Patent Application
20210316088
The present invention generally pertains to a system and methods for delivering aerosolized substance to a natural orifice of the body.
Blow-Fill-Seal (BFS) technology is a manufacturing technique used to produce small (0.1 ml) and large (and up to 500 ml) liquid-filled containers. The basic concept of blow-fill-seal and form-fill-seal (referred to interchangeably hereinafter as BFS) is that a container is formed, filled and sealed in a continuous process without human intervention in a sterile or aseptic enclosed area. Thus, this technology can be used to sterile or aseptically packaging and manufacturing of pharmaceutical liquid dosage forms. Furthermore, this can be applied to any drug container (produced by any production methods) with a laminate at the bottom thereof, which can be pierced (or break) so as to deliver the medicament.
There are several ways of manufacturing. According to one method, the processes begun as pharmaceutical grade plastic resin is vertically heat-extruded through a circular throat to form a hanging tube (parison). This extruded tube is then enclosed within a two-part mold and the tube is cut above the mold. The mold is zone, or a sterile filling space, where filling needles (mandrels) are lowered and used to inflate the plastic to form a container within the mold. Following formation of the container, the mandrel is used to fill the container with the liquid. Following filling, the mandrels are retracted and a secondary top mold seals the container. All actions take place within the sterile enclosed area, a sterile shrouded chamber within the machine. The product can then be discharged to a non-sterile area for labeling, packaging and distribution.
BFS technology reduces personnel intervention, making it a more robust method for aseptic preparation of sterile pharmaceuticals. BFS is used for the filling of vials for parenteral preparations and infusion, eye drops, and inhalation products. Generally, the containers are made of polyethylene and polypropylene or any plastic resin.
It is therefore a long felt need to provide a system which provides an efficient delivery of a substance to a target site from such BFS containers, provides sufficient material to the target site, and ensures reproducibility.
It is one object of the present invention to provide a device for delivering either one or more substances within at least one body cavity, comprising:
It is another object of the present invention to provide the device as defined above, wherein said chamber is made of material being a high barrier film.
It is another object of the present invention to provide the device as defined above, wherein said high barrier film is a high barrier Aluminum film.
It is another object of the present invention to provide the device as defined above, wherein actuation of said base is pressing on the same.
It is another object of the present invention to provide the device as defined above, wherein said nosepiece comprising at least one nosepiece cover configured by means of size and shape to cover, in a sealable manner, at least partially said nosepiece
It is another object of the present invention to provide the device as defined above, wherein said nosepiece cover and said nosepiece are coupled to each other.
It is another object of the present invention to provide the device as defined above, wherein said coupling between nosepiece cover and said nosepiece said is reversible.
It is another object of the present invention to provide the device as defined above, wherein said nosepiece comprises at least one port throughout which said at least one substance exits said device, such that said nosepiece cover seals said at least one port and removal thereof removes said seal.
It is another object of the present invention to provide the device as defined above, wherein said capsule is selected from a group consisting of pierceable container, a blow-fill-seal and a form-fill-seal and any combination thereof.
It is another object of the present invention to provide the device as defined above, wherein said at least one chamber is a container adapted to hold said pressured fluid at said PPF for prolong periods of time.
It is another object of the present invention to provide the device as defined above, wherein capsule is made of at least one material selected from a group consisting of high- or low-density polyethylene, high- or low-density polypropylene, any plastic resin, glass and any combination thereof.
It is another object of the present invention to provide the device as defined above, wherein said one end of said at least one hollow puncturing member and said capsule are formed as a single unit, such that the lower surface of said capsule is integrated with said one end of said at least one hollow puncturing member.
It is another object of the present invention to provide the device as defined above, wherein said volume VPF [ml] of said pressurized fluid at pressure PPF [barg] is released from said chamber within a short period of time, <500 milliseconds (dT), via said fluid inlet port, entrains said substances, erupts via said fluid discharging outlet port into said body cavity, such that the release time of said Vsub [ml or mg] of said substances and said VPF [ml] of said pressurized fluid, dTrelease is less than 500 milliseconds.
It is another object of the present invention to provide the device as defined above, wherein said device is configured to deliver said Vsub substance and VPF pressurized fluid through said fluid discharging outlet of diameter D [mm] wherein at least one of the following is held true:
It is another object of the present invention to provide the device as defined above, wherein at least one of the following is true:
It is another object of the present invention to provide the device as defined above, wherein said nosepiece cover configured to provide an air-tight closure for said port, said port cover slidable along said device, rotatable around said device, rotatable around a hinge on the exterior of said device and any combination thereof.
It is another object of the present invention to provide the device as defined above, further comprising a safety latch, adapted to prevent accidental operation of said device.
It is another object of the present invention to provide the device as defined above, wherein said substance is selected from 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; hormones; Ketamine; Baqsimi product commercially available by Lilly (US); 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, HMGB1; insulin; oxytocin; orexin-A; leptin; benzodiazepine, 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, 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.
It is another object of the present invention to provide the device as defined above, wherein said capsule is a hollow tube characterized by at least two ends interconnect to each other, at least one of which is positioned proximal to said chamber.
It is another object of the present invention to provide the device as defined above, wherein said capsule comprises at least one spherical element positioned by at least one of said ends, adapted to seal said capsule and prevent leakage of said at least one substrate therefrom.
It is another object of the present invention to provide the device as defined above, wherein said capsule comprises two spherical elements, each of which is disposed at each of said ends, such that said at least one substrate is positioned therebetween.
It is another object of the present invention to provide the device as defined above, wherein said two spherical elements, once said pressurized fluid exits said chamber, are adapted to mix said at least one substrate and said at least one substrate.
It is another object of the present invention to provide the device as defined above, wherein said capsule comprises at least one membrane positioned by at least one of said ends, adapted to seal said capsule and prevent leakage of said at least one substrate therefrom.
It is another object of the present invention to provide the device as defined above, wherein said capsule comprises two membranes, each of which is disposed at each of said ends, such that said at least one substrate is positioned therebetween.
It is another object of the present invention to provide the device as defined above, wherein said capsule comprises at least one duckbill valve positioned by at least one of said ends, adapted to seal said capsule and prevent leakage of said at least one substrate therefrom.
It is another object of the present invention to provide the device as defined above, wherein said capsule comprises two duckbill valves, each of which is disposed at each of said ends, such that said at least one substrate is positioned therebetween.
It is another object of the present invention to provide the device as defined above, wherein said capsule comprises at least one spherical element, membrane, uni-directional valve, duckbill valve and any combination thereof.
It is another object of the present invention to provide a method for delivering either one or more substances within at least one body cavity, characterized by steps of
It is another object of the present invention to provide the method as defined above, wherein said chamber is made of material being high barrier film.
It is another object of the present invention to provide the method as defined above, wherein said high barrier film is a high barrier Aluminum film.
It is another object of the present invention to provide the method as defined above, wherein step (b) of actuating said base additionally comprising pressing said base.
It is another object of the present invention to provide the method as defined above, wherein step (b) of actuating said base enables the pressurized fluid to exit said chamber and entrain through said hollow tube of said hollow puncturing member to said capsule, entrain said substance and deliver the same to said body cavity.
It is another object of the present invention to provide the method as defined above, wherein step (b) of actuating said base results in releasing said volume VPF [ml] of said pressurized fluid at pressure PPF [barg] within a short period of time, <500 milliseconds (dT); out of said chamber, via said fluid inlet thereby entraining said substances and erupting via said fluid discharging outlet into said body cavity, such that the release time of said Vsub [ml or mg] of said substances and said VPF [ml] of said pressurized fluid, dTrelease is less than 500 milliseconds.
It is another object of the present invention to provide the method as defined above, wherein said nosepiece comprising a nosepiece cover and said nosepiece are coupled to each other.
It is another object of the present invention to provide the method as defined above, wherein said coupling between nosepiece cover and said nosepiece said is reversible.
It is another object of the present invention to provide the method as defined above, wherein removal of said nosepiece cover results in piercing said capsule to provide said fluid discharging outlet.
It is another object of the present invention to provide the method as defined above, wherein removal of said nosepiece cover is obtained by at least one action selected from a group consisting of sliding said nosepiece cover along said device, rotating said nosepiece cover around said device, rotating said nosepiece cover around a hinge on the exterior of said device and any combination thereof.
It is another object of the present invention to provide the method as defined above, wherein said nosepiece cover comprises at least one nosepiece puncturing member adapted to pierce said capsule to enable said fluid discharging outlet.
It is another object of the present invention to provide the method as defined above, wherein said nosepiece comprises at least one port throughout which said at least one substance exits said device, such that said nosepiece cover seals said at least one port and removal thereof removes said seal.
It is another object of the present invention to provide the method as defined above, wherein said capsule is selected from a group consisting of pierceable container, a blow-fill-seal and a form-fill-seal and any combination thereof.
It is another object of the present invention to provide the method as defined above, wherein said at least one chamber is a container adapted to hold said pressured fluid at said PPF for prolong periods of time.
It is another object of the present invention to provide the method as defined above, wherein capsule is made of at least one material selected from a group consisting of high- or low-density polyethylene, high- or low-density polypropylene, any plastic resin, glass and any combination thereof.
It is another object of the present invention to provide the method as defined above, wherein said device is configured to deliver said Vsub substance and VPF pressurized fluid through said fluid discharging outlet of diameter D [mm] wherein at least one of the following is held true:
It is another object of the present invention to provide the method as defined above, additionally comprising at least one of the following steps:
It is another object of the present invention to provide the method as defined above, wherein said substance is selected from 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; hormones; Ketamine; Baqsimi product commercially available by Lilly (US); 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, HMGB1; 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.
It is another object of the present invention to provide the method as defined above, wherein said puncturing member comprising a plurality of holes throughout which said pressurized fluid exits said chamber and entrains said substance, after activation of said activation mechanism.
It is another object of the present invention to provide the method as defined above, wherein said capsule is a hollow tube characterized by at least two ends interconnect to each other, at least one of which is positioned proximal to said chamber.
It is another object of the present invention to provide the method as defined above, wherein said capsule comprises at least one spherical element position by at least one of said ends, adapted to seal said capsule and prevent leakage of said at least one substrate therefrom.
It is another object of the present invention to provide the method as defined above, wherein said capsule comprises two spherical elements, each of which is disposed at each of said ends, such that said at least one substrate is positioned therebetween.
It is another object of the present invention to provide the method as defined above, wherein said two spherical elements, once said pressurized fluid exits said chamber, are adapted to mix said at least one substrate and said at least one substrate.
It is another object of the present invention to provide the method as defined above, wherein said capsule comprises at least one membrane positioned by at least one of said ends, adapted to seal said capsule and prevent leakage of said at least one substrate therefrom.
It is another object of the present invention to provide the method as defined above, wherein said capsule comprises two membranes, each of which is disposed at each of said ends, such that said at least one substrate is positioned therebetween.
It is another object of the present invention to provide the method as defined above, wherein said capsule comprises at least one duckbill valve positioned by at least one of said ends, adapted to seal said capsule and prevent leakage of said at least one substrate therefrom.
It is another object of the present invention to provide the method as defined above, wherein said capsule comprises two duckbill valves, each of which is disposed at each of said ends, such that said at least one substrate is positioned therebetween.
It is another object of the present invention to provide the method as defined above, wherein said capsule comprises at least one spherical element, membrane, duckbill valve and any combination thereof.
It is another object of the present invention to provide the method as defined above, wherein said at least one hollow puncturing member comprises at least one orifice throughout which said pressurized fluid enters said hollow puncturing member.
It is another object of the present invention to provide the method as defined above, wherein, once said device is actuated, said pressurized fluid exit said chamber and enters said hollow puncturing member through said at least one orifice.
It is another object of the present invention to provide the method as defined above, wherein said at least one hollow puncturing member comprises at least one orifice throughout which said pressurized fluid enters said hollow puncturing member.
It is another object of the present invention to provide the method as defined above, wherein, once said device is actuated, said pressurized fluid exit said chamber and enters said hollow puncturing member through said at least one orifice.
It is an object of the present invention to disclose a device for delivering either one or more substances within at least one body cavity. The device is characterized by at least one pierceable vial comprising Vsub [ml or mg] of the substances; the vial having at least one fluid inlet port of diameter Din [mm] and at least one fluid discharging outlet port of diameter Dout [mm], configured for placement in proximity to the body cavity; the fluid inlet port configured by means of size and shape to interface with at least one puncturing member, configured to, upon coupling to the fluid inlet port, piercing the same, thereby providing the substances in a fluid communication, with at least one chamber configured to accept pressurized fluid at volume VPF [ml] and pressure PPF [barg]; the pressurized fluid flows from the chamber, via the fluid inlet port, entrains the substances, erupts via the fluid discharging outlet port to within the body cavity in the form of aerosol, such that the release time of the Vsub [ml or mg] of the substances and the VPF [ml] of the pressurized fluid, dTrelease is less than 500 milliseconds; In this device, the following held: VPF is in a range of 1 to 50 ml; Vsub is in a range of about 0.01 to about 7 ml or 0.1 mg to 7 g; PPF is in a range of about 0 to about 10 barg; further wherein at least one of the following is being held true: Din or Dout are in a range of 0.2 to 6 mm; the pressure velocity is greater than 0.001 barg/ms; the pressure velocity is greater than 0.01 barg/ms; the volume rate dVsub/dTrelease is greater than 0.0001 ml/ms; the volume rate dVsub/dTrelease is greater than 0.001 ml/ms; the volume rate dVPF/dTrelease is greater than 0.001 ml/ms; the volume rate dVPF/dTrelease is greater than 0.01 ml/ms; any combination thereof. The vial is further selected from a group consisting of a pierceable container, a blow-fill-seal and a form-fill-seal and any combination thereof.
It is another of the present invention to disclose the device as disclosed above, wherein the vial comprises a cap adapted to seal the vial, such that removal thereof provides fluid communication between the vial and the body cavity through the fluid discharging outlet port.
It is another of the present invention to disclose the device as disclosed in any of the above, wherein the at least one puncturing member is adapted to pierce the vial be means of a screw mechanism, such that rotation of the nosepiece cover along the screw mechanism in the base enables the pierce of the fluid inlet port in the vial by means of the puncturing member.
It is another of the present invention to disclose the device as defined in any of the above, wherein at least one of the following is true: (a) The body cavity is selected from a group consisting of nasal cavity, the mouth, the throat, an ear, the eye, the vagina, the rectum, the urethra, and any combination thereof. (b) The pressurized gas is selected from a group consisting of air, nitrogen, oxygen, carbon dioxide, helium, neon, xenon, nitric oxide and any combination thereof. (c) During dispensing of the at least one substance, a mixture of the predetermined volume Vgas [ml] of the pressurized gas with the predetermined volume Vsub [ml or mg] of the substance entrained within it forms a plume of aerosol; the aerosol having a predetermined distribution, the distribution being either homogeneous or heterogeneous, the heterogeneous distribution is selected from a group consisting of: an arbitrary distribution, a distribution in which the density of the at least one substance within the mixture follows a predetermined pattern, and any combination thereof; characteristics of the aerosol selected from a group consisting of: particle size, particle shape, particle distribution, and any combination thereof, are determinable from characteristics of the device selected from a group consisting of: the predetermined volume of the pressurized gas, the predetermined volume of the substance, the predetermined pressure of the pressurized gas, the predetermined orifice size, and any combination thereof. (d) At least one the substance is selected from a group consisting of a gas, a liquid, a powder, an aerosol, a slurry, a gel, a suspension and any combination thereof. (e) The least one the substance is stored under either an inert atmosphere or under vacuum to prevent reactions during storage. (f) A dose-response curve is substantially linear for brain concentration of the substance when administered nasally via the device; and (g) A dose-response curve for brain concentration having a fit selected from a group consisting of logarithmic, parabolic, exponential, sigmoid, power-low, and any combination thereof; of the substance when administered nasally via the device.
It is another of the present invention to disclose the device as disclosed in any of the above, wherein the vial is a capsule having a main longitudinal axis, the capsule comprising a number n of compartments, the capsule configured to contain the predetermined volume Vsub [ml or mg] of the at least one substance, the volume Vsub [ml or mg] of the at least one substance containable in at least one of the n compartments; at least one of the following being true: the number n of the compartments is an integer greater than or equal to 1; at least one the compartment has cross-section with shape selected from a group consisting of: wedge shaped, circular, oval, elliptical, polygonal, annular, and any combination thereof; for the number n of compartments being an integer greater than 1, at least two the compartments have different volumes; for the number n of compartments being an integer greater than 1, at least two the compartments have the same volume; for the number n of compartments being an integer greater than 1, at least two the compartments have different cross-sectional areas; for the number n of compartments being an integer greater than 1, at least two the compartments have the same cross-sectional area; for the number n of compartments being an integer greater than 1, at least two the compartments contain different substances; for the number n of compartments being an integer greater than 1, at least two the compartments contain the same substance; for the number n of compartments being an integer greater than 1, at least two the compartments are disposed coaxially around the main longitudinal axis of the capsule; for the number n of compartments being an integer greater than 1, at least two the compartments are disposed sequentially along the main longitudinal axis of the capsule; for the number n of compartments greater than 1, the plurality of substances mix during the dispensing; and for the number n of compartments greater than 1, the plurality of substances react during the dispensing.
It is another of the present invention to disclose the device as disclosed in any of the above, wherein the vial comprises a port fluidly connectable to the exterior of the device, the port configured such that the at least one substance is insertable into the chamber via the port.
It is another object of the present invention to disclose the device as disclosed above, wherein the device comprises a port cover configured to provide an air-tight closure for the port, the port cover slidable along the device, rotatable around the device, rotatable around a hinge on the exterior of the device and any combination thereof.
It is another of the present invention to disclose the device as disclosed in any of the above, wherein the pressurized fluid entrains the substance in a pulsed manner, such that a plurality of portions VPF erupts via the fluid discharging outlet to within the body cavity
It is another object of the present invention to disclose a method for delivering either one or more substances within at least one body cavity, characterized by steps of providing at least one pierceable vial with Vsub [ml or mg] of the substances; the vial having at least one fluid inlet port of diameter Din [mm] and at least one fluid discharging outlet port of diameter Dout [mm], configured for placement in proximity to the body cavity; configuring the fluid inlet by means of size and shape to interface a puncturing member, so that upon coupling to the fluid inlet port, piercing of the same, thereby providing the substances in a fluid communication, with at least one chamber configured to accept pressurized fluid at volume VPF [ml] and pressure PPF [barg]; and
facilitating the flow of the pressurized fluid from the chamber, via the fluid inlet, entrains the substances, erupts via the fluid discharging outlet port into the body cavity, such that the release time of the Vsub [ml or mg] of the substances and the VPF [ml] of the pressurized fluid, dTrelease is less than 500 milliseconds. The method further held the followings: VPF is in a range of 1 to 50 ml; Vsub is in a range of about 0.01 to about 7 ml or 0.1 mg to 1 g; PPF is in a range of about 0 to about 10 barg/The following is further being held true: Din or Dout are in a range of 0.2 to 6 mm; the pressure velocity is greater than 0.001 barg/ms; the pressure velocity is greater than 0.01 barg/ms; the volume rate or dVsub/dTrelease is greater than 0.0001 ml/ms; the volume rate dVsub/dTrelease is greater than 0.001 ml/ms; the volume rate dVPF/dTrelease is greater than 0.001 ml/ms; the volume rate dVPF/dTrelease is greater than 0.01 ml/ms; and any combination thereof. Additionally, the step of providing the vial additionally comprising step of selecting the vial from a group consisting of a pierceable container, a blow-fill-seal and a form-fill-seal and any combination thereof.
It is another of the present invention to disclose the method as disclosed above, wherein it additionally comprising at least one of the following steps: selecting the body cavity from a group consisting of a nasal cavity, the mouth, the throat, an ear, the eye, the vagina, the rectum, the urethra, and any combination thereof; selecting the gas from a group consisting of: air, nitrogen, oxygen, carbon dioxide, helium, neon, xenon, nitric oxide and any combination thereof; dispensing the at least one substance, and during the step of dispensing, forming a plume of aerosol with predetermined distribution from a mixture of the predetermined volume Vgas [ml] of the pressurized gas and the predetermined volume Vsub [ml] entrained within it; selecting the predetermined distribution from a group consisting of: a homogeneous distribution, a heterogeneous distribution; selecting the heterogeneous distribution from a group consisting of: an arbitrary distribution, a distribution in which the density of the at least one substance within the mixture follows a predetermined pattern, and any combination thereof; selecting characteristics of the aerosol from a group consisting of: particle size, particle shape, particle distribution, and any combination thereof, are determinable from characteristics of the device selected from a group consisting of: the predetermined volume of the pressurized gas, the predetermined volume of the substance, the predetermined pressure of the pressurized gas, the predetermined orifice size, and any combination thereof;
selecting the substance from a group consisting of: a gas, a liquid, a powder, a slurry, a gel, a suspension, and any combination thereof; storing at least one the substance under either an inert atmosphere or under vacuum, thereby preventing reactions during storage; and characterizing a dose-response curve for brain concentration of the substance to be of substantially linear form; and a dose-response curve for brain concentration having a fit selected from a group consisting of logarithmic, parabolic, exponential, sigmoid, power-low, and any combination thereof; of the substance when administered nasally via the device.
The invention is herein described, by way of example only, with reference to the accompanying drawings, wherein:
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.
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).
The term ‘ul’ or ‘μm’ hereinafter refers to the unit micro liters or micro meters, respectively.
The term ‘capsule’ interchangeably ‘container’ interchangeably refer 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 sub stance.
The term ‘high barrier films’ hereinafter refers to any materials in flexible packaging laminations that prevent the permeation of water, water vapor, oil, oxygen, aroma, flavor, gas, or light. Such provision is enabled by low permeability of the film. In some embodiments the film is made of high-density Aluminum films. Thus, according to one embodiment of the present invention, the pressurized gas enclosed within high barrier film that can maintain the pressure of the compressed gas for prolong period of times without leakage therefrom.
The term ‘plurality’ hereinafter refers to an integer greater than or equal to one.
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.
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; Glucagon, 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, HMGB1; 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.
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, nitric oxide and any combination thereof. Devices charged by hand will typically use air as the carrier gas.
The term ‘fluid’ refers to any substance or mixtures of substances that continually deforms (flows) under an applied shear stress, or external force. This term refers to gas, liquids, particulate or granulated solids (powders), aerosols, and any mixtures and combinations thereof.
The term ‘about’ refers hereinafter to a range of 25% below or above the referred value.
The term “body orifice” and “body cavity” are interchangeably refer to one or more of the followings: nasal cavity, a mouth, a throat, an ear, a vagina, a rectum, a urethra, and any combination thereof.
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.
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.
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 combination of the Volume of substance, volume of pressurized gas, pressure of pressurized gas, the orifice diameter, the activation time of the valve that reflects the time for the device to reconfigure from the ACTIVE configuration to the INACTIVE configuration or vice versa and any combination thereof.
The terms ‘the device’, ‘the present device’, ‘the SipNose device’ and ‘SipNose’ will be used interchangeably to refer to a device according to any embodiment of the present invention.
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.
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 eye, the vagina, the rectum and any combination thereof.
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.
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.
However, it should be emphasized that the device can be provided alone as well as in combination with a capsule.
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.
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
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).
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.
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 of activate.
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.
In prior-art devices the aerosol is produced in proximity exit of the device. Typically, the aerosol comprises a wide “fan” 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. In the present invention the aerosol created, due to the pressurized air carrier, reaches the upper regions of the nasal cavity.
Reference is now made to
In the
The pressurized-fluid container (2) will fit over the air chamber gate (3), with the first gate O-ring and the second gate O-ring providing airtight seals before activation so that compressed gas is storable between the air chamber gate (3) and the pressurized-fluid container (2).
As will be disclosed hereinafter, the pierceable drug container (1) (e.g., BFS) in the nosepiece, where there is a puncturing element that punctures the drug container and once the compressed gas is released from the pressurized-fluid container (2), the same entrains the drug and deliver the same to the nasal cavity (see
As shown in the Figs. the base of the device forms the activation button (4); to activate, the activation button (4) is pressed upward, then the air chamber gate (3) is drawn downwardly, which removes the sealing of the upper O-ring (78 in
Reference is now made to
Reference is now made to
Reference is now made to
Reference is now made to
One should also note that this example is shown for the same invention but with another kind of pressurized gas container and a different way of compressed gas discharge (by puncturing the container rather than the gate that is shown in the previous figures.
Reference is now made to
In the following sets of figures, namely
According to another embodiment, the rotation results in a double piercing of the nosepiece substance container and the pressurized air container.
According to another embodiment the pressurized air container is sealed by means of at least one O-ring, such that movement of the o-ring removes the sealing and enables the release of the pressurized air. In some embodiment at least 2 o-rings are used. One o-ring at the bottom of the pressurized air container and the second at the upper portion of the pressurized air container to seal and separate between the pressurized air container and the nosepiece substance container.
At final step (
Reference is now made to
It is well in the scope of the invention wherein the pressurized fluid is accommodated within container for a respectively long time, e.g., by having a pre-pressurized container (step 1A) in a fluid connection (step 2A) with the BFS and releasing the same (step 3A), or alternatively a container suitable to pressuring the fluid in situ within the container, e.g., by introducing a pump or piston mechanism that pressuring ambient air to the container in a first step (step 1B) and accommodating the pressurized fluid along a relatively short time of step 2B, then free the fluid to flow in step 3B.
By the device disclosed herein, the pre-aerosolized mixture of gas and substance exits the device with a significant driving force as a mixture of aerosol and pre-aerosolized material (fluid or powder). When the pre-aerosolized material hits the walls of the nasal passages, it “explodes” into a fine aerosol that is capable of being driven by the pressure deep into the nasal passages to deposit in the desired region.
Reference is now made to
Reference is now made to
According to this embodiment, once the device is activated (the pressurized gas container 3 is pressed against the handle), needle 5 pierces the pressurized gas container 3 and the pressurized gas exits therefrom and enters the medicament container to entrain the medicament into the nasal cavity.
Needle 5 is a hollow needle such that when the same pierces the gas container, the pressurized gas exit the pressurized fluid (e.g., gas) container 3 throughout needle 5.
Needle 5 comprises two ends, one of which is a flat, non-sharp end, in fluid communication with the medicament container (will be disclosed hereinafter) and the second one has a sharp end, adapted to pierce the gas container. The two ends interconnected by means of a hollow tube. Once the gas container is pierced the pressurized gas exits therefrom through the hollow tube.
Reference is now made to
According to this embodiment, at least one spherical element, preferably ball 13, is disposed within the medicament capsule 12. According to another embodiment, at least two spherical elements, preferably ball 13, are disposed within the medicament capsule 12, such that the medicament are disposed between the two balls 13.
The spherical elements are adapted to both (a) seal the medicament capsule 12 and prevent leakage of medicament therefrom; and, (b) once the pressurized air exits the pressurized gas container, the bottom most special element 13 is removed from its position (thereby removing the sealing thereof and enabling the pressurized gas to enter therein) and mixes/compress the medicament enclosed between the two spherical elements 13. Once, the first (bottom most) spherical element is removed, the same compress the medicament disposed between the first and second spherical elements 13 and cases the removal of the second (upper most) spherical element 13. Thereafter, the medicament along with the pressurized gas are delivered to the nasal cavity.
Reference is now made to
Reference is now made to
Reference is now made to
According to this embodiment, the capsule comprises the spherical element 13 being displaced in the bottom most part of the capsule (providing sealing in the bottom part) and a breakable membrane 20 in the upper part thereof (providing sealing in the upper part).
It should be noted that different embodiments of the capsule are available. Reference is now made to
The hole or slot (101A) in the plunger (101) is narrow enough to prevent substance leakage during storage, and wide enough to allow compressed gas passage during activation, wiping the substance from the container during activation. The hole or slot (101A) in the plunger (101) can be designed in many ways to allow delivery that is very efficient, having a residual volume of less than 15% of the original volume. The plunger (101) can be made either from a flexible materials such as, but not limited to, silicone, rubber, flexible plastic or from a hard material such as, but not limited to, a polymer such as Delrin®, a plastic, nylon, metal and any combination thereof.
Ball-type barriers (102) are useful when mixing of several components should occur only upon delivery, when one or more substance should be maintained at low humidity, when the viscosity of the substance varies significantly, and any combination thereof. In addition, contact between the ball (102) and the walls of the capsule (10) can also ensure effective release of the substance from the capsule (10). Examples of substances which tend to cling to walls include, but are not limited to, oils and some powders. The barriers can be balls, as in the embodiment shown, angular dividers or any other shape which can be easily moved by the released compressed gas (low-friction contacts), and still provide effective sealing between the elements to avoid mixing during, for example, shipment and storage.
In a preferred embodiment, each drug containers (103) is made of a soft thin sheet. The sheet can be a polymeric membrane, a continuous sheet or any other form which is thin enough to be easily torn when desired by the released of the compressed air. All drug containers (103) are connected to each other during manufacturing. Mixing occurs only during activation, with the compressed gas tearing the membranes/sheets dividing the compartments. Once the membranes are torn, the substance s are exposed to the compressed gas, mixed and delivered.
This embodiment differs from the previous one in that: (a) the drug containers do not form one unit; (b) the separate zones are separated from each other by membrane which is composed of two layers: one provides the rigidity of the membrane and is made of a rigid material, and the other one is a continuous flexible sheet which seals against the lower rigid part during until activation and which opens when air is pressed against its lower side The membranes (104A, 104B) open only one way, when air presses against their lower side during activation, allowing mixing of the substances during delivery.
These exemplary embodiments allow holding the substances separate during storage and mixing the substances only upon activation and delivery. In some embodiments, the device or the substances therein can be configured to generate a temperature change, either heating or cooling, during mixing and delivery. The device can further be configured so that components for creating a temperature change in the device are not released with the delivered substances.
Heating and cooling can be triggered by mechanical force, by pressure, by chemical reaction and any combination thereof. This can be done inside the drug capsule, around the drug capsule, or outside the device itself in its packaging, to be triggered right before activation of the device.
Such temperature change can be generated during activation (short time temperature change) or prior to activation (long time temperature change). Long time temperature changes require a temperature activation separated from the delivery activation.
Either option, or at least the long time temperature change, further requires proper device sealing to allow temperature to be maintained inside the device and to allow equilibration prior delivery. Such options can further include a temperature indicator, such as by a color change in a dedicated control window, to allow the user to know that the device is ready for activation.
A temperature change can be an increase in temperature, a decrease of temperature, or both.
A temperature change can be useful for example for:
One embodiment comprises two heating agents. These heating agents are in compartments of a capsule. Upon activation of the device, or upon activation of heating (for example, buy pressing a button), a membrane separating the two compartments is torn, allowing the heating agents to mix and to generate heat within the device. Other membranes are not torn by this activity, which keeps the heating agents in a sealed compartment—sealed so as to prevent delivery of heating agent delivery but allow gas passage to other compartments. Passage of the compressed gas then delivers the heated substances or other desired substances. Mixing, as disclosed above, can occur during delivery.
Reference is now made to
The mixing balls need not be spherical; any shape that will provide good sealing during storage and low-friction movement during activation can be used.
Reference is now made to
As noted above, the medicament delivered can either powder, liquids, gas, gel and any mixing thereof.
It should be noted that the medicament delivered can either powder, liquids, gas, gel and any mixing thereof.
Reference is now made to
According to any of the embodiment as described above, the pressurized gas container can be mad of at least one material selected from a group consisting of high- or low-density polyethylene, high- or low-density polypropylene, any plastic resin, glass, plastics, Aluminum and any combination thereof.
Reference is now made to
According to another embodiment, the pressurized fluid (e.g., gas) container (enclosing the pressurized and compressed fluid) is made of material being a high barrier film. According to one embodiment the high barrier film is a high barrier Aluminum film.
According to this embodiment, the high barrier film (e.g., Aluminum film) is ultrasonic soldered to create the pressurized-fluid container. Such ultrasonic soldering of the Aluminum high barrier film results in an airtight container that prevents any air leakage of the compressed and pressurized gas therewithin.
Such container 3 could be sealed by a breakable membrane 51 (that breaks once the pressure of the pressurized gas, enclosed therewithin, reaches a predetermined level), or septum 51, or any other sealable means.
In the foregoing description, embodiments of the invention, including preferred embodiments, have been presented for the purpose of illustration and description. They are not intended to be exhaustive or to limit the invention to the precise form disclosed. Obvious modifications or variations are possible in light of the above teachings. The embodiments were chosen and described to provide the best illustration of the principals of the invention and its practical application, and to enable one of ordinary skill in the art to utilize the invention in various embodiments and with various modifications as are suited to the particular use contemplated. All such modifications and variations are within the scope of the invention as determined by the appended claims when interpreted in accordance with the breadth they are fairly, legally, and equitably entitled.
| Number | Date | Country | Kind |
|---|---|---|---|
| 202013105715.0 | Dec 2013 | DE | national |
This application is a Continuation-in-Part of U.S. application Ser. No. 16/809,994, filed on Mar. 5, 2020, which is a Continuation-in-Part of U.S. application Ser. No. 15/982,996 filed on May 17, 2018, which is a Continuation-in-Part of U.S. application Ser. No. 14/733,143 filed on Jun. 8, 2015, which claims the benefit of and priority to U.S. Provisional Application No. 62/117,986 filed on Feb. 19, 2015, and U.S. Provisional Application No. 62/077,246 filed on Nov. 9, 2014. U.S. application Ser. No. 15/982,996 claims further priority to U.S. Provisional Application No. 62/526,386 filed on Jun. 29, 2017. U.S. application Ser. No. 16/809,994 is also a Continuation-in-Part of U.S. application Ser. No. 16/810,096 filed Mar. 5, 2020, which is a Continuation-in-Part of U.S. application Ser. No. 15/982,630 filed on May 17, 2018, which is a Continuation-in-Part of U.S. application Ser. No. 14/733,143 filed on Jun. 8, 2015, which claims the benefit of and priority to U.S. Provisional Application No. 62/117,986 filed on Feb. 19, 2015, and U.S. Provisional Application No. 62/077,246 filed on Nov. 9, 2014. U.S. application Ser. No. 15/982,630 further claims priority to U.S. Provisional Application No. 62/507,816 filed on May 18, 2017. Further, U.S. application Ser. No. 16/809,994 is a Continuation-in-Part of U.S. application Ser. No. 14/433,048 filed on Apr. 2, 2015, which is a National Phase Entry of PCT/IL2014/050752 filed on Aug. 21, 2014, which claims the benefit of and priority to U.S. Provisional Application No. 61/868,614 filed on Aug. 22, 2013, and U.S. Provisional Application No. 61/868,627 filed on Aug. 22, 2013, and further priority to German Application No. 2020131057150 filed on Dec. 16, 2013. Additionally, this application claims priority to and the benefit of U.S. Provisional Application No. 63/113,833 filed on Nov. 14, 2020. This application is a Continuation-in-Part of International Application No. PCT/IB2021/051834 filed on Mar. 4, 2021. The contents of the above applications are all incorporated by reference as if fully set forth herein in their entirety.
| Number | Date | Country | |
|---|---|---|---|
| 63113833 | Nov 2020 | US | |
| 62526386 | Jun 2017 | US | |
| 62077246 | Nov 2014 | US | |
| 62117986 | Feb 2015 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 16809994 | Mar 2020 | US |
| Child | 17357810 | US | |
| Parent | 15982996 | May 2018 | US |
| Child | 16809994 | US | |
| Parent | 14733143 | Jun 2015 | US |
| Child | 15982996 | US | |
| Parent | PCT/IB2021/051834 | Mar 2021 | US |
| Child | 14733143 | US |
