DRUG DELIVERY DEVICES AND METHODS FOR ADMINISTERING SUBSTANCES TO A BODY CAVITY BY HETEROGENOUS AEROSOLIZATION
20200289768 ยท 2020-09-17
Inventors
Cpc classification
A61M15/009
HUMAN NECESSITIES
A61M11/02
HUMAN NECESSITIES
B05B11/1087
PERFORMING OPERATIONS; TRANSPORTING
A61M2205/3337
HUMAN NECESSITIES
International classification
A61M11/00
HUMAN NECESSITIES
Abstract
The present invention provides means and methods 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 volume V.sub.sub [ml] of the substance; and, (ii) an INACTIVE CONFIGURATION, in which the valve prevents delivery of the predetermined volume V.sub.sub [ml] of the substance from the container to the body cavity; and a fluid tight chamber configured to contain predetermined volume V.sub.gas [ml] of pressurized gas at a predetermined pressure, P.sub.gas [barg].
Claims
1.-20. (canceled)
21. A device for delivering either one or more substances within at least one body cavity, characterized by at least one vial comprising V.sub.sub [ml or mg] of said substances; said vial having fluid inlet and a fluid discharging outlet of diameter D [mm], configured for placement in proximity to said body cavity; said fluid inlet configured by means of size and shape to interface in a sealable manner with at least one puncturing member, configured to, upon coupling to said fluid inlet, piercing the same, thereby providing said substances in a fluid communication, via at least one valve, with at least one chamber configured to accept pressurized fluid at volume V.sub.PF [ml] and pressure P.sub.PF [barg]; said valve is commutable from an CLOSE to an OPEN CONFIGURATION within a short period of time, being less than 500 milliseconds (dT); at said OPEN CONFIGURATION, said pressurized fluid flows from said chamber, via said fluid inlet, entrains said substances, erupts via said fluid discharging outlet to within said body cavity in the form of aerosol, such that the release time of said V.sub.sub [ml or mg] of said substances and said V.sub.PF [ml] of said pressurized fluid, dT.sub.release is less than 500 milliseconds; wherein the aerosol composition exiting said fluid discharging outlet into said body cavity is characterized by a bi-modal spray pattern, comprising a first pattern and a second pattern; further wherein said first pattern is characterized by (a) Plume angle is in the range of 54; (b) width of plume at 6 cm from the nozzle is in the range of 4 mm3 mm; and, said second pattern is characterized by (a) Plume angle is in the range of 3510; (b) width of plume at 6 cm from the nozzle is in the range of 30 mm10 mm; further wherein the mean particle's size in said first pattern is larger than the mean particle's size in said second pattern.
22. The device of claim 1, wherein said vial is selected from a BFS.
23. The device of claim 1, wherein the aerosol composition is characterized by velocities in a range of 5 m/s to 50 m/s.
24. The device of claim 1, wherein said 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.
25. The device of claim 1, wherein at least one of the following is true: a. said body orifice is a nasal cavity, a mouth, a throat, an ear, a vagina, a rectum, a urethra, and any combination thereof; b. said pressurized gas is selected from a group consisting of air, nitrogen, oxygen, carbon dioxide, helium, neon, xenon and any combination thereof; c. during dispensing of said at least one substance, a mixture of said predetermined volume V.sub.gas [ml] of said pressurized gas with said predetermined volume V.sub.sub [ml or mg] 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 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; d. at least one said 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. at least one said substance is stored under one of the followings: an inert atmosphere; under vacuum and a pressure above ambient pressure to prevent reactions during storage; f. a dose-response curve is substantially linear for brain concentration of said substance when administered nasally via said 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 said substance when administered nasally via said device.
26. The device of claim 1, wherein said vial is a capsule having a main longitudinal axis, said capsule comprising a number n of compartments, said capsule configured to contain said predetermined volume V.sub.sub [ml or mg] of said at least one substance, said volume V.sub.sub [ml or mg] 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.
27. The device of claim 1, wherein said container comprises a port fluidly connectable to the exterior of said device, said port configured such that said at least one substance is insertable into said chamber via said port.
28. The device of claim 7, wherein said device comprises a port 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.
29. The device of claim 1, wherein said pressurized fluid entrains said substance in a pulsed manner, such that a plurality of potions V.sub.PF are emitted via said fluid discharging outlet to within said body cavity.
30. The device of claim 1, 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; commercially available by Lilly (US) Baqsimi product; 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]; Midazolam, Insulin, 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, BIIB3033, 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, cells secreation/secrotomes at a therapeutically effective concentration.
31. The device of claim 1, for the delivery of said predetermined volume V.sub.sub [ml or mg] of said substance and said predetermined volume V.sub.PF of said pressurized gas through said orifice of diameter D [mm] in a pressure rate of dP.sub.PF/dT is provided wherein at least one of the following is held true: a. said P.sub.PF is in a range of about 0 to about 10 barg; b. said V.sub.PF is in a range of about 1 to about 50 ml; c. said V.sub.sub is in a range of about 0.01 to about 7 ml; d. said D is in a range of 0.2 to about 6 mm; e. said pressure rate,
32. A method of delivering a predetermined volume V.sub.sub [ml or mg] of at least one substance within at least one body cavity of a subject, comprising steps of: a. providing at least one pierceable vial with V.sub.sub [ml or mg] of said substances; said vial having at least one fluid inlet port of diameter D.sub.in [mm] and at least one fluid discharging outlet port of diameter D.sub.out [mm], configured for placement in proximity to said body cavity; b. placing said delivery end in proximity to said body cavity; c. configuring said fluid inlet by means of size and shape to interface a puncturing member, so that upon coupling to said fluid inlet port, piercing of the same, thereby providing said substances in a fluid communication, with at least one chamber configured to accept pressurized fluid at volume V.sub.PF [ml] and pressure P.sub.PF [barg]; and, d. facilitating the flow of said pressurized fluid from said chamber, via said fluid inlet, entrains said substances, erupts via said fluid discharging outlet port into said body cavity in the form of aerosol, such that the release time of said V.sub.sub [ml or mg] of said substances and said V.sub.PF [ml] of said pressurized fluid, dT.sub.release is less than 500 milliseconds; wherein the aerosol composition exiting said fluid discharging outlet into said body cavity is characterized by a bi-modal spray pattern, comprising a first pattern and a second pattern; further wherein said first pattern is characterized by (a) Plume angle is in the range of 54; (b) width of plume at 6 cm from the nozzle is in the range of 4 mm3 mm; and, said second pattern is characterized by (a) Plume angle is in the 10; (b) width of plume at 6 cm from the nozzle is in the range of 35range of 30 mm10 mm; further wherein the mean particle's size in said first pattern is larger than the mean particle's size in said second pattern.
33. The method of claim 32, wherein said vial is selected from a BFS.
34. The method of claim 32, wherein at least one of the following is being held true: i. V.sub.PF is in a range of 1 to 50 ml; ii. V.sub.sub is in a range of about 0.01 to about 7 ml; iii. P.sub.PF is in a range of about 0 to about 10 barg; iv. D.sub.in or D.sub.out are in a range of 0.2 to 6 mm; v. said pressure velocity is greater than 0.001 barg/ms; vi. said pressure velocity is greater than 0.01 barg/ms; vii. said volume rate or dV.sub.sub/dT.sub.release is greater than 0.0001 ml/ms; viii. said volume rate dV.sub.sub/dT.sub.release is greater than 0.001 ml/ms; ix. said volume rate dV.sub.PF/dT.sub.release is greater than 0.001 ml/ms; x. said volume rate dV.sub.PF/dT.sub.release is greater than 0.01 ml/ms; and xi. any combination thereof;
35. The method of claim 32, wherein the aerosol is characterized by velocities in a range of 5 m/s to 50 m/s.
36. The method of claim 32, wherein said 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.
37. The method of claim 32, wherein at least one of the following is true: a. said body orifice is a nasal cavity, a mouth, a throat, an ear, a vagina, a rectum, a urethra, and any combination thereof; b. said pressurized gas is selected from a group consisting of air, nitrogen, oxygen, carbon dioxide, helium, neon, xenon and any combination thereof; c. during dispensing of said at least one substance, a mixture of said predetermined volume V.sub.gas [ml] of said pressurized gas with said predetermined volume V.sub.sub [ml or mg] 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 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; d. at least one said 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. at least one said substance is stored under one of the followings: an inert atmosphere; under vacuum and a pressure above ambient pressure to prevent reactions during storage; f. a dose-response curve is substantially linear for brain concentration of said substance when administered nasally via said 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 said substance when administered nasally via said device.
38. The method of claim 32, wherein said vial is a capsule having a main longitudinal axis, said capsule comprising a number n of compartments, said capsule configured to contain said predetermined volume V.sub.sub [ml or mg] of said at least one substance, said volume V.sub.sub [ml or mg] 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.
39. The method of claim 32, wherein said container comprises a port fluidly connectable to the exterior of said device, said port configured such that said at least one substance is insertable into said chamber via said port.
40. The method of claim 32, wherein said device comprises a port 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.
41. The method of claim 32, wherein said pressurized fluid entrains said substance in a pulsed manner, such that a plurality of potions V.sub.PF are emitted via said fluid discharging outlet to within said body cavity.
42. The method of claim 32, 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; commercially available by Lilly (US) Baqsimi product; 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]; Midazolam, Insulin, 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, BIB3033, 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, cells secreation/secrotomes at a therapeutically effective concentration
Description
BRIEF DESCRIPTION OF THE DRAWINGS
[0033] The invention is herein described, by way of example only, with reference to the accompanying drawings, wherein:
[0034]
[0035]
[0036]
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0037] This application incorporates herein by reference the contents of U.S. application Ser. No. 15/982,996 in its entirety.
[0038] 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.
[0039] In the present invention, a combination of parameters and forces such as pressure, gas/air volume and orifice diameter and duration of the process (t) 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).
[0040] The term l or ul hereinafter refers to the unit micro liters. The term capsule or container hereinafter refers to a container configured to contain a flowable substance.
[0041] 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. The term flowable refers hereinafter to any liquid, gas, aerosol, powder and any combination thereof.
[0042] The term Substance refers hereinafter to any flowable substance; e.g., gas, liquid or powder. The piercing could be relevant to the gas container, to the drug container (upper or lower area or both), or to both.
[0043] 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.
[0044] 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.
[0045] 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.
[0046] 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.
[0047] The term about refers hereinafter to a range of 25% below or above the referred value.
[0048] 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.
[0049] 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.
[0050] The terms the device, the present device, the SipNose device and SipNose will be used interchangeably to refer to a device were 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.
[0051] The term cannabinoid refers hereinbelow to any of the diverse chemical compounds that act on cannabinoid receptors on cells in the brain, act on orthosteric or allosteric sites and modulate endocannabinoid activity. They include the phytocannabinoids found in cannabis, hempseed oil, other plants, and synthetic cannabinoids manufactured artificially. They include the phytocannabinoids delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinol (CBN) cannabigerol (CBG), cannabigerol (CBG), cannabichromene (CBC), cannabicyclol (CBL), canabivarol (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerol monoethyl ether (CBGM), or the like; or mixtures or combinations thereof. Other botanical cannabimimetics include N-alkylamides from Echinacea and B-caryophyllene. They include mixtures of phytocannabinoids separated from the plant by extraction techniques and high purity cannabinoids obtained by purification from natural sources or via synthesis.
[0052] 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.
[0053] 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.
[0054] 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.
[0055] The drugs to be applied could be, but are not limited to, pharmaceuticals, natural compounds, biologics, hormones, peptides, proteins, viruses, cells, stem cells, cells secreation/secrotomes and any combination thereof.
[0056] However, it should be emphasized that the device can be provided alone as well as in combination with a capsule.
[0057] 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.
[0058] 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
[0059] 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 nanoparticle or microparticle 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).
[0060] 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 delivery of the drug 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 mucous membrane.
[0061] 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 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.
[0062] 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.
[0063] 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.
[0064] Reference is now made to
[0065] It is well in the scope of the invention wherein the pressurized fluid is accommodated within container (2) for a relatively long time, e.g., by having a pre-pressurized container in a fluid connection (with a capsule (e.g., a BFS) enclosing the substance and releasing the same, or alternatively a container suitable for pressuring the fluid in situ within the container, e.g., by introducing a pump or piston mechanism that pressurizes ambient air in the container in a first step and accommodating the pressurized fluid for a relatively short time, then allowing the fluid to flow.
[0066] It is well in the scope of the invention wherein at least one of the above is provided in an intermittent manner, e.g., by train of n pulses, n is an integer equal to or greater than 2, e.g., 2, 5, 10, 30 or more. Pulses are provided by various mechanisms selected in a non-limiting manner from a series of pressurizing events (pulsating piston for example and/or a series of volume changes within the container); a series of releases of pressurized fluid, by having rapid opening and closing actions of the valve and/or applying blowable lips or reed(s) at the end of the orifice, e.g., as those provided in a mouthpiece of a wind instrument.
[0067] The pulses can be identical, e.g., same pressure, same period of time, same volume etc. Additionally, or alternatively, at least one pulse can different for at least one other pulse in e.g., pressure, time, volume, etc. It is well within the scope of the invention wherein the fingerprint of the pulses is of increasing pressure, increasing time; and/or increasing pressure decreasing time; and/or decreasing pressure same time and so on and so forth.
[0068] The device of the present invention (refers hereinafter as SipNose's IN Delivery Device) (See
[0069] It is another object of the present invention to disclose the device a s disclosed in any of the above, wherein at least one of the following is true: (a) The body orifice is a nasal cavity, the mouth, the throat, an ear, the vagina, the rectum, the urethra, and any combination thereof. (b) The pressurized fluid is selected from a group consisting of air, nitrogen, oxygen, carbon dioxide, helium, neon, xenon, HFC and any combination thereof (c) During dispensing of the at least one substance, a mixture of the predetermined volume V.sub.gas [ml] of the pressurized gas with the predetermined volume V.sub.sub [ml] 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) At least one the substance is stored under one of the followings: an inert atmosphere; under vacuum and a pressure above ambient pressure to prevent reactions during storage. (f) A dose-response curve is substantially linear for brain concentration of the substance when administered intranasally via the device. (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 intranasally via the device.
[0070] It is an embodiment of the invention wherein 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 is utilized. The unit dose device comprises at least one predefined volume sized and shaped for containing the predetermined amount M.sub.sub of the at least one substance; a delivery end for placement in proximity to the body cavity, the delivery end being in fluid communication with the container; the delivery end comprises at least one orifice of diameter D; at least one 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 from the container to the body cavity via the delivery end; 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; the valve is reconfigurable from the inactive configuration to the active configuration within a predetermined period of time, dT, in response to activation of the same; and The unit dose as defined above, wherein the 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.
[0071] It is according to yet another embodiment of the invention wherein the unit dose device is configured to deliver the predetermined amount M.sub.sub of the substance and the predetermined volume V.sub.gas of the pressurized gas through the 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; and at least one of the following being held true: P.sub.gas is in a range of 0 to 10 barg; V.sub.gas is in a range of 1 to 50 ml; D is in a range of 0.2 to 6 mm; dP.sub.gas/dT is greater than 0.001 barg/ms; the amount rate dM.sub.sub/dT is greater than 0.0001 ml/ms or greater than 0.0001 mg/ms; the volume rate dV.sub.gas/dT is greater than 0.001 ml/ms; dT is in a range of 0 to 500 millisecond; and any combination thereof.
[0072] It is according to yet another embodiment of the invention wherein a fluid tight chamber configured to contain predetermined volume V.sub.gas of pressurized gas at a predetermined pressure, P.sub.gas. It is according to yet another embodiment of the invention wherein the pressurized gas, once the valve is reconfigured from the inactive configuration to the active configuration, is configured to entrain the substance and deliver the same via the orifice in the delivery end.
Example 1
[0073] Treatment of pain & central nervous system is found useful by utilizing a device of the present invention, see items 1-4,
Example 2Different Medicament Administered Via the Use of the Present Invention
[0074] The following merely lists some of the treatment that could utilize the SipNose device: Puhakka et al. discloses that corticosteroids are anti-inflammatory agents with a wide variety of effects on several inflammatory mediators. Over the past few years, steroids have found a place in the treatment of infectious diseases. Dexamethasone is an established treatment of acute viral-induced laryngitis and Haemophilus influenzae type b-induced meningitis in children. Intranasal corticosteroids decrease the inflammatory reaction in the nasal cavity and shorten the duration and decrease the severity of symptoms in upper respiratory tract virus infection. Coughs and colds can be treated by utilizing a non-BFS/FFS-device for the delivery of various medicaments, such as fluticasone propionate, see Puhakka, Tuomo, et al. The common cold: effects of intranasal fluticasone propionate treatment. Journal of Allergy and Clinical Immunology 101.6 (1998): 726-731.
[0075] US patent application US20090285849 discloses that an immune response to certain antigens which are otherwise weakly immunogenic can be enhanced through the use of vaccine adjuvants. Such adjuvants potentiate the immune response to specific antigens and are therefore the subject of considerable interest and study within the medical community. Cancer, allergic diseases, asthma, and chronic infections such as coronavirus, SARS-associated coronavirus, HIV, HCV, HBV, HSV, COVID-19 or coronavirus, and H. pylori are relevant condition in this sense to treat. Hepatitis, for example, is a systemic disease that predominantly affects the liver. The disease is typified by the initial onset of symptoms such as anorexia, nausea, vomiting, fatigue, malaise, arthralgias, myalgias, and headaches, followed by the onset of jaundice. The application further states that, in the United States, about 20% of patients with chronic hepatitis die of liver failure, and a further 5% develop hepatitis B-associated carcinoma. Vaccines, immunotherapy and antivirals can be administered by a device as defined in BFS-type device of the present invention and a non-BFS/FFS-type device, for the delivery of various medicaments, including thiosemicarbazones.
[0076] Pulmonary endothelial prostacyclin appears to be involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). prostacyclin (PGI.sub.2), a vasodilatory prostanoid released by pulmonary endothelial cells (ECs), is reduced in lung tissue of patients with emphysema. Furthermore, iloprost, a PGI.sub.2 analog, protected against cigarette smoke extract-induced EC apoptosis. Beraprost, another prostacyclin analog, reduced emphysema formation, inflammation, and apoptosis when given as pretreatment prior to cigarette smoke in a murine model of COPD, see Lammi, Matthew R., et al. Treatment with intranasal iloprost reduces disease manifestations in a murine model of previously established COPD. American Journal of Physiology-Lung Cellular and Molecular Physiology 310.7 (2016): L630-L638. Asthma and COPD can be treated by utilizing the SipNose of the present invention for the delivery of various medicaments, including Iloprost.
Example 3
Investigation of the Aerosol Dose Delivery Characteristics of the Sipnose Device
Example 5.1 Topiramate's and Saline's Aerosol
Materials & Equipment
[0077] The investigations of the aerosol characteristics were performed using a Malvern Spraytec instrument and the spray pattern and plume geometry were measured using an Oxford Laser Envision system. The SipNose device was tested with Topiramate API (Manufacturer: MSN; Batch No. TI0020516, Exp. Date: April 2019), and with Saline (0.9% NaCl Teva pharmaceuticals, Lot No: K61229 Exp. Date January 2020) as a control. As the SipNose delivery systems are a single dose disposable product, each of the tests detailed in the report was done on a separate (new) device and reflects consistency between different devices. Two different fill volumes (100 l and 200 l) were tested with the Saline solutions, and 30 mg dry topiramate powder was tested with devices pressurized to 5bar. The delivery system was mounted in a holder throughout the measurements to reduce movements at the time of activation. All devices were actuated manually (and not by an automated pump) to reflect potential use by users.
Delivered Dose
[0078] The determination of the delivered dose was performed to investigate dose consistency and the reproducibility of the dose released from the disposable delivery system. Theoretically, measuring the released dose by activating the device into a collecting container would be the straightforward way to do it, but aerosol evaporation makes this challenging and inconsistent. Delivered dose measurements were done by calculations based on measuring the residual amount of drug (by weight) in the device following activation. The procedure for the delivered dose determination was as follows: [0079] 1. The device parts were weighted (empty) {M.sub.cmp}; [0080] 2. The device was filled with compressed air (at 5 bar); [0081] 3. The device parts were weighed to note the weight of the air in the device {M.sub.air}; [0082] 4. The dose (liquid or powder drug) was inserted into the transparent nose piece (which is also the drug container) with a syringe and needle; [0083] 5. The device was weighed to note the weight of the pre-filled device with the air and drug {M.sub.air+d}; [0084] 6. The dose was released into an aero-chamber; [0085] 7. The device was weighed to note the weight of the device following the activation (M.sub.res) which reflects the device weigh without air (100% release of discharge air in each activation) and with the residual drug that was not released; and [0086] 8. The released dose was calculated by subtracting the weight of the device after release (M.sub.res) from the weight of the device before release (M.sub.air+d) minus the air weight.
[0087] The set-up for determination of the delivered dose determination is schematically illustrated in
Laser Diffraction
[0088] The investigation of the droplet size characteristics was performed using a Malvern Spraytec instrument equipped with software version 3.30. The instrument was used in a rapid collection mode using a dedicated SOP Stare device SOP1.ssop. The investigations were done at a distance of 3 cm from the laser beam and 6 cm from the collecting lens following the guideline recommendations for measurements to be performed within a range of 2 to 7 cm from the orifice. The instrument is verified once a year and the latest verification was performed May 22, 2018 by Malvern Sweden.
[0089] All investigations were done in repeats of 5. The devices were tested at 5 bar. Relative Humidity (RH) and temperature were recorded once during each of the experimental days. RH varied between 46% and 67% and the temperature was between 23 degrees C. and 24 degrees C. The results from the measurements are presented as the mean of the droplet size distribution at the point where the aerosol enters the laser beam and triggers the data collection, which corresponds to the time point where 1% obscuration of the laser beam occurs, to the time point where the obscuration once again falls to 1% obscuration, i.e. when almost all aerosol is cleared from the laser beam detection area.
[0090] Sample placement: horizontally in front of the laser beam at a distance of 3 cm from the beam and 6 cm from the lens. Laser trigger condition: sample collection triggered when transmission drops 1% from 100%; Beam width: 1 cm. Acceptance criteria for laser diffraction measurements for the SipNose delivery system is defined as: Mono or bi-Modal spray pattern with an initial peak (higher peak) with DV50 higher than 100 m and a steady state portion (lower peak) with DV50 lower than 100 m (between 20-100 m). When mono-modal, only the lower peak is present. The overall D50 calculated for each aerosol release shows droplet size averages between 50 and 250 m. Also, less than 10% of the droplets in the overall D10 calculations are below 10 m.
Spray Pattern and Plume Geometry
[0091] The investigation of the aerosol plume geometry and spray pattern characteristics were performed using an Oxford Laser Envision system (300 W fishtail IR laser and camera) equipped with camera software version PFV 0.3541 and Envision Patternate software version 1.3.1 using calibration file Calib_stare_C1S000100 using a NIST calibrated 11 cm11 cm grid. Calculations were done for both spray pattern and plume geometry including 95% in both investigations, i.e. 97.5% on each side of the total overlay droplets visible in the spray. The laser was mounted so that the IR fishtail was spread vertically which allowed for the spray pattern/plume geometry to be captured vertically as the device was mounted in a horizontal position. All spray pattern investigations were done at a distance of 6 cm from the exit of the nozzle i.e. the exit of the nozzle was positioned 6 cm from laser fishtail. All plume geometry measurements were done in such a way that the tip of the nozzle was visible in the picture. This allowed the origin of the aerosol spray to be defined for the calculation of the spray angle. For plume geometry, the angle and width at 6 cm was also calculated by the software. For the spray pattern, the software calculated the smallest and largest pattern diameter at 6 cm, where the point of origin was chosen to be the device nozzle, the point where the aerosol leaves the device. The oblongation index was then calculated in Excel (largest pattern diameter divided by smallest pattern diameter). Three to four disposable devices with formulation were activated and measured for each drug volume. The acceptance criteria, defined by SipNose, for spray pattern and plume geometry of the total overlay droplets visual in the spray measured for the SipNose delivery system in accordance to guidelines, are defined as:
[0092] Aerosol of overall (total) aerosol pattern an ellipsoid of relatively uniform density, where the short axis and the long axis are no longer than 4 cm and the ratio between the longest and the shortest axes (Oblongation) is in the range of 1.51; and/or
[0093] Plume angle of overall (total) aerosol of 3510 is accepted for aerosol release when measured from the device nozzle as the origin, and the width of the plume at 6 cm from the nozzle should be at the range of 31.5.
[0094] More specifically, it is noted by the inventors of the present invention that the bi-modal spray pattern, comprising a first pattern and a second pattern; further wherein the first pattern is characterized by (a) Plume angle is in the range of 54; (b) width of plume at 6 cm from the nozzle is in the range of 4 mm3 mm; and, the second pattern is characterized by (a) Plume angle is in the range of 3510; (b) width of plume at 6 cm from the nozzle is in the range of 3010 mm; further wherein the mean particle's size in the first pattern is larger than the mean particle's size in the second pattern.
[0095] The results shown below contain both aerosol characteristics and the delivered dose for saline (100 l and 200 l) and topiramate dry powder (30 mg) with pressurized devices with 5bars. Reference is now made to
SalineDelivered Dose Determination
[0096] The mean values and standard deviations are presented in Table 1 and in
TABLE-US-00001 TABLE 1 Mean Values for residue volumes (%) following aerosol release. Delivered mass in % of loaded mass Drug Sample Name (X bar) Volume l Mean SD RSD % Saline P1(5b) 1000 l 96.1 3.2 3.3 E1(5b) 200 l 94.3 3.0 3.2
TABLE-US-00002 TABLE 2 Individual Values for saline at 5 bar. Sample Drug Empty- with With After (x bar) # Name Volume before g Air g Drug g dosing g P1(5b) 1 Saline 100 8.5492 8.5651 8.6621 8.5504 2 Saline 100 8.5254 8.54 8.643 8.527 3 Saline 100 8.6404 8.6559 8.759 8.6429 4 Saline 100 8.55 8.5652 8.6657 8.5525 5 Saline 100 8.5228 8.5386 8.6402 8.532 6 Saline 100 8.5382 8.553 8.6585 8.545 E1(5b) 1 Saline 200 8.5455 8.56 8.7589 8.5523 2 Saline 200 8.5267 8.542 8.7474 8.533 3 Saline 200 8.534 8.549 8.754 8.556 4 Saline 200 8.5078 8.523 8.7302 8.524 5 Saline 200 8.5139 8.5293 8.7378 8.522 6 Saline 200 8.5242 8.539 8.743 8.5344 Air Drug Drug drug Delivered Sample loaded Loaded residue released mass % (x bar) mg mg mg mg of loaded Mean SD RSD % P1(5b) 15.9 97.0 1.2 95.8 98.8 96.1 3.2 3.3 14.6 103.0 1.6 101.4 98.4 15.5 103.1 2.5 100.6 97.6 15.2 100.5 2.5 98 97.5 15.8 101.6 9.2 92.4 90.9 14.8 105.5 6.8 98.7 93.6 E1(5b) 14.5 198.9 6.8 192.1 96.6 94.3 3.0 3.2 15.3 205.4 6.3 199.1 96.9 15.0 205.0 22.0 183 89.3 15.2 207.2 16.2 191 92.2 15.4 208.5 8.1 200.4 96.1 14.8 204.0 10.2 193.8 95.0
[0097] The mean results for dose release for Saline formulation is 97 l3.3 for 100 l intended dose and 193.25 l6.3 for 200 l intended dose. For both intended doses (100 and 200 l), the released dose results pass the acceptance criterion (less than 10% of target weight not delivered).
Droplet Size Determination by Malvern Spraytec
[0098] The droplet size distribution values for the Malvern Spraytec measurements are outlined in Table 3 below and typical Graphs are seen in
TABLE-US-00003 TABLE 3 Individual results for Malvern Spraytec Average Average Volume Pressure Dv(50) Dv(10) Actuation Run Label (ul) (Bar) (um) (um) time (ms) 1 Saline E1 200 5 45.9 15.3 54 2 Saline E1 200 5 78.6 18.1 60 3 Saline E1 200 5 64.8 16.6 49 4 Saline E1 200 5 61.4 16.7 69 5 Saline E1 200 5 60 14.8 50 6 Saline E1 200 5 49.8 16.4 68 1 Saline P1 100 5 86.7 23.4 54 2 Saline P1 100 5 76.3 18.5 38 3 Saline P1 100 5 75.2 19.7 54 4 Saline P1 100 5 125 22.5 49 5 Saline P1 100 5 86.3 20 45 6 Saline P1 100 5 48.8 13.7 50 Mean Mean Mean Dv(50) Actuation Dv(10) Run (um) SD time(ms) SD (um) SD 1 60.08 11.61 58.33 8.78 16.32 1.16 2 3 4 5 6 1 83.05 24.75 48.33 6.09 19.63 3.44 2 3 4 5 6
[0099]
[0100] The particle size distribution for both fill volumes shows a bimodal behavior with DV50 values of one peak above 100 m and of the other below 100 m, as seen in both 100 l and 200 l doses (
Spray Pattern and Plume Geometry by Oxford Laser Envision
[0101]
TABLE-US-00004 TABLE 4 Oxford Laser spray pattern results for saline Spray Patten Volume Pressure Short axis Run Label (ul) (Bar) (cm) 1 Saline E1 200 5 2.21 2 Saline E1 200 5 2.19 3 Saline E1 200 5 2.16 4 Saline E1 200 5 1.99 1 Saline P1 100 5 2.47 2 Saline P1 100 5 2.28 3 Saline P1 100 5 2.36 4 Saline P1 100 5 2.06 Long axis Run (cm) Oblongation Mean SD SD % 1 3.33 1.51 1.51 0.050 3.28 2 3.39 1.55 3 3.34 1.55 4 2.87 1.44 1 3.51 1.42 1.52 0.171 11.22 2 3.36 1.47 3 3.33 1.41 4 3.65 1.77
[0102]
Plume Geometry
[0103]
TABLE-US-00005 TABLE 5 Oxford Laser plume geometry results for saline Plume Geometry Volume Pressure Angle Width Run Label (ul) (Bar) (Deg) (at 6 cm) 1 Saline E1 200 5 38.4 2.59 2 Saline E1 200 5 36.4 2.43 3 Saline E1 200 5 38.8 2.39 1 Saline P1 100 5 41.8 2.85 2 Saline P1 100 5 44.4 2.86 3 Saline P1 200 5 35.9 2.54 Angle Width Run Volume Mean SD SD % Mean SD SD % 1-3 200 37.87 1.29 3.40 2.49 0.14 5.68 1-3 100 40.70 4.36 10.70 2.75 0.18 6.62
[0104]
Example 5.2 Aerosol Created from Topiramate Dry Powder Investigation of the Aerosol when Topiramate Dose is DeliveredCharacteristics for the Sipnose Nasal Delivery Device
[0105] The mean values and standard deviations of released dose following activation of SipNose devices loaded with the topiramate powder (n=6), are presented Table 6 and in
TABLE-US-00006 TABLE 6 Mean Values of the delivered mass in %. Drug Sample Name (X bar) Weight mg % Mean SD RSD % Topiramate Powder G1(5b) 30 98.3 1.5 1.5
[0106]
TABLE-US-00007 TABLE 7 Individual topiramate values for the 5 bars investigation. Sample Drug Empty- with With After (x bar) # Name Weight before g Air g Drug g dosing g G1(5b) 1 Topiramate 30 mg 8.5167 8.532 8.5613 8.5167 2 Powder 30 mg 8.5174 8.532 8.561 8.5175 3 30 mg 8.5 8.516 8.5473 8.501 4 30 mg 8.5216 8.536 8.569 8.522 5 30 mg 8.5259 8.542 8.573 8.527 6 30 mg 8.526 8.5415 8.5741 8.5266 Air Drug Drug drug Delivered loaded Loaded residue released mass % # mg mg mg mg of loaded Mean SD RSD % 1 15.3 29.3 0.0 29.3 100.0 98.3 1.5 1.5 2 14.6 29.0 0.1 28.9 99.7 3 16.0 31.3 1.0 30.3 96.8 4 14.4 33.0 0.4 32.6 98.8 5 16.1 31.0 1.1 29.9 96.5 6 15.5 32.6 0.6 32 98.2
[0107] The mean results for dose release for topiramate dry powder formulation is 30.51.49 for the 30 mg intended dose under a pressure of 5 bars. Released dose results pass the acceptance criteria (losses less than 10% of target weight). Droplet size determination by Malvern Spraytec
TABLE-US-00008 TABLE 8 Individual results for Malvern Spraytec Average Average Weight Pressure Dv(50) Dv(10) Actuation Run Label mg (Bar) (um) (um) time(ms) 1 Topi G1 30 5 42.3 12 24 2 Topi G1 30 5 124.7 13.4 30 3 Topi G1 30 5 116.4 12.4 29 4 Topi G1 30 5 132.5 13.6 37 5 Topi G1 30 5 79.2 12.3 20 Mean Mean Mean Dv(50) Actuation Dv(10) Run (um) SD time(ms) SD (um) SD 1 99.02 37.72 28.00 6.44 12.74 0.71 2 3 4 5
[0108]
[0109] The particle size distributions for a 30 mg topiramate dose show a bimodal behavior similar to that shown in the liquid formulations, with one peak above 100 m and one below 100 m. The DV(50) value (indicated by an arrow in
Spray Pattern and Plume Geometry as Measured by the Oxford Laser Envision
[0110]
TABLE-US-00009 TABLE 9 Oxford Laser spray pattern results for topiramate. Spray Pattern Weight Pressure Short axis Long axis Run Label (mg) (Bar) (cm) (cm) Oblongation Mean SD SD % 1 Topi G1 30 5 2.48 3.64 1.47 1.48 0.128 8.64 2 Topi G1 30 5 2.72 3.79 1.39 3 Topi G1 30 5 2.28 3.78 1.66 4 Topi G1 30 5 2.46 3.4 1.38 Comment: no weigh data present
[0111]
Plume Geometry
[0112]
TABLE-US-00010 TABLE 10 Oxford Laser plume geometry results for topiramate Plume Geometry Weigt Pressure Angle Width Run Label (mg) (Bar) (Deg) (at 6 cm) 1 Topi G1 31.25 5 25.1 2.52 2 Topi G1 31.39 5 25.2 2.52 3 Topi G1 29.21 5 26.1 2.78 4 Topi G1 30.46 5 25.8 2.84 Angle Width Run Mean SD SD % Mean SD SD % 1 25.55 0.48 1.88 2.67 0.17 6.35 2 3 4
[0113] The plume geometry results for topiramate:
Example 5.2 Aerosol Created from Midasolam Investigation of the Aerosol when Midazolam Dose is DeliveredCharacteristics for the Sipnose Nasal Delivery Device
Materials and Equipment
[0114] As in EXAMPLE 5.2
Results
[0115] The results below, containing both aerosol characteristics and delivered dose for saline and midazolam with the specified drug volumes (100 l and 200 l for saline and 200 l-800 l formidazolam) and specified pressures (5 and 6 bars) as defined.
SalineDelivered Dose Determination
[0116] The mean values and standard deviations are presented in Table 11 and in
TABLE-US-00011 TABLE 11 Mean Values for delivered mass (%) following aerosol release. Delivered mass in % of loaded mass Drug Sample Name (X bar) Volume l Mean SD RSD % Saline P1(5b) 100 l 96.1 3.2 3.3 E1(5b) 200 l 94.3 3.0 3.2
[0117]
TABLE-US-00012 TABLE 12 Individual values for saline at 5 bars. Empty - Sample Drug Volume before With With After (bar) # Name (ml) (g) Air (g) Drug (g) Dosing (g) P1 (5) 1 Saline 100 8.5492 8.5651 8.6621 8.5504 2 Saline 100 8.5254 8.54 8.643 8.527 3 Saline 100 8.6404 8.6559 8.759 8.6429 4 Saline 100 8.55 8.5652 8.6657 8.5525 5 Saline 100 8.5288 8.5386 8.6402 8.532 6 Saline 100 8.5382 8.553 8.6585 8.545 E1 (5) 1 Saline 200 8.5455 8.56 8.7589 8.5523 2 Saline 200 8.5267 8.542 8.7474 8.533 3 Saline 200 8.534 8.549 8.754 8.556 4 Saline 200 8.5078 8.523 8.7302 8.524 5 Saline 200 8.5139 8.5293 8.7378 8.522 6 Saline 200 8.5242 8.539 8.743 8.5344 Air Drug Drug Drug Delivered Sample loaded loaded residue released (mass % (bar) # (mg) (mg) (mg) (mg) of loaded) Mean SD RSD % P1 (5) 1 15.9 97.0 1.2 95.8 98.8 96.1 3.2 3.3 2 14.6 103.0 1.6 101.4 98.4 3 15.5 103.1 2.5 100.6 97.6 4 15.2 100.5 2.5 98 97.5 5 15.8 101.6 9.2 92.4 90.9 6 14.8 105.5 6.8 98.7 93.6 E1 (5) 1 14.5 198.9 6.8 192.1 96.6 94.3 3.0 3.2 2 15.3 205.4 6.3 199.1 96.9 3 15.0 205.0 22.0 183 89.3 4 15.2 207.2 16.2 191 92.2 5 15.4 208.5 8.1 200.4 96.1 6 14.8 204.0 10.2 193.8 95.0
[0118] The mean results for dose release for the Saline formulation is 97 l3.3 for a 100 l intended dose and 193.25 l6.3 for a 200 l intended dose. For both intended doses (100 and 200 l), the released dose results pass the acceptance criterion (less than 10% difference from target dose).
Droplet Size Determination by the Malvern Spraytec
[0119] The droplet size distribution values from the Malvern Spraytec measurements are outlined in Table 13 below and typical Graphs are seen in
TABLE-US-00013 TABLE 13 Individual saline results for Malvern Spraytec. Average Average Mean Mean Mean Volume Pressure Dv(50) Dv(10) Actuation Dv(50) Actuation Dv(10) Run Label (ul) (Bar) (um) (um) time(ms) (um) SD time(ms) SD (um) SD 1 Saline E1 200 5 45.9 15.3 54 60.08 11.61 58.33 8.78 16.32 1.16 2 Saline E1 200 5 78.6 18.1 60 3 Saline E1 200 5 64.8 16.6 49 4 Saline E1 200 5 61.4 16.7 69 5 Saline E1 200 5 60 14.8 50 6 Saline E1 200 5 49.8 16.4 68 1 Saline P1 100 5 86.7 23.4 54 83.05 24.75 48.33 6.09 19.63 3.44 2 Saline P1 100 5 76.3 18.5 38 3 Saline P1 100 5 75.2 19.7 54 4 Saline P1 100 5 1.25 22.5 49 5 Saline P1 100 5 86.3 20 45 6 Saline P1 100 5 48.8 13.7 50
[0120]
Spray Pattern and Plume Geometry by Oxford Laser Envision
[0121]
TABLE-US-00014 TABLE 14 Oxford Laser spray pattern results for saline. Spray Pattern Volume Pressure Short axis Long axis Run Label (ul) (Bar) (cm) (cm) Oblongation Mean SD SD % 1 Saline E1 200 5 2.21 3.33 1.51 1.51 0.050 3.28 2 Saline E1 200 5 2.19 3.39 1.55 3 Saline E1 200 5 2.16 3.34 1.55 4 Saline E1 200 5 1.99 2.87 1.44 1 Saline P1 100 5 2.47 3.51 1.42 1.52 0.171 11.22 2 Saline P1 100 5 2.28 3.36 1.47 3 Saline P1 100 5 2.36 3.33 1.41 4 Saline P1 100 5 2.06 3.65 1.77
[0122]
Plume Geometry
[0123]
TABLE-US-00015 TABLE 15 Oxford Laser plume geometry results for saline. Plume Geometry Volume Pressure Angle Width Angle Width Run Label (ul) (Bar) (Deg) (at 6 cm) Mean SD SD % Mean SD SD % 1 Saline E1 200 5 38.4 2.59 37.87 1.29 3.40 2.49 0.14 5.86 2 Saline E1 200 5 36.4 2.43 3 Saline E1 200 5 38.8 2.39 1 Saline P1 100 5 41.8 2.85 40.70 4.36 10.70 2.75 0.18 6.62 2 Saline P1 100 5 44.4 2.86 3 Saline P1 100 5 35.9 2.54
[0124]
Midazolam FormulationDelivered Dose Determination
[0125] The mean values and standard deviations are presented in Table 16. All individual data are presented in Table 17
TABLE-US-00016 TABLE 16 Mean values of the delivered mass in % for midazolam. Delivered mass in % of loaded mass Drug Sample Name (X bar) Volume l Mean SD RSD % Midazoalm Y1(5b) 200 93.5 3.3 3.6 Y1(6b) 200 93.8 2.6 2.8 W1(5b) 400 93.5 2.5 2.7 W1(6b) 400 94.4 3.8 4.1 T1(5b) 600 94.3 1.5 1.6 T1(6b) 600 94.7 2.1 2.2 U1(5b) 800 94.8 1.9 2.0 U1(6b) 800 94.6 2.1 2.3
[0126]
TABLE-US-00017 TABLE 17 Individual values for 200-800 l midazolam; with 5 bar and 6 bar pressures Empty - Sample Drug Volume before With With After (bar) # Name (ml) (g) Air (g) Drug (g) Dosing (g) Y1 (5b) 1 Midazolam 200 8.8913 8.90603 9.1217 8.91648 2 8.9039 8.91922 9.12131 8.9222 3 8.8894 8.90464 9.1067 8.8965 4 8.8733 8.88784 9.08607 8.8793 5 8.8789 8.8937 9.0998 8.8903 6 8.8788 8.8944 9.0992 8.8915 Y1 (6b) 1 Midazolam 200 8.864 8.882 9.087 8.872 2 8.8888 8.906 9.113 8.905 3 8.8741 8.891 9.0879 8.882 4 8.8891 8.908 9.1236 8.9084 W1 (5b) 1 Midazolam 400 8.8763 8.8911 9.28976 8.9006 2 8.88081 8.89559 9.2978 8.9069 3 8.8569 8.38718 9.2699 8.8914 4 8.8818 8.89723 9.30461 8.8905 5 8.88571 8.90107 9.30512 8.9229 6 8.868 8.8823 9.2878 8.8942 W1 (6b) 1 Midazolam 400 8.8633 8.881 9.292 8.864 2 8.8722 8.8904 9.304 8.91 3 8.8886 8.9074 9.3218 8.8916 4 8.874 8.8909 9.3 8.901 T1 (5b) 1 Midazolam 600 8.91864 8.9349 9.5391 8.9544 2 8.9007 8.89145 9.5324 8.93953 3 8.89785 8.91264 9.52766 8.9165 4 8.91403 8.9283 9.5388 8.9441 5 8.9215 8.9369 9.5538 8.96327 6 8.90902 8.9235 9.5231 8.951 T1 (6b) 1 Midazolam 600 8.9045 8.921 9.523 8.918 2 8.883 8.9 9.5 8.917 3 8.88 8.8971 9.514 8.921 4 8.892 8.909 9.5174 8.932 U1 (5b) 1 Midazolam 800 8.91637 8.93003 9.7435 8.96922 2 8.87642 8.8911 9.7063 8.938 3 8.86607 8.8819 9.6903 8.9138 4 8.89065 8.9069 9.7185 8.929 5 8.9113 8.9266 9.72042 8.92985 6 8.88098 8.8961 9.69 8.91247 U1 (6b) 1 Midazolam 800 8.877 8.894 9.699 8.9105 2 8.894 8.912 9.708 8.931 3 8.887 8.905 9.724 8.921 4 8.8992 8.9162 9.7167 8.9678 Air Drug Drug Drug Delivered Sample loaded loaded residue released (mass % (bar) # (mg) (mg) (mg) (mg) of loaded) Mean SD RSD % Y1 (5b) 1 14.7 215.7 25.2 190.49 88.3 93.5 3.3 3.6 2 15.3 202.1 18.3 183.79 90.9 3 15.2 202.1 7.1 194.96 96.5 4 14.5 198.2 6.0 192.23 97.0 5 14.8 206.1 11.4 194.7 94.5 6 15.6 204.8 12.7 192.1 93.8 Y1 (6b) 1 18.0 205.0 8.0 197 96.1 93.8 2.6 2.8 2 17.2 207.0 16.2 190.8 92.2 3 16.9 196.9 7.9 189 96.0 4 18.9 215.6 19.3 196.3 91.0 W1 (5b) 1 14.8 398.7 24.3 374.36 93.9 93.5 2.5 2.7 2 14.8 402.2 26.1 376.12 93.5 3 14.9 398.1 34.5 363.6 91.3 4 15.4 407.4 8.7 398.68 97.9 5 15.4 404.1 37.2 366.86 90.8 6 14.3 405.5 26.2 379.3 93.5 W1 (6b) 1 17.7 411.0 0.7 410.3 99.8 94.4 3.8 4.1 2 18.2 413.6 37.8 375.8 90.9 3 18.8 414.4 27.4 387 93.4 4 16.9 409.1 27.0 382.1 93.4 T1 (5b) 1 16.3 604.2 35.8 568.44 94.1 94.3 1.5 1.6 2 14.4 617.9 39.4 578.47 93.6 3 14.8 615.0 18.6 596.37 97.0 4 14.3 610.5 30.1 580.43 95.1 5 15.4 616.9 41.8 575.13 93.2 6 14.5 599.6 42.0 557.62 93.0 T1 (6b) 1 16.5 602.0 13.5 588.5 97.8 94.7 2.1 2.2 2 17.0 600.0 34.0 566 94.3 3 17.1 616.9 41.0 575.9 93.4 4 17.0 608.4 40.0 568.4 93.4 U1 (5b) 1 13.7 813.5 52.8 760.62 93.5 94.8 1.9 2.0 2 14.7 815.2 61.6 753.62 92.4 3 15.8 808.4 47.7 760.67 94.1 4 16.0 811.6 18.1 773.45 95.3 5 15.3 793.8 18.5 775.27 97.7 6 15.1 793.9 31.5 762.41 96.0 U1 (6b) 1 17.0 805.0 33.5 771.5 95.8 94.6 2.1 2.3 2 18.0 796.0 37.0 759 95.4 3 18.0 819.0 34.0 785 95.8 4 17.0 800.5 68.6 731.9 91.4
[0127] The mean results for dose release for the midazolam formulation varied between 93.5%3.3 and 94.81.9 for 200 l to 800 l intended doses at a pressure of 5 bar and 93.8%2.6 to 94.7%2.1 for 200 l to 800 l intended doses at a pressure of 6 bar. In all of the above cases, the released dose results pass the acceptance criteria (less than 10% difference from the target dose). All doses were release with mean of less than 10% of target dose, which is very unique in the field, that same device and technology (with no change at all) can fit such a range of volumes, and particularly high volumes and be so efficient in releasing the aerosolized drug.
Droplet Size Determination by the Malvern Spraytec
[0128] Below is a table and figures showing the mean droplet size distribution for midazolam. The device/formulation was tested primarily at 5 bar pressure for 200 l, 400 l, 600 l and 800 l. 6 bar measurements were performed for 200 l and 400 l fill volume of midazolam.
TABLE-US-00018 TABLE 18 Individual results as measured by the Malvern Spraytec Average Average Mean Mean Mean Volume Pressure Dv(50) Dv(10) Actuation Dv(50) Actuation Dv(10) Run Label (ul) (Bar) (um) (um) time(ms) (um) SD time(ms) SD (um) SD 1 Midazolam R1 200 5 46.8 13.2 84 55.64 67.78 88.00 44.82 16.12 3.84 2 Midazolam R1 200 5 61.6 18.9 124 3 Midazolam R1 200 5 61.5 17.6 58 4 Midazolam R1 200 5 68.4 19.9 80 5 Midazolam R1 200 5 39.9 11 69 1 Midazolam S1 400 5 106.7 20.4 109 74.17 22.80 121.83 31.82 19.50 2.43 2 Midazolam S1 400 5 52.8 17.2 96 3 Midazolam S1 400 5 97.2 23.2 170 4 Midazolam S1 400 5 69.7 19.2 103 5 Midazolam S1 400 5 52.5 17.5 99 6 Midazolam S1 400 5 66.1 19.7 154 1 Midazolam T1 600 5 215.3 30.8 158 146.10 59.13 165.83 21.82 27.24 4.32 2 Midazolam T1 600 5 165.7 28.1 191 3 Midazolam T1 600 5 115.6 22.3 138 4 Midazolam T1 600 5 90.6 23.2 184 5 Midazolam T1 600 5 209.1 31.9 148 6 Midazolam T1 600 5 80.3 19.8 178 1 Midazolam V1 800 5 276.6 30.2 201 261.18 94.61 192.17 28.94 29.90 2.38 2 Midazolam V1 800 5 391.6 31.0 204 3 Midazolam V1 800 5 243.6 30.4 198 4 Midazolam V1 800 5 302.9 32.1 233 5 Midazolam V1 800 5 250.4 25.9 153 6 Midazolam V1 800 5 102 19.2 158 1 Midazolam W1 400 6 146 20.4 122 156.75 48.84 128.67 32.71 23.80 6.16 2 Midazolam W1 400 6 221.1 34.3 79 3 Midazolam W1 400 6 214.9 21.6 117 4 Midazolam W1 400 6 111.4 18.8 174 5 Midazolam W1 400 6 127.2 24.0 126 6 Midazolam W1 400 6 119.9 22.0 154 1 Midazolam Y1 200 6 55.5 15 66 66.23 8.77 95.33 18.45 15.22 1.00 2 Midazolam Y1 200 6 69.4 16.1 116 3 Midazolam Y1 200 6 60.6 13.5 88 4 Midazolam Y1 200 6 63.4 14.9 92 5 Midazolam Y1 200 6 81 15.6 114 6 Midazolam Y1 200 6 67.5 16.2 92
[0129]
Spray Pattern and Plume Geometry as measured by the Oxford Laser Envision
TABLE-US-00019 TABLE 19 Spray Pattern; Individual results as measured by the Oxford Laser Envision Spray Pattern Volume Pressure Short axis Long axis Run Label (ul) (Bar) (cm) (cm) Oblongation Mean SD SD % 1 Midazolam T1 600 6 2 3.13 1.57 1.59 0.092 5.76 2 Midazolam T1 600 6 2.18 3.33 1.53 3 Midazolam T1 600 6 1.77 3.06 1.73 4 Midazolam T1 600 6 2.36 3.66 1.55 1 Midazolam U1 800 6 1.98 3.1 1.57 1.61 0.068 4.24 2 Midazolam U1 800 6 2.05 3.44 1.68 3 Midazolam U1 800 6 2.46 3.77 1.53 4 Midazolam U1 800 6 1.87 3.08 1.65 1 Midazolam W1 400 6 2.07 3.19 1.54 1.53 0.178 11.62 2 Midazolam W1 400 6 2.24 3.28 1.46 3 Midazolam W1 400 6 2.97 4.02 1.35 4 Midazolam W1 400 6 1.95 3.46 1.77 1 Midazolam Y1 200 6 1.94 3.2 1.65 1.57 0.062 3.93 2 Midazolam Y1 200 6 1.82 2.89 1.59 3 Midazolam Y1 200 6 2.1 3.24 1.54 4 Midazolam Y1 200 6 1.6 2.41 1.51
[0130]
Plume Geometry
[0131]
TABLE-US-00020 TABLE 20 Plume Geometry; individual results as measured by the Malvern Spraytec. Plume Geometry Volume Pressure Angle Width Angle Width Run Label (ul) (Bar) (Deg) (at 6 cm) Mean SD SD % Mean SD SD % 1 Midazolam N1 800 5 24.3 2.07 30.80 10.24 33.24 2.59 0.74 28.54 2 Midazolam N1 800 5 25.5 2.27 3 Midazolam N1 800 5 42.6 3.44 1 Midazolam R1 200 5 25.6 2.16 29.57 3.95 13.36 2.39 0.28 11.74 2 Midazolam R1 200 5 33.5 2.7 3 Midazolam R1 200 5 29.6 2.3 1 Midazolam T1 600 6 30.3 2.7 32.87 2.32 7.05 2.85 0.17 5.83 2 Midazolam T1 600 6 34.8 3.03 3 Midazolam T1 600 6 33.5 2.83 1 Midazolam U1 800 6 31.5 2.62 30.57 2.34 7.67 2.60 0.16 6.02 2 Midazolam U1 800 6 32.3 2.74 3 Midazolam U1 800 6 27.9 2.43 1 Midazolam W1 400 6 31.8 2.83 34.10 2.17 6.35 3.07 0.23 7.39 2 Midazolam W1 400 6 34.4 3.11 3 Midazolam W1 400 6 36.1 3.28 1 Midazolam Y1 200 6 35.5 3.23 36.20 1.30 3.59 3.09 0.22 7.22 2 Midazolam Y1 200 6 37.7 3.2 3 Midazolam Y1 200 6 35.4 2.83
[0132]
[0133] The overall characteristics of the SipNose delivery devices showed to have reproducibility of dose released, spray plume geometry and droplet size distribution which satisfied the acceptance criteria. Since all the above parameters can affect delivery of the drug substance to the intended biological target, it was shown that 200 l, 400 l and 600 l and 800 l of midazolam show same general aerosol characteristics, thus delivery of those volumes via the SipNose delivery system is acceptable, with either 5 bar or 6 bar actuation pressure. All results and calculations in this report reflect that the SipNose device passes all the acceptance criteria for SipNose as a nasal delivery device for midazolam and in general any other liquid drug delivery, and is comparable to the performances with Saline as a control. All volumes release highly similar aerosol in terms of aerosol characteristics, which is very unique in the field, that same device and technology (with no change at all) can fit such a range of volumes, and particularly high volumes and be so efficient in releasing the aerosolized drug.
Example 8
Investigation of the Aerosol and Insulin and Dose Delivery Characteristics of the Sipnose Nasal Delivery Device
Materials & Equipment
[0134] As in EXAMPLE 5.2
Results
[0135] The results below, containing both aerosol characteristics and delivered doses corresponding insulin with specified drug volumes (100 l and 200 l) and specified pressures (5 and 6 bar) as defined.
Insulin Drug SolutionDelivered Dose Determination
[0136] The mean values and standard deviations are presented below. All individual data are presented below.
TABLE-US-00021 TABLE 21 Mean values of the delivered mass in %. Delivered mass in % of loaded mass Drug Sample Name (X bar) Volumn l Mean SD RSD % Insulin A1(5b) 100 l 93.8 2.7 2.8 B1(5b) 200 l 95.9 0.5 0.5
TABLE-US-00022 TABLE 22 Individual Insulin values for 5 bars actuation. After Air Drug Drug drug Delivered Sample Drug Empty- with With dosing loaded Loaded residue released mass % (x bar) # Name Volume before g Air g Drug g g mg mg mg mg of loaded Mean SD RSD % A1(5B)| 1 Insulin 100 8.5313 8.54701 8.6487 8.535 15.7 102.7 3.7 98.99 96.4 93.8 2.7 2.8 2 Insulin 100 8.565 8.5805 8.6777 8.5745 15.5 97.2 9.5 87.7 90.2 3 Insulin 100 8.53957 8.5551 8.6574 8.5488 15.5 102.3 9.2 93.07 91.0 4 Insulin 100 8.5313 8.547 8.646 8.5351 15.7 99.0 3.8 95.2 96.2 5 Insulin 100 8.52585 8.5414 8.5485 8.5324 15.5 107.1 6.6 100.55 93.9 6 Insulin 100 8.599 8.61454 8.7183 8.6039 15.5 103.8 4.9 98.86 95.3 B1(5B) 1 Insulin 200 8.5169 8.5325 8.7375 8.5253 15.6 205.0 8.4 196.6 95.9 95.9 0.5 0.5 2 Insulin 200 8.51042 8.5258 8.73075 8.5179 15.4 205.0 7.5 197.51 96.4 3 Insulin 200 8.5201 8.5356 8.7366 8.5283 15.5 201.0 8.2 192.8 95.9 4 Insulin 200 8.5259 8.5419 8.7397 8.5342 16.0 197.8 8.3 189.5 95.8 5 Insulin 200 8.5241 8.5398 8.7468 8.532 15.7 207.0 7.9 199.1 96.2 6 Insulin 200 8.5195 8.5349 8.7385 8.5299 15.3 203.6 10.3 191.3 94.9
[0137] The mean result for dose release for insulin formulation is 95.734.80 l for 100 l intended dose and 194.803.56 l for 200 l intended dose with a pressure of 5 bars. In all of the above cases, the released dose results pass the acceptance criterion (losses less than 10% of target weight).
Droplet Size Determination by Malvern Spraytec
[0138]
TABLE-US-00023 TABLE 23 Individual results for Malvern Spraytec for insulin. Average Average Mean Mean Mean Volume Pressure Dv(50) Dv(10) Actuation Dv(50) Actuation Dv(10) Run Label (ul) (Bar) (um) (um) times(ms) (um) SD time(ms) SD (um) SD 1 Insulin A1 100 5 66.6 19 43 64.45 1.59 50.83 7.73 18.15 0.78 2 Insulin A1 100 5 63.7 17.9 46 3 Insulin A1 100 5 66.3 16.8 62 4 Insulin A1 100 5 63.2 18.8 57 5 Insulin A1 100 5 63.9 18.1 44 6 Insulin A1 100 5 63 18.3 53 1 Insulin B1 200 5 71.5 18.2 67 66.17 6.67 71.50 8.24 16.92 1.68 2 Insulin B1 200 5 75.1 19.3 82 3 Insulin B1 200 5 56.1 14.8 68 4 Insulin B1 200 5 63.9 16.1 64 5 Insulin B1 200 5 63.5 15.7 66 6 Insulin B1 200 5 66.9 17.4 82
[0139] The particle size distribution for 100 l and 200 l insulin dose volumes show a bimodal behavior with one peak above 100 m and one below 100 m. In the time sequence distributions, there is an initial stable part with a higher transmission around 90% to 95%. Following this initial stable part comes a time period where the transmission drops markedly and then again increases to 99%. The DV(50) value of the 100 l insulin volume (64.45 m1.59) and for the 200 l insulin volume (66.17 m6.67) both pass the acceptance criterion. The DV(10) value of the 100 l insulin volume (18.15 m0.78) and for the 200 l insulin volume (16.92 m1.68) also pass the acceptance criterion.
Spray Pattern and Plume Geometry as measured by the Oxford Laser Envision
TABLE-US-00024 TABLE 24 Individual results for the spray pattern as measured by the Oxford Laser Envision Spray Pattern Volume Pressure Short axis Long axis Run Label (ul) (Bar) (cm) (cm) Oblongation Mean SD SD % 1 Insulin A1 100 5 1.69 3.01 1.78 1.67 0.192 11.50 2 Insulin A1 100 5 2.03 3.61 1.78 3 Insulin A1 100 5 2.37 3.43 1.45 1 Insulin B1 200 5 2.25 3.07 1.36 1.46 0.190 13.00 2 Insulin B1 200 5 2.14 3.6 1.68 3 Insulin B1 200 5 2.25 3.02 1.34
Plume Geometry
[0140]
TABLE-US-00025 TABLE 25 Individual results as measured by the Malvern Spraytec Plume Geometry Volume Pressure Angle Width Angle Width Run Label (ul) (Bar) (Deg) (at 6 cm) Mean SD SD % Mean SD SD % 1 Insulin A1 100 5 38.7 2.22 36.90 2.03 5.50 2.69 0.42 15.69 2 Insulin A1 100 5 37.3 3.04 3 Insulin A1 100 5 34.7 2.8 1 Insulin B1 200 5 33.9 2.54 35.23 3.31 9.39 2.77 0.49 17.79 2 Insulin B1 200 5 39 3.34 3 Insulin B1 200 5 32.8 2.44
[0141] The overall (total) spray pattern means oblongation indexes for the 100 l 200 l of Insulin are 1.670.19 and 1.460.19 respectively, thus they pass the acceptance criteria. The overall (total) plume geometry angle mean values are of 36.92 degrees for the 100 l and 35.233.31 for the 200 l, with widths of 2.690.42 cm and 2.6 cm for 100 l and 2.770.49 cm for 200 l measured at a distance of 6 cm from the device orifice, thus they also pass the acceptance criteria.
[0142] It is noted by the inventors of the present invention that the bi-modal spray pattern, comprising a first pattern and a second pattern; further wherein the first pattern is characterized by (a) Plume angle is in the range of 54; (b) width of plume at 6 cm from the nozzle is in the range of 4 mm3 mm; and, the second pattern is characterized by (a) Plume angle is in the range of 3510; (b) width of plume at 6 cm from the nozzle is in the range of 3010 mm; further wherein the mean particle's size in the first pattern is larger than the mean particle's size in the second pattern.
[0143] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.