This disclosure relates generally to a drug delivery device, and specifically to a nasal drug delivery device for delivering drugs to an upper nasal cavity of a user.
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 invasive. 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. 20100074959.
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. For example, some existing devices are manually actuated and may be used in conjunction with a manual pump, such that the actuation of the device is dependent on a user's rate and/or strength of actuation of the pump. Some existing devices require the user to coordinate their breathing with device actuation, which can produce variable results due to differences in a user's breath power. In addition, some drug products are in an encapsulated form, which requires the capsule to be opened or punctured to administer the drug, which may result in particulate matter from the capsule contaminating the drug. Even further, in a metered dose inhaler (MDI) type device, some drug products do not readily mix and/or stay suspended with propellants.
Better mechanisms for administering desired agents to the brain, brain stem, and/or spinal cord are needed.
A device for delivering a compound to the upper nasal cavity is described. In one embodiment, the device includes a housing body comprising an actuator, a stem, and a release button. The actuator is configured to move relative to the housing body, where actuation of the actuator is configured to actuate a canister thereby releasing a contained propellant. The stem protrudes from the housing body and comprises a mating interface that mates with a nozzle containing the compound. The release button is positioned within the housing body and moves relative to the housing body. The release button is directly connected to a securing mechanism that couples the nozzle to the mating interface, where actuation of the release button decouples the nozzle from the mating interface.
In one embodiment, the nozzle comprises a nozzle body, a diffuser, an outlet orifice, a removable seal, and a receiving cavity. The nozzle body comprises a channel that extends between a proximal end and a distal end of the nozzle body, and the diffuser is positioned within the channel. The outlet orifice is disposed at a distal end of the channel, and the removable seal is positioned across the outlet orifice. The compound is contained within the channel between the diffuser and the removable seal, and the removable seal may be removed by a user before the compound is administered. The receiving cavity is disposed about an outer surface of the nozzle body and receives a reciprocal mating interface of the device.
Upon user actuation of the device, the released propellant travels to the channel of the nozzle body, contacts the diffuser, and propels the compound out the outlet orifice for delivery into the upper nasal cavity. In this configuration, the device administers the dose to the upper nasal cavity independent of the user's breathing and/or user's rate and/or strength of actuation. In addition, the nozzle may be coupled to and decoupled from the housing body. The nozzle is used to deliver a single dose of the compound, such that after dispensing the dose, the nozzle may be removed from the housing body and a new nozzle may be attached for delivering a future dose. This configuration maintains the integrity of the compound contained within the detachable nozzle and consistently administers the dose to the upper nasal cavity.
The figures depict embodiments of the present disclosure for purposes of illustration only. One skilled in the art will readily recognize from the following description that alternative embodiments of the structures and methods illustrated herein may be employed without departing from the principles, or benefits touted, of the disclosure described herein.
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, “a” or “an” may mean one or more.
A “diagnostic agent” 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 “diffuser” refers to and encompasses a component for dispersing or deflecting a compound in various directions.
A “frit” is one type of a diffuser and shall refer to and encompass a porous member or filter.
An “imaging agent” 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 “propellant” shall refer to and encompass a compound that acts as a vehicle for creating propulsion or thrust.
The term “therapeutically effective amount” 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 “treatment” and “treat”, 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 “user” or “subject” 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 to the upper nasal cavity offers several advantages over traditional surgical, intravenous or oral routes for administration across the blood brain barrier (BBB). The upper nasal cavity may include the olfactory region and the middle and superior turbinate regions, among other regions within the nasal cavity. Intranasal administration to specifically 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, drug compound, or intranasal dosage form) is propelled from the device with a velocity into the nasal cavity.
The housing body 102 represents the body of the device 100. The housing body 102 is designed to be held in a hand of a user and may include one or more ergonomic features for the comfort of the user. For example, in the embodiment of
The nozzle 104 contains the drug compound. In the embodiment of
The actuator 106 is manually actuated by a user to dispense a dose from the nozzle 104. The actuator 106 moves relative to the housing body 102 (e.g., slides, translates, rotates, or other similar motion). In the embodiment of
The coupling interface 108 couples the nozzle 104 to the housing body 102 and decouples the nozzle 104 from the housing body 102 upon actuation of a release button 116. In the embodiment of
In the embodiments of
In some embodiments, the device 100 includes a dose counter 124. The dose counter 124 tracks the number of actuations of the propellant canister, such that a user may be aware of the amount of propellant remaining in the propellant canister. For example, a propellant canister may have a capacity for distributing propellant for a certain number of doses. In some embodiments, the propellant canister may be replaced with a new propellant canister, such that the device 100 may be reused. In one aspect, when a 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 microliters (μl) and about 200 microliters (μl) inclusive of endpoints, of liquid propellant.
The propellant canister 202 contains propellant. In one embodiment, 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 134a, 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 canister 202 may be a metered dose inhaler (MDI) device that includes a pressurized canister and metering valve 208 (including stem) to meter the propellant upon actuation. In one embodiment, a pump fitment (not shown) secures the metered valve 208 to the canister 202 and holds both components in place during device 100 use. One series of embodiments of the pump fitment consists of securing interfaces that retain the pump fitment within the housing body 102, provide vertical displacement, and prevent rotation during installation of the canister 202. As shown in
The junction 204 is an internal structure that couples the canister 202 to the nozzle 104. The propellant channel 206 extends through the junction 204, thereby creating a flow path from the canister 202 to the nozzle 104. As shown in
The distal end of the second branch 216 couples with the nozzle 104. Specifically, the distal end of the second branch 216 is inserted into a nozzle channel 218 when the nozzle 104 is positioned onto the stem 112. The distal end of the second branch 216 may have a tapered end and/or a chamfer to facilitate insertion into the nozzle channel 218. In the embodiment of
As shown in
The diffuser 224 diffuses propellant released from the canister 202. In one aspect, a majority of the propellant is diffused via the diffuser. In another aspect, a minority of the propellant is diffused via the diffuser. 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. The diffuser 224 is in communication with the nozzle channel 218.
In some aspects, the diffuser 224 functions to convert propellant from a liquid to a gas. Specifically, the diffuser 224 expands the propellant from a liquid state to a gaseous state. In other aspects, the diffuser 224 functions to prevent the drug compound contained in the nozzle channel 218 from coming in contact with the canister 202. In another aspect, the diffuser acts as a one-way check valve. In other aspects, the diffuser 224 functions to convert propellant from a liquid to a gas and to prevent the compound contained in the nozzle channel 218 from coming into contact with the canister 202. In yet another aspect, the diffuser functions to increase the temperature of the propellant. In one aspect, the diffuser converts the liquid propellant into a gaseous state, which then aerosolizes the drug compound and propels the aerosolized drug compound through the nozzle channel 218 and out the outlet orifice 222.
An example of a diffuser 224 includes a frit, a plurality of frits, or a diffuser member or combinations thereof. In one aspect, the diffuser is a frit. In another aspect, the diffuser is a plurality of frits. In another aspect, the diffuser is a diffuser member.
In one aspect, the frit(s) are of any suitable size and shape and are formed using any suitable porous material of any suitable density. In one aspect, the frit is made of a hydrophobic material. In one aspect, the frit is made of an inert material to avoid chemically reacting with any of the compounds. The inert material may be metal or non-metal. In one aspect, the frit is composed of metal. In another aspect, the frit is composed of a non-metal. In one aspect, the inert material is sintered nickel. As one example, a frit formed using a porous stainless steel having a pore size in the range of approximately 1 micron to approximately 100 microns can be used. In another aspect the pore size is in the range of about 1 to about 10, about 10 to about 20, about 20 to about 30, about 30 to about 40, about 40 to about 50, about 50 to about 60, about 60 to about 70, about 70 to about 80, about 80 to about 90, about 90 to about 100 microns, inclusive of endpoints. In another aspect, the frit can be formed using aluminum foam. The number and size of the pores and the overall dimensions (e.g., diameter and thickness) of the frit are set to maximize surface area for vaporization while limiting pressure drops accompanying passage of vaporized propellant through the frit. The frit may be homogenously or heterogeneously porous. In certain aspects, the frit may be constructed of Teflon, glass, metal mesh, screen, porous metal, polyether ether ketone or another plastic material. In one aspect, the passage of liquid propellant through the increased surface area of the frit transitions the liquid to gas and increases the temperature of the resulting gas. In another aspect, the passage of gas propellant through the increased surface area of the frit increases the temperature of the gas.
In the embodiments of
The ledge 412 is a surface within the nozzle channel 408 against which the diffuser 404 is seated. In the embodiments of
The tip seal interface 418 is positioned at a tip of the nozzle 400 and couples to the removable seal 406. In the embodiments of
The ejector sleeve interface 420 is configured to couple to an ejector sleeve, which is described in further detail in
In the embodiments of
The compression spring 602 is positioned about a distal end of the second branch of the junction. In the embodiments of
The ejector sleeve 604 couples to an ejector sleeve interface of a nozzle (as described in
When a nozzle is coupled to the housing body 102, the nozzle couples to the ejector sleeve 604 and compresses the compression spring 602 such that the securing latch of the release button mates with the opening on the nozzle. In this configuration, the ejector sleeve 604 moves between a first position, in which the compression spring 602 is partially compressed, and a second position, in which the compression spring 602 is further partially compressed or fully compressed. In one embodiment, the ejector sleeve 604 moves between a first position, in which the compression spring 602 is at rest, and a second position, in which the compression spring 602 is partially compressed or fully compressed. The ejector sleeve 604 transitions between the first position and the second position as the nozzle is being coupled to the housing body 102 or as the nozzle is being decoupled from the housing body 102.
As previously described, to decouple the nozzle from the housing body 102, a user provides user input to the release button 116, which displaces the securing latch from the opening in the nozzle. Once the securing latch is displaced from the nozzle opening, the ejector sleeve 604 transitions from the second position to the first position. In the embodiment of
The foregoing description of the embodiments of the disclosure has been presented for the purpose of illustration; it is not intended to be exhaustive or to limit the disclosure to the precise forms disclosed. Persons skilled in the relevant art can appreciate that many modifications and variations are possible in light of the above disclosure.
The language used in the specification has been principally selected for readability and instructional purposes, and it may not have been selected to delineate or circumscribe the inventive subject matter. It is therefore intended that the scope of the disclosure be limited not by this detailed description, but rather by any claims that issue on an application based hereon. Accordingly, the disclosure of the embodiments is intended to be illustrative, but not limiting, of the scope of the disclosure, which is set forth in the following claims.
This application claims the benefit of priority to U.S. Provisional Patent Application No. 62/788,093, filed on Jan. 3, 2019, entitled “Nasal Drug Delivery Device” which is incorporated herein by reference in its entirety for all purposes.
Filing Document | Filing Date | Country | Kind |
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PCT/US2019/066921 | 12/17/2019 | WO |
Publishing Document | Publishing Date | Country | Kind |
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WO2020/142206 | 7/9/2020 | WO | A |
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