WO2025189284A1

WO2025189284A1 - Olfactory delivery of therapeutic small molecules

Info

Publication number: WO2025189284A1
Application number: PCT/CA2025/050333
Authority: WO
Inventors: Kenneth Irving; Kenza ENRIGHT; Sohier HALL; Nicholas Allan; Jacob M. HOOKER
Original assignee: Rocket Science Health Corp
Current assignee: Rocket Science Health Corp
Priority date: 2024-03-11
Filing date: 2025-03-10
Publication date: 2025-09-18
Anticipated expiration: 2026-09-11

Abstract

The present disclosure describes methods and devices for delivery of therapeutic small molecules or therapeutic cyclodextrins to a target region in a nasal cavity, such as an olfactory region. Devices and methods of the present disclosure may provide convenient and effective ways to accomplish olfactory delivery of therapeutic small molecules and cyclodextrins.

Description

OLFACTORY DELIVERY OF THERAPEUTIC SMALL MOLECULES

CROSS REFERENCE

[0001] This PCT application claims the benefit to U.S. Provisional Application No. 63/563,697, filed March 11, 2024, U.S. Provisional Application No. 63/696,107, filed September 18, 2024, U.S. Provisional Application No. 63/715,078, filed November 1, 2024, the contents of which are incorporated herein in their entirety by reference.

FIELD

[0002] The present disclosure relates generally to delivery of small molecules and cyclodextrins, and more specifically, intranasal delivery.

BACKGROUND

[0003] Certain small molecules and cyclodextrins are known to provide therapeutic effects to subjects. Small molecules have been found to treat a wide variety of disorders related to the central nervous system While therapeutic effects of small molecules on the central nervous system (or a region, tissue, or organ thereof) is of interest, delivery is known to present challenges. Olfactory delivery is a possibility for therapeutic small molecules.

[0004] The therapeutic potential of drugs targeting the brain through olfactory neural pathways via intranasal application is significant, including decreased systemic absorption, smaller doses, and reduced risk of complications from over-medication. Nasal mist devices are a standard method to deliver drugs to the nasal cavity. Recent research has established the inefficiency of these methods compared to methods designed to deliver drugs more focally into the nasal cavity where drug action is desired. Focal delivery promises to deposit the medication bolus directly to the olfactory cleft immediately below the cribriform plate where the olfactory nerves pass into the brain, whereas standard nasal misters deposit drug dosage throughout the nasal cavity and sinuses with potential significant dilution prior to reaching the olfactory cleft, due to dispersion over a large surface area. Moreover, spray devices typically atomize or vaporize the drug compound, creating small droplets that are degraded by high velocity airflow through the nasal valve. Shear forces can destroy some drug molecules and biologies as they are atomized into droplets. With few exceptions, existing devices typically deliver only 5-8% of a dose to the olfactory cleft. There remains a need for formulations, methods, and devices for targeted delivery of therapeutic small molecules to subregions of the nasal cavity, such as the olfactory cleft. SUMMARY

[0005] It is appreciated by the inventors that challenges related to delivery of therapeutic small molecules and cyclodextrins to certain regions of the central nervous system include difficulty in crossing the blood-brain barrier. For example, the blood brain barrier and/or the blood-cerebrospinal fluid barrier may limit or prevent small molecules or cyclodextrins from having therapeutic effects when they are delivered intravenously. Intranasal delivery efficiencies have typically been low for small-molecule therapeutics. Challenges associated with the delivery of small molecules and cyclodextrins to a target region in the nasal cavity, such as an olfactory region, include difficulties in accommodating for variations in the nasal channel, difficulties in targeting deposition of a composition at the correct location in the nasal channel, and difficulties providing a device which can reliably and repeatably deliver a composition to locations within the nasal channel with a high degree of precision across a population of subjects. Methods and devices of the present invention provide for delivery of therapeutic small molecules and cyclodextrins to a target region of a nasal cavity, such as an olfactory region, to minimize off-target delivery, thereby improving delivery efficiency and therapeutic efficacy. Additional advantages of the present invention may include the avoidance of needles (particularly relevant to subjects with needle-phobia), the possibility of self-administration, and enablement of the delivery of formulations with viscosity too high for intravenous injection.

[0006] It is appreciated by the inventors that difficulties in nasal delivery include anatomical, cognitive, and dexterity related challenges related to providing a reliable and effective nasal delivery device. For example, the internal nasal valve is a flow-limiting segment of the nasal channel bounded medially by the dorsal septum, laterally by the caudal portion of the upper lateral cartilage and inferiorly by the head of the inferior turbinate that together present a physical barrier between the nasal vestibule and the rest of the nasal channel, including the respiratory region and the olfactory cleft. The internal nasal valve is bounded by nasal tissue that can swell or block the path to the nasal channel, which varies based on time of day, environmental factors, and genetically among individuals. Devices may need to be inserted at particular angles or depths in order to target a specific area, and users may struggle with correct placement and actuation of a device. Users with motor skill impairment (e.g., persons with Parkinson’s disease, arthritis) or cognitive impairments (e.g., Alzheimer’s disease) may especially struggle to correctly articulate, position, and actuate an intranasal delivery device.

[0007] To counter such difficulties, this disclosure provides methods and devices for delivery of a therapeutic small molecule to a target region of a nasal cavity. This disclosure provides an introducer device for targeted delivery of a small molecule-containing composition to a target region of a nasal cavity of a subject, which can readily be actuated and positioned by users of various patient populations, and reliably deliver the composition to a target sub-region of the nasal cavity, to enable precision delivery of the small molecules. As a non-limiting example, the olfactory cleft can be a target sub-region of the nasal cavity, such that non-spray, targeted delivery of a therapeutic to the olfactory cleft produces a desired effect. Additional target sub-regions of the nasal cavity may be identified.

[0008] In one aspect is a method for delivery of a therapeutic small molecule to a target region of a nasal cavity of a subject, the method comprising: selectively delivering a formulation comprising a therapeutically effective amount of the small molecule to a target region of the subject; wherein at least a portion of a formulation is delivered to one or more of the group consisting of cerebrospinal fluid, the central nervous system or a region, tissue, or organ thereof.

[0009] In another aspect is a method for delivery of a therapeutic cyclodextrin to a target region of a nasal cavity of a subject, the method comprising: selectively delivering a formulation comprising a therapeutically effective amount of the therapeutic cyclodextrin to a target region of the subject; wherein at least a portion of a formulation is delivered to one or more of the group consisting of cerebrospinal fluid, the central nervous system or a region, tissue, or organ thereof.

[0010] In yet another aspect is a method for delivery of sugammadex to a target region of a nasal cavity of a subject, the method comprising: selectively delivering a formulation comprising a therapeutically effective amount of sugammadex to a target region of the subject; wherein at least a portion of a formulation is delivered to one or more of the group consisting of cerebrospinal fluid, the central nervous system or a region, tissue, or organ thereof.

[0011] In some embodiments, the therapeutic small molecule or cyclodextrin may be delivered to a target or organ system other than the CNS. Non-limiting examples include the lymphatic system, Nasal Associated Lymphatic Tissue (NALT), and Cribriform Lymphatic/Glymphatic, Systemic, etc. Therapeutic small molecules and cyclodextrins may also elicit an immune response in the CNS.

[0012] In some embodiments, the formulation is ejected from a dispensing element, wherein at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% of the formulation passes through a circular opening having a diameter of between about 5 mm and about 6 mm at a distance of about 25 mm from where the formulation is ejected from the dispensing element. In some embodiments, the formulation has a viscosity of between about 0.5 cP and about 100 cP. In some embodiments, the formulation has a viscosity of between about 0.5 cP and about 50 cP. In some embodiments, the formulation has a viscosity of between about 0.5 cP and about 10 cP. In some embodiments, the formulation has a viscosity of between about 45 cP and about 55 cP. In some embodiments, the formulation is ejected from the dispensing element at a velocity of between about 1 m/s and about 30 m/s. In some embodiments, the formulation is ejected from the dispensing element at a velocity of between about 2 m/s and about 4 m/s. In some embodiments, the formulation is ejected from the dispensing element at a velocity of between about 25 m/s and about 30 m/s. In some embodiments, the formulation is ejected from a dispensing element, wherein at least 75% of the formulation passes through a circular opening having a diameter of between about 5 mm and about 6 mm at a distance of about 25 mm from where the formulation is ejected from the dispensing element, wherein the formulation has a viscosity of between about 0.5 cP and about 50 cP, and wherein the formulation is ejected from the dispensing element at a velocity of between about 1 m/s and about 30 m/s.

[0013] In some embodiments, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% of the formulation is delivered to the target region of the subject. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 120 min after delivery that is at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 1.5 times, at least about 2 times, at least about 2.5 times, at least about 3 times, at least about 3.5 times, or at least about 4 times a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic cyclodextrin to the target region of the subject results in a plasma concentration of the therapeutic cyclodextrin about 120 min after delivery that is at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 1.5 times, at least about 2 times, at least about 2.5 times, at least about 3 times, at least about 3.5 times, or at least about 4 times a plasma concentration of the therapeutic cyclodextrin when about the same dose is delivered intravenously.

[0014] In some embodiments, the formulation is delivered as a laminar flow. In some embodiments, the formulation is delivered as a liquid jet. In some embodiments, the formulation is delivered as a flow having a Reynold’s number of 2300 or less. In some embodiments, the delivering of the formulation as a laminar flow, a liquid jet, or a flow having a Reynold’s number of 2300 or less: a) increases on target delivery of the composition to the target region, b) decreases off target delivery of the composition to the nasal cavity, or c) both, compared to delivering the formulation with a spray ejection profile. [0015] In some embodiments, selectively delivering the formulation to the target region of the subject comprises ejecting the formulation from an ejection zone in a nasal cavity of the subject, wherein the ejection zone is: (a) 0mm to 30mm superior to a horizontal line that intersects the anterior aspect of the internal nasal valve, and (b) 0mm to 20mm anterior to an inclined line that intersects the anterior aspect of the middle turbinate and the posterior aspect of the vestibule. In some embodiments, the ejection zone is further: i. 0mm to 40mm inferior to a horizontal line that is parallel to the inferior aspect of the olfactory cleft, ii. 0mm to 20mm posterior to the internal nasal dorsum, iii. 10mm to 50mm superior to a horizontal line that intersects the inferior aspect of the columella, iv. 0mm to 30mm superior to a horizontal line that intersects the superior aspect of the inferior turbinate, v. 0mm to 3mm from the septum, or vi. any combination thereof. In some embodiments, delivering the formulation from the ejection zone: a) increases on target delivery of the composition to the target region, b) decreases off target delivery of the composition to the nasal cavity, or c) both, compared to dispensing the formulation outside the ejection zone.

[0016] In some embodiments, the formulation is delivered by a device comprising the dispensing element, wherein the device is inserted into a nasal cavity of the subject at an angle of between about 30 degrees and about 40 degrees from a vertical line, wherein the vertical line is perpendicular to a horizontal line that is parallel to an inferior aspect of the olfactory cleft of the subject.

[0017] In some embodiments, the formulation delivered to the target region remains at the target region for at least about 10 seconds, at least about 30 seconds, at least about 1 min, at least about 2 min, at least about 3 min, at least about 4 min, at least about 5 min, at least about 6 min, at least about 7 min, at least about 8 min, at least about 9 min, at least about 10 min, at least about 11 min, at least about 12 min, at least about 13 min, at least about 14 min, or at least about 15 min.

[0018] In some embodiments, the therapeutic small molecule is Sulindac (Clinoril), fingolimod (Gilenya), raltegravir (Isentress), naloxone (Narcan), nalmefene (Opvee), butorphanol, midazolam (Nayzilam), diazepam (Valium), dihydroergotamine (Migranal), dihydroergotamine mesylate, sumatriptan (Imitrex/Treximet), zavegepant (Zavzpret), zolmitriptan (Zomig), diphenhydramine (Benadryl), benzatropine (Cogentin), trihexyphenidyl (Artane), procyclidine, temozolomide (Temodar), procarbazine, carmustine (BiCNU), lomustine (CCNU/Gleostine), vincristine (Oncovin), methotrexate (Trexall), cisplatin (Platinol), fluticasone, voriconazole (Vfend), amphotericin B, ampicillin (principen), benzylpenicillin (Pfizerpen), meropenem (Merrem), aztreonam (Azactam), rifampicin (Rifadin), ciprofloxacin (Ciloxan), cefotaxime (Claforan), ceftriaxone (Epicephin), warfarin (Coumadin), apixaban (Eliquis), dabigatran (Pradaxa), edoxaban (Lixiana), Stachybotrys microspora triprenyl phenol-7, cocaine hydrochloride, nicotine, diclofenac (Voltaren), lacosamide (Vimpat), varenicline (Chantix/Champix), a derivative or analog hereof.

[0019] In some embodiments, the therapeutic small molecule is epinephrine or a salt thereof.

[0020] In some embodiments, the therapeutic small molecule or cyclodextrin is conjugated to a therapeutic agent. In some embodiments, the therapeutic agent is a drug or a radioisotope.

[0021] In some embodiments, the therapeutic cyclodextrin is sugammadex.

[0022] In some embodiments, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90% of the therapeutic small molecule or cyclodextrin in the formulation is delivered to one or more of the group consisting of cerebrospinal fluid, the central nervous system, and a region, tissue, or organ thereof.

[0023] In some embodiments, the method provides delivery of a greater amount of the therapeutic small molecule or cyclodextrin to one or more of the group consisting of cerebrospinal fluid, the central nervous system, and a region, tissue, or organ thereof compared to intravenous delivery of an identical dose of the therapeutic small molecule or cyclodextrin. In some embodiments, the therapeutic small molecule or cyclodextrin provides a therapeutic effect upon delivery to the cerebrospinal fluid, the central nervous system or region, tissue, or organ thereof. In some embodiments, the subject has been diagnosed with a disease or disorder related to the central nervous system. In some embodiments, delivery of the therapeutic small molecule or cyclodextrin provides effective treatment for Alzheimer's disease, Parkinson's disease, a cancer of the brain, a cancer of the CNS, a non-CNS disorder, an immunological disorder, an oncological disorder, a hematological disorder, an ophthalmological disorder, a neurological disorder, a respiratory disorder, a cardiovascular disorder, an infectious disease, multiple sclerosis, stroke, epilepsy, seizure, pain, central nervous system trauma, a metabolic disorder, an infectious agent (i.e. Naegleria fowleri) or protein (i.e. Creutzfeldt Jacobs disease), a malignant tumor, a benign tumor, glioblastoma, anosmia, a chronic pain syndromes, a migraine, Huntington’s disease, amyotrophic lateral sclerosis (ALS); a neurodevelopment disorder, autism spectrum disorder (ASD); a sleep disorder, narcolepsy, or an endocrine disorder. In some embodiments, delivery of the therapeutic small molecule or cyclodextrin provides effective treatment for macular degeneration, spinal muscular atrophy, Duchene muscular dystrophy, hereditary transthyretin amyloidosis, amyotrophic lateral sclerosis, Parkinson’s disease, multiple sclerosis, Huntington’s disease, Alexander disease, Alzheimer’s disease, epilepsy, temporal lobe epilepsy, seizure, pain, depression, anxiety, cancer, neuronal ceroid lipofuscinoses, Mucopolysaccharoidosis, Angelman syndrome, Canavan disease, Friedrichs ataxia, or glioblastoma.

[0024] In some embodiments, the formulation is delivered without exposing the therapeutic small molecule or cyclodextrin to shear forces sufficient to damage a significant portion of the therapeutic small molecule or cyclodextrin, without aerosolizing the formulation, or by passing the formulation through a shear disintegrating tip. In some embodiments, the therapeutic small molecule or cyclodextrin bypasses the blood-brain barrier, the blood-cerebrospinal fluid barrier, or the arachnoid membrane. In some embodiments, the non-CNS -target is blood.

[0025] In some embodiments, the formulation is delivered via a device comprising: a. a housing defining first and second insertable portions, each for insertion into a nasal channel of the subject, wherein, upon insertion of at least one of the insertable portions into the nasal channel of the subject, the at least one insertable portion engages tissue within the nasal channel to open or expand an internal nasal valve of the subject thereby positioning the at least one insertable portion for delivery of the formulation to the target region of the subject; and b. an actuator which delivers the formulation from at least one of the insertable portions when the device is actuated.

[0026] In some embodiments, the target region is an olfactory region.

[0027] In another aspect is a device for delivery of a therapeutic small molecule to a target region of a nasal cavity of a subject, the device comprising: a housing comprising an insertable portion comprising a distal end, and a proximal end; and a subject-engaging portion which engages a columella region of the subject to seat the distal end of the insertable portion within an ejection zone of a nasal channel of the subject; wherein the device is configured to deliver a formulation comprising a therapeutically effective amount of the small molecule to the target region of the subject.

[0028] In yet another aspect is a device for delivery of a therapeutic cyclodextrin to a target region of a nasal cavity of a subject, the device comprising: a housing comprising an insertable portion comprising a distal end, and a proximal end; and a subject-engaging portion which engages a columella region of the subject to seat the distal end of the insertable portion within an ejection zone of a nasal channel of the subject; wherein the device is configured to deliver a formulation comprising a therapeutically effective amount of the therapeutic cyclodextrin to the target region of the subject.

[0029] Other features and advantages of the present disclosure will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples while indicating preferred embodiments of the disclosure are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description.

INCORPORATION BY REFERENCE

[0030] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

[0031] The novel features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description and accompanying drawings, that set forth illustrative embodiments in which the principles of the present disclosure are utilized.

[0032] FIG. 1A depicts a bottom view of an exemplary embodiment of a subject’s nose.

[0033] FIG. IB depicts a side view of an exemplary embodiment of a subject’s nose.

[0034] FIG. 1C depicts a side view of a representative subject’s nasal channel.

[0035] FIG. ID depicts a side view of an exemplary embodiment of a representative subject’s nasal channels from the vestibule to the olfactory cleft based on a posteriorly oriented plane.

[0036] FIG. IE depicts a side view of an exemplary embodiment of a representative subject’s nasal channels from the vestibule to the olfactory cleft based on an anteriorly oriented plane.

[0037] FIG. IF depicts a side view of an exemplary embodiment of a representative target ejection zone, according to some embodiments.

[0038] FIG. 1G depicts a front, base and perspective view of an exemplary embodiment of a subject’s nose and the columella region.

[0039] FIG. 1H depicts a side view of an exemplary embodiment of a representative subject’s nasal cavity, including internal anatomical features.

[0040] FIG. II depicts a side view of an exemplary embodiment of a representative subject’s sinus, according to some embodiments.

[0041] FIG. 1J depicts a side view of a subject’s nasal cavity.

[0042] FIG. 2A depicts an exemplary embodiment of an Exemplary Device in a second configuration, according to some embodiments. [0043] FIG. 2B depicts an exemplary embodiment top view of an Exemplary Device in the second configuration, according to some embodiments.

[0044] FIG. 2C depicts an exemplary embodiment trigger button side view of an Exemplary Device in the second configuration, according to some embodiments.

[0045] FIG. 2D depicts an exemplary embodiment chassis side view of an Exemplary Device in the second configuration, according to some embodiments.

[0046] FIG. 2E depicts an exemplary embodiment bottom view of an Exemplary Device in the second configuration, according to some embodiments.

[0047] FIG. 2F depicts an exemplary embodiment perspective view of an Exemplary Device in the first configuration, according to some embodiments.

[0048] FIG. 2G depicts an exemplary embodiment front view of another Exemplary Device in the first configuration, according to some embodiments.

[0049] FIG. 2H depicts an exemplary embodiment front view of an Exemplary Device in the second configuration, according to some embodiment.

[0050] FIG. 21 depicts an exemplary embodiment front view of another Exemplary Device in the first configuration, according to some embodiments.

[0051] FIG. 2J depicts an exemplary embodiment front view of an Exemplary Device in the second configuration, according to some embodiment.

[0052] FIG. 3A depicts an exemplary embodiment of an Exemplary Device in the second configuration with one dispensing element revealed and a side view of an exemplary embodiment of a subject’s nose, according to some embodiments.

[0053] FIG. 3B depicts an exemplary embodiment of an Exemplary Device in the second configuration with one dispensing element revealing along the passageway and a side view of an exemplary embodiment of a representative subject’s nasal channels from the vestibule to the olfactory cleft based on an anteriorly oriented plane, according to some embodiments.

[0054] FIG. 4A depicts an exemplary embodiment of a cartesian reference plane of (left to right) a front, a top, and a side view of an Exemplary Device., according to some embodiments.

[0055] FIG. 4B depicts an exemplary embodiment of the subject plane, according to some embodiments.

[0056] FIG. 4C depicts an exemplary embodiment of (left to right) a front Coronal Plane, a top Transverse Plane, and a back Sagittal Plane view, according to some embodiments. [0057] FIG. 4D depicts an exemplary embodiment of an Exemplary Device Sagittal Angle positioning in the subject, according to some embodiments.

[0058] FIG. 4E depicts an exemplary embodiment of an Exemplary Device Coronal-Medial Angle positioning in the subject, along a front view of the Coronal Plane, and a top view along a transverse plane, according to some embodiments.

[0059] FIG. 4F depicts an exemplary embodiment of an Exemplary Device Depth positioning along a front view of the Coronal Plane, and along a side view of the Sagittal Plane in the subject, according to some embodiments.

[0060] FIG. 4G depicts an exemplary embodiment of an Exemplary Device along a side view of the sagittal plane of delivery to the target region in the subject, according to some embodiments.

[0061] FIG. 4H depicts an exemplary embodiment of an Exemplary Device along a side view of the sagittal plane aiming from the respiratory region in the subject, according to some embodiments.

[0062] FIG. 41 depicts a side view of a target ejection zone, according to some embodiments.

[0063] FIG. 4J depicts a side view of a target ejection zone with respect to other nasal cavity anatomy, according to some embodiments.

[0064] FIGS. 5A-C depict images of a transparent model nasal cavity with a colored solution demonstrating delivery to an olfactory region of the model.

[0065] FIG. 6A depicts a mouse in an olfactory delivery study with a catheter inserted into the nostril to deliver a formulation to the olfactory region.

[0066] FIG. 6B depicts a diagram of the targeted olfactory delivery shown in FIG. 6A.

[0067] FIG. 7A depicts a mouse in an intranasal delivery study with a pipet tip inserted into the nostril to deliver a formulation to the nasal cavity.

[0068] FIG. 7B depicts a diagram of the non-targeted intranasal delivery shown in FIG. 7A.

[0069] FIG. 8A is a graph showing time course of plasma concentration of lacosamide for 200 minutes following intravenous (IV) or olfactory delivery (OD) administrations.

[0070] FIG. 8B is a graph showing time course of plasma concentration of diclofenac for 200 minutes following intravenous (IV) or olfactory delivery (OD) administrations.

[0071] FIG. 8C is a graph showing time course of plasma concentration of sugammadex for 200 minutes following intravenous (IV) or olfactory delivery (OD) administrations.

[0072] FIG. 8D is a graph showing tissue concentrations of lacosamide at 200 minutes following intravenous (IV) or olfactory delivery (OD) administrations. [0073] FIG. 8E is a graph showing tissue concentrations of diclofenac at 200 minutes following intravenous (IV) or olfactory delivery (OD) administrations.

[0074] FIG. 8F is a graph showing tissue concentrations of sugammadex at 200 minutes following intravenous (IV) or olfactory delivery (OD) administrations.

[0075] FIG. 9 shows images of flow time series for olfactory delivery of technetium-99.

DETAILED DESCRIPTION

[0076] This disclosure provides methods and devices for delivery of therapeutic small molecules to a target region of a nasal cavity, such as an olfactory region, of a subject. As used herein, the term “small molecule” refers to a low molecular weight molecule capable of modulating one or more biochemical processes. Some small molecules have a sufficiently low molecular weight to allow for rapid diffusion across a cell membrane. The small molecule category excludes high molecular weight structures such as proteins and polysaccharides. A small molecule may have a molecular weight of less than 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or 1200 Daltons. In some aspects, a small molecule has a hydrodynamic radius less than about 5, 6, 7, 8, 9, or 10 angstroms. In some aspects, a small molecule has a Stokes radius less than about 5, 6, 7, 8, 9, or 10 angstroms. In some aspects, a small molecule has a simple chemical structure.

[0077] This disclosure further provides methods and devices for delivery of therapeutic cyclodextrins to a target region of a nasal cavity, such as an olfactory region, of a subject. As used herein, the term “cyclodextrin” refers to a cyclic oligosaccharide and includes derivatives. Examples of cyclodextrins (CDs) include but are not limited to a-CD, -CD, γ-CD, and derivatives thereof, such as 2-hydroxypropyl-P-cyclodextrin (HP CD), 2-hydroxypropyl-γ-CD (HPyCD), sulphobutylether-P- CD (SBE-P-CD), randomly methylated P-CD (RAMEB), etc. In some aspects, the cyclodextrin is sugammadex.

[0078] The methods provided herein can be use with the intranasal device of WO2019195944 or WO2024224372, the contents of which are incorporated by reference herein.

[0079] This disclosure provides an introducer device for targeted delivery of a composition to a target region of a nasal cavity of a subject, which can be readily actuated and positioned by users of various patient populations, and reliably deliver the composition to the target region of the nasal cavity. Exemplary devices utilize a dual nostril inserter with a columella engaging portion positioned therebetween in order to quickly and reliably seat the insertable portions of the device within a target ejection zone of a subject’s nasal cavity. The exemplary devices disclosed herein can permit for quick, easy, and reliable positioning of a dispensing element within the nasal channel so as to permit for accurate and targeted deposition of compositions to target regions of the nasal cavity. Further, exemplary devices disclosed herein can enable quick, easy, and reliable positioning and targeted deposition across diverse patient populations (e.g., users that are elderly, cognitively impaired, dexterity impaired, or have variations in nasal anatomy), by users of varying skill (e.g., untrained bystanders), and under high stress circumstances (e.g., a medical emergency), which may otherwise prevent proper use of intranasal delivery devices.

[0080] The devices of the present disclosure may comprise housing comprising one or a combination of the following: a subject engaging portion, one or more insertable portions, one or more dispensing elements, and a trigger.

[0081] FIG. 1A depicts a bottom view of an exemplary embodiment of a subject’s nose. FIG. IB depicts a side view of an exemplary embodiment of a subject’s nose. In some embodiment’s the nose 1 has a columella region 10 between the entrance to two nasal channels 20. In some embodiments, the nose 1 has an external nasal valve 12 coupled to the nasal channel 20. In some embodiments, the nose 1 has an internal nasal valve 13 (INV) coupled to the nasal channel 20.

[0082] FIG. 1C depicts a side view of an exemplary embodiment of a subject’s nasal cavity showing an inferior turbinate 16, a middle turbinate 15, and a superior turbinate 14. FIG. ID depicts an angled side view of an exemplary embodiment of a representative subject’s nasal channels 20 from the vestibules 21 to the olfactory clefts 23 based on a posteriorly oriented plane 17 showing the middle turbinates 15. FIG. IE depicts an angled side view of an exemplary embodiment of a representative subject’s nasal channels 20 from the vestibules to the olfactory clefts based on an anteriorly oriented plane 18. FIG. IF depicts a side view of an exemplary embodiment of a representative subject’s target ejection area 19. FIG. 1G depicts a front, base and perspective view of an exemplary embodiment of a representative subject’s nose exposing the columella region 10. The respiratory regions comprise turbinates that present physical obstacles to delivery to the upper reaches of a nasal channels 20, e.g., the olfactory clefts 23. Each respiratory region comprises at least one superior turbinate 14. Each respiratory region comprises at least one middle turbinate 15. Each respiratory region comprises at least one inferior turbinate 16. Each respiratory region comprises at least one posterior pathway 17 that involves at least one middle turbinate 15. Each respiratory region comprises at least one anterior pathway 18 that does not involve at least one middle turbinate 15. [0083] In some cases, the middle turbinate 15 comprises a physical obstruction for composition delivery to an olfactory cleft. In some cases, the middle turbinate 15 comprises a most anterior aspect about aligned with the cheek bone. In some embodiments, the middle turbinate 15 comprises a most anterior aspect not aligned with the cheek bone. In some cases, the nasal channels 20 simplify anteriorly, and comprise angled pathways without one or more turbinates presenting physical obstacles to delivering a composition 111 to the upper nasal channels, including the olfactory clefts 23, or directing compositions 111 down one or more meatuses, e.g., the middle meatus 30, to the nasopharynx. In some cases, the nasal channel 20 comprises one pathway from the vestibule 21 to the olfactory cleft 23 based on an anteriorly oriented plane 18 with a target ejection point 19. In some embodiments, the nose comprises the nasal septum 24, upper lateral cartilage 25, and lower lateral cartilage 26.

[0084] FIG. 1H depicts a side view of an exemplary embodiment of a representative subject’s nasal cavity. In some cases, the subject’s nasal cavity 11 comprises the nasal vestibule 21, inferior turbinate 16, middle turbinate 15, superior turbinate 14, cribriform plate 31 or a combination thereof.

[0085] FIG. 1I depicts a side view of an exemplary embodiment of a representative subject’s sinus. In some cases, the subject’s sinus comprises the inferior turbinate 16, middle turbinate 15, superior turbinate 14, cribriform plate 31, middle meatus 30, or a combination thereof.

[0086] FIG. 1J depicts a side view of an exemplary embodiment of a representative subject’s nasal cavity. In some embodiments, the nasal cavity 11 comprises the nasal bone 33, septal-lateral cartilage junction 27, lower lateral cartilage 26, anterior nasal spine 32, or a combination thereof.

[0087] A description of the nasal anatomy is provided below:

[0088] Columella: this is the firm tissue bridge that separates the nostrils at the base of the nose.

[0089] Nasal Cavity: This is the large, air-filled space behind the nose, where air passes on its way to the throat during inhalation.

[0090] Internal Nasal Valve: This is the narrowest part of the nasal airway, located just beyond the nostril. It's formed by the edge of the nasal septum, the upper lateral cartilage, and the floor of the nose. The internal nasal valve plays a critical role in regulating airflow through the nose. The area of interest is superior (above) to this structure.

[0091] Nasal Septum: This is the thin wall of bone and cartilage that separates the right and left nostrils. It forms the medial (towards the middle) boundary of the region of interest.

[0092] Lateral Nasal Wall: This is the side wall of the nasal cavity, which is opposite to the nasal septum. It's a complex structure that includes the turbinates (long, curled bones that protrude into the nasal cavity) and the meatuses (grooves or channels between the turbinates). The lateral nasal wall forms the lateral (towards the side) boundary of the region of interest.

[0093] Middle and Superior Meatuses: These are the spaces within the nasal cavity located between the turbinates. The middle meatus is located beneath the middle turbinate and above the inferior turbinate, and the superior meatus is located beneath the superior turbinate. The region of interest encompasses parts of these spaces.

[0094] Nostrils (External Nares): These are the two openings of the nose where air enters.

[0095] Nasal Vestibule: The nasal vestibule is the most anterior part of the nasal cavity, just inside the nostrils. It's the area of the nose that protrudes outside the face predominantly. This area is lined with skin and contains hair follicles, and it acts as the initial filtering and warming area for inhaled air before it moves deeper into the nasal cavity. The nasal vestibule extends posteriorly to the nasal valve, which is the narrowest part of the nasal airway and located just beyond the nostril.

[0096] Nasal Septum: This is a thin wall made of bone and cartilage that separates the left and right sides of the nasal cavity.

[0097] Turbinates (Nasal Conchae): These are three pairs of bony projections (inferior, middle, and superior) covered in mucous membrane that protrude into the nasal cavity from the lateral walls. They increase the surface area of the nasal cavity, aiding in the warming, humidification, and filtration of inhaled air.

[0098] Meatuses: These are the spaces located between the turbinates. Each turbinate has a corresponding meatus underneath it (i.e., inferior, middle, and superior meatus).

[0099] Olfactory Region: This is a small area located at the top of the nasal cavity, where the sense of smell is located.

I. Method

[00100] In one aspect, provided herein is a method of delivering a therapeutic small molecule to a subject in need thereof, the method comprising: selectively delivering a formulation comprising a therapeutically effective amount of the therapeutic small molecule to a target region of the subject; wherein at least a portion of formulation is delivered to one or more of the group consisting of cerebrospinal fluid, the central nervous system or a region, tissue, or organ thereof, and a non-CNS target. In one aspect, provided herein is a method of delivering a therapeutic small molecule to a subject in need thereof. The method may comprise delivering a formulation comprising a therapeutically effective amount of the therapeutic small molecule to a target region of the subject. At least a portion of the formulation may be delivered to the cerebrospinal fluid. At least a portion of the formulation may be delivered to the central nervous system. At least a portion of the formulation may be delivered to a region, tissue, or organ of the central nervous system. At least a portion of the formulation may be delivered to a non-CNS target. At least a portion of the formulation may be delivered to one or more of the group consisting of cerebrospinal fluid, the central nervous system, or a region, tissue, or organ thereof, and a non-CNS target.

[00101] In another aspect, provided herein is a method of delivering a therapeutic cyclodextrin to a subject in need thereof, the method comprising: selectively delivering a formulation comprising a therapeutically effective amount of the therapeutic cyclodextrin to a target region of the subject; wherein at least a portion of formulation is delivered to one or more of the group consisting of cerebrospinal fluid, the central nervous system or a region, tissue, or organ thereof, and a non-CNS target.

[00102] In another aspect, provided herein is a method of delivering sugammadex to a subject in need thereof, the method comprising: selectively delivering a formulation comprising a therapeutically effective amount of sugammadex to a target region of the subject; wherein at least a portion of formulation is delivered to one or more of the group consisting of cerebrospinal fluid, the central nervous system or a region, tissue, or organ thereof, and a non-CNS target.

[00103] In one aspect, provided herein is a method of delivering a therapeutic small molecule to a subject in need thereof. In one aspect, provided herein is a method of delivering a therapeutic cyclodextrin to a subject in need thereof. In one aspect, provided herein is a method of delivering sugammadex to a subject in need thereof. The method may comprise delivering a formulation comprising a therapeutically effective amount of the therapeutic small molecule to a target region of the subject. The method may comprise delivering a formulation comprising a therapeutically effective amount of the therapeutic cyclodextrin to a target region of the subject. The method may comprise delivering a formulation comprising a therapeutically effective amount of sugammadex to a target region of the subject. At least a portion of the formulation may be delivered to the cerebrospinal fluid. At least a portion of the formulation may be delivered to the central nervous system. At least a portion of the formulation may be delivered to a region, tissue, or organ of the central nervous system. At least a portion of the formulation may be delivered to a non-CNS target. At least a portion of the formulation may be delivered to one or more of the group consisting of cerebrospinal fluid, the central nervous system, or a region, tissue, or organ thereof, and a non-CNS target.

[00104] In some embodiments, the cyclodextrin is sugammadex. [00105] The method can deliver at least 50% of the formulation comprising the therapeutic small molecule or cyclodextrin to the target region.

[00106] In some embodiments, at least about 50% of the formulation is delivered to the target region of the subject. In some embodiments, at least about 55% of the formulation is delivered to the target region of the subject. In some embodiments, at least about 60% of the formulation is delivered to the target region of the subject. In some embodiments, at least about 65% of the formulation is delivered to the target region of the subject. In some embodiments, at least about 70% of the formulation is delivered to the target region of the subject. In some embodiments, at least about 75% of the formulation is delivered to the target region of the subject. In some embodiments, at least about 80% of the formulation is delivered to the target region of the subject. In some embodiments, at least about 85% of the formulation is delivered to the target region of the subject. In some embodiments, at least about 90% of the formulation is delivered to the target region of the subject. In some embodiments, at least about 95% of the formulation is delivered to the target region of the subject.

[00107] The formulation comprising the therapeutic small molecule or cyclodextrin can be ejected from a dispensing element. In some embodiments, at least about 70% of the formulation can pass through a circular opening having a diameter of between about 5 mm and 6 mm placed about 25 mm from where the formulation is ejected from the dispensing element. In some embodiments, at least about 75% of the formulation can pass through a circular opening having a diameter of between about 5 mm and 6 mm placed about 25 mm from where the formulation is ejected from the dispensing element. In some embodiments, at least about 80% of the formulation can pass through a circular opening having a diameter of between about 5 mm and 6 mm placed about 25 mm from where the formulation is ejected from the dispensing element. In some embodiments, at least about 85% of the formulation can pass through a circular opening having a diameter of between about 5 mm and 6 mm placed about 25 mm from where the formulation is ejected from the dispensing element. In some embodiments, at least about 90% of the formulation can pass through a circular opening having a diameter of between about 5 mm and 6 mm placed about 25 mm from where the formulation is ejected from the dispensing element. In some embodiments, at least about 95% of the formulation can pass through a circular opening having a diameter of between about 5 mm and 6 mm placed about 25 mm from where the formulation is ejected from the dispensing element.

[00108] In some embodiments, the formulation has a viscosity of between about 0.5 cP and about 100 cP. In some embodiments, the formulation has a viscosity of between about 0.5 cP and about 90 cP. In some embodiments, the formulation has a viscosity of between about 0.5 cP and about 80 cP. In some embodiments, the formulation has a viscosity of between about 0.5 cP and about 70 cP. In some embodiments, the formulation has a viscosity of between about 0.5 cP and about 60 cP. In some embodiments, the formulation has a viscosity of between about 0.5 cP and about 50 cP. In some embodiments, the formulation has a viscosity of between about 0.5 cP and about 40 cP. In some embodiments, the formulation has a viscosity of between about 0.5 cP and about 30 cP. In some embodiments, the formulation has a viscosity of between about 0.5 cP and about 20 cP. In some embodiments, the formulation has a viscosity of between about 0.5 cP and about 10 cP. In some embodiments, the formulation has a viscosity of between about 0.15 cP and about 5 cP. In some embodiments, the formulation has a viscosity of between about 5 cP and about 10 cP. In some embodiments, the formulation has a viscosity of between about 10 cP and about 15 cP. In some embodiments, the formulation has a viscosity of between about 15 cP and about 20 cP. In some embodiments, the formulation has a viscosity of between about 20 cP and about 25 cP. In some embodiments, the formulation has a viscosity of between about 25 cP and about 30 cP. In some embodiments, the formulation has a viscosity of between about 30 cP and about 35 cP. In some embodiments, the formulation has a viscosity of between about 35 cP and about 40 cP. In some embodiments, the formulation has a viscosity of between about 40 cP and about 45 cP. In some embodiments, the formulation has a viscosity of between about 45 cP and about 50 cP. In some embodiments, the formulation has a viscosity of between about 50 cP and about 55 cP. In some embodiments, the formulation has a viscosity of between about 55 cP and about 60 cP. In some embodiments, the formulation has a viscosity of between about 60 cP and about 65 cP. In some embodiments, the formulation has a viscosity of between about 65 cP and about 70 cP. In some embodiments, the formulation has a viscosity of between about 70 cP and about 75 cP. In some embodiments, the formulation has a viscosity of between about 75 cP and about 80 cP. In some embodiments, the formulation has a viscosity of between about 85 cP and about 90 cP. In some embodiments, the formulation has a viscosity of between about 95 cP and about 100 cP. In some embodiments, the formulation has a viscosity of higher than 100 cP. In some embodiments, the formulation has a viscosity of between about 45 cP and about 55 cP. In some embodiments, the formulation has a viscosity of between about 48 cP and about 52 cP. In some embodiments, the formulation has a viscosity of about 1 cP. In some embodiments, the formulation has a viscosity of about 50 cP.

[00109] In some embodiments, the formulation is ejected from the dispensing element at a velocity of between about 1 m/s and about 30 m/s. In some embodiments, the formulation is ejected from the dispensing element at a velocity of between about 2 m/s and about 4 m/s. In some embodiments, the formulation is ejected from the dispensing element at a velocity of between about 25 m/s and about 30 m/s. In some embodiments, the formulation is ejected from the dispensing element at a velocity. In some embodiments, the velocity is about 1 m/s. In some embodiments, the velocity is about 2 m/s. In some embodiments, the velocity is about 3 m/s. In some embodiments, the velocity is about 4 m/s. In some embodiments, the velocity is about 5 m/s. In some embodiments, the velocity is about 6 m/s. In some embodiments, the velocity is about 7 m/s. In some embodiments, the velocity is about 8 m/s. In some embodiments, the velocity is about 9 m/s. In some embodiments, the velocity is about 10 m/s. In some embodiments, the velocity is about 11 m/s. In some embodiments, the velocity is about 12 m/s. In some embodiments, the velocity is about 13 m/s. In some embodiments, the velocity is about 14 m/s. In some embodiments, the velocity is about 15 m/s. In some embodiments, the velocity is about 16 m/s. In some embodiments, the velocity is about 17 m/s. In some embodiments, the velocity is about 18 m/s. In some embodiments, the velocity is about 19 m/s. In some embodiments, the velocity is about 20 m/s. In some embodiments, the velocity is about 21 m/s. In some embodiments, the velocity is about 22 m/s. In some embodiments, the velocity is about 23 m/s. In some embodiments, the velocity is about 24 m/s. In some embodiments, the velocity is about 25 m/s. In some embodiments, the velocity is about 26 m/s. In some embodiments, the velocity is about 27 m/s. In some embodiments, the velocity is about 28 m/s. In some embodiments, the velocity is about 29 m/s. In some embodiments, the velocity is about 30 m/s. In some embodiments, the velocity is between about 1 m/s and about 2 m/s. In some embodiments, the velocity is between about 4 m/s and about 6 m/s. In some embodiments, the velocity is between about 6 m/s and about 8 m/s. In some embodiments, the velocity is between about 8 m/s and about 10 m/s. In some embodiments, the velocity is between about 10 m/s and about 12 m/s. In some embodiments, the velocity is between about 12 m/s and about 14 m/s. In some embodiments, the velocity is between about 14 m/s and about 16 m/s. In some embodiments, the velocity is between about 16 m/s and about 18 m/s. In some embodiments, the velocity is between about 18 m/s and about 20 m/s. In some embodiments, the velocity is between about 20 m/s and about 22 m/s. In some embodiments, the velocity is between about 22 m/s and about 24 m/s. In some embodiments, the velocity is between about 24 m/s and about 26 m/s. In some embodiments, the velocity is between about 26 m/s and about 28 m/s. In some embodiments, the velocity is between about 28 m/s and about 30 m/s.

[00110] In some embodiments, the formulation is ejected from a dispensing element, wherein at least about 75% of the formulation passes through a circular opening having a diameter of between about 5 mm and about 6 mm placed about 25 mm from where the formulation is ejected from the dispensing element. In some embodiments, the formulation has a viscosity of about 1 cP and is ejected from the dispensing element at a velocity of between about 2 m/s and about 4 m/s. In some embodiments, the formulation has a viscosity of about 50 cP and is ejected from the dispensing element at a velocity of between about 25 m/s and about 30 m/s. In some embodiments, the formulation has a viscosity of between about 0.5 cP and about 50 cP. In some embodiments, the formulation is ejected from the dispensing element at a velocity of between about 1 m/s and about 30 m/s.

[00111] The formulation comprising the therapeutic small molecule or cyclodextrin can be delivered as a liquid jet or laminar flow. The formulation can be delivered as a flow having a Reynold’s number of 2300 or less.

[00112] Laminar flow can refer to a smooth, regular movement of fluids where adjacent layers of particles experience relatively little mixing.

[00113] In some embodiments, the formulation is delivered as a liquid jet.

[00114] In some embodiments, the formulation is delivered as a laminar flow.

[00115] In some embodiments, delivering the formulation as a laminar flow increases on target delivery of the composition to the target region compared to delivering the formulation with a spray ejection profile. In some embodiments, delivering the formulation as a laminar flow decreases off target delivery of the composition to the nasal cavity compared to delivering the formulation with a spray ejection profile. In some embodiments, delivering the formulation as a laminar flow increases on target delivery of the composition to the target region and decreases off target delivery of the composition to the nasal cavity compared to delivering the formulation with a spray ejection profile.

[00116] In some embodiments, the formulation is delivered as a liquid jet.

[00117] In some embodiments, delivering the formulation as a liquid jet increases on target delivery of the composition to the target region compared to delivering the formulation with a spray ejection profile. In some embodiments, delivering the formulation as a liquid jet decreases off target delivery of the composition to the nasal cavity compared to delivering the formulation with a spray ejection profile. In some embodiments, delivering the formulation as a liquid jet increases on target delivery of the composition to the target region and decreases off target delivery of the composition to the nasal cavity compared to delivering the formulation with a spray ejection profile.

[00118] In some embodiments, the formulation is delivered as a flow having a Reynold’s number of 2300 or less. In some embodiments, the formulation is delivered as a flow having a Reynold’s number of 2200 or less. In some embodiments, the formulation is delivered as a flow having a Reynold’s number of 2100 or less. In some embodiments, the formulation is delivered as a flow having a Reynold’s number of 2000 or less. In some embodiments, the formulation is delivered as a flow having a Reynold’s number of 1900 or less. In some embodiments, the formulation is delivered as a flow having a Reynold’s number of 1800 or less. In some embodiments, the formulation is delivered as a flow having a Reynold’s number of 1700 or less. In some embodiments, the formulation is delivered as a flow having a Reynold’s number of 1600 or less. In some embodiments, the formulation is delivered as a flow having a Reynold’s number of 1500 or less. In some embodiments, the formulation is delivered as a flow having a Reynold’s number of 1400 or less. In some embodiments, the formulation is delivered as a flow having a Reynold’s number of 1300 or less. In some embodiments, the formulation is delivered as a flow having a Reynold’s number of 1200 or less. In some embodiments, the formulation is delivered as a flow having a Reynold’s number of 1100 or less. In some embodiments, the formulation is delivered as a flow having a Reynold’s number of 1000 or less. In some embodiments, the formulation is delivered as a flow having a Reynold’s number of 900 or less. In some embodiments, the formulation is delivered as a flow having a Reynold’s number of 800 or less. In some embodiments, the formulation is delivered as a flow having a Reynold’s number of 700 or less. In some embodiments, the formulation is delivered as a flow having a Reynold’s number of 600 or less. In some embodiments, the formulation is delivered as a flow having a Reynold’s number of 500 or less. In some embodiments, the formulation is delivered as a flow having a Reynold’s number of 400 or less. In some embodiments, the formulation is delivered as a flow having a Reynold’s number of 300 or less.

[00119] In some embodiments, delivering the formulation as a flow having a Reynold’s number of 2300 or less increases on target delivery of the composition to the target region compared to delivering the formulation with a spray ejection profile. In some embodiments, delivering the formulation as a flow having a Reynold’s number of 2300 or less decreases off target delivery of the composition to the nasal cavity compared to delivering the formulation with a spray ejection profile. In some embodiments, delivering the formulation as a flow having a Reynold’s number of 2300 or less increases on target delivery of the composition to the target region and decreases off target delivery of the composition to the nasal cavity compared to delivering the formulation with a spray ejection profile.

[00120] As shown herein, delivery of the therapeutic small molecule or cyclodextrin by the method disclosed herein can result in a plasma concentration of the therapeutic small molecule or cyclodextrin for a period of time after delivery. In some embodiments, the period of time is 5 min after delivery. In some embodiments, the period of time is 15 min after delivery. In some embodiments, the period of time is 30 min after delivery. In some embodiments, the period of time is 60 min after delivery. In some embodiments, the period of time is 90 min after delivery. In some embodiments, the period of time is 120 min after delivery. In some embodiments, the period of time is 150 min after delivery. In some embodiments, the period of time is 180 min after delivery. In some embodiments, the period of time is 200 min after delivery. In some embodiments, the period of time is 250 min after delivery.

[00121] In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 5 min after delivery that is at least about 10% of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 5 min after delivery that is at least about 20% of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 5 min after delivery that is at least about 30% of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 5 min after delivery that is at least about 40% of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 5 min after delivery that is at least about 50% of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 5 min after delivery that is at least about 60% of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 5 min after delivery that is at least about 70% of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 5 min after delivery that is at least about 80% of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 5 min after delivery that is at least about 90% of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 5 min after delivery that is at least about 100% of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 5 min after delivery that is at least about 1.5 times of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 5 min after delivery that is at least about 2 times of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 5 min after delivery that is at least about 2.5 times of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 5 min after delivery that is at least about 3 times of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously.

[00122] In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 30 min after delivery that is at least about 10% of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 30 min after delivery that is at least about 20% of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 30 min after delivery that is at least about 30% of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 30 min after delivery that is at least about 40% of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 30 min after delivery that is at least about 50% of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 30 min after delivery that is at least about 60% of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 30 min after delivery that is at least about 70% of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 30 min after delivery that is at least about 80% of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 30 min after delivery that is at least about 90% of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 30 min after delivery that is at least about 100% of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 30 min after delivery that is at least about 1.5 times of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 30 min after delivery that is at least about 2 times of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 30 min after delivery that is at least about 2.5 times of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 30 min after delivery that is at least about 3 times of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously.

[00123] In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 60 min after delivery that is at least about 10% of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 60 min after delivery that is at least about 20% of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 60 min after delivery that is at least about 30% of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 60 min after delivery that is at least about 40% of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 60 min after delivery that is at least about 50% of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 60 min after delivery that is at least about 60% of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 60 min after delivery that is at least about 70% of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 60 min after delivery that is at least about 80% of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 60 min after delivery that is at least about 90% of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 60 min after delivery that is at least about 100% of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 60 min after delivery that is at least about 1.5 times of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 60 min after delivery that is at least about 2 times of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 60 min after delivery that is at least about 2.5 times of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 60 min after delivery that is at least about 3 times of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously.

[00124] In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 120 min after delivery that is at least about 10% of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 120 min after delivery that is at least about 20% of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 120 min after delivery that is at least about 30% of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 120 min after delivery that is at least about 40% of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 120 min after delivery that is at least about 50% of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 120 min after delivery that is at least about 60% of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 120 min after delivery that is at least about 70% of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 120 min after delivery that is at least about 80% of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 120 min after delivery that is at least about 90% of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 120 min after delivery that is at least about 100% of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 120 min after delivery that is at least about 1.5 times of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 120 min after delivery that is at least about 2 times of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 120 min after delivery that is at least about 2.5 times of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. In some embodiments, delivery of the therapeutic small molecule to the target region of the subject results in a plasma concentration of the therapeutic small molecule about 120 min after delivery that is at least about 3 times of a plasma concentration of the therapeutic small molecule when about the same dose is delivered intravenously. [00125] In some embodiments, delivery of the therapeutic cyclodextrin to the target region of the subject results in a plasma concentration of the therapeutic cyclodextrin about 30 min after delivery that is at least about 25%, at least about 50% , at least about 75% , at least about 100%, at least about 125%, at least about 150%, at least about 175%, at least about 2 times, at least about 3 times, at least about 4 times, at least about 5 times, or more than 5 times of a plasma concentration of the therapeutic cyclodextrin when about the same dose is delivered intravenously.

[00126] In some embodiments, delivery of the therapeutic cyclodextrin to the target region of the subject results in a plasma concentration of the therapeutic cyclodextrin about 60 min after delivery that is at least about 25%, at least about 50% , at least about 75% , at least about 100%, at least about 125%, at least about 150%, at least about 175%, at least about 2 times, at least about 3 times, at least about 4 times, at least about 5 times, or more than 5 times of a plasma concentration of the therapeutic cyclodextrin when about the same dose is delivered intravenously.

[00127] In some embodiments, delivery of the therapeutic cyclodextrin to the target region of the subject results in a plasma concentration of the therapeutic cyclodextrin about 120 min after delivery that is at least about 25%, at least about 50% , at least about 75% , at least about 100%, at least about 125%, at least about 150%, at least about 175%, at least about 2 times, at least about 3 times, at least about 4 times, at least about 5 times, or more than 5 times of a plasma concentration of the therapeutic cyclodextrin when about the same dose is delivered intravenously.

[00128] In some embodiments, delivery of sugammadex to the target region of the subject results in a plasma concentration of sugammadex about 30 min after delivery that is at least about 25% of a plasma concentration of sugammadex when about the same dose is delivered intravenously. In some embodiments, delivery of sugammadex to the target region of the subject results in a plasma concentration of sugammadex about 30 min after delivery that is at least about 50% of a plasma concentration of sugammadex when about the same dose is delivered intravenously. In some embodiments, delivery of sugammadex to the target region of the subject results in a plasma concentration of sugammadex about 30 min after delivery that is at least about 75% of a plasma concentration of sugammadex when about the same dose is delivered intravenously. In some embodiments, delivery of sugammadex to the target region of the subject results in a plasma concentration of sugammadex about 30 min after delivery that is at least about 100% of a plasma concentration of sugammadex when about the same dose is delivered intravenously. [00129] In some embodiments, delivery of sugammadex to the target region of the subject results in a plasma concentration of sugammadex about 60 min after delivery that is at least about 100% of a plasma concentration of sugammadex when about the same dose is delivered intravenously. In some embodiments, delivery of sugammadex to the target region of the subject results in a plasma concentration of sugammadex about 60 min after delivery that is at least about 125% of a plasma concentration of sugammadex when about the same dose is delivered intravenously. In some embodiments, delivery of sugammadex to the target region of the subject results in a plasma concentration of sugammadex about 60 min after delivery that is at least about 150% of a plasma concentration of sugammadex when about the same dose is delivered intravenously.

[00130] In some embodiments, delivery of sugammadex to the target region of the subject results in a plasma concentration of sugammadex about 120 min after delivery that is at least about 100% of a plasma concentration of sugammadex when about the same dose is delivered intravenously. In some embodiments, delivery of sugammadex to the target region of the subject results in a plasma concentration of sugammadex about 120 min after delivery that is at least about 2 times of a plasma concentration of sugammadex when about the same dose is delivered intravenously. In some embodiments, delivery of sugammadex to the target region of the subject results in a plasma concentration of sugammadex about 120 min after delivery that is at least about 3 times of a plasma concentration of sugammadex when about the same dose is delivered intravenously. In some embodiments, delivery of sugammadex to the target region of the subject results in a plasma concentration of sugammadex about 120 min after delivery that is at least about 4 times of a plasma concentration of sugammadex when about the same dose is delivered intravenously. In some embodiments, delivery of sugammadex to the target region of the subject results in a plasma concentration of sugammadex about 120 min after delivery that is at least about 5 times of a plasma concentration of sugammadex when about the same dose is delivered intravenously.

[00131] In some embodiments, selectively delivering the formulation comprising the therapeutic small molecule or cyclodextrin to the target region of the subject comprises inserting a dispensing element into an ejection zone of a nasal cavity of the subject.

[00132] In some embodiments, the method further comprises inserting a dispensing element into a nasal cavity of the subject.

[00133] In some embodiments, the dispensing element is positioned from about 0.1 mm to about 30 mm from the olfactory region or an anterior entry to the olfactory region. In some embodiments, the tip is positioned from about 0.1 mm to about 25 mm from the olfactory region or an anterior entry to the olfactory region. In some embodiments, the tip is positioned from about 0.1 mm to about 3 mm, about 0.1 mm to about 5 mm, about 0.1 mm to about 9 mm, about 0.1 mm to about 12 mm, about 0.1 mm to about 15 mm, about 0.1 mm to about 18 mm, about 0.1 mm to about 20 mm, about 0.1 mm to about 25 mm, about 0.1 mm to about 30 mm, about 3 mm to about 5 mm, about 3 mm to about 9 mm, about 3 mm to about 12 mm, about 3 mm to about 15 mm, about 3 mm to about 18 mm, about 3 mm to about 20 mm, about 3 mm to about 25 mm, about 3 mm to about 30 mm, about 5 mm to about 9 mm, about 5 mm to about 12 mm, about 5 mm to about 15 mm, about 5 mm to about 18 mm, about 5 mm to about 20 mm, about 5 mm to about 25 mm, about 5 mm to about 30 mm, about 9 mm to about 12 mm, about 9 mm to about 15 mm, about 9 mm to about 18 mm, about 9 mm to about 20 mm, about 9 mm to about 25 mm, about 9 mm to about 30 mm, about 12 mm to about 15 mm, about 12 mm to about 18 mm, about 12 mm to about 20 mm, about 12 mm to about 25 mm, about 12 mm to about 30 mm, about 15 mm to about 18 mm, about 15 mm to about 20 mm, about 15 mm to about 25 mm, about 15 mm to about 30 mm, about 18 mm to about 20 mm, about 18 mm to about 25 mm, about 18 mm to about 30 mm, about 20 mm to about 25 mm, about 20 mm to about 30 mm, or about 25 mm to about 30 mm, including increments therein. In some embodiments, the tip is positioned from about 0.1 mm, about 3 mm, about 5 mm, about 9 mm, about 12 mm, about 15 mm, about 18 mm, about 20 mm, about 25 mm, or about 30 mm from the olfactory region or an anterior entry to the olfactory region. In some embodiments, the tip is positioned from at least about 0.1 mm, about 3 mm, about 5 mm, about 9 mm, about 12 mm, about 15 mm, about 18 mm, about 20 mm, or about 25 mm from the olfactory region or an anterior entry to the olfactory region. In some embodiments, the dispensing element is positioned from at most about 3 mm, about 5 mm, about 9 mm, about 12 mm, about 15 mm, about 18 mm, about 20 mm, about 25 mm, or about 30 mm from the olfactory region or an anterior entry to the olfactory region.

[00134] In some embodiments, the method further comprises ejecting the formulation comprising the therapeutic small molecule or cyclodextrin from an ejection zone of the nasal cavity.

[00135] In some embodiments, dispensing the formulation from the ejection zone increases on target delivery of the composition to the target region compared to dispensing the formulation outside the ejection zone. In some embodiments, dispensing the formulation from the ejection zone decreases off target delivery of the composition to the nasal cavity compared to dispensing the formulation outside the ejection zone. In some embodiments, dispensing the formulation from the ejection zone increases on target delivery of the composition to the target region and decreases off target delivery of the composition to the nasal cavity compared to dispensing the formulation outside the ejection zone. [00136] Referring to FIGs. 4A-4J. In some embodiments, the ejection zone 29 is: 0mm to 30mm superior to a horizontal line 627 that intersects the anterior aspect of the internal nasal valve 13, and 0mm to 20mm anterior to an inclined line 610 that intersects the anterior aspect of the middle turbinate 15 and the posterior aspect of the vestibule 21.

[00137] In some embodiments, the ejection zone 29 is further 0 mm to 40mm inferior to a horizontal line 621 that is parallel to the inferior aspect of the olfactory cleft 23, 0mm to 20mm posterior to the internal nasal dorsum 622, 10mm to 50mm superior to a horizontal line 617 that intersects the inferior aspect of the columella 10, 0mm to 30mm superior to a horizontal line 624 that intersects the superior aspect of the inferior turbinate 16, 0mm to 3mm from the septum 24 , or any combination thereof.

[00138] In some embodiments, the ejection zone 29 is a trapezium or irregular quadrilateral comprising (i) an inferior side 29A being a 10-25mm line extending posteriorly and horizontally from the anterior aspect of the internal nasal valve 13, (ii) an anterior side 29B being a 10-35mm line extending superiorly and parallel to the internal nasal dorsum 622 from the anterior aspect of the internal nasal valve 13, (iii) a superior side 29C being a 10-25mm line extending posteriorly and horizontally from a point on the internal nasal dorsum 622 that is 0-10mm inferior to the inferior aspect of the olfactory cleft 23, and (iv) a posterior line 29D being a 10-35mm line extending vertically along a plane that intersects the anterior aspect of the middle turbinate 15.

[00139] In some embodiments, dispensing the formulation from the ejection zone 29 increases on target deposition of the formulation to an olfactory cleft 23.

[00140] In some embodiments, the subject engaging portion 106 engages a columella region 10 of the subject to seat a distal end 128 of the insertable portion 107 within an ejection zone 29 of a nasal cavity 11 of the subject, wherein the ejection zone 29 is: 0mm to 30mm superior to a horizontal line 627 that intersects the anterior aspect of the internal nasal valve 13, and 0mm to 20mm anterior to an inclined line 610 that intersects the anterior aspect of the middle turbinate 15 and the posterior aspect of the vestibule 21, and one or more of the following: 0mm to 40mm inferior to a horizontal line 621 that is parallel to the inferior aspect of the olfactory cleft 23, 0mm to 20mm posterior to the internal nasal dorsum 622, 10mm to 50mm superior to a horizontal line 623 that intersects the inferior aspect of the columella 10, 0mm to 30mm superior to a horizontal line 624 that intersects the superior aspect of the inferior turbinate 16, 0mm to 3mm from the septum 24 or any combination thereof.

[00141] In some embodiments, the ejection zone is superior to a horizontal line that intersects the anterior aspect of the internal nasal valve by about 1 mm to about 30 mm. In some embodiments, the ejection zone is superior to a horizontal line that intersects the anterior aspect of the internal nasal valve by about 1 mm to about 2 mm, about 1 mm to about 4 mm, about 1 mm to about 6 mm, about 1 mm to about 8 mm, about 1 mm to about 10 mm, about 1 mm to about 14 mm, about 1 mm to about 18 mm, about 1 mm to about 22 mm, about 1 mm to about 26 mm, about 1 mm to about 30 mm, about 2 mm to about 4 mm, about 2 mm to about 6 mm, about 2 mm to about 8 mm, about 2 mm to about 10 mm, about 2 mm to about 14 mm, about 2 mm to about 18 mm, about 2 mm to about 22 mm, about 2 mm to about 26 mm, about 2 mm to about 30 mm, about 4 mm to about 6 mm, about 4 mm to about 8 mm, about 4 mm to about 10 mm, about 4 mm to about 14 mm, about 4 mm to about 18 mm, about 4 mm to about 22 mm, about 4 mm to about 26 mm, about 4 mm to about 30 mm, about 6 mm to about 8 mm, about 6 mm to about 10 mm, about 6 mm to about 14 mm, about 6 mm to about 18 mm, about 6 mm to about 22 mm, about 6 mm to about 26 mm, about 6 mm to about 30 mm, about 8 mm to about 10 mm, about 8 mm to about 14 mm, about 8 mm to about 18 mm, about 8 mm to about 22 mm, about 8 mm to about 26 mm, about 8 mm to about 30 mm, about 10 mm to about 14 mm, about 10 mm to about 18 mm, about 10 mm to about 22 mm, about 10 mm to about 26 mm, about 10 mm to about 30 mm, about 14 mm to about 18 mm, about 14 mm to about 22 mm, about 14 mm to about 26 mm, about 14 mm to about 30 mm, about 18 mm to about 22 mm, about 18 mm to about 26 mm, about 18 mm to about 30 mm, about 22 mm to about 26 mm, about 22 mm to about 30 mm, or about 26 mm to about 30 mm, including increments therein. In some embodiments, the ejection zone is superior to a horizontal line that intersects the anterior aspect of the internal nasal valve by about 1 mm, about 2 mm, about 4 mm, about 6 mm, about 8 mm, about 10 mm, about 14 mm, about 18 mm, about 22 mm, about 26 mm, or about 30 mm. In some embodiments, the ejection zone is superior to a horizontal line that intersects the anterior aspect of the internal nasal valve by at least about 1 mm, about 2 mm, about 4 mm, about 6 mm, about 8 mm, about 10 mm, about 14 mm, about 18 mm, about 22 mm, or about 26 mm. In some embodiments, the ejection zone is superior to a horizontal line that intersects the anterior aspect of the internal nasal valve by at most about 2 mm, about 4 mm, about 6 mm, about 8 mm, about 10 mm, about 14 mm, about 18 mm, about 22 mm, about 26 mm, or about 30 mm. In some embodiments, the ejection zone is anterior to an inclined line that intersects the anterior aspect of the middle turbinate and the posterior aspect of the vestibule by about 1 mm to about 20 mm. In some embodiments, the ejection zone is anterior to an inclined line that intersects the anterior aspect of the middle turbinate and the posterior aspect of the vestibule by about 1 mm to about 2 mm, about 1 mm to about 4 mm, about 1 mm to about 6 mm, about 1 mm to about 8 mm, about 1 mm to about 10 mm, about 1 mm to about 12 mm, about 1 mm to about 14 mm, about 1 mm to about 16 mm, about 1 mm to about 18 mm, about 1 mm to about 20 mm, about 2 mm to about 4 mm, about 2 mm to about 6 mm, about 2 mm to about 8 mm, about 2 mm to about 10 mm, about 2 mm to about 12 mm, about 2 mm to about 14 mm, about 2 mm to about 16 mm, about 2 mm to about 18 mm, about 2 mm to about 20 mm, about 4 mm to about 6 mm, about 4 mm to about 8 mm, about 4 mm to about 10 mm, about 4 mm to about 12 mm, about 4 mm to about 14 mm, about 4 mm to about 16 mm, about 4 mm to about 18 mm, about 4 mm to about 20 mm, about 6 mm to about 8 mm, about 6 mm to about 10 mm, about 6 mm to about 12 mm, about 6 mm to about 14 mm, about 6 mm to about 16 mm, about 6 mm to about 18 mm, about 6 mm to about 20 mm, about 8 mm to about 10 mm, about 8 mm to about 12 mm, about 8 mm to about 14 mm, about 8 mm to about 16 mm, about 8 mm to about 18 mm, about 8 mm to about 20 mm, about 10 mm to about 12 mm, about 10 mm to about 14 mm, about 10 mm to about 16 mm, about 10 mm to about 18 mm, about 10 mm to about 20 mm, about 12 mm to about 14 mm, about 12 mm to about 16 mm, about 12 mm to about 18 mm, about 12 mm to about 20 mm, about 14 mm to about 16 mm, about 14 mm to about 18 mm, about 14 mm to about 20 mm, about 16 mm to about 18 mm, about 16 mm to about 20 mm, or about 18 mm to about 20 mm, including increments therein. In some embodiments, the ejection zone is anterior to an inclined line that intersects the anterior aspect of the middle turbinate and the posterior aspect of the vestibule by about 1 mm, about 2 mm, about 4 mm, about 6 mm, about 8 mm, about 10 mm, about 12 mm, about 14 mm, about 16 mm, about 18 mm, or about 20 mm. In some embodiments, the ejection zone is anterior to an inclined line that intersects the anterior aspect of the middle turbinate and the posterior aspect of the vestibule by at least about 1 mm, about 2 mm, about 4 mm, about 6 mm, about 8 mm, about 10 mm, about 12 mm, about 14 mm, about 16 mm, or about 18 mm. In some embodiments, the ejection zone is anterior to an inclined line that intersects the anterior aspect of the middle turbinate and the posterior aspect of the vestibule by at most about 2 mm, about 4 mm, about 6 mm, about 8 mm, about 10 mm, about 12 mm, about 14 mm, about 16 mm, about 18 mm, or about 20 mm. In some embodiments, the ejection zone is inferior to a horizontal line that is parallel to the inferior aspect of the olfactory cleft by about 1 mm to about 35 mm. In some embodiments, the ejection zone is inferior to a horizontal line that is parallel to the inferior aspect of the olfactory cleft by about 1 mm to about 2 mm, about 1 mm to about 3 mm, about 1 mm to about 4 mm, about 1 mm to about 5 mm, about 1 mm to about 8 mm, about 1 mm to about 12 mm, about 1 mm to about 15 mm, about 1 mm to about 18 mm, about 1 mm to about 21 mm, about 1 mm to about 25 mm, about 1 mm to about 30 mm, about 1 mm to about 35 mm, about 2 mm to about 3 mm, about 2 mm to about 4 mm, about 2 mm to about 5 mm, about 2 mm to about 8 mm, about 2 mm to about 12 mm, about 2 mm to about 15 mm, about 2 mm to about 18 mm, about 2 mm to about 21 mm, about 2 mm to about 25 mm, about 2 mm to about 30 mm, about 2 mm to about 35 mm, about 3 mm to about 4 mm, about 3 mm to about 5 mm, about 3 mm to about 8 mm, about 3 mm to about 12 mm, about 3 mm to about 15 mm, about 3 mm to about 18 mm, about 3 mm to about 21 mm, about 3 mm to about 25 mm, about 3 mm to about 30 mm, about 3 mm to about 35 mm, about 4 mm to about 5 mm, about 4 mm to about 8 mm, about 4 mm to about 12 mm, about 4 mm to about 15 mm, about 4 mm to about 18 mm, about 4 mm to about 21 mm, about 4 mm to about 25 mm, about 4 mm to about 30 mm, about 4 mm to about 35 mm, about 5 mm to about 8 mm, about 5 mm to about 12 mm, about 5 mm to about 15 mm, about 5 mm to about 18 mm, about 5 mm to about 21 mm, about 5 mm to about 25 mm, about 5 mm to about 30 mm, about 5 mm to about 35 mm, about 8 mm to about 15 mm, about 8 mm to about 18 mm, about 8 mm to about 21 mm, about 8 mm to about 25 mm, about 8 mm to about 30 mm, about 8 mm to about 35 mm, about 12 mm to about 15 mm, about 12 mm to about 18 mm, about 12 mm to about 21 mm, about 12 mm to about 25 mm, about 12 mm to about 30 mm, about 12 mm to about 35 mm, about 15 mm to about 18 mm, about 15 mm to about 21 mm, about 15 mm to about 25 mm, about 15 mm to about 30 mm, about 15 mm to about 35 mm, about 18 mm to about 21 mm, about 18 mm to about 25 mm, about 18 mm to about 30 mm, about 18 mm to about 35 mm, about 21 mm to about 25 mm, about 21 mm to about 30 mm, about 21 mm to about 35 mm, about 25 mm to about 30 mm, about 25 mm to about 35 mm, or about 30 mm to about 35 mm, including increments therein. In some embodiments, the ejection zone is inferior to a horizontal line that is parallel to the inferior aspect of the olfactory cleft by about 1 mm, about 2 mm, about 3 mm, about 4 mm, about 5 mm, about 8 mm, about 12 mm, about 15 mm, about 18 mm, about 21 mm, about 25 mm, about 30 mm, or about 35 mm. In some embodiments, the ejection zone is inferior to a horizontal line that is parallel to the inferior aspect of the olfactory cleft by at least about 1 mm, about 2 mm, about 3 mm, about 4 mm, about 5 mm, about 8 mm, about 12 mm, about 15 mm, about 18 mm, about 21 mm, about 25 mm, or about 30 mm. In some embodiments, the ejection zone is inferior to a horizontal line that is parallel to the inferior aspect of the olfactory cleft by at most about 2 mm, about 3 mm, about 4 mm, about 5 mm, about 8 mm, about 12 mm, about 15 mm, about 18 mm, about 21 mm, about 25 mm, about 30 mm, or about 35 mm. In some embodiments, the ejection zone is posterior to the internal nasal dorsum by about 1 mm to about 20 mm. In some embodiments, the ejection zone is posterior to the internal nasal dorsum by about 1 mm to about 2 mm, about 1 mm to about 3 mm, about 1 mm to about 4 mm, about 1 mm to about 6 mm, about 1 mm to about 8 mm, about 1 mm to about 10 mm, about 1 mm to about 12 mm, about 1 mm to about 14 mm, about 1 mm to about 16 mm, about 1 mm to about 18 mm, about 1 mm to about 20 mm, about 2 mm to about 3 mm, about 2 mm to about 4 mm, about 2 mm to about 6 mm, about 2 mm to about 8 mm, about 2 mm to about 10 mm, about 2 mm to about 12 mm, about 2 mm to about 14 mm, about 2 mm to about 16 mm, about 2 mm to about 18 mm, about 2 mm to about 20 mm, about 3 mm to about 4 mm, about 3 mm to about 6 mm, about 3 mm to about 8 mm, about 3 mm to about 10 mm, about 3 mm to about 12 mm, about 3 mm to about 14 mm, about 3 mm to about 16 mm, about 3 mm to about 18 mm, about 3 mm to about 20 mm, about 4 mm to about 6 mm, about 4 mm to about 8 mm, about 4 mm to about 10 mm, about 4 mm to about 12 mm, about 4 mm to about 14 mm, about 4 mm to about 16 mm, about 4 mm to about 18 mm, about 4 mm to about 20 mm, about 6 mm to about 8 mm, about 6 mm to about 10 mm, about 6 mm to about 12 mm, about 6 mm to about 14 mm, about 6 mm to about 16 mm, about 6 mm to about 18 mm, about 6 mm to about 20 mm, about 8 mm to about 10 mm, about 8 mm to about 12 mm, about 8 mm to about 14 mm, about 8 mm to about 16 mm, about 8 mm to about 18 mm, about 8 mm to about 20 mm, about 10 mm to about 12 mm, about 10 mm to about 14 mm, about 10 mm to about 16 mm, about 10 mm to about 18 mm, about 10 mm to about 20 mm, about 12 mm to about 14 mm, about 12 mm to about 16 mm, about 12 mm to about 18 mm, about 12 mm to about 20 mm, about 14 mm to about 16 mm, about 14 mm to about 18 mm, about 14 mm to about 20 mm, about 16 mm to about 18 mm, about 16 mm to about 20 mm, or about 18 mm to about 20 mm, including increments therein. In some embodiments, the ejection zone is posterior to the internal nasal dorsum by about 1 mm, about 2 mm, about 3 mm, about 4 mm, about 6 mm, about 8 mm, about 10 mm, about 12 mm, about 14 mm, about 16 mm, about 18 mm, or about 20 mm. In some embodiments, the ejection zone is posterior to the internal nasal dorsum by at least about 1 mm, about 2 mm, about 3 mm, about 4 mm, about 6 mm, about 8 mm, about 10 mm, about 12 mm, about 14 mm, about 16 mm, or about 18 mm. In some embodiments, the ejection zone is posterior to the internal nasal dorsum by at most about 2 mm, about 3 mm, about 4 mm, about 6 mm, about 8 mm, about 10 mm, about 12 mm, about 14 mm, about 16 mm, about 18 mm, or about 20 mm. In some embodiments, the ejection zone is superior to a horizontal line that intersects the inferior aspect of the columella by about 10 mm to about 50 mm. In some embodiments, the ejection zone is superior to a horizontal line that intersects the inferior aspect of the columella by about 10 mm to about 12 mm, about 10 mm to about 16 mm, about 10 mm to about 20 mm, about 10 mm to about 24 mm, about 10 mm to about 28 mm, about 10 mm to about 32 mm, about 10 mm to about 36 mm, about 10 mm to about 40 mm, about 10 mm to about 45 mm, about 10 mm to about 50 mm, about 12 mm to about 16 mm, about 12 mm to about 20 mm, about 12 mm to about 24 mm, about 12 mm to about 28 mm, about 12 mm to about 32 mm, about 12 mm to about 36 mm, about 12 mm to about 40 mm, about 12 mm to about 45 mm, about 12 mm to about 50 mm, about 16 mm to about 20 mm, about 16 mm to about 24 mm, about 16 mm to about 28 mm, about 16 mm to about 32 mm, about 16 mm to about 36 mm, about 16 mm to about 40 mm, about 16 mm to about 45 mm, about 16 mm to about 50 mm, about 20 mm to about 24 mm, about 20 mm to about 28 mm, about 20 mm to about 32 mm, about 20 mm to about 36 mm, about 20 mm to about 40 mm, about 20 mm to about 45 mm, about 20 mm to about 50 mm, about 24 mm to about 28 mm, about 24 mm to about 32 mm, about 24 mm to about 36 mm, about 24 mm to about 40 mm, about 24 mm to about 45 mm, about 24 mm to about 50 mm, about 28 mm to about 32 mm, about 28 mm to about 36 mm, about 28 mm to about 40 mm, about 28 mm to about 45 mm, about 28 mm to about 50 mm, about 32 mm to about 36 mm, about 32 mm to about 40 mm, about 32 mm to about 45 mm, about 32 mm to about 50 mm, about 36 mm to about 40 mm, about 36 mm to about 45 mm, about 36 mm to about 50 mm, about 40 mm to about 45 mm, about 40 mm to about 50 mm, or about 45 mm to about 50 mm, including increments therein. In some embodiments, the ejection zone is superior to a horizontal line that intersects the inferior aspect of the columella by about 10 mm, about 12 mm, about 16 mm, about 20 mm, about 24 mm, about 28 mm, about 32 mm, about 36 mm, about 40 mm, about 45 mm, or about 50 mm. In some embodiments, the ejection zone is superior to a horizontal line that intersects the inferior aspect of the columella by at least about 10 mm, about 12 mm, about 16 mm, about 20 mm, about 24 mm, about 28 mm, about 32 mm, about 36 mm, about 40 mm, or about 45 mm. In some embodiments, the ejection zone is superior to a horizontal line that intersects the inferior aspect of the columella by at most about 12 mm, about 16 mm, about

20 mm, about 24 mm, about 28 mm, about 32 mm, about 36 mm, about 40 mm, about 45 mm, or about 50 mm. In some embodiments, the ejection zone is superior to a horizontal line that intersects the superior aspect of the inferior turbinate by about 1 mm to about 30 mm. In some embodiments, the ejection zone is superior to a horizontal line that intersects the superior aspect of the inferior turbinate by about 1 mm to about 2 mm, about 1 mm to about 4 mm, about 1 mm to about 6 mm, about 1 mm to about 8 mm, about 1 mm to about 10 mm, about 1 mm to about 12 mm, about 1 mm to about 15 mm, about 1 mm to about 18 mm, about 1 mm to about 21 mm, about 1 mm to about 25 mm, about 1 mm to about 30 mm, about 2 mm to about 4 mm, about 2 mm to about 6 mm, about 2 mm to about 8 mm, about 2 mm to about 10 mm, about 2 mm to about 12 mm, about 2 mm to about 15 mm, about 2 mm to about 18 mm, about 2 mm to about 21 mm, about 2 mm to about 25 mm, about 2 mm to about 30 mm, about 4 mm to about 6 mm, about 4 mm to about 8 mm, about 4 mm to about 10 mm, about 4 mm to about 12 mm, about 4 mm to about 15 mm, about 4 mm to about 18 mm, about 4 mm to about

21 mm, about 4 mm to about 25 mm, about 4 mm to about 30 mm, about 6 mm to about 8 mm, about 6 mm to about 10 mm, about 6 mm to about 12 mm, about 6 mm to about 15 mm, about 6 mm to about 18 mm, about 6 mm to about 21 mm, about 6 mm to about 25 mm, about 6 mm to about 30 mm, about 8 mm to about 10 mm, about 8 mm to about 12 mm, about 8 mm to about 15 mm, about 8 mm to about 18 mm, about 8 mm to about 21 mm, about 8 mm to about 25 mm, about 8 mm to about 30 mm, about 10 mm to about 12 mm, about 10 mm to about 15 mm, about 10 mm to about 18 mm, about 10 mm to about 21 mm, about 10 mm to about 25 mm, about 10 mm to about 30 mm, about 12 mm to about 15 mm, about 12 mm to about 18 mm, about 12 mm to about 21 mm, about 12 mm to about 25 mm, about 12 mm to about 30 mm, about 15 mm to about 18 mm, about 15 mm to about 21 mm, about 15 mm to about 25 mm, about 15 mm to about 30 mm, about 18 mm to about 21 mm, about 18 mm to about 25 mm, about 18 mm to about 30 mm, about 21 mm to about 25 mm, about 21 mm to about 30 mm, or about 25 mm to about 30 mm, including increments therein. In some embodiments, the ejection zone is superior to a horizontal line that intersects the superior aspect of the inferior turbinate by about 1 mm, about 2 mm, about 4 mm, about 6 mm, about 8 mm, about 10 mm, about 12 mm, about 15 mm, about 18 mm, about 21 mm, about 25 mm, or about 30 mm. In some embodiments, the ejection zone is superior to a horizontal line that intersects the superior aspect of the inferior turbinate by at least about 1 mm, about 2 mm, about 4 mm, about 6 mm, about 8 mm, about 10 mm, about 12 mm, about 15 mm, about 18 mm, about 21 mm, or about 25 mm. In some embodiments, the ejection zone is superior to a horizontal line that intersects the superior aspect of the inferior turbinate by at most about 2 mm, about 4 mm, about 6 mm, about 8 mm, about 10 mm, about 12 mm, about 15 mm, about 18 mm, about 21 mm, about 25 mm, or about 30 mm. In some embodiments, the ejection zone is away from the septum by about 0.1 mm to about 3 mm. In some embodiments, the ejection zone is away from the septum by about 0.1 mm to about 0.2 mm, about 0.1 mm to about 0.4 mm, about 0.1 mm to about 0.6 mm, about 0.1 mm to about 0.8 mm, about 0.1 mm to about 1 mm, about 0.1 mm to about 1.25 mm, about 0.1 mm to about 1.5 mm, about 0.1 mm to about 1.75 mm, about 0.1 mm to about 2 mm, about 0.1 mm to about 2.5 mm, about 0.1 mm to about 3 mm, about 0.2 mm to about 0.4 mm, about 0.2 mm to about 0.6 mm, about 0.2 mm to about 0.8 mm, about 0.2 mm to about 1 mm, about 0.2 mm to about 1.25 mm, about 0.2 mm to about 1.5 mm, about 0.2 mm to about 1.75 mm, about 0.2 mm to about 2 mm, about 0.2 mm to about 2.5 mm, about 0.2 mm to about 3 mm, about 0.4 mm to about 0.6 mm, about 0.4 mm to about 0.8 mm, about 0.4 mm to about 1 mm, about 0.4 mm to about 1.25 mm, about 0.4 mm to about 1.5 mm, about 0.4 mm to about 1.75 mm, about 0.4 mm to about 2 mm, about 0.4 mm to about 2.5 mm, about 0.4 mm to about 3 mm, about 0.6 mm to about 0.8 mm, about 0.6 mm to about 1 mm, about 0.6 mm to about 1.25 mm, about 0.6 mm to about 1.5 mm, about 0.6 mm to about 1.75 mm, about 0.6 mm to about 2 mm, about 0.6 mm to about 2.5 mm, about 0.6 mm to about 3 mm, about 0.8 mm to about 1 mm, about 0.8 mm to about 1.25 mm, about 0.8 mm to about 1.5 mm, about 0.8 mm to about 1.75 mm, about 0.8 mm to about 2 mm, about 0.8 mm to about

2.5 mm, about 0.8 mm to about 3 mm, about 1 mm to about 1.25 mm, about 1 mm to about 1.5 mm, about 1 mm to about 1.75 mm, about 1 mm to about 2 mm, about 1 mm to about 2.5 mm, about 1 mm to about 3 mm, about 1.25 mm to about 1.5 mm, about 1.25 mm to about 1.75 mm, about 1.25 mm to about 2 mm, about 1.25 mm to about 2.5 mm, about 1.25 mm to about 3 mm, about 1.5 mm to about 1.75 mm, about 1.5 mm to about 2 mm, about 1.5 mm to about 2.5 mm, about 1.5 mm to about 3 mm, about 1.75 mm to about 2 mm, about 1.75 mm to about 2.5 mm, about 1.75 mm to about 3 mm, about 2 mm to about 2.5 mm, about 2 mm to about 3 mm, or about 2.5 mm to about 3 mm, including increments therein. In some embodiments, the ejection zone is away from the septum by about 0.1 mm, about 0.2 mm, about 0.4 mm, about 0.6 mm, about 0.8 mm, about 1 mm, about 1.25 mm, about

1.5 mm, about 1.75 mm, about 2 mm, about 2.5 mm, or about 3 mm. In some embodiments, the ejection zone is away from the septum by at least about 0. 1 mm, about 0.2 mm, about 0.4 mm, about 0.6 mm, about 0.8 mm, about 1 mm, about 1.25 mm, about 1.5 mm, about 1.75 mm, about 2 mm, or about 2.5 mm. In some embodiments, the ejection zone is away from the septum by at most about 0.2 mm, about 0.4 mm, about 0.6 mm, about 0.8 mm, about 1 mm, about 1.25 mm, about 1.5 mm, about 1.75 mm, about 2 mm, about 2.5 mm, or about 3 mm.

[00142] The dispensing element can be a dispensing element of a device for delivery of the therapeutic small molecule or cyclodextrin to a target region of the nasal cavity. The device can be inserted into the nasal cavity of the subject for delivery. The device can be inserted at an angle from a vertical line. In some embodiments, the vertical line is a line perpendicular to a horizontal line that is parallel to the inferior aspect of the olfactory cleft, as depicted as line c-c of FIG. 4J.

[00143] In some embodiments, the device is inserted into the nasal cavity of the subject at an angle of between about 30 degrees to about 40 degrees from a vertical line, the vertical line being perpendicular to a horizontal line that is parallel to an inferior aspect of the olfactory cleft of the subject. In some embodiments, the angle is about 30 degrees from the vertical line. In some embodiments, the angle is about 31 degrees from the vertical line. In some embodiments, the angle is about 32 degrees from the vertical line. In some embodiments, the angle is about 33 degrees from the vertical line. In some embodiments, the angle is about 34 degrees from the vertical line. In some embodiments, the angle is about 35 degrees from the vertical line. In some embodiments, the angle is about 36 degrees from the vertical line. In some embodiments, the angle is about 37 degrees from the vertical line. In some embodiments, the angle is about 38 degrees from the vertical line. In some embodiments, the angle is about 39 degrees from the vertical line. In some embodiments, the angle is about 40 degrees from the vertical line.

[00144] In some embodiments, the formulation has a viscosity of about 1 cP. In some embodiments, delivering the formulation comprises ejecting the formulation from the ejection zone at a velocity of about 1.0 m/s. In some embodiments, delivering the formulation comprises ejecting the formulation from the ejection zone at a velocity of about 1.1 m/s. In some embodiments, delivering the formulation comprises ejecting the formulation from the ejection zone at a velocity of about 1.2 m/s. In some embodiments, delivering the formulation comprises ejecting the formulation from the ejection zone at a velocity of about 1.3 m/s. In some embodiments, delivering the formulation comprises ejecting the formulation from the ejection zone at a velocity of about 1.4 m/s. In some embodiments, delivering the formulation comprises ejecting the formulation from the ejection zone at a velocity of about 1.5 m/s. In some embodiments, delivering the formulation comprises ejecting the formulation from the ejection zone at a velocity of about 1.6 m/s. In some embodiments, delivering the formulation comprises ejecting the formulation from the ejection zone at a velocity of about 1.7 m/s. In some embodiments, delivering the formulation comprises ejecting the formulation from the ejection zone at a velocity of about 1.8 m/s. In some embodiments, delivering the formulation comprises ejecting the formulation from the ejection zone at a velocity of about 1.9 m/s. In some embodiments, delivering the formulation comprises ejecting the formulation from the ejection zone at a velocity of about 2.0 m/s. In some embodiments, delivering the formulation comprises ejecting the formulation from the ejection zone at a velocity of about 2.1 m/s. In some embodiments, delivering the formulation comprises ejecting the formulation from the ejection zone at a velocity of about 2.2 m/s. In some embodiments, delivering the formulation comprises ejecting the formulation from the ejection zone at a velocity of about 2.3 m/s. In some embodiments, delivering the formulation comprises ejecting the formulation from the ejection zone at a velocity of about 2.4 m/s. In some embodiments, delivering the formulation comprises ejecting the formulation from the ejection zone at a velocity of about 2.5 m/s. In some embodiments, delivering the formulation comprises ejecting the formulation n from the ejection zone at a velocity of about 2.6 m/s. In some embodiments, delivering the formulation comprises ejecting the formulation from the ejection zone at a velocity of about 2.7 m/s. In some embodiments, delivering the formulation comprises ejecting the formulation from the ejection zone at a velocity of about 2.8 m/s. In some embodiments, delivering the formulation comprises ejecting the formulation from the ejection zone at a velocity of about 2.9 m/s. In some embodiments, delivering the formulation comprises ejecting the formulation from the ejection zone at a velocity of between about 1.1 m/s and about 1.9 m/s. In some embodiments, delivering the formulation comprises ejecting the formulation from the ejection zone at a velocity of between about 1.0 m/s and about 2.2 m/s. In some embodiments, delivering the formulation comprises ejecting the formulation from the ejection zone at a velocity of between about 1.0 m/s and about 2.8 m/s.

[00145] In some embodiments, the formulation has a viscosity of about 50 cP. In some embodiments, delivering the formulation comprises ejecting the formulation from the ejection zone at a velocity of about 4 m/s. In some embodiments, the formulation has a viscosity of about 50 cP. In some embodiments, delivering the formulation comprises ejecting the formulation from the ejection zone at a velocity of about 4.7 m/s. In some embodiments, delivering the formulation comprises ejecting the formulation from the ejection zone at a velocity of about 5 m/s. In some embodiments, delivering the formulation comprises ejecting the formulation from the ejection zone at a velocity of about 6 m/s. In some embodiments, delivering the formulation comprises ejecting the formulation from the ejection zone at a velocity of about 7 m/s. In some embodiments, delivering the formulation comprises ejecting the formulation from the ejection zone at a velocity of about 8 m/s. In some embodiments, delivering the formulation comprises ejecting the formulation from the ejection zone at a velocity of about 9 m/s. In some embodiments, delivering the formulation comprises ejecting the formulation from the ejection zone at a velocity of about 10 m/s. In some embodiments, delivering the formulation comprises ejecting the formulation from the ejection zone at a velocity of about 11 m/s. In some embodiments, delivering the formulation comprises ejecting the formulation from the ejection zone at a velocity of about 12 m/s. In some embodiments, delivering the formulation comprises ejecting the formulation from the ejection zone at a velocity of about 13 m/s. In some embodiments, delivering the formulation comprises ejecting the formulation from the ejection zone at a velocity of about 14 m/s. In some embodiments, delivering the formulation comprises ejecting the formulation from the ejection zone at a velocity of about 15 m/s. In some embodiments, delivering the formulation comprises ejecting the formulation from the ejection zone at a velocity of about 16 m/s. In some embodiments, delivering the formulation comprises ejecting the formulation from the ejection zone at a velocity of about 17 m/s. In some embodiments, delivering the formulation comprises ejecting the formulation from the ejection zone at a velocity of about 18 m/s. In some embodiments, delivering the formulation comprises ejecting the formulation from the ejection zone at a velocity of about 18.6 m/s. In some embodiments, delivering the formulation comprises ejecting the formulation from the ejection zone at a velocity of about 19 m/s. In some embodiments, delivering the formulation comprises ejecting the formulation from the ejection zone at a velocity of between about 4.7 m/s and about 18.6 m/s. In some embodiments, delivering the formulation comprises ejecting the formulation from the ejection zone at a velocity of between about 13.9 m/s and about 15.8 m/s. In some embodiments, delivering the formulation comprises ejecting the formulation from the ejection zone at a velocity of between about 11.0 m/s and about 15.8 m/s.

[00146] As demonstrated herein, the formulation delivered by the method disclosed herein can remain at the olfactory cleft of the subject for a period of time longer than when the formulation is delivered by a nasal spray.

[00147] In some embodiments, the formulation delivered to the olfactory cleft of the subject remains at the olfactory cleft for at least about 10 seconds. In some embodiments, the formulation delivered to the olfactory cleft of the subject remains at the olfactory cleft for at least about 30 seconds. In some embodiments, the formulation delivered to the olfactory cleft of the subject remains at the olfactory cleft for at least about 1 min. In some embodiments, the formulation delivered to the olfactory cleft of the subject remains at the olfactory cleft for at least about 2 min. In some embodiments, the formulation delivered to the olfactory cleft of the subject remains at the olfactory cleft for at least about 3 min. In some embodiments, the formulation delivered to the olfactory cleft of the subject remains at the olfactory cleft for at least about 4 min. In some embodiments, the formulation delivered to the olfactory cleft of the subject remains at the olfactory cleft for at least about 5 min. In some embodiments, the formulation delivered to the olfactory cleft of the subject remains at the olfactory cleft for at least about 6 min. In some embodiments, the formulation delivered to the olfactory cleft of the subject remains at the olfactory cleft for at least about 7 min. In some embodiments, the formulation delivered to the olfactory cleft of the subject remains at the olfactory cleft for at least about 8 min. In some embodiments, the formulation delivered to the olfactory cleft of the subject remains at the olfactory cleft for at least about 9 min. In some embodiments, the formulation delivered to the olfactory cleft of the subject remains at the olfactory cleft for at least about 10 min. In some embodiments, the formulation delivered to the olfactory cleft of the subject remains at the olfactory cleft for at least about 11 min. In some embodiments, the formulation delivered to the olfactory cleft of the subject remains at the olfactory cleft for at least about 12 min. In some embodiments, the formulation delivered to the olfactory cleft of the subject remains at the olfactory cleft for at least about 13 min. In some embodiments, the formulation delivered to the olfactory cleft of the subject remains at the olfactory cleft for at least about 14 min. In some embodiments, the formulation delivered to the olfactory cleft of the subject remains at the olfactory cleft for at least about 15 min. In some embodiments, the formulation delivered to the olfactory cleft of the subject remains at the olfactory cleft for longer than 15 min. In some embodiments, the formulation delivered to the olfactory cleft of the subject remains at the olfactory cleft for a period of time longer than if the formulation was delivered by nasal spray.

[00148] Any suitable therapeutic small molecule or cyclodextrin may be used with the methods disclosed herein.

[00149] In some embodiments, the therapeutic small molecule has a molecular weight of less than about 1200 Daltons, less than about 1100 Daltons, less than about 1000 Daltons, less than about 900 Daltons, less than about 800 Daltons, less than about 700 Daltons, less than about 600 Daltons, less than about 500 Daltons, less than about 400 Daltons, less than about 300 Daltons, less than about 200 Daltons, or less than about 100 Daltons.

[00150] The therapeutic small molecule can be a nonsteroidal anti-inflammatory drug (NSAID), an immunosuppressant, an antiretroviral drug, an opioid antagonist, a benzodiazepine, a migraine drug, an antiparkinson agent, a brain tumor chemotherapy drug, a meningitis drug, a central nervous system (CNS) infection drug, an anticoagulant, a thrombolytic drug, a anxiolytic agent, an antipsychotic agent, an antidepressant, an anti-seizure drug, a CNS stimulant, or any other types of small molecules.

[00151] For example, the nonsteroidal anti-inflammatory drug (NSAID) can be sulindac (Clinoril), diclofenac (Voltaren), or any other suitable nonsteroidal anti-inflammatory drugs. The anti-seizure drug can be lacosamide (Vimpat) or any other suitable anti-seizure drugs. The immunosuppressant can be fingolimod (Gilenya) or any other suitable immunosuppressants. The antiretroviral drug can be raltegravir (Isentress) or any other suitable antiretroviral drugs. The opioid antagonist can be naloxone (Narcan), nalmefene (Opvee), butorphanol, or any other opioid antagonists. The benzodiazepine can be midazolam (Nayzilam), diazepam (Valium), or any other suitable enzodiazepines. The migraine drug can be dihydroergotamine (Migranal), dihydroergotamine mesylate, sumatriptan (Imitrex/Treximet), zavegepant (Zavzpret), zolmitriptan (Zomig), or any other suitable migraine drugs. The antiparkinson agent can be diphenhydramine (Benadryl), benzatropine (Cogentin), trihexyphenidyl (Artane), procyclidine, or any other suitable antiparkinson agents. The brain tumor chemotherapy drug can be temozolomide (Temodar), procarbazine, carmustine (BiCNU), lomustine (CCNU/Gleostine), vincristine (Oncovin), methotrexate (Trexall), cisplatin (Platinol), or any other suitable brain tumor chemotherapy drugs. The meningitis or central nervous system infection drug can be fluticasone, voriconazole (Vfend), amphotericin B, ampicillin (principen), benzylpenicillin (Pfizerpen), meropenem (Merrem), aztreonam (Azactam), rifampicin (Rifadin), ciprofloxacin (Ciloxan), cefotaxime (Claforan), ceftriaxone (Epicephin), or any other suitable meningitis or central nervous system infection drugs. The anticoagulant can be warfarin (Coumadin), apixaban (Eliquis), dabigatran (Pradaxa), edoxaban (Lixiana), or any other suitable anticoagulants. The thrombolytic drug can be Stachybotrys microspora triprenyl phenol-7, or any other suitable thrombolytic drugs. The central nervous system stimulant can be cocaine hydrochloride, nicotine, or any other suitable central nervous system stimulants.

[00152] The therapeutic small molecule can be conjugated to a lipid, an antibody, or a peptide. The therapeutic small molecule can be conjugated to a therapeutic agent, such as a drug or a radioisotope. [00153] In some embodiments, the therapeutic small molecule is selected from the group consisting of: Sulindac (Clinoril), fingolimod (Gilenya), raltegravir (Isentress), naloxone (Narcan), nalmefene (Opvee), butorphanol, midazolam (Nayzilam), diazepam (Valium), dihydroergotamine (Migranal), dihydroergotamine mesylate, sumatriptan (Imitrex/Treximet), zavegepant (Zavzpret), zolmitriptan (Zomig), diphenhydramine (Benadryl), benzatropine (Cogentin), trihexyphenidyl (Artane), procyclidine, temozolomide (Temodar), procarbazine, carmustine (BiCNU), lomustine (CCNU/Gleostine), vincristine (Oncovin), methotrexate (Trexall), cisplatin (Platinol), fluticasone, voriconazole (Vfend), amphotericin B, ampicillin (principen), benzylpenicillin (Pfizerpen), meropenem (Merrem), aztreonam (Azactam), rifampicin (Rifadin), ciprofloxacin (Ciloxan), cefotaxime (Claforan), ceftriaxone (Epicephin), warfarin (Coumadin), apixaban (Eliquis), dabigatran (Pradaxa), edoxaban (Lixiana), Stachybotrys microspora triprenyl phenol-7, cocaine hydrochloride, nicotine, diclofenac (Voltaren), lacosamide (Vimpat), varenicline (Chantix/Champix), or a derivative or analog thereof.

[00154] In some embodiments, the therapeutic small molecule is Sulindac (Clinoril).

[00155] In some embodiments, the therapeutic small molecule is diclofenac (Voltaren).

[00156] In some embodiments, the therapeutic small molecule is lacosamide (Vimpat).

[00157] In some embodiments, the therapeutic small molecule is fingolimod (Gilenya).

[00158] In some embodiments, the therapeutic small molecule is raltegravir (Isentress).

[00159] In some embodiments, the small molecule is epinephrine or a salt thereof. In some embodiments, the small molecule is epinephrine. In some embodiments, the small molecule is epinephrine bitartrate. In some embodiments, the small molecule is epinephrine hydrochloride.

[00160] In some embodiments, the small molecule can be administered in combination with one or more additional active ingredients.

[00161] In some embodiments, the small molecule can be administered as a formulation. The epinephrine or salt thereof can be formulated with one or more pharmaceutically acceptable excipients for administration using the device disclosed herein. [00162] Commercially available epinephrine may be used with the device and method of the present disclosure.

[00163] In some embodiments, the epinephrine or salt thereof can be formulated as Neffy®. For example, the epinephrine or salt thereof can be formulated with one or more of: benzalkonium chloride, disodium edetate, n-dodecyl beta-D -maltoside, sodium chloride, sodium metabisulfite, hydrochloric acid or sodium hydroxide, and water for injection.

[00164] In some embodiments, the epinephrine or salt thereof can be formulated as Primatene®. For example, the epinephrine or salt thereof can be formulated with one or more of: dehydrated alcohol, hydrofluoroalkane, polysorbate 80, and thymol.

[00165] In some embodiments, the small molecule is epinephrine and the epinephrine is formulated with benzalkonium chloride, disodium edetate, n-dodecyl beta-D-maltoside, sodium chloride, sodium metabisulfite, hydrochloric acid or sodium hydroxide to adjust pH, and water for injection.

[00166] In some embodiments, the small molecule is epinephrine and the epinephrine is formulated with dehydrated alcohol, hydrofluoroalkane, polysorbate 80, and thymol.

[00167] The therapeutic cyclodextrin can be a natural cyclodextrin or a derivative thereof.

[00168] In some embodiments, the therapeutic cyclodextrin (CD) is a a-CD, a β-CD, a γ-CD, or a derivative thereof.

[00169] In some embodiments, the therapeutic cyclodextrin (CD) is 2-hydroxypropyl-P-cyclodextrin (HPβCD). In some embodiments, the therapeutic cyclodextrin (CD) is 2-hydroxypropyl- γ-CD (HPγCD). In some embodiments, the therapeutic cyclodextrin (CD) is sulphobutylether-P-CD (SBE- P-CD). In some embodiments, the therapeutic cyclodextrin (CD) is randomly methylated P-CD (RAMEB).

[00170] In some embodiments, the therapeutic cyclodextrin is sugammadex.

[00171] It is demonstrated herein that the method disclosed herein can result in delivery of the therapeutic small molecule or cyclodextrin to a non-CNS target.

[00172] In some embodiments, the non-CNS target is blood.

[00173] The method disclosed herein is capable of delivering the therapeutic small molecule or cyclodextrin to one or more of the group consisting of cerebrospinal fluid, the central nervous system, and a region, tissue, or organ thereof. In some embodiments, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% of the therapeutic small molecule or cyclodextrin in the formulation is delivered to one or more of the group consisting of cerebrospinal fluid, the central nervous system, and a region, tissue, or organ thereof.

[00174] The method disclosed herein can provide delivery of a greater amount of the therapeutic small molecule or cyclodextrin to one or more of the group consisting of cerebrospinal fluid, the central nervous system, and a region, tissue, or organ thereof compared to intravenous delivery of an identical dose of the therapeutic small molecule or cyclodextrin.

[00175] The therapeutic small molecule or cyclodextrin can provide a therapeutic effect upon delivery to the cerebrospinal fluid, the central nervous system, or region, tissue, or organ thereof via the method disclosed herein.

[00176] In some embodiments, the subject has been diagnosed with a disease or disorder related to the central nervous system.

[00177] In some embodiments, the delivery of the therapeutic small molecule or cyclodextrin provides effective treatment for Alzheimer's disease, Parkinson's disease, a cancer of the brain, a cancer of the CNS, a non-CNS disorder, an immunological disorder, an oncological disorder, a hematological disorder, an ophthalmological disorder, a neurological disorder, a respiratory disorder, a cardiovascular disorder, an infectious disease, multiple sclerosis, stroke, epilepsy, seizure, pain, central nervous system trauma, a metabolic disorder, an infectious agent (i.e. Naegleria fowleri) or protein (i.e. Creutzfeldt Jacobs disease), a malignant tumor, a benign tumor, glioblastoma, anosmia, a chronic pain syndromes, a migraine, Huntington’s disease, amyotrophic lateral sclerosis (ALS); a neurodevelopment disorder, autism spectrum disorder (ASD); a sleep disorder, narcolepsy, or an endocrine disorder.

[00178] In some embodiments, the delivery of the therapeutic small molecule or cyclodextrin provides effective treatment for macular degeneration, spinal muscular atrophy, Duchene muscular dystrophy, hereditary transthyretin amyloidosis, amyotrophic lateral sclerosis, Parkinson’s disease, multiple sclerosis, Huntington’s disease, Alexander disease, Alzheimer’s disease, epilepsy, temporal lobe epilepsy, seizure, pain, depression, anxiety, cancer, neuronal ceroid lipofuscinoses, Mucopolysaccharoidosis, Angelman syndrome, Canavan disease, Friedrichs ataxia, or glioblastoma. [00179] Conditions that can be treated by epinephrine or a salt thereof include, for example, emergency treatment of allergic reactions, including anaphylaxis, for example anaphylaxis to stinging insects, allergen immunotherapy, foods, drugs, diagnostic testing substances, and other allergens, as well as idiopathic anaphylaxis or exercise-induced anaphylaxis. Epinephrine or a salt thereof can also be used, for example, for temporary relief of mild symptoms of intermittent asthma, such as wheezing, tightness of chest, and shortness of breath.

[00180] In some embodiments, the delivery of the therapeutic small molecule provides effective treatment for allergic reactions. In some embodiments, the delivery of the therapeutic small molecule provides effective relief of mild symptoms of intermittent asthma.

[00181] In another aspect, provided herein is a method of delivering sugammadex to a subject in need thereof, the method comprising: selectively delivering a formulation comprising a therapeutically effective amount of sugammadex to an olfactory region of the subject; wherein at least a portion of formulation is delivered to one or more of the group consisting of cerebrospinal fluid, the central nervous system, or a region, tissue, or organ thereof, and a non-CNS target.

[00182] In some embodiments, delivery of sugammadex to the target region of the subject results in a plasma concentration of sugammadex about 120 min after delivery that is at least about 1.5 times, at least about 2 times, at least about 2.5 times, or at least about 3 times of a plasma concentration of sugammadex when about the same dose is delivered intravenously.

[00183] The method disclosed herein can minimize shear forces exposed to the therapeutic small molecule or cyclodextrin.

[00184] In some embodiments, the formulation is delivered without exposing the therapeutic small molecule or cyclodextrin to shear forces sufficient to damage a significant portion of the therapeutic small molecule or cyclodextrin, without aerosolizing the formulation, or by passing the formulation through a shear disintegrating tip.

[00185] In some embodiments, the therapeutic small molecule or cyclodextrin bypasses the blood- brain barrier, the blood-cerebrospinal fluid barrier, or the arachnoid membrane.

[00186] In some embodiments, the subject is a mammal. In some embodiments, the subject is a non- human primate. In some embodiments, the subject is a human.

II. Device

[00187] In another aspect, provided herein is a device for delivery of a therapeutic small molecule to a target region of a nasal cavity of a subject, the device comprising: (a) a housing comprising an insertable portion comprising a distal end, and a proximal end; and (b) a subject-engaging portion which engages a columella region of the subject to seat the distal end of the insertable portion within an ejection zone of a nasal channel of the subject; wherein the device is configured to deliver a formulation comprising a therapeutically effective amount of the small molecule to the target region of the subject. In another aspect, provided herein is a device for delivery of a therapeutic small molecule to a target region of a nasal cavity of a subject. The device can comprise a housing comprising an insertable portion comprising a distal end and a proximal end. The device can comprise a subject- engaging portion which engages a columella region of the subject. The subject-engaging portion can seat the distal end of the insertable portion within an ejection zone of a nasal channel of the subject. The device can be configured to deliver a formulation comprising a therapeutically effective amount of the small molecule to the target region of the subject.

[00188] In yet another aspect, provided herein is a device for delivery of a therapeutic cyclodextrin to a target region of a nasal cavity of a subject, the device comprising: (a) a housing comprising an insertable portion comprising a distal end, and a proximal end; and (b) a subject-engaging portion which engages a columella region of the subject to seat the distal end of the insertable portion within an ejection zone of a nasal channel of the subject; wherein the device is configured to deliver a formulation comprising a therapeutically effective amount of the therapeutic cyclodextrin to the target region of the subject.

[00189] In yet another aspect, provided herein is a device for delivery of sugammadex to a target region of a nasal cavity of a subject, the device comprising: (a) a housing comprising an insertable portion comprising a distal end, and a proximal end; and (b) a subject-engaging portion which engages a columella region of the subject to seat the distal end of the insertable portion within an ejection zone of a nasal channel of the subject; wherein the device is configured to deliver a formulation comprising a therapeutically effective amount of sugammadex to the target region of the subject.

[00190] In some embodiments, the target region is an olfactory region.

[00191] In some embodiments, the device dispenses the formulation comprising the therapeutic small molecule or cyclodextrin as a laminar jet.

[00192] In some embodiments, application of pressure by the subject-engaging portion to the columella region of the subject enables and/or causes delivery of the formulation comprising the therapeutic small molecule or cyclodextrin to the subject from the insertable portion.

[00193] In some embodiments, the insertable portion comprises a dispensing element for delivery of the formulation comprising the therapeutic small molecule or cyclodextrin to the target region of the subject.

[00194] The housing can comprise two insertable portions. In some embodiments, the two insertable portions comprise at least one dispensing element, each insertable portion for insertion into a nasal channel of the subject, wherein, upon insertion of at least one insertable portion into a nasal channel of the subject, the at least one insertable portion engages tissue within the nasal channel to open or expand an internal nasal valve of the subject thereby positioning the at least one dispensing element for delivery of the formulation comprising the therapeutic small molecule or cyclodextrin to the subject. In some embodiments, the subject engaging portion comprises a trigger, wherein upon application of pressure to the subject engaging portion, the trigger permits actuation of the device to deliver the formulation comprising the therapeutic small molecule or cyclodextrin to the subject through the dispensing element.

[00195] The device can be used with the methods disclosed herein.

III. Definitions

[00196] 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 to which this disclosure pertains. [00197] The term “about” or “approximately” when used in reference to a particular recited value, means the value may vary from the recited value by no more than 10%, 5%, 2% or 1%. Where a particular value is recited, it can be understood that the value is modified by the term “about” or “approximately”, unless indicated otherwise.

[00198] The term “comprise”, “comprising”, or the like means additional elements or components other than those recited may be present. Other terms such as “include”, “contain”, “have” and the like have similar meaning.

[00199] The term “consist of’, “consisting of’ or the like means no additional component is present. [00200] As used herein, the singular forms “a,” “an,” and “the” include plural references, unless indicated otherwise. For example, a reference to “a molecule” can be a reference to more than one molecule.

[00201] The term “or” is used to mean “and/or”, unless it is indicated explicitly to refer to alternatives only. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise. These terms can convey that any combination is specifically contemplated. Solely for illustrative purposes, the expression “A, B, and/or C” can mean A individually; B individually; C individually; A and B; B and C; A and C; and A, B, and C.

[00202] As used herein, a “therapeutically effective amount” means an amount of a substance (e.g., a therapeutic agent, composition, and/or formulation) that elicits a desired biological response. In some embodiments, a therapeutically effective amount of a substance is an amount that is sufficient, when administered as part of a dosing regimen to a subject suffering from or susceptible to a disease, disorder, and/or condition, to treat, diagnose, prevent, and/or delay the onset of the disease, disorder, and/or condition. As will be appreciated by those of ordinary skill in this art, the effective amount of a substance may vary depending on such factors as the desired biological endpoint, the substance to be delivered, the target cell or tissue, etc. For example, the effective amount of a provided compound in a formulation to treat a disease, disorder, and/or condition is the amount that alleviates, ameliorates, relieves, inhibits, prevents, delays onset of, reduces severity of and/or reduces incidence of one or more symptoms or features of the disease, disorder, and/or condition. In some embodiments, a “therapeutically effective amount” is at least a minimal amount of a provided compound, or composition containing a provided compound, which is sufficient for treating one or more symptoms of a disease or disorder.

[00203] The “columella” is the firm tissue bridge that separates the nostrils at the base of the nose. The “columella” is the most anteroinferior portion of the nasal septum. The term “columella” or “columella region” is the subnasale, or an anterior nasale spine, or a combination thereof. The columella region may comprise a subnasale, or a combination thereof. The columella shape may be defined by an anterior nasal spine located posteriorly to the columella.

[00204] The “introduction pathway” is, in sequence, the vestibule, the anterior aspect of the internal nasal valve, and the anterior aspect of the respiratory region - anterior of the turbinates.

[00205] The “internal nasal valve” (INV) is a space bounded medially by the dorsal septum 24 (or just septum), laterally by the caudal portion of the upper lateral cartilage, and inferiorly by the head of the inferior turbinate.

[00206] The term “nasal cavity” includes two nasal channels, each comprises a vestibule, respiratory region and olfactory cleft, and a nasopharynx.

[00207] The term “turbinates” refers to superior turbinate, middle turbinate, or inferior turbinate, or a combination thereof.

[00208] The above disclosure generally describes the present application. A more complete understanding can be obtained by reference to the following specific examples. These examples are described solely for the purpose of illustration and are not intended to limit the scope of the application. Changes in form and substitution of equivalents are contemplated as circumstances might suggest or render expedient. Although specific terms have been employed herein, such terms are intended in a descriptive sense and not for purposes of limitation.

EXAMPLES

Example 1: Laminar Fluid Ejection Method [00209] The primary goal of the study was to develop a method of ejecting fluid through a cannula for deposition at the olfactory cleft. In general, all devices consisted of a ImL polycarbonate syringe filled to 0.20mL of formulation. The syringe was capped with a cannula (inner diameter = 1.35mm) and mounted on a carbon-fiber reinforced mechanism. A coil spring housed within the mechanism provided the force to compress the syringe. The spring preload was adjustable with the use of an external threaded collar and shims. The spring surrounded an orifice-based damper that could be filled with different weight silicone oils and orifice plates with different sized holes and quantity of holes. The mechanism used a simple trigger that released a syringe plunger guided by aluminum rails. This bar pushed the plunger shaft of the syringe. The syringe was held accurately and firmly in place in front of the mechanism.

[00210] Aperture testing was conducted to evaluate the coherence of fluid post-ejection and to visually assess the laminar qualities of the ejected fluid. Fluids at two different viscosities (IcP and 50cP) were tested, each at a range of ejection velocities (2m/s - 27.7m/s). Device settings for a selection of velocities within this range were determined experimentally prior to conducting aperture testing. Velocity was determined using high-speed camera-footage of ejected fluid traveling a fixed distance from the tip of the canula. A small aperture (5.64mm in diameter) was placed 25mm away from the tip of the canula. The canula was supported by magnetic supports to reduce wobbling. A catching tray was placed on the opposite side of the aperture. The percent mass transferred from the syringe to the catching tray was calculated for each test-run (Mass in catching tray / Mass Ejected from syringe * 100). Tests of each combination of viscosity and speed were repeated three times. The mean percent mass transferred for each condition is presented in Table 1. (Note that the ejected mass is smaller than the total fill mass, as it does not include the residual left in the device.).

Table 1. Aperture Testing

Percent mass transferred from the device through a small 5.64mm aperture and into a catching tray for low/high fluid viscosities and velocities.

[00211] In general, higher speeds were associated with reduced mass transfer, possibly due to increased cannula movement and splatter off the aperture edge. Qualitatively, it was observed that the device ejected fluid in a cohesive stream with a narrow diameter, especially compared to the plume emitted from a traditional spray device.

[00212] Next, a series of in-vitro deposition tests was conducted to determine the range of velocities that would optimally deposit fluid in the olfactory cleft of the human nasal passages. To test this, the mechanism was inserted into a transparent 3D-printed model of the nasal cavity. Optimal delivery was considered to be in the target zone, which represents the approximate location of the olfactory cleft in the model. If ejected too slowly, the fluid would deposit anterior to the front boundary of the target zone; too quickly and it would deposit beyond the back boundary. Two fluid viscosities (IcP and 50cP) were tested at each of three different insertion angles (30, 35, 40 degrees from the vertical). The cannula’s insertion depth was held constant at 37.5mm. The minimum velocity necessary to reach the Front Boundary (vf), the olfactory cleft (vopt), and the back boundary (vb), for each of the viscosities and deposition angles are presented in Table 2.

Table 2. In-vitro Deposition Testing

Table presents optimal velocities (Vopt) for fluids of low/high viscosity across three device angles. The Vf and Vb columns show the velocity limits at which the deposition was in front of or behind the target area, respectively.

[00213] For velocities within the optimal range, residence times were observed to exceed 10 minutes. Notably, angles of 35-40 degrees permitted a wider range of velocities, but using an angle of 30- degrees did not dramatically shift the optimal velocity. This suggested the device is adaptable to a wide range of angles. Optimal velocities (+/-20%) were found to be 1.6m/s for IcP fluid and 14.0m/s for 50cP fluid. These optimal velocities may be associated with laminar flow.

[00214] A Reynold’s number (R_e= p* V*L/p, where p is the density of the fluid, V is the velocity of the flow, L is the diameter of the passage, and p is the dynamic viscosity of the fluid) can be computed to quantify whether a fluid exhibits laminar or turbulent flow. The Reynold’s number for water at a velocity of 1.6m/s and viscosity of IcP is approximately 2,160 with a 1.35 mm diameter (density of water is approximately 1000 kg/m³). Similarly for a fluid of 50cP (with the same density as water), the Reynold’s number at 15m/s is approximately equal to 405 with a 1.35 mm diameter. Both Reynold’s numbers fall below 2,300 which is the commonly accepted threshold for laminar flow. Example 2: In-Vivo Evaluation of Laminar Fluid Ejection Method

[00215] The primary goal of these studies is to visualize delivery to the olfactory cleft (first with technetium-99, and then with methylene blue). The device was tuned to eject the fluid at a specific velocity. This velocity was chosen based on the viscosity of the fluid and the studies in Example 1, to maximize the extent of laminar flow.

[00216] Visualizing Olfactory Cleft Delivery with Technetium-99

[00217] Participants'. Nine healthy participants (ages 19+) with no history of abnormal nasal or sinus symptoms or contraindications for nasal cannulation, Magnetic Resonance Imaging (MRI), or Single- Photon Emission Computed Tomography (SPECT). Participants completed one study visit undergoing magnetic resonance imaging (MRI) and single-photon emission computed tomography (SPECT) to visualize the deposition of a radiolabeled tracer (technetium-99) in their nasal passages. In total, nine participants were enrolled in the study, and eight completed all study procedures (Participant 1.02 withdrew before completing all imaging procedures). All study procedures were approved by the Horizon Health Network’s Human Research Protection Program. Prior to participating in the study, all participants were assessed by a licensed otolaryngologist physician to confirm their eligibility. Study Design: On Day 1 of the study, anatomical (T1 -weighted) magnetic resonance images were collected from participants at the Moncton MRI clinic (Moncton, NB, Canada) using a Siemens Skyra VD13 3T scanner. MRI data provided anatomical information regarding soft tissue structure in the nasal cavity and the location of each participant’s olfactory region.

[00218] On Day 2 of the study, a saline solution including the technetium-99 radiotracer (mean dose 4.6 mCi) was delivered to participants using the Laminar Fluid Ejection method described above. Day 2 study procedures were conducted at the Nuclear Imaging Department of Saint John Regional Hospital (Saint John, NB, Canada). At the time of delivery and for five minutes afterwards, 2D SPECT Flow images were acquired every three seconds using a gamma camera. Flow images were acquired in a single sagittal plane (128x128 with voxels 4.8mm diameter).

[00219] Image Analysis: Image analysis was completed in Vivoquant (4.0). SPECT Flow data was resampled to match MRI resolution (320 x 320 with voxels 1.918mm isotropic) and manually registered to T1 images in x and y space with minimal rotation in the z-plane. This procedure enabled landmarking to nasal passage characteristics minimally visible in the SPECT data alone. Flow data was visually inspected to determine (1) the point in the time series when the bolus was dispensed, (2) the time of cannula removal, (3) the median time point in the series where the bolus initially lodged between points 2 and 4, (4) the time point at which the bolus began additional migration, and (5) the time point of the final image acquired during the five-minute SPECT series. All subjects’ SPECT Flow images are presented in FIG. 9.

[00220] Results: In seven out of eight participants imaging results demonstrated delivery of the radiotracer to the cribriform area. The radiotracer was detected in the cribriform area without any movement for at least 1.5 minutes in six of those seven participants. Additionally, clearance of the radiotracer was minor for the duration of the study for six out of those seven cases. In the two cases where sub-optimal outcomes were reached, it was the result of (i) bolus delivery anterior and superior to the cribriform (Participant 1.07), and (ii) bolus that cleared quickly after reaching the target, possibly due to the bolus remaining well intact as it directly impacted the cribriform (Participant 1.05). See

Table 3 for a summary of the results in each participant.

Table 3. Visualizing Olfactory Cleft Delivery with Technetium-99

[00221] Visualizing Olfactory Cleft Delivery with Methylene Blue

[00222] Participants'. Five healthy participants (ages 19+) with no history of sinonasal symptoms and no evidence of nasal inflammation were recruited for this study. Prior to recruitment of participants study procedures were approved by Providence Health Care research ethics board, (British Columbia, Canada) and conducted under Health Canada Investigational Testing Authorization #314993. All participants were assessed by a licensed otolaryngologist physician to confirm their eligibility. Participants completed two study visits during which a licensed otolaryngologist physician administered 0.1 mL of the visual dye tracer, methylene blue.

[00223] Study Design: During the first visit, the methylene blue was administered using the Laminar Fluid Ejection method (1.5mm cannula; velocity = 4.5m/s). During the second visit, methylene blue was administered using a conventional nasal spray device (Pharma systems Item #10272, UPC:063636802714). The Pharma systems spray device was used in these experiments because it was the device normally used by the compounding pharmacy for intranasal delivery. It was the device patients and clinicians were used to at this clinic. [00224] Following delivery, the physician used a nasal endoscope to image the deposition of methylene blue to the olfactory cleft at up to five time points (1, 5, 8, 12, and 15 minutes following delivery). From each image, the physician judged whether at least 50% of the methylene blue fluid was delivered to the olfactory cleft. If <50% of the methylene blue was judged to have deposited in the olfactory cleft, imaging was stopped and that session’s trial was completed.

[00225] Results: Four of the five participants demonstrated successful delivery of >50% of the methylene blue to the olfactory cleft using the Laminar Fluid Ejection method. In each of the five participants, the conventional nasal spray failed to deliver at least 50% of the dye to the olfactory cleft (Table 4).

Table 4. Visualization of Delivery to the Olfactory Clef Using Methylene Blue

Results from in-human tests of the Laminar Fluid Ejection (LFE) method using the dye methylene blue.

Example 3

[00226] A subject with limited fine motor control experiences an allergic reaction. The subject takes out a device of the present disclosure preloaded with epinephrine. The subject inserts the device into their nasal cavity. Once inserted, the movement of the inserted portion within the nasal cavity is restricted as the inserted portion engages the tissues of the subject’s nasal cavity. The subject continues to push the device into the nasal cavity until a subject-engaging portion of the device engages the columella of the subject, causing the device to actuate and delivery of the epinephrine.

Example 4: Plasma and tissue concentrations of diclofenac, lacosamide, and sugammadex via olfactory delivery compared to intravenous administration in rodents

[00227] Drug Administration and Sample Collection: Intravenous (IV) administration was conducted by lOOpL tail vein injection. Olfactory delivery (OD) administration was conducted by a 0.699 mm diameter cannula inserted into the right nostril with a minimal angle of 20-degrees to the target of the correct meatus.

[00228] Sample Preparation: An aliquot of 30 pL plasma was spiked into a 1.5 mL tube, and 120 pL of acetonitrile containing internal standard were added for protein precipitation. The mixture was vortexed, centrifuged at 14000 rpm for 10 min. 50 pL of supernatant was resolved with 150 pL H2O, then injected for LC-MS/MS analysis. Brain or olfactory sample was homogenized with ice-cold phosphate buffer saline (pH 7.4) at a ratio of 4 (buffer): 1 (tissue) (v/w). An aliquot of 30 pL homogenate was spiked into 1.5 mL tube, and 120 pL of acetonitrile containing internal standard was added for protein precipitation. The mixture was vortexed, centrifuged at 14000 rpm for 10 min. 50 pL of supernatant was mixed with 150 pL of water and the final solution was injected for LC-MS/MS analysis.

[00229] Liquid Chromatography/Mass Spectrometry: An Ultra Performance Liquid Chromatography (UPLC) chromatographic system (Waters), equipped with an AB Sciex QTRAP 6500 mass spectrometer was used to analyze the samples. Chromatographic separation was achieved on the Waters HSS T3 column 50*2.1mm ID. Mobile phase conditions and flow rate differed slightly for each compound and are shown in Table 5. Analyst 1.6 software packages (Applied Biosystems) were used to control the LC/MS/MS system, as well as for data acquisition and processing. A calibration curve was constructed in blank olfactory bulb homogenate.

Table 5. LC/MS/MS Parameters

[00230] Time course experiment and tissue concentration: Three compounds (diclofenac, lacosamide, sugammadex) were tested for each of two routes of administration (OD and IV), resulting in 6 experimental conditions. Five rats were used for each condition. Animals were anesthetized using Sutai/Xylazine. Plasma time courses for 200 minutes were generated. Concentration of compound in brain, olfactory bulb, and plasma at t = 200 minutes was quantified using LC/MS/MS. [00231] Results

[00232] Diclofenac (5mpk) demonstrated overall non-inferior blood-plasma uptake when comparing OD and IV administration (See Tables 6 and 7, and FIG. 8B). At early time points (t < 60 min.) IV administration exhibited greater plasma concentration compared to OD administration. Additionally, diclofenac showed similar brain, olfactory, and liver uptake across the two routes of administration (FIG. 8E). Compared to lacosamide, diclofenac shows some evidence for reduced overall brain penetrance across both routes of administration. Lacosamide (Impk) demonstrated non- inferior blood-plasma uptake when comparing OD and IV administration (See Tables 8 and 9, and FIG. 8A). Additionally, lacosamide showed similar brain, and liver uptake across the two routes of administration (FIG. 8D). A greater concentration of lacosamide was observed in the olfactory bulb following IV administration compared to OD administration. Sugammadex (5mpk) demonstrated non- inferior blood-plasma uptake when comparing OD and IV administration (See Tables 10 and 11, and FIG. 8C). At early time points (t < 30 min.) IV administration exhibited greater plasma concentration compared to OD administration. Ex-vivo data demonstrated that OD administration of sugammadex resulted in significantly reduced delivery to the liver, a trending effect of increased delivery to the olfactory cleft (p = 0.072) (FIG. 8F).

Table 6. Mean plasma concentration of diclofenac at different time points

Table 7. Mean tissue concentration of diclofenac at 200 min

Table 8. Mean plasma concentration of lacosamide at different time points

Table 9. Mean tissue concentration of lacosamide at 200 min

Table 10. Mean plasma concentration of sugammadex at different time points

Table 11. Mean tissue concentration of sugammadex at 200 min

Example 5: Additional examples of administration of therapeutic small molecules via olfactory delivery

[00233] Studies similar to Example 4 will be performed to demonstrate olfactory delivery of one or more small molecules selected from the group comprising Sulindac (Clinoril), fingolimod (Gilenya), raltegravir (Isentress), naloxone (Narcan), nalmefene (Opvee), butorphanol, midazolam (Nayzilam), diazepam (Valium), dihydroergotamine (Migranal), dihydroergotamine mesylate, sumatriptan (Imitrex/Treximet), zavegepant (Zavzpret), zolmitriptan (Zomig), diphenhydramine (Benadryl), benzatropine (Cogentin), trihexyphenidyl (Artane), procyclidine, temozolomide (Temodar), procarbazine, carmustine (BiCNU), lomustine (CCNU/Gleostine), vincristine (Oncovin), methotrexate (Trexall), cisplatin (Platinol), fluticasone, voriconazole (Vfend), amphotericin B, ampicillin (principen), benzylpenicillin (Pfizerpen), meropenem (Merrem), aztreonam (Azactam), rifampicin (Rifadin), ciprofloxacin (Ciloxan), cefotaxime (Claforan), ceftriaxone (Epicephin), warfarin (Coumadin), apixaban (Eliquis), dabigatran (Pradaxa), edoxaban (Lixiana), Stachybotrys microspora triprenyl phenol-7, cocaine hydrochloride, nicotine, varenicline (Chantix/Champix), and an analog of any of the proceeding.

[00234] While the present disclosure has been described with reference to examples, it is to be understood that the scope of the claims should not be limited by the embodiments set forth in the examples, but should be given the broadest interpretation consistent with the description as a whole. [00235] All publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety. Where a term in the present disclosure is found to be defined differently in a document incorporated herein by reference, the definition provided herein is to serve as the definition for the term.

[00236] The scope of the claims should not be limited by the embodiments and examples, but should be given the broadest interpretation consistent with the description as a whole.

Claims

CLAIMS What is claimed is:

1. A method of delivering a therapeutic small molecule to a subject in need thereof, the method comprising: selectively delivering a formulation comprising a therapeutically effective amount of the therapeutic small molecule to a target region of a nasal cavity of the subject; wherein at least a portion of formulation is delivered to one or more of the group consisting of cerebrospinal fluid, the central nervous system, or a region, tissue, or organ thereof, and a non-CNS target.

2. The method of claim 1 , wherein the formulation is delivered as a liquid jet.

3. The method of any one of claims 1-2, wherein the formulation is delivered as a laminar flow.

4. The method of any one of claims 1-3, wherein the formulation is delivered as a flow having a Reynold’s number of 2300 or less.

5. The method of any one of claims 1-4, wherein the formulation is ejected from a dispensing element, wherein at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% of the formulation passes through a circular opening having a diameter of between about 5 mm and about 6 mm at a distance of about 25 mm from where the formulation is ejected from the dispensing element.

6. The method of any one of claims 1-5, wherein the formulation has a viscosity of between about 0.5 cP and about 100 cP.

7. The method of any one of claims 1-5, wherein the formulation has a viscosity of between about 0.5 cP and about 50 cP.

8. The method of any one of claims 1-5, wherein the formulation has a viscosity of between about 0.5 cP and about 10 cP.

9. The method of any one of claims 1-5, wherein the formulation has a viscosity of between about 45 cP and about 55 cP.

10. The method of any one of claims 1-9, wherein the formulation is ejected from the dispensing element at a velocity of between about 1 m/s and about 30 m/s.

11. The method of any one of claims 1 -9, wherein the formulation is ejected from the dispensing element at a velocity of between about 2 m/s and about 4 m/s.

12. The method of any one of claims 1-9, wherein the formulation is ejected from the dispensing element at a velocity of between about 25 m/s and about 30 m/s.

13. The method of any one of claims 1-4, wherein the formulation is ejected from a dispensing element, wherein at least 75% of the formulation passes through a circular opening having a diameter of between about 5 mm and about 6 mm at a distance of about 25 mm from where the formulation is ejected from the dispensing element, wherein the formulation has a viscosity of between about 0.5 cP and about 50 cP, and wherein the formulation is ejected from the dispensing element at a velocity of between about 1 m/s and about 30 m/s.

14. The method of any one of claims 1-13, wherein at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% of the formulation is delivered to the target region of the subject.

15. The method of any one of claims 2-4, wherein delivering the formulation as a laminar flow, a liquid jet, or a flow having a Reynold’s number of 2300 or less: a) increases on target delivery of the composition to the target region, b) decreases off target delivery of the composition to the nasal cavity, or c) both, compared to delivering the formulation with a spray ejection profile.

16. The method of any one of claims 1-15, wherein selectively delivering the formulation to the target region of the subject comprises ejecting the formulation from an ejection zone in a nasal cavity of the subject, wherein the ejection zone is:

(a) 0mm to 30mm superior to a horizontal line that intersects the anterior aspect of the internal nasal valve, and

(b) 0mm to 20mm anterior to an inclined line that intersects the anterior aspect of the middle turbinate and the posterior aspect of the vestibule.

17. The method of claim 16, wherein the ejection zone is further: i. 0mm to 40mm inferior to a horizontal line that is parallel to the inferior aspect of the olfactory cleft, ii. 0mm to 20mm posterior to the internal nasal dorsum, iii. 10mm to 50mm superior to a horizontal line that intersects the inferior aspect of the columella, iv. 0mm to 30mm superior to a horizontal line that intersects the superior aspect of the inferior turbinate, v. 0mm to 3mm from the septum, or vi. any combination thereof.

18. The method of claim 16 or 17, wherein delivering the formulation from the ejection zone: a) increases on target delivery of the composition to the target region, b) decreases off target delivery of the composition to the nasal cavity, or c) both, compared to dispensing the formulation outside the ejection zone.

19. The method of any one of claims 16-18, wherein the formulation is delivered by a device comprising the dispensing element, wherein the device is inserted into a nasal cavity of the subject at an angle of between about 30 degrees and about 40 degrees from a vertical line, wherein the vertical line is perpendicular to a horizontal line that is parallel to an inferior aspect of the olfactory cleft of the subject.

20. The method of any one of claims 1-19, wherein the formulation delivered to the target region remains at the target region for at least about 10 seconds, at least about 30 seconds, at least about 1 min, at least about 2 min, at least about 3 min, at least about 4 min, at least about 5 min, at least about 6 min, at least about 7 min, at least about 8 min, at least about 9 min, at least about 10 min, at least about 11 min, at least about 12 min, at least about 13 min, at least about 14 min, or at least about 15 min.

21. The method of any one of claims 1-20, wherein the therapeutic small molecule has a molecular weight below 1000 daltons.

22. The method of any one of claims 1-21, wherein the therapeutic small molecule has a molecular weight below 800 daltons.

23. The method of any one of claims 1-22, wherein the therapeutic small molecule is a nonsteroidal anti-inflammatory drug (NSAID), an immunosuppressant, an antiretroviral drug, an opioid antagonist, a benzodiazepine, a migraine drug, an antiparkinson agent, a brain tumor chemotherapy drug, a meningitis drug, a CNS infection drug, an anticoagulant, a thrombolytic drug, a anxiolytic agent, an antipsychotic agent, an antidepressant, an anti- seizure drug, or a CNS stimulant.

24. The method of any one of claims 1-23, wherein the therapeutic small molecule is delivered via a lipid nanoparticle (LNP).

25. The method of any one of claims 1-24, wherein the therapeutic small molecule is Sulindac (Clinoril), fingolimod (Gilenya), raltegravir (Isentress), naloxone (Narcan), nalmefene (Opvee), butorphanol, midazolam (Nayzilam), diazepam (Valium), dihydroergotamine (Migranal), dihydroergotamine mesylate, sumatriptan (Imitrex/Treximet), zavegepant (Zavzpret), zolmitriptan (Zomig), diphenhydramine (Benadryl), benzatropine (Cogentin), trihexyphenidyl (Artane), procyclidine, temozolomide (Temodar), procarbazine, carmustine (BiCNU), lomustine (CCNU/Gleostine), vincristine (Oncovin), methotrexate (Trexall), cisplatin (Platinol), fluticasone, voriconazole (Vfend), amphotericin B, ampicillin (principen), benzylpenicillin (Pfizerpen), meropenem (Merrem), aztreonam (Azactam), rifampicin (Rifadin), ciprofloxacin (Ciloxan), cefotaxime (Claforan), ceftriaxone (Epicephin), warfarin (Coumadin), apixaban (Eliquis), dabigatran (Pradaxa), edoxaban (Lixiana), Stachybotrys microspora triprenyl phenol-7, cocaine hydrochloride, nicotine, diclofenac (Voltaren), lacosamide (Vimpat), or varenicline (Chantix/Champix).

26. The method of any one of claims 1-24, wherein the therapeutic small molecule is an analog of one of the group consisting of Sulindac (Clinoril), fingolimod (Gilenya), raltegravir (Isentress), naloxone (Narcan), nalmefene (Opvee), butorphanol, midazolam (Nayzilam), diazepam (Valium), dihydroergotamine (Migranal), dihydroergotamine mesylate, sumatriptan (Imitrex/Treximet), zavegepant (Zavzpret), zolmitriptan (Zomig), diphenhydramine (Benadryl), benzatropine (Cogentin), trihexyphenidyl (Artane), procyclidine, temozolomide (Temodar), procarbazine, carmustine (BiCNU), lomustine (CCNU/Gleostine), vincristine (Oncovin), methotrexate (Trexall), cisplatin (Platinol), fluticasone, voriconazole (Vfend), amphotericin B, ampicillin (principen), benzylpenicillin (Pfizerpen), meropenem (Merrem), aztreonam (Azactam), rifampicin (Rifadin), ciprofloxacin (Ciloxan), cefotaxime (Claforan), ceftriaxone (Epicephin), warfarin (Coumadin), apixaban (Eliquis), dabigatran (Pradaxa), edoxaban (Lixiana), Stachybotrys microspora triprenyl phenol-7, cocaine hydrochloride, nicotine, diclofenac (Voltaren), lacosamide (Vimpat), and varenicline (Chantix/Champix).

27. The method of any one of claims 1-24, wherein the therapeutic small molecule is Sulindac (Clinoril) or another Nonsteroidal anti-inflammatory drug (NSAID).

28. The method of any one of claims 1-24, wherein the therapeutic small molecule is diclofenac (Voltaren) or another Nonsteroidal anti-inflammatory drug (NSAID).

29. The method of any one of claims 1-24, wherein the therapeutic small molecule is lacosamide (Vimpat) or another suitable anti-seizure drug.

30. The method of any one of claims 1-24, wherein the therapeutic small molecule is fingolimod (Gilenya) or another suitable immunosuppressant.

31. The method of any one of claims 1-24, wherein the therapeutic small molecule is raltegravir (Isentress) or another suitable antiretroviral drug.

32. The method of any one of claims 1-24, wherein the therapeutic small molecule is naloxone (Narcan), nalmefene (Opvee), butorphanol, or another suitable opioid antagonist.

33. The method of any one of claims 1-24, wherein the therapeutic small molecule is midazolam (Nayzilam), diazepam (Valium), or another suitable benzodiazepine.

34. The method of any one of claims 1-24, wherein the therapeutic small molecule is dihydroergotamine (Migranal), dihydroergotamine mesylate, sumatriptan (Imitrex/Treximet), zavegepant (Zavzpret), zolmitriptan (Zomig), or another suitable migraine drug.

35. The method of any one of claims 1-24, wherein the therapeutic small molecule is diphenhydramine (Benadryl), benzatropine (Cogentin), trihexyphenidyl (Artane), procyclidine, or another suitable antiparkinson agent.

36. The method of any one of claims 1-24, wherein the therapeutic small molecule is temozolomide (Temodar), procarbazine, carmustine (BiCNU), lomustine (CCNU/Gleostine), vincristine (Oncovin), methotrexate (Trexall), cisplatin (Platinol), or another suitable brain tumor chemotherapy drug.

37. The method of any one of claims 1-24, wherein the therapeutic small molecule is fluticasone, voriconazole (Vfend), amphotericin B, ampicillin (principen), benzylpenicillin (Pfizerpen), meropenem (Merrem), aztreonam (Azactam), rifampicin (Rifadin), ciprofloxacin (Ciloxan), cefotaxime (Claforan), ceftriaxone (Epicephin), or another suitable meningitis or central nervous system infection drug.

38. The method of any one of claims 1-24, wherein the therapeutic small molecule is warfarin (Coumadin), apixaban (Eliquis), dabigatran (Pradaxa), edoxaban (Lixiana), or another suitable anticoagulant.

39. The method of any one of claims 1-24, wherein the therapeutic small molecule is Stachybotrys microspora triprenyl phenol-7 or another suitable thrombolytic drug.

40. The method of any one of claims 1-24, wherein the therapeutic small molecule is cocaine hydrochloride, nicotine, or another suitable central nervous system stimulant.

41. The method of any one of claims 1-24, wherein the therapeutic small molecule is varenicline (Chantix/Champix) or another suitable small molecule therapeutic.

42. The method of any one of claims 1-24, wherein the therapeutic small molecule is epinephrine or a salt thereof.

43. The method of any one of claims 1-42, wherein the therapeutic small molecule is conjugated to a lipid, an antibody, or a peptide.

44. The method of any one of claims 1-42, wherein the therapeutic small molecule is conjugated to a therapeutic agent.

45. The method of claim 44, wherein the therapeutic agent is a drug or a radioisotope.

46. The method of any one of claims 1-45, wherein at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90% of the therapeutic small molecule in the formulation is delivered to one or more of the group consisting of cerebrospinal fluid, the central nervous system, or a region, tissue, or organ thereof.

47. The method of any one of claims 1-46, wherein the method provides delivery of a greater amount of the therapeutic small molecule to one or more of the group consisting of cerebrospinal fluid, the central nervous system, or a region, tissue, or organ thereof than would be predicted via intravenous delivery of an identical dose of the therapeutic small molecule.

48. The method of any one of claims 1-47, wherein the therapeutic small molecule provides a therapeutic effect upon delivery to the cerebrospinal fluid, the central nervous system, or region, tissue, or organ thereof.

49. The method of any one of claims 1-48, wherein the subject has been diagnosed with a disease or disorder related to the central nervous system.

50. The method of any one of claims 1-49, wherein delivery of the therapeutic small molecule provides effective treatment for Alzheimer's disease, Parkinson's disease, a cancer of the brain, a cancer of the CNS, a non-CNS disorder, an immunological disorder, an oncological disorder, a hematological disorder, an ophthalmological disorder, a neurological disorder, a respiratory disorder, a cardiovascular disorder, an infectious disease, multiple sclerosis, stroke, epilepsy, seizure, pain, central nervous system trauma, a metabolic disorder, an infectious agent (i.e. Naegleria fowleri) or protein (i.e. Creutzfeldt Jacobs disease), a malignant tumor, a benign tumor, glioblastoma, anosmia, a chronic pain syndromes, a migraine, Huntington’s disease, amyotrophic lateral sclerosis (ALS); a neurodevelopment disorder, autism spectrum disorder (ASD); a sleep disorder, narcolepsy, or an endocrine disorder.

51. The method of any one of claims 1-49, wherein delivery of the therapeutic small molecule provides effective treatment for macular degeneration, spinal muscular atrophy, Duchene muscular dystrophy, hereditary transthyretin amyloidosis, amyotrophic lateral sclerosis, Parkinson’s disease, multiple sclerosis, Huntington’s disease, Alexander disease, Alzheimer’s disease, epilepsy, temporal lobe epilepsy, seizure, pain, depression, anxiety, cancer, neuronal ceroid lipofuscinoses, Mucopolysaccharoidosis, Angelman syndrome, Canavan disease, Friedrichs ataxia, or glioblastoma.

52. The method of any one of claims 1-51, wherein the formulation is delivered without exposing the therapeutic small molecule to shear forces sufficient to damage a significant portion of the therapeutic small molecule, without aerosolizing the formulation, or by passing the formulation through a shear disintegrating tip.

53. The method of any one of claims 1-52, wherein the therapeutic small molecule bypasses the blood-brain barrier, the blood-cerebrospinal fluid barrier, or the arachnoid membrane.

54. The method of any one of claims 1-53, wherein the formulation is delivered via a device comprising: a. a housing defining first and second insertable portions, each for insertion into a nasal channel of the subject, wherein, upon insertion of the first insertable portion into the nasal channel of the subject, the at least one insertable portion engages tissue within the nasal channel to open or expand an internal nasal valve of the subject thereby positioning at least one of the insertable portions for delivery of the formulation to the target region of the nasal cavity of the subject; and b. an actuator which delivers the formulation from the either or both of the insertable portions when the device is actuated.

55. The method of any one of claims 1-54, wherein the target region is an olfactory region.

56. A device for delivery of a therapeutic small molecule to a target region of a nasal cavity of a subject, the device comprising: a. a housing comprising an insertable portion comprising a distal end, and a proximal end; and b. a subject-engaging portion which engages a columella region of the subject to seat the distal end of the insertable portion within an ejection zone of a nasal channel of the subject; wherein the device is configured to deliver a formulation comprising a therapeutically effective amount of the small molecule to the target region of the nasal cavity of the subject.

57. The device of claim 56, wherein the device dispenses the formulation as a laminar jet.

58. The device of claim 56 or 57, wherein the device comprises a compliant dispensing tip comprising a compliant and flexible soft nib.

59. The device of any one of claims 56-58, wherein application of pressure by the subject- engaging portion to the columella region of the subject enables and/or causes delivery of the formulation to the subject from the insertable portion.

60. The device of any one of claims 56-59, wherein the insertable portion comprises a dispensing element for delivery of the formulation to the target region of the nasal cavity of the subject.

61. The device of any one of claims 56-60, wherein the target region is an olfactory region.

62. A method of delivering sugammadex to a subject in need thereof, the method comprising: selectively delivering a formulation comprising a therapeutically effective amount of sugammadex to an olfactory region of the subject; wherein at least a portion of formulation is delivered to one or more of the group consisting of cerebrospinal fluid, the central nervous system, or a region, tissue, or organ thereof, and a non-CNS target.

63. A method of delivering a therapeutic cyclodextrin to a subject in need thereof, the method comprising: selectively delivering a formulation comprising a therapeutically effective amount of the therapeutic cyclodextrin to an olfactory region of the subject; wherein at least a portion of formulation is delivered to one or more of the group consisting of cerebrospinal fluid, the central nervous system, or a region, tissue, or organ thereof, and a non-CNS target.

64. The method of claim 63, wherein the therapeutic cyclodextrin is sugammadex or an analog thereof.

65. The method of claim 62 or 63, wherein the formulation is delivered as a liquid jet.

66. The method of any one of claims 62-65, wherein the formulation is delivered as a laminar flow.

67. The method of any one of claims 62-66, wherein the formulation is delivered as a flow having a Reynold’s number of 2300 or less.

68. The method of any one of claims 62-67, wherein the formulation is ejected from a dispensing element, wherein at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% of the formulation passes through a circular opening having a diameter of between about 5 mm and about 6 mm at a distance of about 25 mm from where the formulation is ejected from the dispensing element.

69. The method of any one of claims 62-68, wherein the formulation has a viscosity of between about 0.5 cP and about 100 cP.

70. The method of any one of claims 62-68, wherein the formulation has a viscosity of between about 0.5 cP and about 50 cP.

71. The method of any one of claims 62-68, wherein the formulation has a viscosity of between about 0.5 cP and about 10 cP.

72. The method of any one of claims 62-68, wherein the formulation has a viscosity of between about 45 cP and about 55 cP.

73. The method of any one of claims 62-72, wherein the formulation is ejected from the dispensing element at a velocity of between about 1 m/s and about 30 m/s.

74. The method of any one of claims 62-73, wherein the formulation is ejected from the dispensing element at a velocity of between about 2 m/s and about 4 m/s.

75. The method of any one of claims 62-74, wherein the formulation is ejected from the dispensing element at a velocity of between about 25 m/s and about 30 m/s.

76. The method of any one of claims 62-75, wherein the formulation is ejected from a dispensing element, wherein at least 75% of the formulation passes through a circular opening having a diameter of between about 5 mm and about 6 mm at a distance of about 25 mm from where the formulation is ejected from the dispensing element, wherein the formulation has a viscosity of between about 0.5 cP and about 50 cP, and wherein the formulation is ejected from the dispensing element at a velocity of between about 1 m/s and about 30 m/s.

77. The method of any one of claims 62-76, wherein at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% of the formulation is delivered to the target region of the subject.

78. The method of any one of claims 62-77, wherein delivering the formulation as a laminar flow, a liquid jet, or a flow having a Reynold’s number of 2300 or less: a) increases on target delivery of the composition to the target region, b) decreases off target delivery of the composition to the nasal cavity, or c) both, compared to delivering the formulation with a spray ejection profile.

79. The method of any one of claims 62-78, wherein selectively delivering the formulation to the target region of the subject comprises ejecting the formulation from an ejection zone in a nasal cavity of the subject, wherein the ejection zone is:

(a) 0mm to 30mm superior to a horizontal line that intersects the anterior aspect of the internal nasal valve, and (b) 0mm to 20mm anterior to an inclined line that intersects the anterior aspect of the middle turbinate and the posterior aspect of the vestibule.

80. The method of claim 79, wherein the ejection zone is further: vii. 0mm to 40mm inferior to a horizontal line that is parallel to the inferior aspect of the olfactory cleft, viii. 0mm to 20mm posterior to the internal nasal dorsum, ix. 10mm to 50mm superior to a horizontal line that intersects the inferior aspect of the columella, x. 0mm to 30mm superior to a horizontal line that intersects the superior aspect of the inferior turbinate, xi. 0mm to 3mm from the septum, or xii. any combination thereof.

81. The method of claim 79 or 80, wherein delivering the formulation from the ejection zone: a) increases on target delivery of the composition to the target region, b) decreases off target delivery of the composition to the nasal cavity, or c) both, compared to dispensing the formulation outside the ejection zone.

82. The method of any one of claims 79-81, wherein the formulation is delivered by a device comprising the dispensing element, wherein the device is inserted into a nasal cavity of the subject at an angle of between about 30 degrees and about 40 degrees from a vertical line, wherein the vertical line is perpendicular to a horizontal line that is parallel to an inferior aspect of the olfactory cleft of the subject.

83. The method of any one of claims 62-82, wherein the formulation delivered to the target region remains at the target region for at least about 10 seconds, at least about 30 seconds, at least about 1 min, at least about 2 min, at least about 3 min, at least about 4 min, at least about 5 min, at least about 6 min, at least about 7 min, at least about 8 min, at least about 9 min, at least about 10 min, at least about 11 min, at least about 12 min, at least about 13 min, at least about 14 min, or at least about 15 min.

84. The method of any one of claims 62-83, wherein the target region is an olfactory region.

85. The method of any one of claims 62-84, wherein at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, or at least about 90% of the therapeutic cyclodextrin or sugammadex in the formulation is delivered to one or more of the group consisting of cerebrospinal fluid, the central nervous system, or a region, tissue, or organ thereof.

86. The method of any one of claims 62-83, wherein the method provides delivery of a greater amount of the therapeutic cyclodextrin or sugammadex to one or more of the group consisting of cerebrospinal fluid, the central nervous system, or a region, tissue, or organ thereof than would be predicted via intravenous delivery of an identical dose of the therapeutic cyclodextrin or sugammadex.

87. The method of any one of claims 62-84, wherein the therapeutic cyclodextrin or sugammadex provides a therapeutic effect upon delivery to the cerebrospinal fluid, the central nervous system, or region, tissue, or organ thereof.

88. The method of any one of claims 62-85, wherein the formulation is delivered without exposing the therapeutic cyclodextrin or sugammadex to shear forces sufficient to damage a significant portion of the therapeutic cyclodextrin or sugammadex, without aerosolizing the formulation, or by passing the formulation through a shear disintegrating tip.

89. The method of any one of claims 62-86, wherein the therapeutic cyclodextrin or sugammadex bypasses the blood-brain barrier, the blood-cerebrospinal fluid barrier, or the arachnoid membrane.

90. The method of any one of claims 62-87, wherein the non-CNS target is blood.

91. The method of any one of claims 62-88, wherein delivery of the therapeutic cyclodextrin or sugammadex to the olfactory region of the subject results in a plasma concentration of the therapeutic cyclodextrin or sugammadex about 120 min after delivery that is at least about 1.5 times, at least about 2 times, at least about 2.5 times, or at least about 3 times of a plasma concentration of sugammadex when about the same dose is delivered intravenously.

92. The method of any one of claims 62-91, wherein the formulation is delivered via a device comprising: a. a housing defining first and second insertable portions, each for insertion into a nasal channel of the subject, wherein, upon insertion of the first insertable portion into the nasal channel of the subject, the at least one insertable portion engages tissue within the nasal channel to open or expand an internal nasal valve of the subject thereby positioning at least one of the insertable portions for delivery of the formulation to the target region of the nasal cavity of the subject; and b. an actuator which delivers the formulation from the either or both of the insertable portions when the device is actuated.