Dry powder drug delivery device

Abstract

Described is a dry powder drug nasal-pulmonary delivery device comprising: a drug container, such as a cartridge, containing a unit dose of a dry powder drug; a body optionally provided with an air source; and a medicament dispensing assembly, the medicament dispensing assembly comprising: a dispensing nozzle; a holding chamber; and a nasal lung adapter.

Description

Technical Field

[0001] The present invention relates to a novel dry powder drug delivery device and use thereof.

[0002] More specifically, the present invention relates to novel dry powder drug delivery devices suitable for use as, for example, nasopulmonary drug delivery devices for delivering drugs, for example, for treating respiratory disorders; in particular for delivering vaccines or hormones such as glucagon in dry powder form; or for treating pulmonary disorders such as asthma, COPD, cystic fibrosis and lung cancer.

[0003] The nasal pulmonary delivery device is particularly suitable for delivering small doses and can therefore be used in infants (including newborns) or small animals. Therefore, the delivery device is particularly useful in animal models, such as preclinical studies. Background Art

[0004] In recent years, pharmaceutical preparations in dry powder form have been developed, for example for delivery by inhalation, or by mixing in a solution for delivery by intravenous infusion. Such dry powder preparations include existing compounds and newly developed compounds reformulated into dry powder form for the treatment of many conditions and diseases.

[0005] Drug formulations in the form of inhaled dry powders, dry powders passively delivered to the lungs or nasal cavity, etc. offer advantages over other forms such as liquids and tablets, particularly when storage, stability and bioavailability are considered.

[0006] Oral (pulmonary) or nasal delivery of drugs using dry powder drug delivery devices is a particularly attractive method of drug administration because such devices can be relatively easy for an individual to use. In addition to delivering drugs to treat localized diseases of the airways and other respiratory disorders, dry powder drug delivery devices have recently been used to deliver drugs to the bloodstream via the lungs or nasal passages, thereby avoiding the need for injections, for example; and for direct delivery to the brain via the olfactory region.

[0007] It is well known that nasal drug delivery is used to treat common ailments such as colds, coughs, hay fever, rhinitis, etc. Many problems are associated with oral, parenteral, rectal, injection and other routes of drug administration. Therefore, there is an increased interest in the intranasal delivery of various drugs for systemic use, including peptides, proteins, vaccines, etc.

[0008] Nasal delivery offers many advantages over traditional methods of vaccine administration. These benefits include easy administration without needles, which reduces problems associated with needle injury and disposal, reduces the need for advanced administration training and facilitates self-administration.

[0009] In addition, dry powder intranasal vaccines have recently been developed. There are many advantages to intranasal delivery of drugs, especially in dry powder form. Intranasal drug delivery achieves rapid uptake into the bloodstream through absorption through nasal mucus, has the potential to reduce or eliminate cold chain management of vaccines during storage and transportation, and eliminates the use of needles and the possibility of needle stick injuries.

[0010] Intranasal vaccination represents an attractive non-invasive alternative to needle injections and offers excellent protection of 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.

[0011] Vaccines and other pharmaceutically active agents formulated as liquids can be subject to chemical degradation, such as aggregation, denaturation, hydrolysis, and oxidation, which can cause them to become inactive. Liquid vaccine formulations can also be sensitive to temperature: high temperatures can increase inactivation, while freezing temperatures can produce ice, which can damage the antigens in the vaccine. Therefore, to prevent inactivation, liquid vaccines must generally be stored within a temperature range of 2°C-8°C.

[0012] The mode of administration of a vaccine may affect its efficacy. One mode of administration, i.e., non-parenteral (e.g., nasal) administration, can induce and promote mucosal and systemic immune responses. In addition, nasal mucus can help bind viruses or other pathogens on the mucosal surface, preventing pathogens from entering deeper tissues and / or reducing the possibility of full-blown infection.

[0013] However, this focus presents many difficulties, including the small doses required for delivery when treating infants, including neonates.

[0014] Furthermore, drug and medical device development and approval by pharmaceutical regulatory agencies often requires the use of preclinical animal models.

[0015] Intranasal delivery in animal models, particularly in the subfamily Muridae such as rats and mice, presents particular difficulties. The volume of the mouse nasal cavity is only one-fourth the size of the rat nasal cavity, and rats themselves present several delivery issues. With conventional intranasal devices, the pressure and volume of air exiting the device can be potentially lethal to the subfamily Muridae. For example, when delivering air pulses to rats, the air pulses should not exceed 2 mL / pulse.

[0016] Attempts have been made to solve this problem. Penn-Century Dry Powder Insufflator TM - DP-4 is commercially available from Penn-Century Corporation. The primary application of this insufflator device is for delivery to the lungs, but it is also advertised as suitable for intranasal delivery. However, the Penn-Century device has been discontinued for sale and has not been on the shelves for several years.

[0017] Additionally, the PADA (Powder Administration Device for Animals) starter kit is commercially available from Aptar Pharma. This kit is designed to enable direct intratracheal administration of powders into the lungs of mice.

[0018] International patent application number WO 2013 / 088112 describes a single-dose disposable dry powder drug delivery device, which includes a drug container containing a unit dose of dry powder drug, a drug dispensing component and an air source. However, in order to deliver low doses of dry powder drugs, such as for use in infants or animal models, further improvements are needed, and these infants include newborns.

[0019] The present invention seeks to provide a dry powder drug delivery device which overcomes or significantly alleviates the problems of conventional inhalation devices. Summary of the invention

[0020] We have now surprisingly found that the use of a holding chamber can reduce the pressure and volume of air leaving a nasal inhalation device.

[0021] Therefore, according to a first aspect of the present invention, a dry powder drug nasal pulmonary delivery device is provided, the dry powder drug nasal pulmonary delivery device comprising:

[0022] a pharmaceutical container, such as a kit, that holds a unit dose of a dry powdered drug;

[0023] a body optionally provided with an air source; and

[0024] A drug dispensing assembly, the drug dispensing assembly comprising:

[0025] Dispensing nozzle;

[0026] Holding room; and

[0027] Nose-lung adapter.

[0028] Dispensing nozzle

[0029] The dispensing nozzle typically includes an airway, for example having an inlet end and an outlet end. The inlet end of the dispensing nozzle is adapted to be attached to the body of the nasal lung delivery device. The outlet end of the dispensing nozzle is adapted to be attached to a holding chamber. Alternatively, the nasal lung adapter may be provided with an integrated holding chamber, in which case the outlet end of the dispensing nozzle may be adapted to be attached to the nasal lung adapter. A nasal lung adapter provided with an integrated holding chamber is a preferred embodiment of the present invention. According to one aspect of the present invention, the nasal lung adapter is a nasal adapter. In another aspect of the present invention, the nasal lung adapter is a pulmonary adapter.

[0030] Holding Room

[0031] The holding chamber is provided with an inlet at one end to receive the dispensed dry powder and an outlet to transfer the dry powder into the nose-lung adapter. In one embodiment of the present 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 nose-lung adapter.

[0032] In another embodiment of the invention, the holding chamber is integral with the nasal lung adapter.

[0033] Nose-lung adapter

[0034] The nasal-pulmonary adapter is provided with an inlet at one end to receive the dispensed dry powder and an outlet to deliver the dry powder into the nasal cavity or lungs of the individual when administered. In one embodiment of the invention, the inlet end of the nasal-pulmonary adapter is adapted to be attached to the outlet end of the holding chamber. In another embodiment, the holding chamber is integral with the nasal-pulmonary adapter, in which case the nasal-pulmonary adapter is adapted to be attached to the outlet end of the dispensing nozzle. Preferably, the holding chamber is integral with the nasal-pulmonary adapter.

[0035] Pill Box

[0036] The drug container comprises a medicine box provided with a well cavity suitable for accommodating a drug, which is usually in the form of a dry powder. The medicine box may be provided with a protective sleeve, which is adapted to be retracted. In a first position, the protective sleeve covers and protects the dry powder drug, but when the protective sleeve is retracted, it places the medicine box in an open position and exposes the well cavity and the dry powder drug therein.

[0037] In another embodiment, the medicine box is provided with a support, such as an integral support or a pair of integral supports. When the assembly is actuated and the medicine box is moved to the open position, a pair of supports, such as in the form of "wings" around the medicine box, is used to create a stop. In addition, the use of a pair of supports helps to provide a seal around the medicine box.

[0038] According to this aspect of the present invention, there is provided a dry powder drug nasal pulmonary delivery device, the dry powder drug nasal pulmonary delivery device comprising:

[0039] a pharmaceutical container, such as a kit, that holds a unit dose of a dry powdered drug;

[0040] a body optionally provided with an air source; and

[0041] A drug dispensing assembly, the drug dispensing assembly comprising:

[0042] a dispensing nozzle; and

[0043] A nose-lung adapter, wherein the nose-lung adapter includes an integral holding chamber.

[0044] According to one aspect of the invention, the nose-lung adapter is a nasal adapter. In another aspect of the invention, the nose-lung adapter is a pulmonary adapter. The pulmonary adapter may optionally be provided with a cannula to facilitate delivery of dry powder medication to the individual's lungs.

[0045] The outlet of the nasal lung adapter will typically include a catheter with an aperture at the outlet end. The shape and size of the outlet aperture may vary, among other things, depending on the characteristics of the individual being treated and the dry powder being delivered. For an intranasal insufflator, the size and shape of the outlet aperture is ideally suited for placement in the nostril of an individual (infant, murine or other small animal such as rabbit, guinea pig, etc.). For administration of dry powder to infants and / or murines, the outlet aperture may have an outer diameter of about 0.5 mm to about 2 mm, including neonates. For example, for use with rats, the outlet aperture may have an outer diameter of about 1.6 mm, or for use with mice, the outlet aperture may have an outer diameter of about 0.5 mm. Typically, for use with murines, the outlet is about the size of a hypodermic needle, such as a hypodermic needle of gauge (Birmingham gauge) 10 to 25, for example, for use with rats, the outlet aperture may have an outer diameter of about 16 gauge, or for use with mice, the outlet aperture may have an outer diameter of about 25 gauge. Those skilled in the art will appreciate that for use with infants, including neonates, the outlet aperture may have a generally larger outer diameter or have a larger gauge.

[0046] In some cases, by using a smaller diameter hole, back pressure can reduce the pickup of powder. Therefore, an airflow restrictor can be optionally included, depending on the outlet hole diameter of the nasal lung adapter attached to the device. Such an airflow restrictor, when present, can be incorporated into the nasal lung delivery device of the present invention between the air source, such as a syringe, and the body of the nasal lung adapter. The use of an airflow restrictor can be advantageous, particularly in that it improves the performance of the nasal lung delivery device, for example, by adjusting the ratio of the outlet mouth of the tip to the diameter of the restrictor hole, the pickup of powder from the drug container can be significantly improved.

[0047] As an alternative to using an airflow restrictor, the drug dispensing assembly may be provided with a valve located between the air source and the drug dispensing assembly, so that if the valve is in a closed position when the air source is actuated, a pressurized air pocket will be created; and the opening of the valve will provide a burst of pressurized air to the drug dispensing assembly. It should be understood that various valves can be used appropriately. An example of a valve is a stopcock, such as a two-way manual stopcock adapted to be manually switched from a closed position to an open position. However, although a valve may generally be used in place of an airflow restrictor, it is also within the scope of the present invention that the drug dispensing assembly is provided with an airflow restrictor and a valve. The use of a valve such as a stopcock may be advantageous because it helps to remove dry powder medicament from the dispensing assembly. It has been found that by using a valve, about 25% w / w or more of the dry powder medicament is removed from the dispensing assembly and delivered to the nasal cavity or lungs of an individual.

[0048] The dry powder drug delivery device may be mounted on a movable plate. The movable plate may desirably be provided with a releasable locking mechanism. An example of a locking mechanism comprises a retractable plate provided with a tongue adapted to fit into a groove in the movable plate where the syringe is located. The movable plate may be locked by the tongue located in the groove. By retracting the plate, the tongue may be withdrawn from the groove, thereby allowing the movable plate to move freely and allowing the syringe plunger to charge air into the delivery device.

[0049] In the dry powder drug nasopulmonary delivery device of the present invention, if back pressure is expected to occur, the drug container can be optionally clamped to the body of the device. Any conventionally known clamping mechanism can be used, but in one aspect of the present invention, the clamp can include a thumb screw clamp.

[0050] The size of the delivered dose may be varied, for example, by changing the size of the drug container.

[0051] When the nose-lung adapter includes an integral holding chamber, the holding chamber may include a conical, truncated conical or tapered chamber. The holding chamber may be provided with an inner conduit, such as a longitudinal conduit, which is an airway having a first end adjacent to the connection to the dispensing nozzle and a second end protruding into the holding chamber. The inner conduit may have an outer diameter of about 0.1 mm to about 2.0 mm. The use of a holding chamber and an inner conduit is advantageous, particularly in that the pressure of the airflow is reduced. In a preferred aspect of the present invention, the nose-lung adapter includes a truncated conical or tapered holding chamber. The use of a truncated conical or tapered holding chamber is generally more conducive to the delivery of drugs. In addition, when approaching the critical exit hole size, the use of a truncated conical or tapered holding chamber provides additional distance to reduce pressure accumulation in the holding chamber. Alternatively, the nose-lung adapter may be in the form of a pipette tip.

[0052] In another aspect of the invention, the nasal-pulmonary adapter may include a bifurcated adapter. The bifurcated adapter may be suitably adapted to fit the mouth; alternatively, the bifurcated adapter may be adapted to fit over the end of the nasal-pulmonary adapter described herein. The use of a bifurcated adapter is particularly advantageous in the nasal delivery of dry powder medications because it enables the dry powder medication to be delivered to each nostril of an individual simultaneously.

[0053] Luer lock

[0054] The means for attaching the nasopulmonary adapter and / or holding chamber to the dispensing nozzle may include snap fit, threaded fit, bayonet fit, Luer lock or Luer connector, etc. In a preferred aspect of the present invention, the releasable attachment includes a Luer lock or Luer connector connection, that is, the means for attaching the nasopulmonary adapter and / or holding chamber to the dispensing nozzle may include a tabbed female hub on the dispensing nozzle and a slotted or threaded male hub on the nasopulmonary adapter or holding chamber.

[0055] According to another aspect of the present invention, a dry powder drug delivery device includes an air source.

[0056] The drug dispensing assembly of the present invention generally comprises a body and a mouth. More specifically, the drug dispensing assembly comprises a body, a mouth and an airway, such as one or two airways, an inlet and an outlet. For an intranasal insufflator device, the size and shape of the mouth may be ideally adapted for placement within the nostrils of an individual. However, it is preferred that the drug dispensing assembly is provided with a nasal-pulmonary adapter such that the adapter is placed within the nostrils of an individual. This is particularly true when the drug dispensing assembly is used to administer drugs to infants or murines. Those skilled in the art will further appreciate that the drug dispensing assembly may also be designed to be suitable for oral delivery, such as an insufflator for delivery to the lungs (respiratory tract).

[0057] The air source may comprise a delivery pump, for example, which may comprise a syringe. Such a syringe may, for example, comprise a conventionally known suitable syringe, such as a disposable syringe, or may comprise conventionally known means for expelling a gas flow, such as an insufflator or other such device adapted to blow air or gas upon actuation, such as a cartridge and piston, a bellows, a squeezable bulb, or a source of compressed air or gas such as a compressed air tank or from a compressed air system equipped with suitable volume and pressure control devices.

[0058] Thus, according to the present invention, we provide a method of producing an aerosol of a dry powder for nasal pulmonary administration, the method comprising positioning a dispersible dry powder material, such as a drug material, downstream of a nasal pulmonary adapter; wherein the nasal pulmonary adapter comprises an optional integral holding chamber; and wherein the nasal pulmonary adapter is attached to a dispensing nozzle of a dry powder drug nasal pulmonary delivery device as described herein. The method according to this aspect of the invention is particularly useful for delivering dry powder drug materials to infants and / or murines, including newborns.

[0059] The dry powder drug delivery device according to this aspect of the invention may be suitable for delivering a variety of drugs, and may be suitable for treating a variety of disorders.

[0060] Thus, for example, when used as an insufflator, such as an insufflator for oral drug delivery, or a nasal pulmonary dry powder drug delivery device, such as a nasal pulmonary insufflator, a variety of drugs can be administered. Such drugs are generally suitable for treating asthma, COPD and respiratory infections. Such drugs include, but are not limited to, [β]2-agonists, such as fenoterol, formoterol, pirbuterol, reproterol, remiterol, salbutamol, salmeterol and terbutaline; non-selective beta agonists such as isoproterenol; xanthine bronchodilators, such as theophylline, aminophylline and choline; anticholinergics, such as ipratropium bromide; mast cell stabilizers, such as sodium cromoglycate and ketotifen; bronchial anti-inflammatory agents, such as nedocromil sodium; and steroids, such as beclomethasone dipropionate, fluticasone, budesonide, flunisolide and ciclesonide, and isomers and / or salts or derivatives thereof.

[0061] Specific combinations of drugs that 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. Combinations of one or more of the above steroids with one or more of the above β2-agonists are also included within the scope of the present invention.

[0062] However, there is an increasing interest in pulmonary or intravenous delivery of drugs, especially because of their rapid onset of effective action. Thus, further drugs that may be mentioned include systemically active substances, 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 drugs that may be mentioned are drugs for treating neurological disorders such as Parkinson's disease, such as levodopa, carbidopa, benserazide, selegiline, tolcapone, entacapone, bromocriptine, lisuride, pergolide, ropinirole and cabergoline, or drugs for treating migraine, such as divalproex sodium, ergotamine, methysergide, metoprolol, propranolol, zolmitriptan, vigabatrin, clonidine, ganaxolone, lysine acetylsalicylate, sumatriptan, naratriptan, timolol, almotriptan, cyproheptadine, rizatriptan, timolol, dotalizine, dihydroergotamine, methysergide, pizotifen, eletriptan, prochlorperazine, nadolol and frovatriptan. In addition, drugs for treating sexual dysfunction may be mentioned. Such disorders include erectile dysfunction, where treatment involves administration of phosphodiesterase type 5 (PDTE5) inhibitors, such as tadalafil, vardenafil, and sildenafil; and premature ejaculation, where treatment involves administration of selective serotonin reuptake inhibitors, such as dapoxetine.

[0063] The medicines described herein may include compositions suitable for controlled or targeted release of medicines. For example, these compositions may be designed to provide slow, delayed or positioned release of medicines. Delayed release may be achieved by simply slowly disintegrating coatings. Suitable compositions for delayed or positioned release include film coating formulations, wherein the coating may be waterproof, pH sensitive or fall off at a slow but regular rate when wetted. Suitable coating materials include, but are not limited to, polymers of hydroxypropyl methylcellulose, ethylcellulose, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, methacrylic acid and esters thereof, and combinations thereof. Suitable excipients may include, but are not limited to, hydrolyzed palm oil and palm kernel oil (C 8 -C 18 excipients obtained by transesterification of triglycerides), esterification of glycerol and specific fatty acids or polyglycosylated glycerides; stabilizers, thickeners and emulsifiers, such as carboxymethylcellulose and its salts, polyacrylic acid and its salts, carboxyvinyl polymers and their salts, alginic acid and its salts, propylene glycol alginate, chitosan, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, ethyl cellulose, methyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, N-vinylacetamide polymers, polyvinyl methacrylate, polyethylene glycol, pluronic, gelatin, methyl vinyl ether-maleic anhydride copolymer, soluble starch, pullulan and copolymers of methyl acrylate and 2-ethylhexyl acrylate, lecithin, lecithin derivatives, propylene glycol fatty acid esters, glycerol 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 a suitable buffer system in the pH range of 6.5 to 8.

[0064] However, one particular aspect of the invention provides a dry powder drug delivery device as described herein as a nasopulmonary dry powder drug delivery device. The nasopulmonary dry powder drug delivery device according to this aspect of the invention may be suitable for delivering any of the drugs described herein.

[0065] An important use of the delivery device of the present invention is for the delivery of emergency treatments. The intranasal or intravenous route of drug delivery allows for rapid absorption of the drug into the blood circulation. For example, the intranasal route can also provide a less invasive route for drug administration than some other routes such as intravenous or intramuscular injection. This rapid and effective drug delivery can be used to treat critical situations such as pain, convulsions, severe hypoglycemic reactions, etc.

[0066] It has been found that the delivery device of the present invention is particularly advantageous for delivering drugs in emergency situations, such as when the patient is unconscious. The nasal pulmonary delivery device of the present invention is particularly useful in situations where there is no medical staff. A specific such therapy is the intranasal administration of a therapeutically effective amount of glucagon to a diabetic patient who is experiencing a severe hypoglycemic reaction. Glucagon is a hormone that causes the liver to release glucose into the blood and is used to quickly increase the blood sugar level of a diabetic patient suffering from hypoglycemia (low blood sugar). Glucagon is typically provided in powder form and is typically given to an unconscious patient in the form of an injection into a vein, an arm or leg muscle, or under the skin. The glucagon powder must first be dissolved in a diluent and must be used immediately after mixing.

[0067] Thus, according to a particular aspect of the present invention, there is provided a method of delivering glucagon to an individual, the method comprising use of a drug delivery device as described herein, in particular a dry powder nasopulmonary dry powder drug delivery device.

[0068] For certain categories of individuals, intravenous or intramuscular injections may be problematic in infants, and therefore the use of the delivery device of the present invention as an intranasal drug delivery device may be beneficial, including neonates.

[0069] Furthermore, when used as an insufflator, such as an oral insufflator, and particularly a nasopulmonary dry powder drug delivery device, a drug delivery device as described herein may be suitably used to deliver one or more dry powder vaccines.

[0070] Dry powder vaccine compositions for intranasal delivery are described in International Patent Application No. WO 2011 / 129120. Thus, dry powder vaccines used in conjunction with a drug delivery device of the present invention, such as a nasopulmonary dry powder drug delivery device, can be used to prevent and / or treat infection by any virus.

[0071] Thus, according to a preferred aspect of the present invention, a dry powder drug delivery device comprises the device described in International Patent Application No. WO2011 / 129120; provided with a nasal-pulmonary adaptor having an integrated holding chamber.

[0072] It will be appreciated that the above description is applicable to the treatment of animals as well as humans.

[0073] The present invention also provides a method of delivering a drug, such as a dry powder drug, to an individual, such as an infant or a murine, the method comprising using a dry powder drug delivery device as described herein.

[0074] The present invention also provides a method of treating an individual suffering from a disorder, the method comprising administering a drug using a drug delivery device as described herein.

[0075] The method of treatment according to this aspect of the invention may comprise administering any one or more of the therapeutically active agents described herein.However, in particular there is provided a method of delivering an emergency treatment such as glucagon or a vaccine, eg a dry powder vaccine, to an individual.

[0076] More particularly, the present invention provides a method of treating an individual comprising administering a therapeutically effective amount of glucagon to a diabetic patient experiencing a hypoglycemic reaction or having induced a hypoglycemic reaction using a dry powder drug nasopulmonary delivery device as described herein.

[0077] In another aspect of the invention, a method of delivering therapy for treating pulmonary disorders such as asthma, COPD, cystic fibrosis, and lung cancer is provided.

[0078] The nose-lung adapter provided with an integrated holding chamber is novel in itself. Therefore, according to another aspect of the present invention, a nose-lung adapter for use with a dry powder medicament delivery device is provided, wherein the nose-lung adapter is provided with an integrated holding chamber. More specifically, a nose-lung adapter provided with an integrated holding chamber for use in conjunction with a dry powder medicament nasal-lung delivery device; in particular, for use in conjunction with the dry powder medicament nasal-lung delivery device described herein is provided.

[0079] The assembly and / or nasopulmonary adapter 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, such as a plastic material.

[0080] Ideally, the assembly comprises a suitable first plastic material and the nose-lung adapter comprises an alternative second plastic material. The preferred device, i.e., the device comprising the first plastic material and the second plastic material, can be manufactured by a variety of methods, including a method preferably referred to as overmolding. Overmolding is a molding process that allows the production of a combined component, i.e., a member (first plastic material) and a sleeve (second plastic material) in a single machine cycle without the need for subsequent assembly. Such a method significantly saves costs.

[0081] The dry powder drug nasal pulmonary delivery device as described herein is advantageous, in particular, in that it allows the nasal pulmonary delivery of low doses of dry powder, which is particularly suitable for infants and small animals such as the subfamily of murines, including newborns. In addition, the dry powder drug nasal pulmonary delivery device can be reused by replacing the dispensing nozzle and inserting a new pre-filled drug container.

[0082] According to another aspect of the present invention, a dry powder drug nasal and pulmonary delivery device kit is provided, the dry powder drug nasal and pulmonary delivery device kit comprising:

[0083] A dry powder medication nasopulmonary delivery device as described herein, the dry powder medication nasopulmonary delivery device comprising a dispensing nozzle;

[0084] Holding room;

[0085] Nose-lung adapter;

[0086] Optionally, at least one unit dose of a dry powder medicament.

[0087] In a preferred aspect of the invention, the kit includes a nasal-pulmonary adapter including an integral holding chamber.

[0088] In one aspect of the invention, the kit comprises an air source. The air source of the kit as described herein may comprise a delivery pump such as a syringe or bellows or the like.

[0089] According to this aspect of the invention, the kit may be suitable for administering any one or more of the therapeutically active agents described herein. However, in particular there is provided a kit suitable for delivering an emergency treatment such as glucagon or a vaccine, eg a dry powder vaccine, to an individual. BRIEF DESCRIPTION OF THE DRAWINGS

[0090] The present invention will now be described by way of example only and with reference to the accompanying drawings, in which:

[0091] Figure 1 is a side view of a drug delivery device of the present invention, the drug delivery device including a drug dispensing assembly and a nasal-pulmonary adapter;

[0092] 2( a ) and 2( b ) are side views of a medicament container, such as a medicine box, containing a unit dose of a dry powder medicament, with a protective sleeve retracted ( FIG. 2( a ) ) and in place ( FIG. 2( b ));

[0093] Figure 3 is a side view of the drug delivery device of the present invention, wherein the drug container is placed in place;

[0094] Figure 4 is a side view of the drug delivery device of the present invention provided with a nasal-pulmonary adapter, the drug delivery device being actuated;

[0095] Figure 5 is a cross-sectional view of the nose-lung adapter;

[0096] Figure 6 is a cross-sectional view of an alternative conical nose-lung adapter;

[0097] Figures 7(a) and (b) are perspective views of an airflow restrictor;

[0098] Figure 8 is an exploded view of the drug delivery device of the present invention, including an airflow restrictor;

[0099] Figures 9(a) and (b) show alternative drug containers;

[0100] Fig.10 A bifurcated adapter is shown;

[0101] Figures 11(a) and (b) show a dry powder drug delivery device with the syringe pulled out (a) and the syringe depressed (b);

[0102] Fig.12 A dry powder drug delivery device mounted on a base is shown;

[0103] Figures 13(a) and (b) show a loaded dry powder drug delivery device; and

[0104] Figures 14(a) and (b) illustrate the locking assembly. DETAILED DESCRIPTION

[0105] refer to Figure 1 , the dry powder drug delivery device 1 comprises a drug dispensing assembly 2 and a syringe 3 provided with a plunger 4. The syringe 3 and the 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 a tool 9 for storing and engaging a drug container (not shown).

[0106] The nose-lung adapter 10 is adapted to be positioned at the outlet end 8 of the dispensing nozzle 6. The nose-lung adapter 10 comprises an inlet end 11 and an outlet end 12. The inlet end 11 is adapted to be positioned 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 nose-lung adapter 10 is provided with a catheter 14 which is approximately the size of a hypodermic needle.

[0107] 2(a) and 2(b), the drug container 15 comprises a protective sleeve 19 and a medicine box 16 provided with a well 17 for containing a drug 18, which is usually in powder form. In Fig. 2(a), the protective sleeve 19 is retracted so that the medicine box 16 is in an open position and the well 17 is exposed. In Fig. 2(b), the protective sleeve 19 is in a closed position and the well 17 is covered and protected.

[0108] refer to Figure 3 The drug 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 drug container 15. The protective sleeve 19 of the drug container 15 is in a closed position.

[0109] refer to Figure 4, showing a drug dispensing assembly 2 in use. The air source includes a bellows 16 attached to the inlet end 7 of the dispensing assembly 2. The nose-lung adapter 10 is positioned at the outlet end 8 of the dispensing assembly 2. The drug container 15 is positioned in the housing 9 of the dispensing assembly 2. When the drug container 15 is pushed into the housing 9, the protective sleeve 19 of the drug container 15 is retracted (not shown), thereby exposing the well cavity (not shown) and the drug.

[0110] The user depresses the bellows 16, forcing air through the drug dispensing assembly 2 and entraining the dry powder drug (not shown) in the airway (not shown). The entrained dry powder drug 17 is dispensed from the conduit 14 at the outlet end 12 of the nose-lung adapter 10.

[0111] refer to Figure 5 , a nose-lung adapter 10 suitable for use in a mouse model is shown. The nose-lung adapter 10 includes a body 18 including a truncated conical or tapered holding chamber 19 having an inlet end 20 and an outlet end 21. The inlet end 20 of the nose-lung adapter body 18 is provided with a conduit 22 extending from the inlet end 20 and protruding into the holding chamber 19. The outer portion of the inlet end 20 is provided with a Luer lock fitting so that the nose-lung adapter 10 can be securely positioned on 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 a dry powder drug (not shown) is dispensed.

[0112] refer to Figure 6 , a nose-lung adapter 22 suitable for a rat model is shown. The nose-lung adapter 22 includes a body 23 including a truncated conical or tapered holding chamber 24 having an inlet end 25 and an outlet end 26. The inlet end 25 of the nose-lung adapter body 23 is provided with a conduit 27 extending from the inlet end 25 and protruding into the holding chamber 24.

[0113] The outer portion of the inlet end 25 is provided with a Luer lock fitting, enabling the nose-lung adapter 22 to be securely positioned onto the outlet end 8 of the dispensing assembly 2. The inlet end 25 of the nose-lung adapter 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 a dry powder medicament (not shown) is dispensed.

[0114] 7 (a) and (b), the airflow restrictor 30 includes a body 31 provided with a longitudinal conduit 32. The body 31 includes a first end 33 and a second end 34. The first end 33 is provided with a tool 35 for connecting, for example, snap-fitting, with a drug dispensing assembly body (not shown). The second end 34 includes a tool 36 for connecting, for example, threading, with a dispensing nozzle (not shown).

[0115] The diameter of the longitudinal conduit 32 is typically narrower than the connection aperture at the end of the drug dispensing assembly body (not shown).

[0116] refer to Figure 8 , the dry powder drug delivery device 37 includes a drug dispensing assembly 38 and a syringe 39 provided with a plunger 40. The syringe 39 and the plunger 40 act as an air source. The dispensing assembly 38 includes 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.

[0117] 9(a) and (b), the drug container 15 comprises a drug box 16 (see FIG. 2(a)) provided with a well 17. In an alternative embodiment, the drug container 15 comprises a drug box 16, wherein the drug box 16 is provided with a pair of integral supports 46 and 47, for example in the form of "wings" surrounding the drug box 16. When the delivery device (not shown) is actuated, the supports 46 and 47 produce stops 48 and 49, respectively. In FIG. 9(b), the drug container 15 is provided with a protective sleeve 19.

[0118] refer to Fig.10 The bifurcated adapter 50 includes a connector 51 adapted to connect the bifurcated adapter 50 to the outlet end of the dispensing nozzle 6 (not shown), the connector 51 being located adjacent to a bifurcated chamber 52, and a pair of outlet conduits 53 and 54 extending from the bifurcated chamber 51.

[0119] Referring to Figures 11 (a) and (b), the dry powder drug delivery device 1 includes a drug dispensing assembly 2 and a syringe 3 provided with a plunger 4. The syringe 3 and the plunger 4 act as an air source. The syringe 3 is provided with a syringe stopper (55). The dispensing assembly 2 includes a main 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 tool 9 for storing and engaging with a drug container 15, and the drug container 15 is provided with supports 46 and 47. The stopcock 54 is provided between the syringe 3 and the dispensing assembly 2. In Figure 11 (a), the syringe 3 is pulled out and the protective sleeve 19 is maintained in an appropriate position above the drug container 15. In Figure 11 (b), the syringe 3 is pressed down (filled), and the drug container 15 is fully inserted until the supports 46 and 47. The stopcock 54 is closed.

[0120] refer to Fig.12 The dry powder drug delivery device 1 is mounted on a base 55 , which is provided with a plunger holder 56 and a locking plate 57 .

[0121] 13( a) and (b), in FIG13( a) the dry powder drug delivery device 1 is loaded by opening the stopcock 54 and the plunger 4 of the syringe 3 being pulled back to its maximum position; and in FIG13( b) the desired air volume is set by positioning the syringe locking plate 57.

[0122] 14(a) and (b), the locking plate 57 comprises a retractable plate 58 provided with a tongue 59 adapted to fit into a groove 60 in a movable plate 61 in which the syringe 3 is located. In FIG14(a), the movable plate 61 is locked by the tongue 59 located in the groove 60. In FIG14(b), the retractable plate 58 is retracted and the tongue 59 is withdrawn from the groove 60, thereby allowing the movable plate 61 to move freely and allowing the syringe plunger 4 to charge air into the delivery device 1.

[0123] experiment

[0124] Example 1 - Clearing (Emptying) of Delivery Device

[0125] The delivery device ( Fig.11a Cleaning of the body and dispensing nozzle of the device):

[0126] 1. Clean the dispensing tip (10 μL pipette tip, such as Figure 6 ) and weigh on a tared scale; record the result.

[0127] 2. Clean the body of the device with compressed air and weigh it on a tared scale; record the result.

[0128] 3. Separate the drug (medication) box and protective sleeve and clean with compressed air. Place the protective sleeve over the open end of the box and weigh on a tared scale; record the result. The drug used is a spray-dried placebo formulation.

[0129] 4. Fill the drug cartridge with powdered medication and tap three (3) times until level. Move the protective sleeve into position covering the well and clean the capped cartridge with compressed air to remove any excess powder. Place the filled and capped cartridge on a tared scale; record the result.

[0130] 5. The delivery device is assembled, primed and triggered.

[0131] 6. Remove the dispensing nozzle and weigh it on a tared scale; record the result.

[0132] 7. Remove the pill box and protective sleeve and weigh them on a tared scale without disassembling; record the result.

[0133] 8. Remove the body of the device and weigh it on a tared scale; record the result.

[0134] The above procedure was repeated sixty (60) times.

[0135] A summary of the results is provided in Table 1.

[0136] in conclusion

[0137] Results indicated average device clearance in excess of 93% (w / w), in contrast to commercially available alternatives claiming over 70%.

[0138]

Claims

1. A dry powder drug nasal and pulmonary delivery device, comprising: a pharmaceutical container, such as a kit, that holds a unit dose of a dry powdered drug; a body optionally provided with an air source; and A drug dispensing assembly, the drug dispensing assembly comprising: Dispensing nozzle; Holding room; and Nose-lung adapter.

2. The dry powder medication nasopulmonary delivery device of claim 1, wherein the dispensing nozzle comprises an airway having an inlet end and an outlet end; wherein the inlet end of the dispensing nozzle is adapted to be attached to the body of the nasal lung delivery device; and The outlet end of the dispensing nozzle is adapted to be attached to the holding chamber.

3. A dry powder medication nasopulmonary delivery device according to claim 1, wherein the nasopulmonary adapter is provided with an integrated holding chamber; and the outlet end of the dispensing nozzle is adapted to be attached to the nasopulmonary adapter.

4. A dry powder drug nasal and pulmonary delivery device, comprising: a pharmaceutical container, such as a kit, that holds a unit dose of a dry powdered drug; a body optionally provided with an air source; and A drug dispensing assembly, the drug dispensing assembly comprising: Dispensing nozzle; and A nose-lung adapter, wherein the nose-lung adapter includes an integral holding chamber.

5. The dry powder medication nasopulmonary delivery device of any one of the preceding claims, wherein the nasopulmonary adapter is a nasal adapter.

6. The dry powder medication nasopulmonary delivery device according to any one of claims 1 to 4, wherein the nasopulmonary adapter is a pulmonary adapter.

7. A dry powder medicament nasopulmonary delivery device according to any one of the preceding claims, wherein the medicament container is provided with a holder, such as an integral holder or a pair of integral holders.

8. The dry powder medication nasopulmonary delivery device of claim 6, wherein the pulmonary adapter can be optionally provided with a cannula to facilitate delivery of the dry powder medication to the lungs of the individual.

9. The dry powder medication nasopulmonary delivery device of claim 1, wherein the nasopulmonary adapter comprises an outlet, and the outlet of the nasopulmonary adapter comprises a conduit having a hole at an outlet end.

10. The dry powder medication nasopulmonary delivery device of claim 9, wherein the outlet orifice has an outer diameter of about 0.5 mm to about 2 mm.

11. A dry powder drug nasopulmonary delivery device according to claim 9 or 10, wherein the outlet hole is the size of a hypodermic needle, such as a hypodermic needle with a gauge (Birmingham gauge) of 10 to 25.

12. A dry powder medication nasopulmonary delivery device according to any one of claims 4 to 11, wherein the integrated holding chamber comprises a conical, frustoconical, tapered chamber or a pipette tip.

13. A dry powder medicament nasal pulmonary delivery device according to any one of claims 4 to 12, wherein the holding chamber is provided with an inner conduit, such as a longitudinal conduit, which is an airway having a first end adjacent to the connection to the dispensing nozzle and a second end protruding into the holding chamber.

14. The dry powder medication nasopulmonary delivery device of claim 13, wherein the inner conduit can have an outer diameter of about 0.3 mm to about 1.1 mm.

15. A dry powder drug nasal pulmonary delivery device according to any of the preceding claims, wherein the means for attaching the nasal pulmonary adapter and / or the holding chamber to the dispensing nozzle includes a snap fit, a threaded fit, a bayonet fit, a Luer lock or a Luer connector, etc.

16. A dry powder medication nasopulmonary delivery device according to claim 15, wherein the means for attaching the nasopulmonary adapter and / or the holding chamber to the dispensing nozzle comprises a Luer lock.

17. A dry powder medication nasopulmonary delivery device according to claim 16, wherein the Luer lock comprises a tabbed female hub portion on the dispensing nozzle and a slotted or threaded male hub portion on the nasopulmonary adapter or the holding chamber.

18. A dry powder medication nasopulmonary delivery device according to any one of the preceding claims, wherein the medication dispensing assembly comprises a body, a mouth and an airway.

19. The dry powder medicament nasopulmonary delivery device of any one of the preceding claims, wherein the dry powder medicament delivery device comprises an air source.

20. The dry powder medication nasopulmonary delivery device of claim 19, wherein the air source comprises a delivery pump such as a syringe comprising a barrel and a piston, a bellows, a squeezable bulb, or a compressed air or gas source such as a compressed air tank.

21. The dry powder medication nasopulmonary delivery device of any one of the preceding claims, wherein the nasopulmonary dry powder medication delivery device is used for the delivery of emergency treatment.

22. The dry powder drug nasopulmonary delivery device of claim 21, wherein the dry powder drug delivery device is used to deliver a therapeutically effective amount of glucagon to a diabetic patient experiencing a hypoglycemic reaction.

23. A dry powder medication nasopulmonary delivery device according to any one of claims 1 to 20, wherein the device is suitable for delivering one or more dry powder vaccines.

24. A dry powder medication nasopulmonary delivery device according to any one of claims 1 to 20, wherein the device is suitable for delivering therapy for treating pulmonary disorders such as asthma, COPD, cystic fibrosis and lung cancer.

25. A dry powder medicament nasopulmonary delivery device according to any one of the preceding claims, wherein the delivery device comprises the device described in International Patent Application No. WO 2011 / 129120; provided with a nasopulmonary adapter having an integral holding chamber.

26. A dry powder medication nasopulmonary delivery device according to any one of the preceding claims, wherein the device comprises an airflow restrictor.

27. A dry powder medication nasopulmonary delivery device according to any one of claims 20 to 26, wherein the assembly is provided with a valve located between the air source and the medication dispensing assembly.

28. The dry powder medication nasopulmonary delivery device of claim 27, wherein the valve is a stopcock.

29. A dry powder medicament nasopulmonary delivery device according to any one of the preceding claims, wherein the delivery device is mounted on a movable plate provided with a releasable locking mechanism.

30. A dry powder medication nasopulmonary delivery device according to claim 29, wherein the locking mechanism comprises a retractable plate provided with a tongue adapted to engage a recess in the movable plate in which the syringe is located.

31. A dry powder drug delivery device according to any one of the preceding claims, wherein the device comprises means for clamping a drug container to the body of the device.

32. The dry powder medication nasopulmonary delivery device of claim 31 , wherein the means for clamping comprises a thumb screw clamp.

33. A method of producing an aerosol of a dry powder for nasal pulmonary administration, the method comprising positioning a dispersible dry powder material, such as a drug material, downstream of a nasal pulmonary adapter; wherein the nasal pulmonary adapter includes an optional integral holding chamber; and wherein the nasal pulmonary adapter is attached to a dispensing nozzle of a dry powder drug nasal pulmonary delivery device according to any one of claims 1 to 30.

34. The method of claim 33, wherein the nose-lung adapter is a nasal adapter.

35. The method of claim 33, wherein the nose-lung adapter is a lung adapter.

36. The method of any one of claims 33 to 35, wherein the nose-lung adapter comprises an integral holding chamber.

37. A method according to any one of claims 33 to 35, wherein the device comprises an airflow restrictor.

38. A method of delivering a dry powder medicament to a subject, the method comprising using a dry powder medicament delivery device according to any one of claims 1 to 32.

39. The method of claim 38, wherein the nose-lung adapter is a nasal adapter.

40. The method of claim 38, wherein the nose-lung adapter is a lung adapter.

41. The method of any one of claims 38 to 40, wherein the nose-lung adapter comprises an integral holding chamber.

42. The method of any of the preceding claims, wherein the nose-lung adapter is a nasal adapter.

43. The method of any of the preceding claims, wherein the nose-lung adapter is a lung adapter.

44. A method according to any preceding claim, wherein the drug container is provided with a holder, such as an integral holder or a pair of integral holders.

45. The method of claim 6, wherein the pulmonary adapter can optionally be provided with a cannula to facilitate delivery of a dry powder medication to the individual's lungs.

46. ​​A method of treating an individual suffering from a disorder, the method comprising administering a drug using a drug delivery device according to any one of claims 1 to 32.

47. The method of claim 46, wherein the nose-lung adapter is a nasal adapter.

48. The method of claim 46, wherein the nose-lung adapter is a lung adapter.

49. The method of treatment according to any one of claims 46 to 48, wherein the individual is an infant.

50. The method of treatment of claim 46, wherein the subject is an animal, such as one or more of the subfamily Murinae.

51. A method of treatment according to any one of claims 46 to 50, wherein the method comprises delivering emergency treatment.

52. The method of treatment of claim 51, wherein the drug is glucagon.

53. The method of treatment of any one of claims 46 to 50, wherein the drug is a vaccine.

54. A method of treatment according to any one of claims 46 to 50, wherein the medicament is a therapy for the treatment of a pulmonary disorder such as asthma, COPD, cystic fibrosis and lung cancer.

55. A nasal-pulmonary adapter for use with a dry powder drug delivery device, wherein the nasal-pulmonary adapter is provided with an integral holding chamber.

56. The nose-lung adapter of claim 55, wherein the nose-lung adapter comprises a cone, a frustoconical shape, a tapered chamber, or a pipette tip.

57. The nose-lung adapter of claim 55 or 56, wherein the nose-lung adapter is a nasal adapter.

58. The nose-lung adapter of claim 55 or 56, wherein the nose-lung adapter is a lung adapter.

59. A nasopulmonary adapter according to any one of claims 55 to 57, wherein the nasopulmonary adapter is provided with an integral holding chamber for use in conjunction with a dry powder medication nasopulmonary delivery device according to any one of claims 1 to 31.

60. A dry powder drug nasal and pulmonary delivery device kit, comprising: A dry powder medication nasopulmonary delivery device, the dry powder medication nasopulmonary delivery device comprising a dispensing nozzle; Holding room; Nose-lung adapter; Optionally, at least one unit dose of a dry powder medicament.

61. The dry powder medication nasopulmonary delivery device kit of claim 60, wherein the nasopulmonary adapter is a nasal adapter.

62. The dry powder medication nasopulmonary delivery device kit of claim 60, wherein the nasopulmonary adapter is a pulmonary adapter.

63. A dry powder medication nasopulmonary delivery device kit according to any one of claims 60 to 62, wherein the kit includes a nasopulmonary adapter including an integral holding chamber.

64. The dry powder medication nasopulmonary delivery device kit according to any one of claims 60 to 62, wherein the kit comprises a nasopulmonary adapter comprising an air source.

65. A dry powder medication nasopulmonary delivery device kit according to any one of claims 60 to 62, wherein the kit comprises an airflow restrictor.

66. A dry powder medicament nasopulmonary delivery device kit according to any one of claims 60 to 65, wherein the kit includes a valve adapted to be positioned between the air source and the medicament dispensing assembly.

67. A dry powder nasopulmonary delivery device, method, nasopulmonary adapter or kit as herein described with reference to the accompanying drawings.

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