ABSTRACT
Abstract
A compound delivery device for delivering a plume derived from a propellant and a drug formulation. The drug formulation is in an intranasal dosage form in the form of powder, suspension, dispersion or liquid. The propelled intranasal dosage form is deposited within the olfactory region of the nasal cavity. The drug deposited within the olfactory region is delivered to the brain avoiding the blood-brain-barrier. Hydrofluoroalkane propellant from a pressurized canister is channeled to a diffuser and drug-containing chamber where the intra-nasal dosage form is aerosolized. The aerosolized intra-nasal dosage form passes through a nozzle thus delivering a plume to the olfactory region of a user's nasal cavity.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a continuation of U.S. application Ser. No. 16/664,588, filed Oct. 25, 2019, which is a continuation of U.S. patent application Ser. No. 15/338,097, filed on Oct. 28, 2016, (now U.S. Pat. No. 10,507,295), which is a continuation of U.S. patent application Ser. No. 14/017,048, (now U.S. Pat. No. 9,550,036), filed on Sep. 3, 2013, entitled âNasal Drug Delivery Device,â which claims priority to an international patent application PCT/US2012/027754, filed Mar. 5, 2012, which claims priority to U.S. Application No. 61/449,008, filed Mar. 3, 2011, U.S. Application No. 61/451,935, filed Mar. 11, 2011, U.S. Application No. 61/484,025, filed May 9, 2011, and U.S. Application No. 61/498,974, filed Jun. 20, 2011, the entire contents of each priority application are hereby incorporated by reference in their entirety.
STATEMENT CONCERNING GOVERNMENT INTEREST
This invention was made with U.S. government support pursuant to US Army SBIR grant W81XWH-10-C-0238. The Government may have certain rights in this application.
BACKGROUND
The central nervous system (CNS) includes the brain, the brain stem, and the spinal cord. The CNS is isolated from the external world by several membranes that both cushion and protect the brain, the brain stem, and the spinal cord. For example, the membranes that form the blood-brain barrier (BBB) protect the brain from certain contents of the blood. The blood-cerebrospinal fluid barrier (BCSFB) protects other portions of the CNS from many chemicals and microbes.
Traditional methods for delivering compounds to the CNS are typically mvas 1 ve. For example, a pump implanted in the skull, such as an intracerebroventricular pump, can deliver a variety of compounds to the brain. However, implanting such a pump requires brain surgery, which can entail a variety of serious complications. Certain compounds, for example epidural painkillers, can be injected directly through the protective membrane into the CNS. However, such injection is impractical for most compounds.
Intranasal administration has traditionally focused on the distribution of drug solutions as a mist for topical delivery to the nasal epithelium. Because of the nasal cavity's easily accessed vascular bed, nasal administration of medications has focused the delivery of medications either locally to the nasal cavity or directly to the blood stream.
Much of the current brain research is focused on the enhancement of the drug being delivered to the brain by various formulations. The traditional approaches to improve uptake of compounds to the brain by formulation enhancement include (1) mucoadhesive formulations; 2) penetration enhancers; 3) liposomes; 4) vasoconstrictors; and 5) nanoparticles. Examples of various compounds with have enhanced formulations include various cytokines, for example, tumor necrosis factors, interleukins, and interferons discussed in U.S. Pat. No. 6,991,785 and growth and differentiation factor-5 (GDF-5) and related proteins discussed in US Publication No.
Targeting of drugs to the central nervous system (CNS) is a challenging task. A great number of drugs, including biotechnology products, are candidates for treatment of CNS diseases, but drug delivery is a problem for brain targeting. A limitation in the treatment of brain tumors is that less than 1% of most therapeutic agents administered systemically are able to cross the BBB. The transport of small molecules across the BBB is the exception rather than the rule, and 98% of all small molecules do not cross the BBB (Pardride, NeuroRx. 2005 January; 2(1): 1-2. 2005); approximately 100% of large-molecule drugs or genes do not cross the BBB (Pardride, NeuroRx. 2005 January; 2(1): 1-2. 2005). The BBB allows small (about less than 500 Da), lipophilic molecules from the bloodstream to enter the CNS (Pardridge, Arch Neurol. 2002; 59:35-40). Many larger therapeutic agents are prevented from reaching the brain for treating CNS disorders such as but not limited to Parkinson's disease, Alzheimer's disease, depression, stroke, and epilepsy (Pardridge, NeuroRx. 2005 January; 2(1): 3-14). Disorders including autism, lysosomal storage disorders, fragile X syndrome, ataxis, and blindness, are serious disorders where there is little effective treatment. In many of these cases, the gene underlying the disease is known, but BBB delivery is the rate-limiting problem in gene therapy or enzyme replacement therapy, and no therapeutics have been developed. Drug delivery of therapeutic compounds, for example proteins, faces several challenges because of their instability, high enzymatic metabolism, low gastrointestinal absorption, rapid renal elimination, and potential immunogenicity.
There is a need for devices that can deliver compounds to the upper nasal cavity for direct nose-to-brain delivery. Certain existing nasal drug delivery devices do not adequately propel the drug from the device. Inconsistent propulsion of drug due to inconsistent user actuation is also far from optimal. Still further, the plume generated by such existing devices is too wide. Even further, some drug products do not readily mix and/or stay suspended with propellants in a MDI type device. Certain existing nasal drug devices rely on circumferential velocity to propel medicaments to the olfactory epithelium. Traditional circumferential devices result in a lower percentage of compound deposited on the olfactory epithelium. A circumferential component in the aerosol plume tends to result in a wider spray plume with a portion of the aerosol particles targeted to the sides of the nasal cavity in the lower part of the nasal cavity.
Better mechanisms for administering desired agents to the brain, brain stem, and/or spinal cord are needed.
SUMMARY
A device for delivering a compound to the olfactory region of the nasal cavity is described including a canister capable of containing a propellant, a diffuser in communication with the canister, a compound chamber in communication with the diffuser, and a nozzle in communication with the compound chamber, wherein the device is capable of delivering the compound to the olfactory region of the nasal cavity.
In one aspect, the device includes a canister that is pressurized.
In another aspect, the propellant includes HFA, nitrogen, or CFC.
In another aspect, the device includes a compound chamber containing a drug or an imaging agent.
In yet another aspect, the drug is an oxime.
In yet another aspect, the diffuser is a frit.
In yet another aspect, the imaging agent is FDG or FLT.
In yet another aspect, the device includes a propellant, where the propellant is a pressurized liquid.
In yet another aspect, the pressurized liquid is HFA.
In another aspect, the pressurized liquid HFA is released from the canister and comes into contact with the diffuser, whereby the diffuser converts the pressurized liquid HFA to gaseous HFA.
In another aspect, the diffuser converts a minority of the pressurized liquid HFA to gaseous HFA
In a further aspect, the diffuser converts a majority of the pressurized liquid HFA to gaseous HFA.
In yet another aspect, the device delivers at least 62.6% of the compound to the olfactory region.
In yet another aspect, the he device delivers greater than 64.2% of the compound to the olfactory region.
In another aspect, the device delivers at least 64.3% of the compound to the olfactory region.
In yet another aspect, the device includes a canister where the canister is a syringe, syrette, or barrel.
In yet another aspect, the compound is not an imaging agent.
In further aspect, the compound is not FDG.
In one aspect, the drug is in the form of a liquid suspension, a liquid dispersion, a powder, or an aqueous solution.
In yet another aspect, the device further includes an aiming guide.
In yet another aspect, the aiming guide aides in positioning of the nozzle of the device at the user's olfactory region.
In yet another aspect, the devices further includes an insertion port m communication with the compound chamber.
In yet another aspect, the device further includes an indicator provided to alert the user to the length or amount of a capsule's insertion into the user's nasal cavity.
In one aspect, the diffuser is porous.
In another aspect, the diffuser is heterogeneously porous.
In another aspect, the diffuser is homogenously porous.
In another aspect, the diffuser is extended.
In yet another aspect, the diffuser is a disk-shaped member including conical shaped members having distal apertures.
In yet another aspect, the canister is a metered dose inhaler.
In another embodiment, a device for delivering a compound is described including a canister capable of containing a propellant, a diffuser in communication with the canister, a compound chamber in communication with the diffuser, and a nozzle in communication with the compound chamber, where the device is capable of delivering the compound to ear, skin, buccal cavity, or eyes.
In another embodiment, a method is described for delivering drug to the olfactory region of the nasal cavity including providing a canister capable of containing a propellant, a diffuser in communication with the canister, a compound chamber in communication with the diffuser, and a nozzle in communication with the compound chamber, where when actuated the device is capable of delivering the compound to the olfactory region of the nasal cavity.
In one aspect, the method includes the delivery of a drug for the treatment of an infectious disease, oncology, or immunological disease.
In one aspect, the method includes actuating the device to deliver propellant from the canister, whereby the diffuser diffuses the liquid propellant from the canister to a gaseous propellant, the gaseous propellant contacts the compound in the compound chamber and the compound and gaseous propellant exits the nozzle of the device.
In another aspect of the method, the diffuser converts a minority of the pressurized liquid HFA to gaseous HFA.
In another aspect of the method, the diffuser converts a majority of the pressurized liquid HFA to gaseous HFA.
In yet another aspect of the method, at least 64.2% of the compound is delivered to the olfactory region.
In yet another aspect of the method, greater than 64.2% of the compound is delivered to the olfactory region.
In another aspect of the method, the compound is a drug or diagnostic agent.
In another aspect of the method, the compound is a drug.
In yet another aspect of the method, the diagnostic agent is an imaging agent.
In yet another aspect of the method, the drug is an oxime.
In yet another aspect of the method, the imaging agent is fluorodeoxyglucose or fluorothymidine.
In yet another aspect of the method, the compound is not fluorodeoxyglucose.
In yet another aspect of the method, the compound is not an imaging agent.
In yet another aspect of the method, the drug is in the form of a liquid suspension, a liquid dispersion, a powder, liposome, or an aqueous solution and combinations thereof.
In yet another aspect of the method, the device includes one or more aiming guides.
In yet another aspect of the method, the aiming guide assists m the positioning of the nozzle of the device at the user's olfactory region.
In another aspect of the method, the device includes an insertion port in communication with the compound chamber.
In an aspect of the method, the device includes an indicator provided to alert the user to the depth of insertion of the device into the user's nasal cavity.
In another aspect of the method, the diffuser is porous.
In another aspect of the method, the diffuser is heterogeneously porous.
In another aspect of the method, the diffuser is homogenously porous.
In an aspect of the method, the diffuser is extended.
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a continuation of U.S. application Ser. No. 16/664,588, filed Oct. 25, 2019, which is a continuation of U.S. patent application Ser. No. 15/338,097, filed on Oct. 28, 2016, (now U.S. Pat. No. 10,507,295), which is a continuation of U.S. patent application Ser. No. 14/017,048, (now U.S. Pat. No. 9,550,036), filed on Sep. 3, 2013, entitled âNasal Drug Delivery Device,â which claims priority to an international patent application PCT/US2012/027754, filed Mar. 5, 2012, which claims priority to U.S. Application No. 61/449,008, filed Mar. 3, 2011, U.S. Application No. 61/451,935, filed Mar. 11, 2011, U.S. Application No. 61/484,025, filed May 9, 2011, and U.S. Application No. 61/498,974, filed Jun. 20, 2011, the entire contents of each priority application are hereby incorporated by reference in their entirety.
STATEMENT CONCERNING GOVERNMENT INTEREST
This invention was made with U.S. government support pursuant to US Army SBIR grant W81XWH-10-C-0238. The Government may have certain rights in this application.
BACKGROUND
The central nervous system (CNS) includes the brain, the brain stem, and the spinal cord. The CNS is isolated from the external world by several membranes that both cushion and protect the brain, the brain stem, and the spinal cord. For example, the membranes that form the blood-brain barrier (BBB) protect the brain from certain contents of the blood. The blood-cerebrospinal fluid barrier (BCSFB) protects other portions of the CNS from many chemicals and microbes.
Traditional methods for delivering compounds to the CNS are typically mvas 1 ve. For example, a pump implanted in the skull, such as an intracerebroventricular pump, can deliver a variety of compounds to the brain. However, implanting such a pump requires brain surgery, which can entail a variety of serious complications. Certain compounds, for example epidural painkillers, can be injected directly through the protective membrane into the CNS. However, such injection is impractical for most compounds.
Intranasal administration has traditionally focused on the distribution of drug solutions as a mist for topical delivery to the nasal epithelium. Because of the nasal cavity's easily accessed vascular bed, nasal administration of medications has focused the delivery of medications either locally to the nasal cavity or directly to the blood stream.
Much of the current brain research is focused on the enhancement of the drug being delivered to the brain by various formulations. The traditional approaches to improve uptake of compounds to the brain by formulation enhancement include (1) mucoadhesive formulations; 2) penetration enhancers; 3) liposomes; 4) vasoconstrictors; and 5) nanoparticles. Examples of various compounds with have enhanced formulations include various cytokines, for example, tumor necrosis factors, interleukins, and interferons discussed in U.S. Pat. No. 6,991,785 and growth and differentiation factor-5 (GDF-5) and related proteins discussed in US Publication No.
Targeting of drugs to the central nervous system (CNS) is a challenging task. A great number of drugs, including biotechnology products, are candidates for treatment of CNS diseases, but drug delivery is a problem for brain targeting. A limitation in the treatment of brain tumors is that less than 1% of most therapeutic agents administered systemically are able to cross the BBB. The transport of small molecules across the BBB is the exception rather than the rule, and 98% of all small molecules do not cross the BBB (Pardride, NeuroRx. 2005 January; 2(1): 1-2. 2005); approximately 100% of large-molecule drugs or genes do not cross the BBB (Pardride, NeuroRx. 2005 January; 2(1): 1-2. 2005). The BBB allows small (about less than 500 Da), lipophilic molecules from the bloodstream to enter the CNS (Pardridge, Arch Neurol. 2002; 59:35-40). Many larger therapeutic agents are prevented from reaching the brain for treating CNS disorders such as but not limited to Parkinson's disease, Alzheimer's disease, depression, stroke, and epilepsy (Pardridge, NeuroRx. 2005 January; 2(1): 3-14). Disorders including autism, lysosomal storage disorders, fragile X syndrome, ataxis, and blindness, are serious disorders where there is little effective treatment. In many of these cases, the gene underlying the disease is known, but BBB delivery is the rate-limiting problem in gene therapy or enzyme replacement therapy, and no therapeutics have been developed. Drug delivery of therapeutic compounds, for example proteins, faces several challenges because of their instability, high enzymatic metabolism, low gastrointestinal absorption, rapid renal elimination, and potential immunogenicity.
There is a need for devices that can deliver compounds to the upper nasal cavity for direct nose-to-brain delivery. Certain existing nasal drug delivery devices do not adequately propel the drug from the device. Inconsistent propulsion of drug due to inconsistent user actuation is also far from optimal. Still further, the plume generated by such existing devices is too wide. Even further, some drug products do not readily mix and/or stay suspended with propellants in a MDI type device. Certain existing nasal drug devices rely on circumferential velocity to propel medicaments to the olfactory epithelium. Traditional circumferential devices result in a lower percentage of compound deposited on the olfactory epithelium. A circumferential component in the aerosol plume tends to result in a wider spray plume with a portion of the aerosol particles targeted to the sides of the nasal cavity in the lower part of the nasal cavity.
Better mechanisms for administering desired agents to the brain, brain stem, and/or spinal cord are needed.
SUMMARY
A device for delivering a compound to the olfactory region of the nasal cavity is described including a canister capable of containing a propellant, a diffuser in communication with the canister, a compound chamber in communication with the diffuser, and a nozzle in communication with the compound chamber, wherein the device is capable of delivering the compound to the olfactory region of the nasal cavity.
In one aspect, the device includes a canister that is pressurized.
In another aspect, the propellant includes HFA, nitrogen, or CFC.
In another aspect, the device includes a compound chamber containing a drug or an imaging agent.
In yet another aspect, the drug is an oxime.
In yet another aspect, the diffuser is a frit.
In yet another aspect, the imaging agent is FDG or FLT.
In yet another aspect, the device includes a propellant, where the propellant is a pressurized liquid.
In yet another aspect, the pressurized liquid is HFA.
In another aspect, the pressurized liquid HFA is released from the canister and comes into contact with the diffuser, whereby the diffuser converts the pressurized liquid HFA to gaseous HFA.
In another aspect, the diffuser converts a minority of the pressurized liquid HFA to gaseous HFA
In a further aspect, the diffuser converts a majority of the pressurized liquid HFA to gaseous HFA.
In yet another aspect, the device delivers at least 62.6% of the compound to the olfactory region.
In yet another aspect, the he device delivers greater than 64.2% of the compound to the olfactory region.
In another aspect, the device delivers at least 64.3% of the compound to the olfactory region.
In yet another aspect, the device includes a canister where the canister is a syringe, syrette, or barrel.
In yet another aspect, the compound is not an imaging agent.
In further aspect, the compound is not FDG.
In one aspect, the drug is in the form of a liquid suspension, a liquid dispersion, a powder, or an aqueous solution.
In yet another aspect, the device further includes an aiming guide.
In yet another aspect, the aiming guide aides in positioning of the nozzle of the device at the user's olfactory region.
In yet another aspect, the devices further includes an insertion port m communication with the compound chamber.
In yet another aspect, the device further includes an indicator provided to alert the user to the length or amount of a capsule's insertion into the user's nasal cavity.
In one aspect, the diffuser is porous.
In another aspect, the diffuser is heterogeneously porous.
In another aspect, the diffuser is homogenously porous.
In another aspect, the diffuser is extended.
In yet another aspect, the diffuser is a disk-shaped member including conical shaped members having distal apertures.
In yet another aspect, the canister is a metered dose inhaler.
In another embodiment, a device for delivering a compound is described including a canister capable of containing a propellant, a diffuser in communication with the canister, a compound chamber in communication with the diffuser, and a nozzle in communication with the compound chamber, where the device is capable of delivering the compound to ear, skin, buccal cavity, or eyes.
In another embodiment, a method is described for delivering drug to the olfactory region of the nasal cavity including providing a canister capable of containing a propellant, a diffuser in communication with the canister, a compound chamber in communication with the diffuser, and a nozzle in communication with the compound chamber, where when actuated the device is capable of delivering the compound to the olfactory region of the nasal cavity.
In one aspect, the method includes the delivery of a drug for the treatment of an infectious disease, oncology, or immunological disease.
In one aspect, the method includes actuating the device to deliver propellant from the canister, whereby the diffuser diffuses the liquid propellant from the canister to a gaseous propellant, the gaseous propellant contacts the compound in the compound chamber and the compound and gaseous propellant exits the nozzle of the device.
In another aspect of the method, the diffuser converts a minority of the pressurized liquid HFA to gaseous HFA.
In another aspect of the method, the diffuser converts a majority of the pressurized liquid HFA to gaseous HFA.
In yet another aspect of the method, at least 64.2% of the compound is delivered to the olfactory region.
In yet another aspect of the method, greater than 64.2% of the compound is delivered to the olfactory region.
In another aspect of the method, the compound is a drug or diagnostic agent.
In another aspect of the method, the compound is a drug.
In yet another aspect of the method, the diagnostic agent is an imaging agent.
In yet another aspect of the method, the drug is an oxime.
In yet another aspect of the method, the imaging agent is fluorodeoxyglucose or fluorothymidine.
In yet another aspect of the method, the compound is not fluorodeoxyglucose.
In yet another aspect of the method, the compound is not an imaging agent.
In yet another aspect of the method, the drug is in the form of a liquid suspension, a liquid dispersion, a powder, liposome, or an aqueous solution and combinations thereof.
In yet another aspect of the method, the device includes one or more aiming guides.
In yet another aspect of the method, the aiming guide assists m the positioning of the nozzle of the device at the user's olfactory region.
In another aspect of the method, the device includes an insertion port in communication with the compound chamber.
In an aspect of the method, the device includes an indicator provided to alert the user to the depth of insertion of the device into the user's nasal cavity.
In another aspect of the method, the diffuser is porous.
In another aspect of the method, the diffuser is heterogeneously porous.
In another aspect of the method, the diffuser is homogenously porous.
In an aspect of the method, the diffuser is extended.
In another aspect of the method, the diffuser is a disk-shaped member including conical shaped members having distal apertures.
In an aspect of the method, the canister is a metered dose inhaler.
In another embodiment, an intranasal formulation of an oxime for use in treating exposure to an organophosphate is described.
In yet another embodiment, a method is described for delivering an oxime across the blood brain barrier to a subject in need thereof including administering to the subject a therapeutically effective dosage of an oxime, wherein the dosage is delivered to the upper olfactory region of the nasal cavity.
In one aspect of the method, the therapeutically effective amount of an oxime administered to the user is within the range of about 0.001 mg/kg to about 100 mg/kg. In another aspect of the method, the therapeutically effective amount of an oxime
administered to the user is within the range of about 0.01 mg/kg to about 10 mg/kg.
In yet another aspect of the method, the therapeutically effective amount of an oxime administered to the user is within the range of about 0.1 mg/kg to about 1 mg/kg.
In yet another aspect, the method described for delivering an oxime is for treatment of organophosphate exposure.
In another embodiment, a method of delivering an oxime intranasally to a user is described including providing a nasal dosage form of the oxime, propelling the nasal dosage form with a propellant, and delivering the nasal dosage form to the nasal cavity of the user, so that the oxime is delivered to the nasal cavity and subsequently to the central nervous system and/or brain of the user.
In one aspect, the oxime delivered includes 2-PAM, MMB4, HI6, TMB4 or Hlo7 and combinations thereof.
In another aspect, the nasal dosage form of the ox 1 me is a powder, an aqueous solution, a suspension or a lipid containing product and combinations thereof.
In another aspect, the user has been exposed to an organophosphate drug including sarin, tabun, soman, Russian VX or diisopropylfluorophosphate and combinations thereof.
In another aspect, a majority of the oxime in nasal dosage form is deposited within the nasal cavity.
In another aspect, a nasal dosage form of a muscarinic receptor agonist or a muscarinic receptor antagonist is delivered intranasally.
In yet another aspect, a nasal dosage form of atropine or scopolamine or combinations thereof is provided intranasally.
In yet another aspect, a nasal dosage form a benzodiazepine antagonist is provided intranasally.
In yet another aspect, the benzodiazepine antagonist includes diazepam, midazolam or lorazepam or combinations thereof.
In yet another aspect, the nasal dosage form is a benzodiazepine antagonist, a muscarinic receptor agonist or a muscarinic receptor antagonist or combinations thereof.
In yet another aspect, the intranasal dosage form includes diazepam, midazolam, lorazepam, atropine or scopolamine or combinations thereof.
In yet another aspect, the nasal dosage form is delivered to the nasal cavity of the user exposed to an organophosphate.
In another aspect, the nasal dosage form is delivered to the nasal cavity of the user before the exposure to an organophosphate.
In yet another aspect, the nasal dosage form is delivered to the nasal cavity of the user after the exposure to an organophosphate.
In yet another aspect, exposure to the oxime increases oxime exposure to the CNS. In yet further aspects, at least 53% of the oxime is directly transported (DTP) to the brain.
The invention will best be understood by reference to the following detailed description of various embodiments, taken in conjunction with the accompanying drawings. The discussion below is descriptive, illustrative and exemplary and is not to be taken as limiting the scope defined by any appended claims.
BRIEF DESCRIPTION OF DRAWINGS
FIG. 1 is a schematic drawing of one embodiment of the invention.
FIG. 2 shows an embodiment of the invention.
FIG. 3 shows an embodiment of the invention.
FIG. 4 shows another embodiment of the invention.
FIG. 5 shows another embodiment of the invention.
FIG. 6 shows another embodiment of the invention.
FIG. 7 shows another embodiment of the invention.
FIG. 8 shows another embodiment of the invention with a nasal guide attached.
FIG. 9 shows an embodiment of a diffuser and compound chamber, whereby the diffuser is cylindrical and homogeneously porous.
FIG. 10 shows an embodiment of a diffuser and compound chamber, whereby the diffuser is cylindrical and homogeneously porous with a non-porous open tipped cone extending into the drug product.
FIG. 11 shows an embodiment of a diffuser and compound chamber, whereby the diffuser is cylindrical with an open tipped cone extending into the drug product and is homogeneously porous.
FIG. 12 shows an embodiment of a diffuser and compound chamber, whereby the diffuser is cylindrical with many open tipped cones extending from it which allow gaseous propellant to enter the compound chamber.
FIG. 13 shows an embodiment of a diffuser and compound chamber, whereby the diffuser is cylindrical with many cones extending from it which allow gaseous propellant to enter the drug chamber. It also includes a tube which allows propellant to enter the compound chamber ahead of the drug to assist in aerosolization.
FIG. 14 shows an embodiment of a diffuser and compound chamber, whereby the diffuser is cylindrical and homogeneously porous. It also includes a tube which allows propellant to enter the compound chamber ahead of the drug to assist in aerosolization.
FIG. 15 shows an embodiment of the invention where the propellant is created by manual air compression.
FIG. 16 A shows an embodiment of the device which has a compound chamber within the device body which allows for propellant flow through and around the compound chamber. FIG. 16 B shows a cross section of the device of FIG. 16 A .
FIG. 17 shows a schematic drawing of the device used to administer 2-PAM drug to rats in Example 1.
FIG. 18 demonstrates deposition testing of the POD device in the rat nasal cavity of 2-PAM (dark shading) being deposited on the olfactory region (light circle). Little drug was deposited on either the respiratory region of the nasal cavity and none was found in the trachea or esophagus.
FIG. 19 is a graph demonstrating POD administration of a 2.5 mg dose of 2-PAM that resulted in significantly lower plasma values at every point in the first 60 minutes and overall lower plasma AUC. *=p<0.05
FIG. 20 is a graph demonstrating POD administration of a 2.5 mg dose of 2-PAM that resulted in significantly higher brain values at 5 and 120 minutes and an overall higher brain AUC. *=p<0.05
FIG. 21 shows the human nasal cavity model which was used m the deposition testing of the model drug fluorescein described in Example 3.
FIG. 22 shows a processed image of human nasal cavity deposition as described in Example 3. Five separate parts, vestibule 2200 , turbinates 2202 , olfactory 2204 , base 2206 , and esophagus 2208 , were analyzed for deposition after a spray of the device. FIG. 22 shows a majority of the spray to be in the olfactory region.
FIG. 23 is a schematic showing the experimental setup for the impaction testing described in Example 4.
FIG. 24 is a schematic of the experimental setup for estimating any temperature changes on a surface that the device is targeting, which is described in Example 5. A laser thermometer was used to measure the surface temperature of a target. The device sprayed either only HFA gas or HFA gas mixed with a liquid dose and any temperature fluctuations were noted.
DETAILED DESCRIPTION OF THE EMBODIMENTS
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art pertinent to the methods and compositions described. As used herein, the following terms and phrases have the meanings ascribed to them unless specified otherwise:
As used herein the specification, âaâ or âanâ may mean one or more.
A âdiagnostic agentâ refers to and encompasses an atom, molecule, or compound that is useful in diagnosing a disease. Diagnostic agents include, but are not limited to, radioisotopes, dyes, contrast agents, fluorescent compounds or molecules and enhancing agents (e.g., paramagnetic ions). A non-radioactive diagnostic agent is a contrast agent suitable for magnetic resonance imaging, computed tomography or ultrasound. The diagnostic agent can be used to perform positron emission tomography (PET), MRI, X-ray, CT, ultrasound, operative, intravascular, laparoscopic, or endoscopic procedure.
A âdiffuserâ refers to and encompasses a device for dispersing or deflecting a compound in various directions.
A âfritâ shall refer to and encompass a porous member or filter.
An âimaging agentâ refers to and encompasses an atom, molecule or compound that is useful in detecting physical changes or produces images of internal body tissues. In some aspects, the imaging agent may be a diagnostic agent.
A âpropellantâ shall refer to and encompass a compound that acts as a vehicle for creating propulsion or thrust.
The term âtherapeutically effective amountâ refers to and encompasses an amount of a drug effective to treat a disease or disorder in a mammal. In one aspect, the therapeutically effective amount refers to a target CNS concentration that has been shown to be effective in, for example, slowing disease progression. Efficacy can be measured in conventional ways, depending on the condition to be treated.
The term âtreatmentâ and âtreatâ, and the like, refers to and encompasses therapeutic or suppressive measures for a disease or disorder leading to any clinically desirable or beneficial effect, including, but not limited to, alleviation or relief of one or more symptoms, regression, slowing or cessation of progression of the disease or disorder. Treatment can be evidenced as a decrease in the severity of a symptom, the number of symptoms, or frequency of relapse.
A âuserâ or âsubjectâ shall refer to and encompass a human or other animal. For example, the animal may be a primate or a non primate and may include a rabbit, bovine, equine, pig, rat, mouse, dog or cat.
The device may be used in treatment, prevention, palliative care for humans and veterinary purposes. The device may be used in research and industrial uses. For example, the device may be used to deposit compound in agricultural settings.
When trade names are used herein, applicants intend to independently include the trade name product formulation, the generic drug, and the active pharmaceutical ingredient(s) of the trade name product.
For clarity of disclosure, and not by way of limitation, the detailed description of the invention is divided into the subsections which follow.
Intranasal administration of compounds offers several advantages over traditional surgical, intravenous or oral routes for administration across the blood brain barrier (BBB). Intranasal administration to the olfactory region avoids gastrointestinal destruction and hepatic first pass metabolism, such as destruction of drugs by liver enzymes, allowing more drug to be cost-effectively, rapidly, and predictably bioavailable than if it were administered orally. Intranasal administration provides ease, convenience and safety. Intranasal drug administration is generally painless (taking into consideration that pain may be a subjective measurement which varies by patient) and does not require sterile technique, intravenous catheters or other invasive devices, and is generally immediately and readily available for all patients. Intranasal administration can rapidly achieve therapeutic brain and spinal cord drug concentrations.
Nasally administered compounds contact the upper olfactory region and molecular transport occurs directly across this tissue and into compartments of the central nervous system. (Henry, R. J., et al., Pediatr Dent, 1998. 20(5): p. 321-6; Sakane, T., et al., J Pharm Pharmacol, 1991. 43(6): p. 449-51; Banks, W. A., et al., J Pharmacol Exp Ther, 2004. 309(2): p. 469-75; Westin, et al., Pharm Res, 2006. 23(3): p. 565-72). The olfactory mucosa is located in the upper nasal cavity, just below the cribriform plate of the skull. It contains olfactory cells which traverse the cribriform plate and extend up into the cranial cavity. When compounds come in contact with this specialized mucosa, they are rapidly transported directly into the brain, they bypass the BBB, and are rapidly transported directly into the central nervous system, often faster than if the compound is given intravenously.
The olfactory mucosa includes the olfactory epithelium. The olfactory epithelium is located at the top of the nose between the superior turbinate and the roof of the nasal cavity, just beneath the cribriform plate of the ethmoid bone. In humans, it covers about 10 to about 20 cm2, or about 8% of the total nasal surface area, and is composed of four main cell types: epithelial cells, olfactory receptor neurons, supporting cells, and basal cells. (Mathison S. et al., (1998) Journal of Drug Targeting 5: 415-441). Although 3% of the nasal cavity is occupied by olfactory epithelium (Morrison and Costanzo, 1990), this route is direct, since the olfactory neurons do not have a synapse between the receptive element and the afferent path (Ding and Dahl, 2003). The olfactory epithelium is more than twice the depth of the respiratory epithelium, with the olfactory nerve cell bodies typically located in the middle and deeper regions of the epithelium while nuclei of the supporting cells are organized in a single layer closer to the mucosal surface. Tight junctions exist between the supporting cells and between the supporting cells and olfactory nerve cells. Morrison E. E, et al. (1992) Journal of Comparative Neurology 297(1): 1-13.
When a nasal drug formulation is delivered deep and high enough into the nasal cavity, the olfactory mucosa is reached and drug transport into the brain and/or CSF via the olfactory receptor neurons occurs. The transfer of compounds from the nose to the brain is referred to as the nose-brain pathway. The nose-brain pathway has implications when centrally acting medications such as but not limited to sedatives, anti-seizure drugs and opiates are delivered nasally. The present device allows for delivery via the nose-brain pathway allowing for nearly immediate delivery of nasal medications to the central nervous system and brain, by-passing the blood brain barrier.
The current challenge in nose-to-brain drug delivery is also due to the complex architecture of the nose, which is naturally designed to channel drugs into the lower nasal airway toward the lungs making it difficult for drugs to reach the olfactory region. Most of the drug dispensed from traditional nasal devices such as sprayers or pumps is subjected to the natural air movement in the nasal cavity towards the esophagus. The majority of the spray dispensed from traditional devices encounters the natural downward airflow displacement within the nasal cavity. The remaining fraction from traditional devices is found in the respiratory epithelium and cleared by the mucocilliary clearance mechanism or absorbed into the blood stream. While nasal catheter instillation and nose drops are less impacted by this natural downward air movement, it requires subjects to be in a supine position, is often associated with user discomfort, and is not optimal for frequent clinical administration.
Moreover, a reservoir of residual air exists at the top of the nasal cavity that is not removed during normal respiration; thus remaining in the olfactory region and acting as a barrier to deposition. This residual air must be displaced in order to deliver aerosolized drug to the olfactory epithelium in the upper nasal cavity in a consistent manner. The device described herein delivers a majority of the aerosolized drug to the upper part of the nasal cavity to increase exposure of the drug at the olfactory epithelium, a site of nose-to-brain pathway, by both avoiding the natural downward air movement and displacing the residual air of the upper nasal cavity.
The device herein advantageously and consistently deposits a large fraction of dose into the more distal parts of the nasal cavity such as the olfactory region. A drug product (also referred to herein as drug formulation or nasal dosage form) is propelled from the device with a velocity into the nasal cavity.
FIG. 1 shows one embodiment of the device where a container 10 contains a propellant. The propellant may be pressurized. The propellant is a fluid, for example, a liquid or gas. In one aspect, the propellant is a liquid. In another aspect, the propellant is a gas. Propellants include pharmaceutically suitable propellants. Some examples of pharmaceutically suitable propellants include hydrofluoroalkane (HFA) including but not limited to HFA, HFA 227 , HFA 134 a , HFA-FP, HFA-BP and the like HFA's. In one aspect, the propellant is liquid HFA In another aspect, the propellant is gaseous HFA. Additional examples of suitable propellants include nitrogen or choloroflourocarbons (CFC). Additionally, propellants may be pressurized air (e.g. ambient air). The container 10 may be a conventional metered dose inhaler (MDI) device that includes a pressurized canister, metering valve (including stem) to meter the propellant upon actuation. In certain aspects, the propellant is not metered upon actuation. In one aspect, the container 10 does not contain drug. In another aspect, the container includes a propellant and a drug.
The container 10 is in communication with a diffuser 12 . For example, when the diffuser 12 is in communication with the container 10 , âcommunicationâ shall refer to and encompass congruousness or fluid communication. The propellant from the container 10 is diffused via the diffuser 12 . In one aspect, a majority of the propellant is diffused via the diffuser 12 . In another aspect, a minority of the propellant is diffused via the diffuser 12 . Majority refers to and encompasses at least 50 percent. Minority refers to and encompasses less than 50 percent. In another aspect, at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or about 100%, inclusive of endpoints, of the propellant is diffused via the diffuser 12 . The diffuser 12 is in communication with the compound chamber 14 . The compound chamber 14 is capable of holding a compound, such as but not limited to a drug or/and a diagnostic agent. In one aspect, the diagnostic agent is an imaging agent. In an example, the imaging agent is fluorodeoxyglucose (FDG) or fluorothymidine (FLT). In another aspect, the compound is a drug. In another aspect, the compound is not an imaging agent. In one aspect, the compound is a liquid. In another aspect, the compound is a powder. In yet another aspect, the compound is an intranasal formulation of a drug in a liquid or powdered state. The intranasal formulation may contain suitable intranasal carriers and excipients known in the art.
The propellant in the container 10 acts as a vehicle to deliver propulsion or thrust to expel from the compound chamber 14 the compound. The compound chamber 14 is in communication with a nozzle 16 . The propulsion or thrust from the propellant is capable of expelling the compound from the compound chamber 14 and nozzle 16 when in communication with the compound chamber 14 .
In one aspect, when the MDI device is actuated, a discrete amount of pressurized HFA fluid is released. The MDI may contain between about 30 to about 300 actuations, inclusive of endpoints, of HFA propellant. The amount of fluid propellant released upon actuation may be between about 20 and about 200 μl, inclusive of endpoints, of liquid propellant.
FIG. 2 shows one embodiment of the device. The actuator body 20 houses a container 10 , in one aspect the container 10 is a metered dose inhaler that includes a propellant canister 18 having a neck 19 and a metering valve assembly 21 . A valve stem 23 is in communication with a connection channel 22 . The propellant exiting the valve stem 23 is a fluid. The fluid may be liquid, gas, or a combination. A diffuser 28 is in communication with the propellant exiting the container 10 and the compound chamber 14 .
Propellant exiting the container 10 comes into contact with the diffuser 28 . The diffuser 28 is capable of converting liquid propellant exiting the container 10 into gaseous propellant. In one aspect, the diffuser 28 is capable of converting all or a majority of the liquid propellant into gaseous propellant. In another aspect, the diffuser is capable of converting a minority of the liquid propellant into gaseous propellant. Majority refers to and encompasses at least 50 percent.
Minority refers to and encompasses less than 50 percent. In another aspect, at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or about 100%, inclusive of endpoints, of the liquid propellant is converted into gaseous propellant. Following contact with the diffuser 28 , the diffused propellant comes into contact with the compound in the compound chamber 14 . The diffused propellant and the compound come into contact with each other as the propellant propels the compound in the compound chamber 14 . The nozzle 16 is in fluid communication with the compound chamber 14 . The compound is propelled by the diffused propellant into communication with the nozzle 16 . The propellant propels the compound to be expelled via the distal end of the nozzle 16 . Exiting from the nozzle 16 is compound, propellant, or a combination thereof.
In some aspects, the diffuser 28 functions to convert propellant from a liquid to a gas. In other aspects, the diffuser 28 functions to prevent the compound contained in the compound chamber 14 from coming in contact with the container 10 . In another aspect, the diffuser acts as a one way check valve. In other aspects, the diffuser 28 functions to convert propellant from a liquid to a gas and to prevent the compound contained in the compound chamber 14 from coming into contact with the container 10 . In yet another aspect, the diffuser functions to increase the temperature of the propellant.
An examp
CLAIMS
Claims ( 20 )
What is claimed is:
1 . A device for delivery of a compound to a nasal cavity, the device comprising:
an air compression chamber; a manual pressure actuator that causes air to be released from the air compression chamber upon actuation; a diffuser in communication with the air compression chamber; a drug chamber in communication with the diffuser, the drug chamber configured to hold the compound; and a nozzle in communication with the drug chamber, wherein air released from the air compression chamber is configured to contact the diffuser, and propel the compound out of the nozzle forming a plume.
2 . The device of claim 1 , wherein the manual pressure actuator further comprises a lock pin, wherein the lock pin is configured to maintain high pressure air in the air compression chamber.
3 . The device of claim 1 , further comprising a trigger valve in communication with the air compression chamber such that when the trigger valve is rotated from an open state to a closed state, air in the air compression chamber is blocked from contacting the diffuser and propelling the compound out of the nozzle.
4 . The device of claim 1 , wherein the manual pressure actuator comprises a piston.
5 . The device of claim 1 , wherein the manual pressure actuator comprises a syringe.
6 . The device of claim 1 , wherein the manual pressure actuator comprises a syrette.
7 . The device of claim 1 , wherein the diffuser is heterogeneously porous or homogenously porous.
8 . The device of claim 1 , wherein the compound is a drug or diagnostic agent.
9 . The device of claim 8 , wherein the diagnostic agent is an imaging agent.
10 . The device of claim 1 , wherein the diffuser is porous, the porous diffuser being a disk-shaped member including at least one conical shaped member having a distal aperture.
11 . The device of claim 1 , wherein the diffuser is configured to act as a one-way check valve.
12 . The device of claim 1 , wherein the diffuser extends into the compound in the drug chamber.
13 . A device for delivering a compound to a nasal cavity, the device comprising:
an air compression chamber; a manual pressure actuator comprising a lock pin, the manual pressure actuator configured to release air from the air compression chamber, the lock pin configured to maintain high pressure air in the air compression chamber, a trigger valve configured to be in communication with the air compression chamber such that when the trigger valve is rotated from an open state to a closed state, air in the air compression chamber is blocked from exiting the air compression chamber; a diffuser in communication with the trigger valve; a drug chamber in communication with the diffuser, the drug chamber configured to hold the compound; and a nozzle in communication with the drug chamber, wherein air released from the air compression chamber is configured to contact the diffuser, and propel the compound out of the nozzle forming a plume.
14 . The device of claim 13 , wherein the manual pressure actuator further comprises a piston.
15 . The device of claim 13 , wherein the manual pressure actuator further comprises a syringe.
16 . The device of claim 13 , wherein the manual pressure actuator further comprises a syrette.
17 . The device of claim 13 , wherein the diffuser is heterogeneously porous or homogenously porous.
18 . The device of claim 13 , wherein the diffuser is configured to act as a one-way check valve.
19 . The device of claim 13 , wherein the diffuser is porous, the porous diffuser being a disk-shaped member including at least one conical shaped member having a distal aperture.
20 . The device of claim 13 , wherein the diffuser extends into the compound in the drug chamber.
US18/346,244
2011-03-03
2023-07-02
Nasal drug delivery device
Pending
US20240181183A1
( en )
Priority Applications (1)
Application Number
Priority Date
Filing Date
Title
US18/346,244
US20240181183A1
( en )
2011-03-03
2023-07-02
Nasal drug delivery device
Applications Claiming Priority (9)
Application Number
Priority Date
Filing Date
Title
US201161449008P
2011-03-03
2011-03-03
US201161451935P
2011-03-11
2011-03-11
US201161484025P
2011-05-09
2011-05-09
US201161498974P
2011-06-20
2011-06-20
PCT/US2012/027754
WO2012119153A2
( en )
2011-03-03
2012-03-05
Nasal drug delivery device
US14/017,048
US9550036B2
( en )
2011-03-03
2013-09-03
Nasal drug delivery device
US15/338,097
US10507295B2
( en )
2011-03-03
2016-10-28
Nasal drug delivery device
US16/664,588
US11730903B2
( en )
2011-03-03
2019-10-25
Nasal drug delivery device
US18/346,244
US20240181183A1
( en )
2011-03-03
2023-07-02
Nasal drug delivery device
Related Parent Applications (1)
Application Number
Title
Priority Date
Filing Date
US16/664,588
Continuation
US11730903B2
( en )
2011-03-03
2019-10-25
Nasal drug delivery device
Publications (1)
Publication Number
Publication Date
US20240181183A1
true
US20240181183A1 ( en )
2024-06-06
Family
ID=46758525
Family Applications (4)
Application Number
Title
Priority Date
Filing Date
US14/017,048
Active
2032-09-05
US9550036B2
( en )
2011-03-03
2013-09-03
Nasal drug delivery device
US15/338,097
Active
2032-12-25
US10507295B2
( en )
2011-03-03
2016-10-28
Nasal drug delivery device
US16/664,588
Active
2034-09-26
US11730903B2
( en )
2011-03-03
2019-10-25
Nasal drug delivery device
US18/346,244
Pending
US20240181183A1
( en )
2011-03-03
2023-07-02
Nasal drug delivery device
Family Applications Before (3)
Application Number
Title
Priority Date
Filing Date
US14/017,048
Active
2032-09-05
US9550036B2
( en )
2011-03-03
2013-09-03
Nasal drug delivery device
US15/338,097
Active
2032-12-25
US10507295B2
( en )
2011-03-03
2016-10-28
Nasal drug delivery device
US16/664,588
Active
2034-09-26
US11730903B2
( en )
2011-03-03
2019-10-25
Nasal drug delivery device
Country Status (9)
Country
Link
US
( 4 )
US9550036B2
( en )
EP
( 3 )
EP2680913B1
( en )
JP
( 1 )
JP6339371B2
( en )
CN
( 1 )
CN103917265B
( en )
AU
( 3 )
AU2012223160B2
( en )
BR
( 2 )
BR122021002471B8
( en )
CA
( 2 )
CA2828884C
( en )
RU
( 2 )
RU2612506C2
( en )
WO
( 1 )
WO2012119153A2
( en )
Families Citing this family (54)
* Cited by examiner, â Cited by third party
Publication number
Priority date
Publication date
Assignee
Title
RU2612506C2
( en )
2011-03-03
2017-03-09
Ðмпел ÐÑÑÑоÑаÑма Ðнк.
Nasal drug delivery device
WO2012154859A1
( en )
2011-05-09
2012-11-15
Impel Neuropharma Inc.
Nozzles for nasal drug delivery
EP2991713B1
( en )
*
2013-04-28
2019-06-19
Impel Neuropharma Inc.
Medical unit dose container
WO2015044782A2
( en )
2013-09-24
2015-04-02
Shin Nippon Biomedical Laboratories, Ltd.
Intranasal dhe for the treatment of headache
GB201401659D0
( en )
*
2014-01-31
2014-03-19
3M Innovative Properties Co
Actuator for an inhaler
EP3145567B1
( en )
*
2014-05-19
2019-01-30
Inhaletech LLC
Device for administering medicaments to the brain by the nasal route
US11559483B2
( en )
*
2015-07-10
2023-01-24
Sanjay Gupta
Nasal foam via cribriform plate for medication delivery to the brain and/or body and for nasal moisturization and hygiene
NZ741171A
( en )
*
2015-09-10
2022-01-28
Impel Neuropharma Inc
In-line nasal delivery device
EP3162404B1
( en )
*
2015-10-29
2018-02-14
W & H Dentalwerk Bürmoos GmbH
Dental device for delivering a powdery medium
WO2017085362A1
( en )
2015-11-18
2017-05-26
Herantis Pharma Plc
Compositions comprising cdnf or manf for use in the intranasal treatment of central nervous system diseases
US10940274B2
( en )
2015-12-01
2021-03-09
Cipla Limited
Nasal spray assembly
FR3046553B1
( en )
*
2016-01-07
2018-02-16
Aptar France Sas
NASAL DISTRIBUTION SET OF FLUID PRODUCT.
KR101978554B1
( en )
*
2016-05-17
2019-05-16
íìëíêµ ì°ííë ¥ë¨
Drug Delivery Device for nasal cavity to brain
WO2017205610A1
( en )
*
2016-05-25
2017-11-30
University Of Florida Research Foundation, Inc.
Use of angiotensin ii receptor agonists in the treatment and prevention of stroke
GB201619637D0
( en )
2016-11-21
2017-01-04
Pekna Marcela And Pekny Milos And Stokowska Anna
C3a receptor agonists
EP3634528B1
( en )
2017-06-07
2023-06-07
Shifamed Holdings, LLC
Intravascular fluid movement devices, systems, and methods of use
EP3682922B1
( en )
2017-09-15
2024-02-28
Shin Nippon Biomedical Laboratories, Ltd.
Medicine storage cartridge with nozzle, sprayer therefor, and powdered medicine dispensing device for nasal cavity
US10368502B2
( en )
2017-09-25
2019-08-06
Multiple Energy Technologies Llc
Bioceramic and carbon-based hydroponic systems, methods and devices
US11511103B2
( en )
2017-11-13
2022-11-29
Shifamed Holdings, Llc
Intravascular fluid movement devices, systems, and methods of use
KR102168749B1
( en )
*
2017-11-17
2020-10-22
íìëíêµ ì°ííë ¥ë¨
Brain drug delivery device through nasal cavity and brain drug delivery method through nasal cavity
CA3081680A1
( en )
*
2017-11-21
2019-05-31
Impel Neuropharma, Inc.
Intranasal device with inlet interface
US10391269B2
( en )
*
2017-11-29
2019-08-27
Meshil A. M. O. H. Al-Jarba
Nasal sprayer with multiple applicators
US11918646B2
( en )
*
2017-12-11
2024-03-05
Board Of Regents, The University Of Texas System
Dry adjuvanted immune stimulating compositions and use thereof for mucosal administration
JP7317020B2
( en )
2018-01-05
2023-07-28
ã¤ã³ãã« ãã¡ã¼ãã·ã¥ã¼ãã£ã«ã«ãº ã¤ã³ã³ã¼ãã¬ã¤ããã
Intranasal delivery of dihydroergotamine by a precision olfactory device
BR112020013749A2
( en )
*
2018-01-05
2020-12-01
Impel Neuropharma, Inc.
intranasal dispensing of levodopa powder by precision olfactory device
US11278492B2
( en )
*
2018-01-05
2022-03-22
Impel Neuropharma, Inc.
Intranasal delivery of olanzapine by precision olfactory device
EP3746149B1
( en )
2018-02-01
2025-08-06
Shifamed Holdings, LLC
Intravascular blood pumps
DK3773834T3
( en )
2018-04-12
2025-05-19
Rocket Science Health Corp
INTRANASAL FLUID ADMINISTRATION DEVICE
JP2021532098A
( en )
2018-07-19
2021-11-25
ã¤ã³ãã« ãã¥ã¼ããã¡ã¼ã ã¤ã³ã³ã¼ãã¬ã¤ããã
Respiratory tract delivery of levodopa and dopa decarboxylase inhibitors for the treatment of Parkinson's disease
WO2020028537A1
( en )
2018-07-31
2020-02-06
Shifamed Holdings, Llc
Intravascaular blood pumps and methods of use
WO2020073047A1
( en )
2018-10-05
2020-04-09
Shifamed Holdings, Llc
Intravascular blood pumps and methods of use
EP3893877A4
( en )
2018-12-11
2022-09-14
Satsuma Pharmaceuticals, Inc.
COMPOSITIONS, DEVICES AND METHODS FOR THE TREATMENT OR PREVENTION OF HEADACHES
AU2019418744B2
( en )
*
2019-01-03
2023-08-03
Impel Pharmaceuticals Inc.
Nasal drug delivery device
US11433063B1
( en )
*
2019-03-12
2022-09-06
Belhaven Biopharma, Inc.
Intranasal composition of pharmaceutical countermeasures for chemical warfare nerve agents and accidental exposure to organophosphate pesticides
US20220304980A1
( en )
*
2019-07-04
2022-09-29
SW Holdings, Inc
Metered dosing compositions and methods of use of psychedelic compounds
WO2021011473A1
( en )
2019-07-12
2021-01-21
Shifamed Holdings, Llc
Intravascular blood pumps and methods of manufacture and use
US11654275B2
( en )
2019-07-22
2023-05-23
Shifamed Holdings, Llc
Intravascular blood pumps with struts and methods of use and manufacture
US12465748B2
( en )
2019-08-07
2025-11-11
Supira Medical, Inc.
Catheter blood pumps and collapsible pump housings
EP4501393A3
( en )
2019-09-25
2025-04-09
Shifamed Holdings, LLC
Catheter blood pumps and collapsible pump housings
US11724089B2
( en )
2019-09-25
2023-08-15
Shifamed Holdings, Llc
Intravascular blood pump systems and methods of use and control thereof
WO2021062260A1
( en )
2019-09-25
2021-04-01
Shifamed Holdings, Llc
Catheter blood pumps and collapsible blood conduits
EP4072650A4
( en )
2019-12-11
2024-01-10
Shifamed Holdings, LLC
DESCENDING AORTA AND VEINA CAVA BLOOD PUMPS
EP4077947A4
( en )
2019-12-19
2024-01-10
Shifamed Holdings, LLC
Intravascular blood pumps, motors, and fluid control
AU2021209916A1
( en )
*
2020-01-22
2022-07-21
Virginia Commonwealth University
Air-jet dry power inhaler for rapid delivery of pharmaceutical aerosols to infants
WO2021185343A1
( en )
*
2020-03-20
2021-09-23
æ±èæçå»è¯è¡ä»½æéå ¬å¸
Glyburide liposome composition and preparation method therefor
WO2021191904A1
( en )
*
2020-03-26
2021-09-30
Tree Of Life Pharma Ltd.
Methods for preventing and treating viral infection
RU2745231C9
( en )
*
2020-06-08
2021-04-27
ÐкÑионеÑное обÑеÑÑво "СÑолеÑика"
Spray inhaler with preparation and storage functions
US20230395254A1
( en )
*
2020-07-27
2023-12-07
Takeda Pharmaceutical Company Limited
Nausea and Vomiting Management System
GB202011729D0
( en )
2020-07-29
2020-09-09
Kindeva Drug Delivery Lp
Device for delivery of a compound to a region of the nasal cavity
WO2022049077A1
( en )
*
2020-09-01
2022-03-10
Janssen Pharmaceutica Nv
Drug delivery device with a spinning nozzle
FR3120534B1
( en )
*
2021-03-09
2023-06-30
Aptar France Sas
Nasal dispensing head for fluid product and device comprising such a head
CN113491608B
( en )
*
2021-05-18
2023-05-30
æå¯è´¢
Pneumatic supporting plug for shaping after rhinoplasty
US12005185B2
( en )
2021-12-17
2024-06-11
Belhaven BioPharma Inc.
Medical counter measures including dry powder formulations and associated methods
GB2701066A
( en )
*
2023-08-30
2026-04-15
Envirohale Malta Holdings Ltd
Nasal and pulmonary drug delivery
Citations (10)
* Cited by examiner, â Cited by third party
Publication number
Priority date
Publication date
Assignee
Title
US2574339A
( en )
*
1945-02-03
1951-11-06
Marshall L Lockhart
Hypodermic syringe
US3957033A
( en )
*
1973-08-15
1976-05-18
General Electric Company
Ventilation study system
US4154309A
( en )
*
1977-11-14
1979-05-15
J & D Tool and Supply, Inc.
Housing for fluid actuated hand tool
US4949715A
( en )
*
1987-08-12
1990-08-21
Stephan Brugger
Transportable inhalation device
US20030021775A1
( en )
*
2001-07-27
2003-01-30
Ramot University Authority For Applied Research & Industrial Development Ltd.
Device for and method of controlled enzymatic removal and retrieval of tissue
US20040134494A1
( en )
*
2001-03-15
2004-07-15
Papania Mark James
Systems and methods for aerosol delivery of agents
US20050240147A1
( en )
*
2004-04-21
2005-10-27
Exploramed Ii, Inc.
Devices, systems and methods for diagnosing and treating sinusitus and other disorders of the ears, nose and/or throat
US20090223513A1
( en )
*
2004-04-02
2009-09-10
Mark J Papania
Aerosol delivery systems and methods
US20110045088A1
( en )
*
2009-07-31
2011-02-24
Shin Nippon Biomedical Laboratories, Ltd.
Intranasal granisetron and nasal applicator
US10507295B2
( en )
*
2011-03-03
2019-12-17
Impel Neuropharma, Inc.
Nasal drug delivery device
Family Cites Families (202)
* Cited by examiner, â Cited by third party
Publication number
Priority date
Publication date
Assignee
Title
GB806284A
( en )
1955-11-14
1958-12-23
Chi Ah Lai
A new or improved nasal inhaler
US3425414A
( en )
*
1965-05-28
1969-02-04
William J La Roche
Inhalant dispenser
US3888253A
( en )
1972-08-04
1975-06-10
Beecham Group Ltd
Device for administration of medicines
FR2224175B1
( en )
1973-04-04
1978-04-14
Isf Spa
GB1479283A
( en )
1973-07-23
1977-07-13
Bespak Industries Ltd
Inhaler for powdered medicament
US3971377A
( en )
1974-06-10
1976-07-27
Alza Corporation
Medicament dispensing process for inhalation therapy
US3908654A
( en )
1974-08-02
1975-09-30
Rit Rech Ind Therapeut
Dispensing package for a dry biological and a liquid diluent
YU41046B
( en )
*
1974-08-22
1986-10-31
Schering Ag
Medicine inholating device
US3998226A
( en )
1975-09-22
1976-12-21
Edward G. Gomez
Inhalation device for encapsulated concentrates
ZA758010B
( en )
1975-11-14
1977-08-31
Syntex Inc
Nasal spray adapter
SE408265B
( en )
1975-12-12
1979-06-05
Draco Ab
DEVICE FOR CARBON DIOXIDE POWERED ENDOSAEROSOL, INTENDED FOR INHALATION
US4095596A
( en )
1976-11-26
1978-06-20
Smithkline Corporation
Nasal inhaler
US4227522A
( en )
1978-09-05
1980-10-14
Syntex Puerto Rico, Inc.
Inhalation device
US4187985A
( en )
1978-12-08
1980-02-12
The Continental Group, Inc.
Aerosol valve for barrier type packages
IT1116047B
( en )
1979-04-27
1986-02-10
Sigma Tau Ind Farmaceuti
DEVICE FOR THE QUICK INHALATION OF POWDER DRUGS BY PERSONS SUFFERING FROM ASTHMA
BR8007911A
( en )
1979-12-06
1981-06-16
Glaxo Group Ltd
PERFECTED INHALER
US4412573A
( en )
1981-12-28
1983-11-01
Baxter Travenol Laboratories, Inc.
Injection site
US4446990A
( en )
1982-04-03
1984-05-08
David J. Stevenson
Self-defense spray device
EP0162854A1
( en )
1983-11-28
1985-12-04
Vortran Corporation
Gas-powered nebulizer
AU3439884A
( en )
1983-11-28
1985-06-13
Vortran Corp.
Single inlet prepackaged inhaler
WO1986001731A1
( en )
1984-09-18
1986-03-27
Vortran Corporation
All purpose nebulizer
US4896832A
( en )
1987-09-07
1990-01-30
Bespak Plc
Dispensing apparatus for metered quantities of pressurised fluid
IT1228459B
( en )
1989-02-23
1991-06-19
Phidea S R L
INHALER WITH REGULAR AND COMPLETE EMPTYING OF THE CAPSULE.
US5624898A
( en )
1989-12-05
1997-04-29
Ramsey Foundation
Method for administering neurologic agents to the brain
SG45171A1
( en )
*
1990-03-21
1998-01-16
Boehringer Ingelheim Int
Atomising devices and methods
NZ250988A
( en )
1990-06-14
1995-09-26
Rhone Poulenc Rorer Ltd
Powder inhaler: swirling chamber with anti-static walls
DE4038049C2
( en )
1990-11-29
1994-12-01
Anschuetz & Co Gmbh
Implantable infusion pump
US5331954A
( en )
1990-12-21
1994-07-26
Novo Nordisk A/S
Device for nasal delivery of liquid medications
IT1249600B
( en )
1991-02-21
1995-03-09
Elettro Plastica Spa
NASAL DISPENSER OF SPRAYED PHARMACEUTICAL SUBSTANCES
US6681767B1
( en )
1991-07-02
2004-01-27
Nektar Therapeutics
Method and device for delivering aerosolized medicaments
IT1250691B
( en )
1991-07-22
1995-04-21
Giancarlo Santus
THERAPEUTIC COMPOSITIONS FOR INTRANASAL ADMINISTRATION INCLUDING KETOROLAC.
GB9125699D0
( en )
1991-12-03
1992-01-29
Glaxo Group Ltd
Device
US5785049A
( en )
*
1994-09-21
1998-07-28
Inhale Therapeutic Systems
Method and apparatus for dispersion of dry powder medicaments
DE4239402A1
( en )
*
1992-11-24
1994-05-26
Bayer Ag
Multiple dosage powder inhaler - has acceleration channel and dwell chamber for uniformly high drug dispersion
US5899201A
( en )
*
1993-05-26
1999-05-04
Minnesota Mining And Manufacturing Company
Aerosol actuator
US5819730A
( en )
1993-06-09
1998-10-13
Glaxo Wellcome Australia Ltd.
Device for administering pharmaceutical substances
US5349947A
( en )
1993-07-15
1994-09-27
Newhouse Michael T
Dry powder inhaler and process that explosively discharges a dose of powder and gas from a soft plastic pillow
US5516006A
( en )
1993-07-30
1996-05-14
Meshberg; Philip
Nasal dispenser
US5398850A
( en )
1993-08-06
1995-03-21
River Medical, Inc.
Gas delivery apparatus for infusion
IT1266794B1
( en )
1993-11-09
1997-01-21
Faustino Ballini
MICRONIZED SHOWER DEVICE FOR WASHING THE NASAL AND NEIGHBORING CAVITIES
DE4342174C1
( en )
1993-12-10
1995-05-11
Lohmann Therapie Syst Lts
Transdermal therapeutic system and a method for producing a transdermal therapeutic system for the combined transdermal application of physostigmine and scopolamine for the prophylaxis and pretreatment of poisoning by highly toxic organophosphorus neurotoxins, in particular Soman and its use
JP3911290B2
( en )
1994-05-13
2007-05-09
ã¢ã©ãã¤ã ã³ã¼ãã¬ã¼ã·ã§ã³
Anesthesia prescription with aerosol
US5435282A
( en )
1994-05-19
1995-07-25
Habley Medical Technology Corporation
Nebulizer
JP3372105B2
( en )
1994-05-26
2003-01-27
æ ªå¼ä¼ç¤¾æ¥ç«ã¦ãã·ã¢ãªã¼ãã¢ãã£ã
Inhalation type dispenser
US5901703A
( en )
1995-02-06
1999-05-11
Unisia Jecs Corporation
Medicine administering device for nasal cavities
DE19518580A1
( en )
1995-05-20
1996-11-21
Thomas Ossinger
Electrically heated dip soldering crucible
JPH08322934A
( en )
1995-05-29
1996-12-10
Unisia Jecs Corp
Nasal drug dispenser
DE19523516C1
( en )
1995-06-30
1996-10-31
Asta Medica Ag
Inhaler for administering medication from blister packs
US5823183A
( en )
1995-08-02
1998-10-20
Innovative Devices
Dry powder medicament inhalator having an inhalation-activated flow diverting means for triggering delivery of medicament
GB9516984D0
( en )
1995-08-18
1995-10-18
Pharmasol Ltd
Spray applicator
IE77523B1
( en )
1995-09-11
1997-12-17
Elan Med Tech
Medicament delivery device
US5711488A
( en )
1995-10-13
1998-01-27
The Procter & Gamble Company
High pressure swirl atomizer
<tr itemprop="ba