conical or tapered holding chamber is generally better for delivery of the medicament. In addition, as a critical exit orifice size is approached, the use of a frusto conical or tapered holding chamber provides additional distance to reduce the pressure build up within the holding chamber. Alternatively, the naso-pulmonary adaptor may be in the form of a pipette tip.

In another aspect of the invention the naso-pulmonary adaptor may comprise a bifurcated adaptor. A bifurcated adaptor may suitably be adapted to fit the nozzle; alternatively a bifurcated adaptor may be adapted to fit on the end of the naso- pulmonary adaptor herein described. Use of a bifurcated adaptor is especially advantageous in nasal delivery of a dry powder medicament, since it enables the dry powder medicament to be delivered simultaneously to each nostril of an individual. Luer Lock

Means for attaching the naso-pulmonary adaptor and/or the holding chamber to the dispensing nozzle may comprise a snap-fit, screw fit, bayonet fit, Luer-lock or Luer- taper and the like. In a preferred aspect of the invention the releasable attachment comprises a Luer-lock or Luer-taper connection, that is, the means for attaching the naso-pulmonary adaptor and/or the holding chamber to the dispensing nozzle may comprise a tabbed female hub on the dispensing nozzle and a slotted or threaded male hub on the naso-pulmonary adaptor or the holding chamber.

According to a further aspect of the invention the dry powder medicament delivery device includes an air source.

The medicament dispensing assembly of the invention generally comprises a body and a nozzle. More particularly, the medicament dispensing assembly comprises a body, a nozzle and an airway, e.g. one or two airways, an inlet and an outlet. For an intranasal insufflator device, the nozzle may desirably be sized and shaped to be suitable for placing inside the nostril of an individual. However, it is preferred that the medicament dispensing assembly is provided with a naso-pulmonary adaptor, such that the adaptor is placed inside the nostril of an individual. This is especially the case when the medicament dispensing assembly is for use in administering a medicament to an infant or murinae. It will further be understood by the person skilled in the art that the medicament dispensing assembly may also be designed so as to be suitable for oral delivery, such as an insufflator for delivery to the lungs (respiratory tract). The air source may comprise a delivery pump e.g. it may comprise a syringe. Such a syringe may, for example, comprise a conventionally known propriety syringe, e.g. a disposable syringe, or may comprise a conventionally known means for ejecting an air stream, for example, an insufflator or other such apparatus suitable for blowing air or gas upon activation, such as a cylinder and piston, bellows, a squeezable bulb or a compressed air or gas source such as a compressed air canister or from a compressed air system fitted with suitable volume and pressure control apparatus.

Thus, according to the invention we provide a method of producing an aerosol of a dry powder for naso-pulmonary administration, said method comprising positioning a dispersible dry powder material, e.g. a medicament material, downstream of a naso- pulmonary adaptor; wherein said naso-pulmonary adaptor includes an optionally integral holding chamber; and wherein said naso-pulmonary adaptor is attached to a dispensing nozzle of a dry powder medicament naso-pulmonary delivery device as herein described. The method according to this aspect of the invention is especially useful for the delivery of a dry powder medicament material to infants, including neonates, and/or murinae.

The dry powder medicament delivery device according to this aspect of the invention may be suitable for delivery of a variety of medicaments and may be suitable for use in the treatment of a variety of disorders.

Thus, for example, for use as an insufflator, e.g. an insufflator for oral drug delivery, or a naso-pulmonary dry powder medicament delivery device, e.g. a naso-pulmonary insufflator, a variety of medicaments may be administered. Such medicaments are generally suitable for the treatment of asthma, COPD and respiratory infections. Such medicaments include, but are not limited to [beta] 2-agonists, e.g. fenoterol, formoterol, pirbuterol, reproterol, rimiterol, salbutamol, salmeterol and terbutaline; non-selective beta-stimulants such as isoprenaline; xanthine bronchodilators, e.g. theophylline, aminophylline and choline theophyllinate; anticholinergics, e.g. ipratropium bromide; mast cell stabilisers, e.g. sodium cromoglycate and ketotifen; bronchial anti-inflammatory agents, e.g. nedocromil sodium; and steroids, e.g. beclomethasone dipropionate, fluticasone, budesonide, flunisolide and ciclesonide, and isomers and/or salts or derivatives thereof.

Specific combinations of medicaments which may be mentioned include combinations of steroids, such as, beclomethasone dipropionate and formoterol; beclomethasone dipropionate and salmeterol; fluticasone and formoterol; fluticasone and salmeterol; budesonide and formoterol; budesonide and salmeterol; flunisolide and formoterol; and flunisolide and salmeterol. It is also within the scope of this invention to include combinations of one or more of the aforementioned steroids with one or more of the aforementioned P2-agonists.

However, there is increasing interest in the pulmonary delivery or intravenous delivery of medicaments due, inter alia, to the rapid onset of their efficacious effect. Thus, further medicaments which may be mentioned include systemically active materials, such as, proteinaceous compounds and/or macromolecules, for example, hormones and mediators, such as insulin, glucagon, human growth hormone, leuprolide and alpha interferon, growth factors, anticoagulants, immunomodulators, cytokines and nucleic acids. Other medicaments which may be mentioned are those for the treatment of neurological disorders, such as Parkinsonism, such as, levodopa, carbidopa, benserazide, selegiline, tolcapone, entacapone, bromocriptine, lysuride, pergolide, ropinirole and cabergoline; or migraine, such as divalroex sodium, ergotamine, methysergide, metoprolol, propranolol, zolmitriptan, vigabatrine, clonidine, ganaxolone, lysine acetylsalicylate, sumatriptan, naratriptan, timolol, almotriptan, cyproheptadine, rizatriptan, timotol, dotarizine, dihydroergotamine, metysergide, pizotifen, eletriptan, prochlorperazine, nadolol and frovatriptan. In addition, medicaments for the treatment of sexual dysfunction may be mentioned. Such disorders include erectile dysfunction where treatments include administration of phosphodiesterase type-5 (PDTE5) inhibitors, such as tadalafil, vardenafil and sildenafil; and premature ejaculation, where treatments include administration of selective serotonin reuptake inhibitors, such as dapoxetine.

Medicaments described herein may comprise compositions suitable for controlled or targeted release of the medicament. For example, the compositions are may be designed to be provide slow, delayed or positioned release of the medicament. Delayed release may be achieved by a coating that is simply slow to disintegrate. Suitable compositions for delayed or positioned release include film coated formulations wherein the coating may be water resistant, pH sensitive or sloughed off at a slow but regular rate when moistened. Suitable coating materials include, but are not limited to, hydroxypropyl methylcellulose, ethyl cellulose, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, polymers of methacrylic acid and its esters, and combinations thereof. Suitable excipients may include, but shall not be limited to, excipients obtained by interesterification of hydrogenated palm oil and palm kernel oil (Cg-Cis triglycerides), esterification of glycerol and specific fatty acids, or polyglycosylated glycerides; stabilizing agents, thickeners and emulsifiers like carboxymethylcellulose and salts thereof, polyacrylic acid and salts thereof, carboxyvinyl polymers and salts thereof, alginic acid and salts thereof, propylene glycol alginate, chitosan, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxy ethylcellulose, ethylcellulose, methylcellulose, polyvinyl alcohol, polyvinyl pyrrolidone, N- vinylacetamide polymer, polyvinyl methacrylate, polyethylene glycol, pluronic, gelatin, methyl vinyl ether-maleic anhydride copolymer, soluble starch, pullulan and a copolymer of methyl acrylate and 2-ethylhexyl acrylate lecithin, lecithin derivatives, propylene glycol fatty acid esters, glycerin fatty acid esters, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyethylene glycol fatty acid esters, polyoxyethylene hydrated castor oil, polyoxyethylene alkyl ethers, and pluronic and an appropriate buffer system in pH range of 6.5 to 8.

However, one particular aspect of the present invention provides the dry powder medicament delivery device as herein described as a naso-pulmonary dry powder medicament delivery device. A naso-pulmonary dry powder medicament delivery device according to this aspect of the invention may be suitable for the delivery of any of the medicaments herein described.

An important use of the delivery device of the present invention is for the delivery of an emergency therapy. The intranasal or intravenous route of drug delivery can afford rapid absorption of drugs into the blood circulation. For example, the intranasal route can also offer a less invasive route of drug administration compared with some other routes such intravenous or intramuscular injection. Such rapid and effective drug delivery can be useful in the treatment of crisis situations such as pain, convulsions, serious hypoglycaemic reaction, etc.

The delivery device of the present invention is found to be especially advantageous in the delivery of a medicament in an emergency situation, for example, where the patient is unconscious. The naso-pulmonary delivery device of the invention is especially useful in a situation where medical staff are not available. One specific such therapy is the intranasal administration of a therapeutically effective amount of glucagon to a diabetic who is experiencing a serious hypoglycaemic reaction. Glucagon is a hormone that causes the liver to release glucose into the blood and is used to quickly increase blood sugar levels in diabetics with hypoglycaemia (low blood sugar). Glucagon is usually provided in powder form and given as an injection either into a vein, an arm or leg muscle or under the skin as directed, usually to an unconscious patient. The glucagon powder must first be dissolved in a diluting fluid and must be used immediately after it has been mixed.

Therefore, according to a particular aspect of the present invention there is provided a method of delivering glucagon to an individual which comprises the use of a medicament delivery device as herein described, especially the use of a dry powder naso-pulmonary dry powder medicament delivery device.

A particular category of individuals for whom intravenous or intramuscular injection may be problematical in infants, including neonates, therefore the use of the delivery device of the present invention as an intranasal drug delivery device may be beneficial. In addition, when used as an insufflator, e.g. an oral insufflator and especially a naso- pulmonary dry powder medicament delivery device, the medicament delivery device as herein described may suitably be used for the delivery of one or more dry powder vaccines.

Dry powder vaccine compositions for intranasal delivery are described in International Patent application No. WO 2011/129120. Therefore, a dry powder vaccine for use in association with a medicament delivery device, such as a naso- pulmonary dry powder medicament delivery device, of the present invention, can be useful for the prevention and/or treatment of infection by any virus.

Thus, according to a preferred aspect of the invention the dry powder medicament delivery device comprises a device described in International Patent application No. WO 2011/129120; provided with a naso-pulmonary adaptor with an integral holding chamber.

It will be appreciated that the above descriptions can apply to the treatment of animals as well as humans.

The invention further provides a method of delivering a medicament, e.g. a dry powder medicament, to an individual, such as an infant or murina, said method comprises the use of a dry powder medicament delivery device as herein described. The invention further provides a method of treatment of an individual with a disorder which comprises the administration of a medicament using a medicament delivery device as herein described.

The method of treatment according to this aspect of the invention may comprise the administration of any one or more of the therapeutically active agents described herein. However, there is especially provided a method of delivering an emergency therapy, such as, glucagon, or a vaccine, e.g. a dry powder vaccine to an individual.

More especially, the invention provides a method of treating an individual which comprises the administration of a therapeutically effective amount of glucagon to a diabetic experiencing a hypoglycaemic reaction or in which a hypoglycaemic reaction has been induced using the dry powder medicament naso-pulmonary delivery device herein described.

In a further aspect of the invention there is provided a method of delivering a therapy for the treatment of pulmonary disorders, such as asthma, COPD, cystic fibrosis and lung cancers.

A naso-pulmonary adaptor provided with an integral holding chamber is novel per se. Therefore, according to a further aspect of the present invention there is provided a naso-pulmonary adaptor for use with a dry powder medicament delivery device wherein the naso-pulmonary adaptor is provided with an integral holding chamber. More specifically, there is provided a naso-pulmonary adaptor provided with an integral holding chamber for use in conjunction with a dry powder medicament naso- pulmonary delivery device; especially for use in conjunction with a dry powder medicament naso-pulmonary delivery device herein described.

The assembly and/or the naso-pulmonary adaptor may comprise a variety of suitable materials and may be made by a variety of methods, and the member and sleeve may optionally comprise the same material e.g. a plastics material.

Desirably the assembly comprises a suitable first plastics material and the naso- pulmonary adaptor comprises an alternative second plastics material. The preferred device, i.e. comprising first and second plastics materials may be manufactured by a variety of methods, including, preferably a method known as two shot moulding. The two shot moulding method is a process of moulding that allows the combined components, i.e. the member (first plastics material) and sleeve (second plastics material) to be produced in a single machine cycle with no subsequent assembly. Such a method produces clear savings on economy.

The dry powder medicament naso-pulmonary delivery device as herein described is advantageous in that, inter alia, it permits the naso-pulmonary delivery of low dosages of a dry powder, which is especially suitable for use with infants, including neonates, and small animals, such as murinae. Furthermore, the dry powder medicament naso-pulmonary delivery device may be reusable by changing the dispensing nozzle and inserting a new pre- filled medicament container.

According to a further aspect of the invention there is provided a dry powder medicament naso-pulmonary delivery device kit comprising: a dry powder medicament naso-pulmonary delivery device as herein described, which includes a dispensing nozzle; a holding chamber; a naso-pulmonary adaptor; optionally, at least one unit dose of a dry powder medicament.

In a preferred aspect of the invention the kit includes a naso-pulmonary adaptor which includes an integral holding chamber.

In one aspect of the invention the kit includes an air source. The air source of the kit as herein described may comprise a delivery pump, such as a syringe or a bellows, etc.

According to this aspect of the invention the kit may be suitable for the administration of any one or more of the therapeutically active agents described herein. However, there is especially provided a kit suitable for delivering an emergency therapy, such as, glucagon, or a vaccine, e.g. a dry powder vaccine to an individual.

The invention will now be described by way of example only and with reference to the accompanying drawings in which:

Figure 1 is a side view of a medicament delivery device of the invention comprising a medicament dispensing assembly and a naso-pulmonary adaptor;

Figures 2(a) and 2(b) are side views of a medicament container, e.g. a cartridge, containing a unit dose of dry powder medicament with a protective sleeve retracted (Fig 2(a)) and in situ (Fig 2(b)); Figure 3 is a side view of a medicament delivery device of the invention with a medicament container being placed in position;

Figure 4 is a side view of a medicament delivery device of the invention, provided with a naso-pulmonary adaptor, the medicament delivery device is being actuated;

Figure 5 is a cross-sectional view of a naso-pulmonary adaptor;

Figure 6 is a cross-sectional view of an alternative tapered naso-pulmonary adaptor;

Figures 7(a) and (b) are perspective views of an air flow restrictor;

Figure 8 is a disassembled view of a medicament delivery device of the invention with an air flow restrictor included;

Figures 9(a) and (b) illustrate alternative medicament containers;

Figure 10 illustrates a bifurcated adaptor;

Figures 11(a) and (b) illustrate a dry powder medicament delivery device with the syringe extended (a) and the syringe depressed (b);

Figure 12 illustrates a dry powder medicament delivery device mounted on a base;

Figures 13(a) and (b) illustrate a dry powder medicament delivery device being primed; and

Figures 14(a) and (b) illustrates a locking assembly.

Referring to Figure 1, a dry powder medicament delivery device 1 comprises a medicament dispensing assembly 2 and a syringe 3, provided with plunger 4. The syringe 3 and plunger 4 act as an air source. The dispensing assembly 2 comprises a body 5, a dispensing nozzle 6, and an airway (not shown) provided with an inlet end 7 and an outlet end 8. The dispensing assembly 2 is provided with means 9 for housing and engaging with a medicament container (not shown). A naso-pulmonary adaptor 10 is adapted to be located at the outlet end 8 of the dispensing nozzle 6. The naso-pulmonary adaptor 10 comprises an inlet end 11 and an outlet end 12. The inlet end 11 is adapted to be located on the outlet end 8 of the dispensing nozzle 6. . The inlet end 11 is provided with a Luer-lock fixing 13 to cooperate with the outlet end 8 of the dispensing nozzle 6. The outlet end 12 of the naso-pulmonary adaptor 10 is provided with a conduit 14 about the size of a hypodermic needle.

Referring to Figures 2(a) and 2(b), a medicament container 15 comprises a cartridge 16 provided with a well cavity 17 for holding a medicament 18, usually in the form of a powder and a protective sleeve 19. In Figure 2(a) the protective sleeve 19 is retracted, rendering the cartridge 16 in an open position and the well cavity 17 is exposed. In Figure 2(b) the protective sleeve 19 is in a closed position, and the well cavity 17 is covered and protected.

Referring to Figure 3 the medicament dispensing assembly 2 comprises a body 5, a dispensing nozzle 6, and an airway (not shown) provided with an inlet end 7 and an outlet end 8. The dispensing assembly 2 is provided with a housing 9 adapted to engage with a medicament container 15. The protective sleeve 19 of the medicament container 15 is in the closed position.

Referring to Figure 4 the medicament dispensing assembly 2 is shown in use. The air source comprises bellows 16 attached to the inlet end 7 dispensing assembly 2. A naso-pulmonary adaptor 10 is located at the outlet end 8 dispensing assembly 2. The medicament container 15 is located in the housing 9 of the dispensing assembly 2. As the medicament container 15 is pushed into the housing 9, the protective sleeve 19 of the medicament container 15 is retracted (not shown) exposing the well cavity (not shown) and the medicament.

A user depresses the bellows 16 forcing air through the medicament dispensing assembly 2 and entraining the dry powder medicament (not shown) in the airway (not shown). The entrained dry powder medicament 17 is dispensed from the conduit 14 at the outlet end 12 of the naso-pulmonary adaptor 10.

Referring to Figure 5 a naso-pulmonary adaptor 10, suitable for use with a mouse model is shown. The naso-pulmonary adaptor 10 comprises a body 18, the body comprises a frusto conical or tapered holding chamber 19 with an inlet end 20 and an outlet end 21. The inlet end 20 of the naso-pulmonary adaptor body 18 is provided with a conduit 22 which extends from the inlet end 20 and protrudes into the holding chamber 19. An external portion of the inlet end 20 is provided a Luer-lock fitment enabling the naso-pulmonary adaptor 10 to be securely located onto the outlet end 8 of the dispensing assembly 2. The outlet end 21 of the holding chamber 19 is provided with a conduit 14 through which the dry powder medicament (not shown) is dispensed.

Referring to Figure 6 a naso-pulmonary adaptor 22, suitable for use with a rat model is shown. The naso-pulmonary adaptor 22 comprises a body 23, the body comprises a frusto conical or tapered holding chamber 24 with an inlet end 25 and an outlet end 26. The inlet end 25 of the naso-pulmonary adaptor body 23 is provided with a conduit 27 which extends from the inlet end 25 and protrudes into the holding chamber 24.

An external portion of the inlet end 25 is provided a Luer-lock fitment enabling the naso-pulmonary adaptor 22 to be securely located onto the outlet end 8 of the dispensing assembly 2. The inlet end 25 of the naso-pulmonary adaptor body 23 is also provided with external support ribs 28. The outlet end 26 of the holding chamber 24 is provided with a conduit 29 through which the dry powder medicament (not shown) is dispensed.

Referring to Figures 7(a) and (b) an air flow restrictor 30 comprises a body 31 provided with a longitudinal conduit 32. The body 31 comprises a first end 33 and a second end 34. The first end 33 is provided with means 35 for connecting, e.g. a snap-fit, with a medicament dispensing assembly body (not shown). The second end 34 comprises means 36 for connecting, e.g. a screw thread, with a dispensing nozzle (not shown).

The longitudinal conduit 32 is generally of narrower diameter than the connecting orifice at the end of the medicament dispensing assembly body (not shown).

Referring to Figure 8 a dry powder medicament delivery device 37 comprises a medicament dispensing assembly 38 and a syringe 39, provided with plunger 40. The syringe 39 and plunger 40 act as an air source. The dispensing assembly 38 comprises a body 41, an air flow restrictor 42, a dispensing nozzle 43, and an airway (not shown) provided with an inlet end 44 and an outlet end 45. Referring to Figures 9(a) and (b) a medicament container 15 comprises a cartridge 16 provided with a well cavity 17 (reference Figure 2(a)). In an alternative embodiment a medicament container 15 comprises a cartridge 16 wherein the cartridge 15 is provided with a pair of integral abutments 46 and 47 e.g. in the form of “wings” around the cartridge 16. The abutments 46 and 47 create a stop 48 and 49 respectively when the delivery device (not shown) is actuated. In Figure 9(b) the medicament container 15 is provided with a protective sleeve 19.

Referring to Figure 10 a bifurcated adaptor 50 comprises a connector 51 adapted to connect the bifurcated adaptor 50 to the outlet end of a dispensing nozzle 6 (not shown), the connector 51 sits adjacent a bifurcation chamber 52 and a pair of outlet conduits 53 and 54 extend from the bifurcation chamber 51.

Referring to Figures 11(a) and (b) a dry powder medicament delivery device 1 comprises a medicament dispensing assembly 2 and a syringe 3, provided with plunger 4. The syringe 3 and plunger 4 act as an air source. The syringe 3 is provided with a syringe stop (55). The dispensing assembly 2 comprises a body 5, a dispensing nozzle 6, and an airway (not shown) provided with an inlet end 7 and an outlet end 8. The dispensing assembly 2 is provided with means 9 for housing and engaging with a medicament container 15, said medicament container 15 being provided with abutments 46 and 47. A stopcock 54 is provided between the syringe 3 and the dispensing assembly 2. In Figure 11(a) the syringe 3 is extended and the protective sleeve 19 is in place over the medicament container 15. In Figure 11(b) the syringe 3 is depressed (primed) and the medicament container 15 is fully inserted up to the abutments 46 and 47. The stopcock 54 is closed.

Referring to Figure 12 a dry powder medicament delivery device 1 is mounted on a base 55, said base 55 being provided with a plunger holder 56 and a locking plate 57.

Referring to Figures 13(a) and (b) a dry powder medicament delivery device 1 being primed in Figure 13(a) by opening the stopcock 54 and the plunger 4 of the syringe 3 being drawn back to its maximum position; and in Figure 13(b) setting the desired air volume by positioning the syringe locking plate 57.

Referring to Figures 14(a) and (b) a locking plate 57 comprises a retractable plate 58 provided with a tongue 59 adapted to fit a groove 60 in a moveable plate 61 on which the syringe 3 sits. In Figure 14(a) the moveable plate 61 is locked with the tongue 59 sitting in the groove 60. In Figure 14(b) the retractable plate 58 is retracted and the tongue 59 withdrawn from the groove 60, allowing the moveable plate 61 to freely move and allowing the syringe plunger 4 to prime the delivery device 1 with air.

Experimental

Example 1 - Clearance (Emptying) of Delivery Device

The clearance of the body and dispensing nozzle of the delivery device (the device of Figure I la) was measured using the following methodology: 1. The dispensing nozzle (a lOpL pipette tip, as shown in Figure 6) was cleaned with compressed air and weighed on a tared scale; the result was recorded.

2. The main body of the device was cleaned with compressed air and weighed on a tared scale; the result was recorded.

3. The drug (medicament) cartridge and protective sleeve were separated and cleaned with compressed air. The protective sleeve was placed over the open end of the cartridge and weighed on a tared scale; the result was recorded. The drug used was a spray dried placebo formulation.

4. The drug cartridge was filled with a powdered medicament and tapped three (3) times to level. The protective sleeve was moved into position to cover the well cavity and covered cartridge was cleaned with compressed air to remove any excess powder. The filled and covered cartridge was placed on a tared scale; the result was recorded.

5. The delivery device was assembled, primed and fired.

6. The dispensing nozzle was removed and weighed on a tared scale; the result was recorded.

7. The cartridge and protective sleeve were removed and weighed on a tared scale without disassembly; the result was recorded. 8. The main body of the device was removed and weighed on tared scale; the result was recorded. The above procedure was repeated sixty (60) times.

A summary of the results are provided in Table 1.

Conclusion The results illustrate an average device clearance in excess of 93% (w/w) which compares claims of over 70% for the commercially available alternatives.

Table 1

Average (n=60) 0.1056 0.1057 0.0001 1.5049 1.5130 0.0081 1.5053 0.0004 94.88 0.7310 0.7310 0.0001

RSD %