DEVICE AND METHOD FOR AEROSOLIZED DELIVERY OF SUBSTANCE TO A NATURAL ORIFICE OF THE BODY

Abstract

The present invention provides a device for delivering a predetermined volume of a substance, within at least one body cavity of a subject, comprising a predefined volume for containing the predetermined volume of the at least one substance; a delivery end for placement in proximity to the body cavity; the delivery end comprises at least one orifice of diameter D [mm]; a valve mechanically connectable to the container, characterized by at least two configurations: (i) an active configuration in which the valve enables delivery of predetermined amount M.sub.sub of the substance; and, (ii) an inactive configuration, in which the valve prevents delivery of the predetermined amount M.sub.sub of the substance from the container to the body cavity; and a fluid tight chamber configured to contain predetermined volume V.sub.gas of pressurized gas at a predetermined pressure, P.sub.gas.

Claims

1. A unit dose device for delivering a predetermined amount M.sub.sub of at least one substance, within at least one body cavity of a subject, said unit dose device comprising: a. at least one predefined volume sized and shaped for containing said predetermined amount M.sub.sub of said at least one substance; b. a delivery end for placement in proximity to said body cavity, said delivery end being in fluid communication with said container; said delivery end comprises at least one orifice of diameter D; c. at least one valve mechanically connectable to said container, characterized by at least two configurations: (i) an active configuration in which said valve enables delivery of predetermined amount M.sub.sub of said substance from said container to said body cavity via said delivery end; and, (ii) an inactive configuration, in which said valve prevents delivery of said predetermined amount M.sub.sub of said substance from said container to said body cavity; said valve is configurable from said inactive configuration to said active configuration within a predetermined period of time, dT, in response to activation of the same; and d. a fluid tight chamber configured to contain predetermined volume V.sub.gas of pressurized gas at a predetermined pressure, P.sub.gas; said pressurized gas, once said valve is reconfigured from said inactive configuration to said active configuration, is configured to entrain said substance and deliver the same via said orifice in said delivery end; wherein said predetermined amount M.sub.sub is no more than 100 l of a liquid substance per transition to the active configuration and no more than 190 mm.sup.3 of a powder substance per transition to the active configuration.

2. The unit dose device of claim 1, wherein said unit dose device has a configuration selected from a group consisting of configured to deliver a single unit dose or configured to deliver two-unit doses.

3. The unit dose device of claim 1, wherein said inactive configuration, gas that was pressurized beforehand and at a remote location is maintained in its container until activation.

4. The unit dose device of claim 2, wherein said unit dose device configured to deliver a single unit dose delivers no more than 140 mm.sup.3 of a powder substance per transition to the active configuration.

5. The unit dose device of claim 1, wherein said unit dose device is configured to deliver said predetermined amount M.sub.sub of said substance and said predetermined volume V.sub.gas of said pressurized gas through said orifice of diameter D in (a) pressure rate of dP.sub.gas/dT; (b) volume rate of dV.sub.gas/dT; and (c) amount rate of dM.sub.sub/dT; at least one of the following being held true: a. P.sub.gas is in a range of 1 to 10 barg; b. V.sub.gas is in a range of 1 to 50 ml; c. D is in a range of 0.2 to 6 mm; d. said pressure velocity dP.sub.gas/dT is greater than 0.001 barg/ms; e. said amount rate dM.sub.sub/dT is greater than 0.0001 ml/ms or greater than 0.0001 mg/ms; f. said volume rate dV.sub.gas/dT is greater than 0.001 ml/ms; g. plume of said aerosol by a plume angle , said plume angle subtending the full width of said plume, said plume angle subtending an angle of less than about 25 ; h. dT is in a range of 0 to 500 millisecond; and i. any combination thereof.

6. The unit dose device of claim 1, wherein at least one of the following is true: a. said body orifice is a nasal cavity, the mouth, the throat, an ear, the vagina, the rectum, the urethra, and any combination thereof b. viscosity of said substance is in a range of 110.sup.3 poise to 1 poise; c. DV50 diameter of particles of said substance, after exit from said unit dose device, is less than 100 m; d. DV90 diameter of said particles is less than 1000 m; e. a full width of a plume of aerosol comprising said substance and said gas subtends an angle of less than 25; f. particles in said plume have velocities in a range of 5 m/s to 50 m/s; g. said pressurized gas comprises air, nitrogen, oxygen, carbon dioxide, helium, neon, xenon and any combination thereof; h. during dispensing of said at least one substance, a mixture of said predetermined volume V.sub.gas of said pressurized gas with said predetermined amount M.sub.sub of said substance entrained within it forms a plume of aerosol; said aerosol having a predetermined distribution, said distribution being either homogeneous or heterogeneous, said heterogeneous distribution is selected from a group consisting of: an arbitrary distribution, a distribution in which the density of said at least one substance within said mixture follows a predetermined pattern, and any combination thereof; characteristics of said aerosol selected from a group consisting of: particle size, particle shape, particle distribution, and any combination thereof, are determinable from characteristics of said unit dose device selected from a group consisting of: said predetermined volume of said pressurized gas, said predetermined volume of said substance, said predetermined pressure of said pressurized gas, said predetermined orifice size, and any combination thereof; i. at least one said substance is stored under either an inert atmosphere or under vacuum to prevent reactions during storage; j. a dose-response curve is substantially linear for brain concentration of said substance when administered nasally via said unit dose device; and k. a dose-response curve for brain concentration having a fit selected from a group consisting of logarithmic, parabolic, exponential, sigmoid, power-law, and any combination thereof; of said substance when administered nasally via said unit dose device.

7. The unit dose device of claim 1, wherein said volume is stored in a container.

8. The unit dose device of claim 5, wherein said container is a capsule having a main longitudinal axis, said capsule comprising a number n of compartments, said capsule configured to contain said predetermined amount M.sub.sub of said at least one substance, said amount M.sub.sub of said at least one substance containable in at least one of said n compartments; at least one of the following being true: a. the number n of said compartments is an integer greater than or equal to 1; at least one said compartment has cross-section with shape selected from a group consisting of: wedge shaped, circular, oval, elliptical, polygonal, annular, and any combination thereof; b. for said number n of compartments being an integer greater than 1, at least two said compartments have different volumes; c. for said number n of compartments being an integer greater than 1, at least two said compartments have the same volume; d. for said number n of compartments being an integer greater than 1, at least two said compartments have different cross-sectional areas; e. for said number n of compartments being an integer greater than 1, at least two said compartments have the same cross-sectional area; f. for said number n of compartments being an integer greater than 1, at least two said compartments contain different substances; g. for said number n of compartments being an integer greater than 1, at least two said compartments contain the same substance; h. for said number n of compartments being an integer greater than 1, at least two said compartments are disposed coaxially around said main longitudinal axis of said capsule; i. for said number n of compartments being an integer greater than 1, at least two said compartments are disposed sequentially along said main longitudinal axis of said capsule; j. for said number n of compartments greater than 1, said plurality of substances mix during said dispensing; and k. for said number n of compartments greater than 1, said plurality of substances react during said dispensing.

9. The unit dose device of claim 1, wherein said container comprises a port fluidly connectable to the exterior of said unit dose device, said port configured such that said at least one substance is insertable into said chamber via said port.

10. The unit dose device of claim 5, wherein said unit dose device comprises a port cover configured to provide an air-tight closure for said port, said port cover slidable along said unit dose device, rotatable around said unit dose device, rotatable around a hinge on the exterior of said unit dose device and any combination thereof.

11. A method of delivering a predetermined amount M.sub.sub of at least one substance within at least one body cavity of a subject, comprising: a. providing a unit dose device comprising: i. at least one predefined volume sized and shaped for containing said predetermined amount M.sub.sub of said at least one substance; ii. a delivery end in fluid communication with said container; said delivery end comprising at least one orifice of diameter D; iii. at least one valve mechanically connected to said container, characterized by at least two configurations: (i) an active configuration in which said valve enables delivery of said predetermined amount M.sub.sub of said substance from said container to said body cavity via said delivery end; and, (ii) an inactive configuration, in which said valve prevents delivery of said predetermined amount M.sub.sub of said substance from said container to said body cavity; said valve is reconfigurable from said inactive configuration to said active configuration within a predetermined period of time, dT, in response to activation of the same; and iv. a fluid tight chamber configured to contain predetermined volume V.sub.gas of pressurized gas at a predetermined pressure, P.sub.gas; b. emplacing said substance in said predefined volume; c. setting said valve in said inactive configuration; d. pressurizing said fluid-tight chamber with said gas to said predetermined pressure; e. placing said delivery end in proximity to said body cavity; f. reconfiguring said valve from said inactive configuration to said active configuration thereby entraining said substance in said predetermined volume V.sub.gas of said pressurized gas; thereby g. delivering said predetermined amount M.sub.sub of said substance and said predetermined volume V.sub.gas of said pressurized gas through said orifice of diameter D in a pressure rate of dP.sub.gas/dT; wherein said predetermined amount M.sub.sub is less than 100 l of a liquid substance and less than 190 mm.sup.3 of a powder substance.

12. The method of claim 11, additionally comprising a step of selecting a configuration for said unit dose device from a group consisting of configured to deliver a single unit dose or configured to deliver two-unit doses.

13. The method of claim 11, additionally comprising a step of said unit dose device configured to deliver a single unit dose delivering no more than 140 mm.sup.3 of a powder substance per transition to the active configuration.

14. The method of claim 11, additionally comprising at least one of the following steps: a. selecting P.sub.gas to be in a range of 1 to 10 barg; b. selecting V.sub.gas to be in a range of 1 to 50 ml; c. selecting D to be in a range of 0.2 to 6 mm; d. selecting said pressure rate to be greater than 0.001 barg/ms; e. selecting said volume rate dM.sub.sub/dT to be greater than 0.0001 ml/ms or greater than 0.0001 mg/ms; f. selecting said volume rate dV.sub.gas/dT to be greater than 0.001 ml/ms; g. selecting dT to be in a range of 0 to 500 millisecond and h. any combination thereof.

15. The method of claim 11, additionally comprising at least one of the following steps: a. selecting said body orifice from a group consisting of a nasal cavity, the mouth, the throat, an ear, the vagina, the rectum, the urethra, and any combination thereof; b. selecting viscosity of said substance to be in a range of 110.sup.3 poise to 1 poise; c. characterizing particles of said substance in a delivered aerosol, said aerosol a mixture of said at least one substance and said gas, by a DV50 diameter, said DV50 diameter being less than 150 m; d. characterizing said particles by a DV90 diameter of less than 1000 m; e. characterizing a plume of said aerosol by a plume angle , said plume angle subtending the full width of said plume, said plume angle subtending an angle of less than 25; f. characterizing velocities of particles in said plume as being in a range of 5 m/s to 50 m/s; g. selecting said gas from a group consisting of: air, nitrogen, oxygen, carbon dioxide, helium, neon, xenon and any combination thereof; h. dispensing said at least one substance, and during said step of dispensing, forming a plume of aerosol with predetermined distribution from a mixture of said predetermined volume V.sub.gas of said pressurized gas and said predetermined amount M.sub.sub entrained within it; selecting said predetermined distribution from a group consisting of: a homogeneous distribution, a heterogeneous distribution; selecting said heterogeneous distribution from a group consisting of: an arbitrary distribution, a distribution in which the density of said at least one substance within said mixture follows a predetermined pattern, and any combination thereof; selecting characteristics of said aerosol from a group consisting of: particle size, particle shape, particle distribution, and any combination thereof, are determinable from characteristics of said unit dose device selected from a group consisting of: said predetermined volume of said pressurized gas, said predetermined volume of said substance, said predetermined pressure of said pressurized gas, said predetermined orifice size, and any combination thereof; i. storing at least one said substance under either an inert atmosphere or under vacuum, thereby preventing reactions during storage; and j. characterizing a dose-response curve for brain concentration of said substance to be of substantially linear form; and k. a dose-response curve for brain concentration having a fit selected from a group consisting of logarithmic, parabolic, exponential, sigmoid, power-law, and any combination thereof; of said substance when administered nasally via said unit dose device.

16. The method of claim 11, wherein said volume is a container.

17. The method of claim 16, additionally comprising steps of providing said container comprising a capsule having a main longitudinal axis, said capsule comprising a number n of compartments, configuring said capsule to contain said predetermined amount M.sub.sub of said at least one substance, containing said amount M.sub.sub of said substance in at least one of said n compartments; additionally comprising at least one of the following steps: a. providing said capsule with n compartments; n is an integer greater than or equal to 1; b. selecting a cross-sectional shape of at least one of said n compartments from a group consisting of: wedge shaped, circular, oval, elliptical, polygonal, annular, and any combination thereof; c. for said number n of compartments being an integer greater than 1, providing at least two of said plurality of said compartments having different volumes; d. for said number n of compartments being an integer greater than 1, providing at least two said compartments having the same volume; e. for said number n of compartments being an integer greater than 1, providing at least two said compartments having different cross-sectional areas; f. for said number n of compartments being an integer greater than 1, providing at least two said compartments having the same cross-sectional area; g. for said number n of compartments being an integer greater than 1, providing at least two of said compartments containing different substances; h. for said number n of compartments being an integer greater than 1, providing at least two of said compartments containing the same substance; i. for said number n of compartments being an integer greater than 1, disposing said plurality of compartments coaxially around said main longitudinal axis of said capsule; j. for said number n of compartments being an integer greater than 1, disposing said plurality of compartments sequentially along said main longitudinal axis of said capsule; k. for said number n of compartments being an integer greater than 1, mixing said plurality of substances during said dispensing; and l. for said number n of compartments being an integer greater than 1, reacting said plurality of substances during said dispensing.

18. The method of claim 11, additionally comprising a step of inserting said predetermined volume M.sub.sub of said at least one substance into said container via a port fluidly connectable to the exterior of said unit dose device.

19. The method of claim 18, additionally comprising a step of providing an air-tight closure for said port, and of moving said port cover relative to said unit dose device in at least one motion selected from a group consisting of: sliding said port cover along said unit dose device, rotating said port cover around said unit dose device, rotating said port cover around a hinge on the exterior of said unit dose device and any combination thereof.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0027] The drawings from the priority applications are incorporated by reference. The invention is herein described, by way of example only, with reference to the accompanying drawings, wherein FIGS. 1A-H illustrate embodiments of nozzles for devices of the present invention; FIGS. 2A-D, 3, 4A-B, 5A-D, 6A-D, 7A-C, 8A-C, 9, 10A-D, 11A-D, 12A-D illustrate embodiments of devices of the present invention; and FIG. 13A-D discloses another embodiment of the invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0028] This application incorporates herein by reference the contents of U.S. application Ser. No. 15/982,996 in its entirety.

[0029] The following description is provided, alongside all chapters of the present invention, so as to enable any person skilled in the art to make use of the invention and sets forth the best modes contemplated by the inventor of carrying out this invention. Various modifications, however, will remain apparent to those skilled in the art, since the generic principles of the present invention have been defined specifically to provide a device capable of improving the transfer of medicament to a predetermined desired location and to provide a device capable of improving the delivery of medicament through the tissue.

[0030] In the present invention, a combination of parameters and forces such as pressure, gas/air volume orifice diameter enable the formation of optimized aerosol characteristics for both improved delivery of aerosol to the target area (such as the olfactory epithelium in the nasal cavity) and enhanced absorption at that area for better delivery to a desired tissue (such as the brain).

[0031] The term l or m hereinafter refers to the unit micro liters.

[0032] The term capsule or container hereinafter refers to a container configured to contain a flowable substance. The term flowable refers hereinafter to any liquid, gas, aerosol, powder and any combination thereof. It should be emphasized that the term capsule can also refer to a predefined volume within the same in which a flowable substance is placed. In other words, the predefined volume is sized and shaped to enclose a predefined volume of the substance.

[0033] The term plurality hereinafter refers to an integer greater than or equal to one.

[0034] The term olfactory epithelium hereinafter refers to a specialized epithelial tissue inside the nasal cavity. The olfactory epithelium lies in the upper top portion of the nasal cavity.

[0035] The term substance hereinafter refers to any substance capable of flowing. Such a substance can be a granular material, including a powder; a liquid; a gel; a slurry; a suspension; and any combination thereof. The term substance hereinafter refers to any substance capable of flowing. Such a substance can be a granular material, including a powder; a liquid; a gel; a slurry; a suspension; and any combination thereof. The term further refers to one or more members of a group consisting of proteins; stem-cells; cells, organs, portions, extracts, and isolations thereof; macro-molecules; RNA or other genes and proteins-encoding materials; neurotransmitters; receptor antagonists; biologic response modifiers; hormones; Ketamine; commercially available by Lilly (US) Baqsimi product; biologic response modifiers; Glucagon; substrates to treat one of eth followings: anaphylaxis, Parkinson, seizures and opioid overdose; epinephrine; atropine; metoclopramide; commercially available Naloxone or Narcan products; Esketamine (Spravato); Radicava [edaravone]; Ingrezza [valbenazine]; Austedo [deutetrabenazine]; Ocrevus [ocrelizumab]; Xadago [safinamide]; Spinraza [nusinersen]; Zinbryta [daclizumab]; Nuplazid [pimavanserin]; Aristada [aripiprazole lauroxil]; Vraylar [cariprazine]; Rexulti [brexpiprazole]; Aptiom [eslicarbazepine acetate]; Vizamyl [flutemetamol F18 injection]; Brintellix [vortioxetine]; Tecfidera [dimethyl fumarate]; Dotarem [gadoterate meglumine]; Antibody mediated brain targeting drug delivery including aducanumab, gantenerumab, bapineuzumab, solanezumab, ofatumumab CD20, BIIB033, LCN2, HMGB 1; insulin; oxytocin; orexin-A; leptin; benzodiazepine i.e. midazolam; naloxone; perillyl alcohol; camptothecin; phytochemicals including curcumin and chrysin; nucleotides; olanzapine; risperidone; Venlafaxin; GDF-5; zonisamide; ropinirole; plant-originated and synthetically-produced terpenes and cannabinoids, including THC and CBD; valproric acid; rivastigmine; estradiol; topiramate or an equivalent preparation comprising CAS No. 97240-79-4; MFSD2 or MFSD2A or sodium-dependent lysophosphatidylcholine symporter; and any esters, salts, derivatives, mixtures, combinations thereof, with or without a carrier, liposomes, lyophilic or water-miscible solvents, surfactants, cells, cells fractions, at a therapeutically effective concentration.

[0036] The term gas refers to any fluid that can be readily compressed. Gases as used herein include, but are not limited to, air, nitrogen, oxygen, carbon dioxide, helium, neon, xenon and any combination thereof. Devices charged by hand will typically use air as the carrier gas.

[0037] The term channel hereinafter refers to a passageway allowing passage of a fluid through at least a portion of a mixing mechanism. The channel can be disposed within a portion of the mixing mechanism, forming a closed bore; it can be on an exterior of a portion of the mixing mechanism, forming a groove on the portion of the mixing mechanism, and any combination thereof.

[0038] The term about refers hereinafter to a range of 25% below or above the referred value.

[0039] The term biologic or biologic response modifier hereinafter refers to material manufactured in or extracted from biological sources such as a genetically engineered protein derived from human genes, or a biologically effective combination of such proteins.

[0040] All pressures herein are gauge pressures, relative to atmospheric pressure. Pressure units will be written herein using the standard abbreviation for gauge, namely, g. For example, atmospheric pressure is 0 barg and a pressure of 1 bar above atmospheric is 1 barg.

[0041] The term release time refers hereinafter to the time for the drug and carrier gas to substantially completely exit the device. Typically, the release time is affected by the activation time and reflects the time for the device to reconfigure from the inactive configuration to the active configuration.

[0042] The terms the device, the present device, the SipNose device and SipNose will be used interchangeably to refer to the device of the present invention.

[0043] In all of the embodiments of the device shown hereinbelow, identical numbers refer to identical functions. All figures shown herein are illustrative and none is to scale.

[0044] The present invention teaches a device for delivering a predetermined amount of a substance, preferably comprising a medication or combination of medications, into a body orifice of a subject, the orifice comprising any of the body's natural orifices, including a nostril, the mouth, the ear, the throat, the urethra, the vagina, the rectum and any combination thereof.

[0045] In preferred embodiments of the device, the device comprises a delivery mechanism and a medicament capsule, as described hereinbelow. The device can apply a broad range of drugs and materials to the nasal cavity for local effect, deliver a broad range of drugs and materials through the nasal cavity to the systemic circulation, deliver a broad range of drugs and materials through the nasal cavity to the central nerve system (CNS) the brain, spinal cord and associated nerves, and any combination thereof.

[0046] The drugs to be applied could be, but are not limited to, pharmaceuticals, natural compounds, biologics, hormones, peptides, proteins, viruses, cells, stem cells and any combination thereof.

[0047] However, it should be emphasized that the device can be provided alone as well as in combination with a capsule.

[0048] In some cases, the capsule would be provided with a known medicament within the same and in other cases the capsule would be filled with the medicament just before use.

[0049] In some embodiments of the present invention, the device operating characteristics and the substance characteristics can be jointly optimized to maximize uptake of the substance at the desired site. In preferred variants of such embodiments, uptake is further optimized by exploiting synergies between delivery characteristics generated by the device and by the formulation or composition of the delivered material

[0050] In some embodiments, the substance comprises one or more agents to optimize delivery through the mucosal membrane by means of mucoadhesive agent and/or a permeability enhancer agent and/or a particulate formulation in the nano-particle or macro-particle range, and any combination thereof. In such embodiments, the combination of the device and substance enhance the delivery of the active agent to the target area (nasal epithelium and more specifically olfactory epithelium) and from there to the target tissue (for example the brain).

[0051] A non-limiting example is a composition comprising a drug to be delivered and at least one chemical permeation enhancer (CPE). In a preferred embodiment, the composition contains two or more CPEs which, by using a nasal delivery device, affect in an additive manner or behave synergistically to increase the permeability of the epithelium, while providing an acceptably low level of cytotoxicity to the cells. The concentration of the one or more CPEs is selected to provide the greatest amount of overall potential (OP). Additionally, the CPEs are selected based on the treatment. CPEs that behave primarily by transcellular transport are preferred for delivering drugs into epithelial cells. CPEs that behave primarily by paracellular transport are preferred for delivering drugs through epithelial cells. Also provided herein are mucoadhesive agents that enable the extension of the exposure period of the target tissue/mucus membrane to the active agent, for the enhancement of delivery of the active agent to and through the mucus membrane.

[0052] In contrast to prior-art nasal delivery devices and technologies, the devices of the present invention can produce a fine aerosol in the nasal cavity or other desired body orifice at the target area and at the location of the target tissue instead of producing the aerosol only within the device or immediately after exit from the device. Utilizing the pressure as a driving force and the air as a carrier allows the material to be released from the nozzle as a mixture of aerosol and a pre-aerosolized state. The properties of the resultant aerosol are typically dependent on the properties of the device and of the medium into which the device is discharged. The properties of the device which affect the aerosol characteristics are the delivery pressure, the volume of the delivery gas, the characteristics of its orifice and time to activate.

[0053] In some embodiments, the aerosol properties are fairly independent of the delivered substance, while, in other embodiments, the pressure, volume, orifice characteristics, and delivered substance properties can be co-optimized.

[0054] In prior-art devices the aerosol is produced in proximity exit of the device. Typically, the aerosol comprises a wide fan (plume) of aerosol and a low driving force. Therefore, large droplets typically deposit very close to the exit from the device, while smaller droplets tend to quickly contact the walls of the passage, so that deposition is typically predominantly close to the delivery end of the device, with little of the substance reaching desired sites deeper in the body orifice, such as the middle and superior turbinates of the nose.

[0055] In contrast, in the present device, the aerosol is generated within the device and the mixture of gas and substance is fully aerosolized before it reaches the device exit, thereby making the quality of the aerosol substantially independent of the diameter of the exit.

[0056] Unlike the device of the present invention, none of the prior-art devices provide accurate control of all of the delivery parameters, which include dose volume, carrier volume, pressure, and delivery velocity.

[0057] A further advantage of the device of the present invention (the SipNose device) is that, unlike the prior art devices, it can be configured to accurately deliver large volumes (>100 l) at high pressure, such that the high-velocity aerosol can be as reliably and reproducibly produced for large volumes as for small.

[0058] In some embodiments, including embodiments intended for use in emergencies or daily home use, the device is a single-use device with only two states, a loaded state (pre-activated state) and an activated state. The device is provided in the loaded state; activation of the trigger mechanism discharges the gas and substance.

[0059] In other embodiments, the device is provided in the pre-activated state. The user transforms the device into the loaded state, pressurizing the gas, and activates the trigger mechanism to discharge the gas and substance.

[0060] Capsules can be single-compartment or multi-compartment. Single-compartment capsules can comprise a flexible silicone tube, preferably sealed at both ends.

[0061] Multi-compartment capsules can contain different components of a substance in the different compartments; at least one compartment can contain a carrier gas, and any combination thereof.

[0062] In some embodiments, there is a single capsule for the carrier gas and the substance. Some embodiments have separate capsules for substance and gas.

[0063] Some embodiments have the gas held in a gas holding chamber. The gas holding chamber can be filled at the time of manufacture or can be filled to the predetermined pressure by a charging mechanism.

[0064] Some embodiments have the substance held in a holding chamber. The holding chamber can be filled at the time of manufacture or can be filled by a filling mechanism such as, but not limited to, a syringe.

[0065] It should be emphasized that the present invention refers to both one compartment capsules as well as multi-compartment capsules.

[0066] In FIG. 1, the nozzle (1100) has a tip extension (1110) with a larger diameter than the nozzle, the tip extension substantially surrounding the distal end of the nozzle (1100). In the exemplary embodiment of FIG. 1, the tip extension (1110) has holes (1112) in it to allow substance to exit laterally from the extension, and the tip (1110) has at least one hole (1113) in its distal end to allow substance to exit longitudinally from the nozzle (1100). FIG. 1 shows an embodiment of a nozzle with a tip extension (1110) and an expandable portion (1120). FIGS. 1E and 1G show perspective views of the nozzle from the proximal end, while FIGS. 1A and 1C show side views of the nozzle (1100). FIGS. 1B and 1D show cross-sections of the nozzle (1100) along the lines AA in FIG. 1A and BB in FIG. 1C, respectively. FIG. 1F shows an enlarged view of the circled region C in the center of the nozzle in FIG. 1B, while FIG. 1H shows an enlarged view of the circled region D in the center of the nozzle in FIG. 1D.

[0067] FIGS. 1A, 1B, 1E and 1F show the nozzle with unexpanded expandable portion, while FIGS. 1C, 1D, 1G and 1H show the nozzle with expanded expandable portion.

[0068] In the exemplary embodiments of FIG. 1, the tip extension and the expanded medial extension are substantially toroidal; in other embodiments, they can be substantially spherical, substantially ovoid, substantially ellipsoidal, substantially the frustum of a cone (preferably with a rounded distal edge), substantially conic (preferably with a rounded distal edge) and any combination thereof.

[0069] The nozzle tip and the tip extension (1110) have a number of holes (1112, 1113) which fluidly connect the bore of the nozzle (1100) to the exterior of the device, allowing material to exit from the interior of the device. In the exemplary embodiments shown, there is a hole (1113) (not shown in FIG. 1) in the distal end of the nozzle and four holes (1112) in the tip extension (1100). Both the extension and the distal end of the nozzle can have more or fewer holes and, in some embodiments, one or the other can have no holes. The holes (1112) can be regularly spaced around the periphery of the extension, the holes (1112) can be irregularly spaced around the periphery, the holes (1112) can be concentrated in a predetermined part of the periphery, and any combination thereof. Similarly, the holes in the distal end of the tip can be regularly or irregularly spaced in the tip.

[0070] In some embodiments, the extension (1110) can be padded, can comprise soft material, can comprise flexible material and any combination thereof.

[0071] Extensions, both tip extensions and medial extensions, can have a number of functions. A non-limiting list of such functions is (1) ensuring proper positioning of the nozzle (1100) in the nasal passages, where the proper position can be the nozzle (1100) centralized in the nasal passages, the nozzle (1100) touching a predetermined portion of the nasal passages, or the nozzle (1100) closer to a predetermined portion of the nasal passages, (2) sealing the nasal passages so that material cannot escape therefrom, (3) sealing the nasal passage so that substance does not contact undesired portions thereof, (4) sealing the nasal passage so that substance remains in a predetermined region of the nasal passage, (5) reducing the discomfort of contact between the nozzle and the nasal passages, especially in embodiments where the extension is intended to seal against the walls of the nasal passages, by providing a soft and/or flexible contact region and any combination thereof. Proper positioning can be for the purpose of improving delivery of a substance to a predetermined area, preventing clogging of the holes by nasal secretions, preventing clogging of the holes by contact with the nasal passages, mucosa and any combination thereof.

[0072] Nozzle extensions, both those that are expanded during the activation procedure and those that have a predetermined shape and do not expand, can either (1) be attached to the nozzle in a way that they are removed from the nasal cavity with the nozzle tip itself, or (2) have the option of being releasable from the nozzle tip so that they stay in the nasal cavity until they are pulled out by the user or by a caregiver, or any combination thereof. In embodiments where at least one nozzle extension remains in a nasal cavity, preferably, the nozzle extension or extensions are removed after a predetermined time, preferably a short time.

[0073] In some embodiments, the holes (1112) in the nozzle (1100) do not lie substantially in a plane perpendicular to the main longitudinal axis of the nozzle (1100). In such embodiments, the holes (1112) can lie along a line parallel to the main longitudinal axis of the nozzle (1100), along a line forming a spiral around the nozzle (1100), irregularly in the distal portion of the nozzle (1100), regularly spaced in the distal portion of the nozzle (1100), and any combination thereof.

[0074] Therefore, dispersion of the drug can be substantially from a ring perpendicular to the main longitudinal axis of the nozzle (1100) (holes (1112) around the edge of the extension (1110), from a circle perpendicular to the main longitudinal axis of the nozzle (1100) (holes (1113) in the distal tip of the nozzle (1100), from a line (holes (1112) parallel to the main longitudinal axis of the nozzle (1100) or in a spiral around the main longitudinal axis of the nozzle (1100), or from at least part of the surface of a volume extending along the side of the nozzle (1100).

[0075] In some embodiments, the size of the tip extension (1110) is selected so that the extension (1110) is in contact with the nasal passages substantially along its entire circumference. In such embodiments, material exiting holes (1113) in the distal tip of the nozzle (1100) or holes (1112) on the distal face of the extension (1110) cannot reach regions proximal to the extension (1110) and will reach only regions deeper in the nasal passages than the extension (1110). In such embodiments, the substance will reach the upper parts of the nasal passages.

[0076] Material exiting from holes (1112) in locations where the extension (1110) is in contact with the nasal passages will deposit directly on the walls of the nasal passages. In such embodiments, deposition is in a very narrow band; the location of the band can be tailored for the material of interest.

[0077] Material exiting holes (1112) proximal to the region of the extension (1110) in contact with the walls of the nasal passages will be unable to reach locations distal to the region of the extension (1110) in contact with the walls of the nasal passages and will therefore deposit in the lower parts of the nasal passages.

[0078] Returning to FIG. 1, in this embodiment, the expandable portion (1120) surrounds the nozzle (1100). In other embodiments, the expandable portion (1120) can partially surround the nozzle (1100). A single expandable portion (1120) or a plurality of expandable portions (1120) can be used. An expandable portion can be on the surface of the nozzle or it can be stored within the nozzle, popping out when it expands. An expandable portion can have a predetermined shape when expanded. The shape of the outward-facing part of an expandable portion can be part of the surface of a spheroid, can be part of a cylinder, a part of a cone, or can conform to the shape of a predetermined portion of a nasal passage. Such shaping can help ensure that, on inflation, the expandable portion or portions gently guide the nozzle so that it rests in the position with respect to the nasal passages or in the correct portion of the nasal passages. It can also reduce the user's discomfort when the device is in place or, if detachable from the device, it can seal the nasal passage for a time, before being removed by the user or a caretaker.

[0079] The expandable portion (1120) is preferably inflated after insertion of the device into the nasal passage. Inflation can be before or at the time of activation of the device.

[0080] FIG. 2A-D shows an embodiment of the device. FIGS. 2A and 2D show the exterior of the device, with FIG. 2A in plain view and FIG. 2D in perspective view, FIG. 2B shows a cross-section along the line A-A in FIG. 2A, and FIG. 2C shows the body (10, 15, 42) separate from the medicine capsule (45) and nosepiece (48).

[0081] FIG. 3 shows an exploded view of the device. The device comprises 5 main sections, a body (1), a capsule section (2), a nosepiece (3), a cover (4) and an activation safety lock (5). The activation safety lock prevents accidental activation of the device and also prevents reuse of the device if such is undesirable.

[0082] FIG. 4A-B shows an embodiment of the body (10, 15) of a nasal delivery device, with FIG. 4B showing the exterior of the body and FIG. 4A showing an exploded view. The nosepiece is not shown. The body comprises a base (10), an air chamber gate (12) with a first gate O-ring (11) at its proximal end and a second gate O-ring (13) at its distal end. The distal end of the air chamber gate (12) is covered by a drug container base cover (14) which comprises a biocompatible material to ensure that substance that is to contact living tissue only contacts biocompatible material before the contact with living tissue. The compressed gas chamber (15) will fit over the air chamber gate (12), with the first gate O-ring (11) and the second gate O-ring (13) providing airtight seals before activation so that compressed gas is storable between the air chamber gate (12) and the compressed gas chamber (15). The compressed gas chamber (15) is connectable at its distal end with a nose piece (not shown). The distal portion of the compressed gas chamber (15) comprises activation holders (15C)

[0083] FIG. 12A-D shows an embodiment of the body of FIG. 11, as assembled, before activation. FIG. 12A shows the exterior of the body, while. FIG. 12B shows a cross-section taken along the line A-A in FIG. 12A. FIG. 12C is an enlarged view of the circled section B in FIG. 12B, while FIG. 12D is a perspective view of the body of FIG. 12A. Activation is by compressing the upper end of the device toward its base, by holding the activation holders (15C) with the fingers and the bottom of the base (10) with the thumb, and bringing the fingers toward the thumb.

[0084] As shown in FIGS. 4A and 4D, in the embodiment of FIGS. 4-6, the base of the device forms the activation button (10); to activate, the activation button (10) is pressed upward while the compressed gas chamber (gas chamber (15) is held stationary by fingers on the activation holders (15C). The nosepiece is attachable to the compressed gas chamber (15) by means of the nose piece connector slot(s) (15C); a protuberance(s) on the nose piece engages with the nose piece connector slot(s) (15C); permitting fast and easy replacement of the nose piece.

[0085] As shown in FIG. 5B, the activation button (10) comprises a gate anchor (10A), a shoulder on which the air chamber gate stopper (12A) rests before activation. This to prevent movement of the air chamber gate (12) before activation. The first gate O-ring (11), at the proximal end of the gate anchor (10A) and the second gate O-ring (13), at its distal end, provide airtight seals before activation so that compressed gas is storable between the air chamber gate (12) and the compressed gas chamber (15). The distal end of the air chamber gate (12) is covered by a drug container base cover (14) which comprises a biocompatible material to ensure that substance that is to contact living tissue only contacts biocompatible material before the contact with living tissue. The compressed gas chamber (15) is connectable at its distal end with a nose piece (not shown) by means of the nose piece connector slot (15B).

[0086] FIG. 5C, the enlargement of the area within the circle B of FIG. 5B, clearly shows the gate anchor (10A), with the air chamber gate stopper (12A) resting on it.

[0087] FIG. 6A-D shows an embodiment of the body of FIG. 4, as assembled, after activation. FIG. 6A shows the exterior of the body, while. FIG. 6B shows a cross-section taken along the line A-A in FIG. 6A. FIG. 6C is an enlarged view of the circled section B in FIG. 6B, while FIG. 6D is an enlarged view of the circled section C in FIG. 6B. Activation is by compressing the upper end of the device toward its base, by holding the activation holders (15C) with the fingers and the bottom of the base (10) with the thumb, and bringing the fingers toward the thumb.

[0088] As shown in FIGS. 6A and 6D, in the embodiment of FIGS. 5-6, the base of the device forms the activation button (10), to activate, the activation button (10) is pressed upward while the compressed gas chamber (gas chamber (15) is held stationary by fingers on the activation holders (30). The nosepiece is attachable to the compressed gas chamber (15) by means of the nose piece connector slot(s) (15B); a protuberance(s) on the nose piece engages with the nose piece connector slot(s) (15B), permitting fast and easy replacement of the nose piece.

[0089] As shown in FIG. 6B, the activation button (10) comprises a gate anchor (10A), a shoulder on which the air chamber gate stopper (12A) rested before activation. During activation, the air chamber gate stopper (12A) is pressed inwards, so that the air chamber gate (12) moves proximally, opening up a gap (17) between the air chamber gate (12) and the distal end of the compressed gas chamber (15), allowing the gas (16) to exit the compressed gas chamber (15) through the gap, and to enter the nosepiece and forma an aerosol with the substance. The first gate O-ring (11), at the proximal end of the gate anchor (10A) still provide an airtight seal after activation, but the second gate O-ring (13), at its distal end, so that compressed gas is storable between the air chamber gate (12) and the compressed gas chamber (15) is no longer in contact with the compressed gas chamber (15). The distal end of the air chamber gate (12) is covered by a drug container base cover (14) which comprises a biocompatible material to ensure that substance that is to contact living tissue only contacts biocompatible material before the contact with living tissue. The compressed gas chamber (15) is connectable at its distal end with a nose piece (not shown) by means of the nose piece connector slot (15B).

[0090] FIG. 6C, the enlargement of the area within the circle B of FIG. 6B, clearly shows the gate anchor (10A), with the air chamber gate stopper (12A) no longer in contact with it, but is resting near the base of the activation button.

[0091] FIG. 6D, the enlargement of the area within the circle C of FIG. 6B, clearly shows the distal end of the air chamber gate (12), the drug container base cover (14), the second gate O-ring (13) and the gap (17, FIG. 6B) permitting air to escape (arrow, 15D) from the compressed gas chamber into the intermediate space and then to the nose piece (not shown).

[0092] The device also comprises a latching mechanism (10A, 12A) to prevent re-use. The latching mechanism (10A, 12A) comprises an air chamber gate stopper (12A), which is an extension downward of the air chamber gate (12).

[0093] Before use (FIG. 6C), the air chamber gate stopper (12A) sits above a catch (10A). During activation, the sloped portion of the outer edge of the air chamber gate stopper (12A) slides down past the catch (10A). After the body has been fully compressed (FIG. 7C), a shoulder on the air chamber gate stopper (12A) rests underneath a shoulder 15A on the catch (10A), preventing the activation button (10) from moving proximally relative to the compressed gas chamber (15) and expanding the body.

[0094] FIG. 7A-C shows an embodiment of the device with the primary drug container in the nose piece cover. The medicament or substance is delivered from the primary drug container to a secondary drug volume in the nose piece. The nose piece cover can then be removed and the device activated to aerosolize and deliver the drug.

[0095] FIG. 7A shows the exterior of the device. It comprises an activation button (10), a compressed gas chamber (15), and a nosepiece (not shown) protected by a nose piece cover (20). In the distal portion of the nose piece cover (20) is a primary drug container (not shown) in a drug container housing (21). The drug container housing is slidable relative to the nose piece cover (20). The embodiment also comprises an indicator window (22) to determine the quantity of drug remaining in the primary drug container and a safety lock (23).

[0096] FIG. 7B shows a cross-section of the device, taken along the line A-A in FIG. 7A. The base and aerosol generation and delivery mechanism are similar to those disclosed above in FIGS. 5-6. The device comprises a nose piece (28) with an integral drug volume (29) in its proximal portion. The deliverable substance is stored in a primary drug container (24) in the distal portion of the nose piece cover (20). The primary drug container (24) is sealed at its proximal end by a plunger stopper (25). A loading needle (26) is fixed to the nose piece cover (20), with a needle adaptor (27) to guide the loading needle's (26) proximal end so that the proximal end of the needle adaptor (27) passes through the orifice at the tip of the nose piece (28). As shown in FIG. 7B, unless drug is being loaded into the integral drug volume (29), the needle does not pierce the plunger stopper (25) and the primary drug container (24) remains sealed.

[0097] FIG. 7C shows a perspective view of the device. The drug container housing (21) can be seen, as well as the nose piece cover (20), which terminates at its proximal end in a safety lock (23) to prevent unwanted activation of the device. Movement of the drug container housing (21) relative to the nose piece cover (20) is controlled by a volume scale (30), in this embodiment a ratchet comprising a toothed rack (21A) on the drug container housing (21) and a pin (20A) on the nose piece cover (20). When the nose piece cover (20) is pressed downward relative to the drug container housing (21), the distance traveled and, therefore, the amount of drug to be dispensed, is controllable by the volume scale (30); each click will dispense a predetermined volume of the drug.

[0098] FIG. 8A-C shows the embodiment of the device of FIG. 7 during loading of the drug into the integral drug volume (29) from the primary drug container (24).

[0099] FIG. 8A shows the exterior of the device. It comprises an activation button (10), a compressed gas chamber (15), and a nosepiece (not shown) protected by a nose piece cover (20). In the distal portion of the nose piece cover (20) is a primary drug container (not shown) in a drug container housing (21). The drug container housing is slidable relative to the nose piece cover (20). The embodiment also comprises an indicator window (22) to determine the quantity of drug remaining in the primary drug container and a safety lock (23). The volume scale (30), here a ratchet, allows adjustment of the size of the dose.

[0100] FIG. 8B shows a cross-section of the device, taken along the line B-B in FIG. 8A. The base and aerosol generation and delivery mechanism are similar to those disclosed above in FIGS. 5-6. As shown in FIG. 8B, a drug or medicament (24A) is being loaded from the primary drug container into the integral drug volume (29). Loading is activated by pressing the primary drug container (24) proximally. It then slides along the nose piece (28). The loading needle (26) is steadied by the needle adaptor (27). Pressing the primary drug container (24) proximally forces the loading needle (26) through the plunger stopper (25) and into the primary drug container (24). Drug (24A) can then flow through the loading needle (26) into the integral drug volume (29). Releasing the primary drug container (24) will cause it to move distally and remove the loading needle (26) from the plunger stopper (25). The nose piece cover (20) can then be removed and a dose of the drug can be administered.

[0101] FIG. 8C shows a perspective view of the device. The drug container housing (21) can be seen, as well as the nose piece cover (20), which terminates at its proximal end in a safety lock (23) to prevent unwanted activation of the device. Movement of the drug container housing (21) relative to the nose piece cover (20) is controlled by the volume scale (30), in this embodiment a ratchet comprising a toothed rack (21A) on the drug container housing (21) and a pin (20A) on the nose piece cover (20). When the nose piece cover (20) is pressed downward relative to the drug container housing (21), the distance traveled and, therefore, the amount of drug to be dispensed, is controllable by the volume scale (30); each click will dispense a predetermined volume of the drug.

[0102] FIG. 9 illustrates removal of the nose piece cover or medicine chamber (5) from an aerosol delivery device (1) by pulling (arrow) the medicine chamber (5) away from the aerosol delivery device (9), FIG. 10A-D illustrates a device with a replaceable nose piece preloaded with a single dose of a medicament. The medicament can comprise one or more substances, as disclosed above. The device further comprises a nose piece cover with a removable top. FIGS. 10A and 10D show the exterior of the device with the nose piece cover in place, with FIG. 10A showing it from the side and FIG. 10C showing a perspective view. FIG. 10B shows a cross section taken along the line A-A in FIG. 10A and FIG. 17C provides a partially exploded view.

[0103] FIGS. 10A and 10D show an activation button (10) and compressed gas chamber (15), as disclosed above. The nose piece cover (40) has a removable orifice closure (41) at its distal end.

[0104] FIG. 10B shows a cross-section of the device. The nose piece cover (40) has a reversibly removable nose piece orifice cover (41). The nose piece (42), which comprises an integral drug volume (43), has, at its distal end, a nose piece cover pin (41A) to protect the distal end of the nose piece. The nose piece (42) is reversibly connectable to the compressed gas chamber (15) by means of a nose piece connecting pin (42A) which slots into a connector slot (15B, FIG. 10C) at the distal end of the compressed gas chamber (15)

[0105] FIG. 10C shows a partially-exploded view of the device. The nose piece (42) is reversibly connectable to the compressed gas chamber (15) by means of a nose piece connecting pin (42A) which slots into a connector slot (15B) at the distal end of the compressed gas chamber (15). The activation button (10) is shown at the proximal end of the compressed gas chamber (15). The removable orifice closure (41) is shown separated from the nose piece cover (40). By this means, only the removable orifice closure (41) needs to be removed to replace a nose piece (28); there is no need to remove the entire nose piece cover (40). The safety lock (2A) to prevent accidental activation of the device is also shown.

[0106] FIG. 11A-D illustrates a device which can be loaded with a medicament, drug or substance via a syringe. FIGS. 11A and 11D show the exterior of the device, FIG. 11A from the side and FIG. 11D from an angle. FIG. 11B shows a cross section taken along the line A-A in FIG. 11A and FIG. 11C shows the loading needle.

[0107] As shown in FIG. 11A, the device comprises an activation button (10) and compressed gas chamber, as disclosed above. The nose piece cover (40) comprises a drug loading adaptor (45) and a reversibly removable drug loading adaptor cap (46) at its distal end. In the embodiment shown, the drug loading adaptor cap (46) is attached to the nose piece cover (40) by an integral flexible strip (46A), to prevent the drug loading adaptor cap (46) from getting lost.

[0108] As shown in FIG. 11B, a drug loading needle (47) is held firmly within the drug loading adaptor (45). The drug loading needle (47) extends from the top of the nose piece cover (40) through the distal end of the nose piece (42) to a drug storage volume near the proximal end of the nose piece (42). The distal portion of the drug loading needle (47) is configured by means of shape and size to accept the delivery end of a syringe (not shown). During storage and transport, the drug loading needle (47) is retained firmly in place with its distal portion help firmly between the closed drug loading adaptor cap (46) and the distal tip of the nose piece (42).

[0109] FIG. 18C shows the drug loading adaptor (45) with the drug loading needle (47) extending proximally therefrom.

[0110] FIG. 11D shows the nose piece cover (40), the drug loading adaptor cap (46) and the drug delivery device with activation button (10).

[0111] FIG. 12A-D shows the device of FIG. 11A-D with a syringe in place. The syringe can be a proprietary syringe, with a tip matched in shape and size to the opening in the distal portion of the drug loading needle (47) or it can be a commercial syringe with a tip that fits into the opening in the distal portion of the drug loading needle (47).

[0112] FIG. 12A shows a side view of the device with a loading syringe (48) in place. The drug loading adaptor cap (46) is open and the tip (not shown) of the loading syringe (48) is resting in the distal portion of the drug loading adaptor (45) and nose piece cover (40), with the nose piece cover in communication with the activation button (10) and compressed gas chamber (15) of the delivery device.

[0113] FIG. 12B shows a cross-section of the set-up of FIG. 12A, taken along the line A-A. The loading syringe (48) is resting in the distal portion of the drug loading needle (47). The drug (49) is contained within the loading syringe (48); compression (arrow) of the loading syringe will force the drug out of the loading syringe (48). The proximal portion of the drug loading needle (47) passes through the nose piece (42). The nose piece (42) is attached, either reversibly or fixedly, to the activation button (10) and compressed gas chamber (15) of the delivery device.

[0114] FIG. 12C-D shows how a loading syringe (48), in place in a drug loading adaptor (45), is connectable to a drug delivery device, comprising nose piece (42), compressed gas chamber (15) and activation button (10). FIG. 19C shows the loading syringe (48) in place in a drug loading adaptor (45), with the drug loading adaptor (45) in position to be attached to the delivery device. FIG. 12D shows the loading syringe (48) and drug loading adaptor (45), with the drug loading adaptor cap (46) open, attached to the compressed gas chamber (15) and activation button (10) of the delivery device.

[0115] Both UD and BD devices are configured to provide delivery of either a powder or a liquid, with accurate dosing and without need for priming. They are configured to be actuated by a single hand and can be used in any position; for example, a device does not need to be held upright.

[0116] The maximum dose for a liquid is 100 l for a unit dose and 2100 l for two doses. The maximum dose for a powder is 140 mm.sup.3 for a unit dose and 190 mm.sup.3 per chamber for two doses.

[0117] The unit dose devices are configured for use with therapies where a small and very precise amount of an active drug formulation is required in a single nasal or sub-lingual shot. If the required dose is larger than about 100 l or when a single dose into each nostril is desired, two-dose device is used.

[0118] FIG. 13A-D discloses another embodiment of the invention, especially showing plunger stopper(s) (25), drug (24A) and container (25).

[0119] In preferred embodiments, the device comprises a protective cover, removable before use.

[0120] In some embodiments, the device is reusable. In other embodiments, it comprises a safety device/use indicator that must be removed or otherwise damaged before use, so that it is clear that the device has been used and, preferably, prevents re-use of the device.