Intranasal nerve block formulations for the treatment of headache pain and disorders

Abstract

Formulations for the nasal delivery of a local anesthetic agent such as lidocaine are disclosed.

Description

Attorney Docket 1344.0002-1 WOINTRANASAL NERVE BLOCK FORMULATIONS FOR THE TREATMENT OF HEADACHE PAIN AND DISORDERSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit to U.S. Provisional Application No. 63 / 752,334, filed January 31, 2025, which is hereby incorporated by reference in its entirety.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

[0002] This invention was made with government support under USAMRAA HT94252310280 awarded by the U.S. Department of Defense. The government has certain rights in the invention.FIELD OF INVENTION

[0003] The subject disclosure relates to formulations and systems for nasally administering an anesthetic agent for the treatment of headache pain and disorders, such as, but not limited to, migraine headaches.BACKGROUND

[0004] Lidocaine hydrochloride is an amide-type local anesthetic agent with a long history of safety and effectiveness. It is believed to stabilize neuronal membranes by inhibiting ionic fluxes required for the initiation and conduction of impulses.

[0005] Administration of anesthetics to the Sphenopalatine Ganglion nerve region are known for the treatment of migraine headaches and colloquially referred to as (SPG) blocks. According to conventional wisdom, a proposed method of action for SPG blocks is anesthetizing the sphenopalatine ganglion via precise delivery of lidocaine to the sphenopalatine fossa, under a clinical setting. Traditionally, these procedures are carried out in a controlled, hospital or clinical setting. Thus, a major setback to current SPG block therapy is that a patient undergoing a sudden migraine episode must transport themselves to a medical facility to receive immediate treatment while under duress.

[0006] There remains a need for treatment modalities, and pharmaceutical formulations designed for such treatments, for patients to receive effective, and self-administered treatment on demand (e.g., at home) without the need to visit a clinic or health care facility.Attorney Docket No. 1344.0002-1WOSUMMARY

[0007] One aspect of the subject disclosure provides an aqueous formulation for nasal delivery of an anesthetic to the posterior nasal cavity that includes lidocaine, or pharmaceutically acceptable salt thereof; glycerol; and polyethylene glycol at a molecular weight of from about 300 to about 500 daltons. In an exemplary embodiment, the lidocaine (e.g., lidocaine hydrochloride) is between about 3.0% (w / v) to about 9.5% (w / v) of the total formulation, of from about 4% (w / v) to about 8% (w / v) of the total formulation. In one particular embodiment, the lidocaine is 8% (w / v) of the total formulation.

[0008] In an exemplary embodiment, the glycerol is from about 0.25% (w / w) to about 15% (w / w) of the total weight of the formulation (w / w), and / or wherein the polyethylene glycol (e.g., PEG 400) is from about 2.5% (w / w) to about 20% (w / w) of the total weight of the formulation (w / w).

[0009] In an exemplary embodiment, the osmolality of the formulation is from about 1000 to about 5000 mOsm / kg, and / or the pH is from about 6 to about 7. In yet another exemplary embodiment, the formulation is provided in an amount, such that when dispensed by a device, the spray actuation content (SAC) of the lidocaine, or pharmaceutically acceptable salt thereof delivered from the device is about 12 mg per spray.BRIEF DESCRIPTION OF THE DRAWINGS

[0010] FIG. 1 is an isometric view of an exemplary device capable of administering formulations of the instant disclosure;

[0011] FIG. 2 is a second isometric view of the exemplary device;

[0012] FIG. 3 is an exploded view of the exemplary device;

[0013] FIG. 4 is a detailed view of the exemplary device illustrating the nozzle cap;

[0014] FIG. 5 is a detailed view of the exemplary device illustrating the nozzle;

[0015] FIG. 6 is a detailed view of the exemplary device illustrating features of the lock channel;

[0016] FIG. 7A is a detailed view of the exemplary device illustrating the plunger in a first plunger position;24938-7673-0763, v. 2Attorney Docket No. 1344.0002-1WO

[0017] FIG. 7B is a detailed view of the exemplary device illustrating the plunger in a second plunger position with the sliding lock depressed;

[0018] FIG. 7C is a detailed view of the exemplary device illustrating the plunger in a second plunger position with the sliding lock released;

[0019] FIG. 7D is a detailed view of the exemplary device illustrating the plunger in a third plunger position;

[0020] FIG. 8 is a cross-sectional view of the exemplary device;

[0021] FIG. 9 is an in-use view of the exemplary device;

[0022] FIG. 10 is a schematic of the experimental set-up of Example 1 employing a PermeaPad® bio-mimetic membrane;

[0023] FIG. 11 depicts the results of Example 1;

[0024] FIG. 12 and FIG. 13 depicts results of the nasal cast deposition testing described in Example 3;

[0025] FIG. 14 and FIG. 15 depict the results of repeatability results for formulations from three different nozzles, as described in Example 3.DETAILED DESCRIPTION

[0026] Traditional SPG nerve block therapy, according to conventional wisdom, is based on the theory of anesthetizing the sphenopalatine ganglion via precise delivery of lidocaine to the sphenopalatine fossa. It has instantly been found, however, that nerve fibers within the posterior nasal cavity contribute to the analgesic effect. Specifically, a nasal atomizer can be provided to anesthetize afferent trigeminal sensory fibers within the respiratory epithelium of the posterior nasal cavity, rather than the SPG itself. These fibers provide sensory input to the SPG via the posterior superior lateral nasal nerve which lies on the middle and superior nasal turbinates and the nasopalatine nerve which lies on the posterior aspect of the nasal septum. These two nerves, along with the sphenopalatine artery, form the contents of the sphenopalatine foramen. The instantly disclosed formulations, devices, and micropore assemblies are provided to maximize deposition of lidocaine in these areas.

[0027] In certain embodiments, the formulation is provided in an amount, such that when dispensed by a device, the spray actuation content (SAC) of the lidocaine delivered from the device is about 12 mg. SAC can be determined by a gravimetric testing method.34938-7673-0763, v. 2Attorney Docket No. 1344.0002-1WO

[0028] Intranasal administration of the instant formulations, as compared to IV administration, effectively provides higher local therapeutic benefit while reducing systemic absorption and exposure to lidocaine. In certain embodiments, the plasma exposure to lidocaine in a subject at, e.g., 0-lh, 0-2h, and / or at 0-4h, upon intranasal delivery of the instantly disclosed formulations from a device, administered once or twice, meets one or more of the specifications described below:

[0029] a.) even when multiplied 2-fold, intranasal administration provides a plasma exposure that is still less than IV administration of the same amount of lidocaine (over the same period of time), or

[0030] b .) even when multiplied 4-fold, intranasal administration provides a plasma exposure that is still less than IV administration of the same amount of lidocaine (over the same period of time).

[0031] In certain embodiments, the plasma levels of lidocaine in a subject at, e.g., at 0.25 h, 0.50 h, 1 h and / or 2h, upon intranasal delivery of the instantly disclosed formulations from a device, administered once or twice, meets one or more of the specifications described below: a.) even when multiplied 2-fold, intranasal administration provides plasma levels that are still less than IV administration of the same amount of lidocaine (at the same time point), or b.) even when multiplied 3-fold, intranasal administration provides plasma levels that are still less than IV administration of the same amount of lidocaine (at the same time point), b.) even when multiplied 4-fold, intranasal administration provides plasma levels that are still less than IV administration of the same amount of lidocaine (at the same time point).

[0032] In certain embodiments, the plasma level at 6h upon intranasal delivery of the instantly disclosed formulations from a device, once or twice, is the same, or about the same (±5%) as IV administration of the same amount of anesthetic agent at 6h. In certain embodiments, the plasma level at 6h upon intranasal delivery from a device is less than IV administration of the same amount of anesthetic agent at 6h.

[0033] In certain embodiments, the total brain uptake upon intranasal delivery of the instantly disclosed formulations from a device, once or twice, is the same, or about the same (±5%) as IV administration of the same amount of anesthetic agent. In certain embodiments, the total brain uptake upon intranasal delivery from a device is 1.5-2-fold < IV administration of the same amount of anesthetic agent.44938-7673-0763, v. 2Attorney Docket No. 1344.0002-1WO

[0034] In certain embodiments, the total liver uptake upon intranasal delivery of the instantly disclosed formulations, from a device, once or twice, is the same, or about the same (±5%) as IV administration of the same amount of anesthetic agent. In certain embodiments, the total liver uptake upon intranasal delivery from a device is 1.5-2-fold < IV administration of the same amount of anesthetic agent.

[0035] In certain embodiments, the elimination half-life of the instantly disclosed formulations, upon intranasal delivery from a device is the same, or about the same (±5%) as IV administration of the same amount of anesthetic agent.

[0036] In certain embodiments, the spray content uniformity in the formulation as administered from a device nozzle, is about NMT 15%.

[0037] In certain embodiments, the osmolality of the formulation is about 1000-5000 mOsm / kg, or 1000-3000 mOsm / kg, (e.g., about 2000 mOsm / kg).

[0038] In certain embodiments, the formulation is stable over 3, over 6, or 12 or over 24 months (100%, ±10%) under one or more of ACC and LTC conditions (e.g., under ICH LTC and / or ACC conditions).

[0039] The instantly disclosed formulations can be used to prevent or treat any headache pain or disorder, including headache pain caused or otherwise resulting from headaches, including, but not limited to, migraines, hemicrania continua, allergy or sinus headaches, cluster headaches, tension headaches, hormone headaches, hypertension headaches, and idiopathic head pain or headaches, and other head pain. In a preferred embodiment, the instantly disclosed formulations can be used to prevent or treat migraines. For example, the instantly disclosed formulations can be used treat a migraine attack and can be administered by the subject after the onset of the migraine.Humectants

[0040] In certain embodiments, the formulations of the instant disclosure include one or more humectants. In certain embodiments, any humectant known in the art and safe for administration to a human for pharmaceutical applications can be employed. In certain embodiments, the humectant is selected from, for example, a glycol (e.g., propylene glycol, hexylene glycol and butylene glycol), a polyglycol (e.g., a PEG, such as PEG400) an alpha hydroxy acid (e.g., lactic acid), triacetin (i.e., propane- 1,2, 3 -triyl triacetate), glycerol (i.e., propane- 1,2, 3 -tri ol), leucine, panthenol (provitamin B5) and sorbitol.54938-7673-0763, v. 2Attorney Docket No. 1344.0002-1WO

[0041] In one preferred embodiment, the humectant includes, or consists of, glycerol. In one particularly preferred embodiment, the humectant includes a humectant with viscosity modifying properties (e.g., a polyethylene glycol (PEG), most preferably in combination with glycerol).Viscosity Modifiers

[0042] In certain embodiments, the formulations of the instant disclosure include one or more viscosity modifier or thickener. In certain embodiments, any viscosity modifier or thickener known in the art and safe for administration to a human for pharmaceutical applications can be employed. In certain embodiments, the viscosity modifier or thickener is selected from, for example, polyvinyl alcohol, hydroxypropyl methyl cellulose (HPMC), hydroxyethyl cellulose (HEC), dextran, a poloxamer (a block copolymer of ethylene oxide and propylene oxide), carboxy methyl cellulose (CMC), xantham gum, gellan gum, sodium alginate and a polyethylene glycol (e.g., PEG300-500 such as PEG400).

[0043] In one preferred embodiment, the viscosity modifier or thickener is a polyethylene glycol, preferably having a molecular weight from about 100 to about 700 daltons (i.e., about PEG100 to about PEG700), or from about 200 to about 700 daltons (i.e., about PEG200 to about PEG700), or from about 300 to about 500 daltons (i.e., about PEG300 to about PEG500). In one embodiment, the viscosity modifier is PEG400. As used throughout this disclosure, molecular weights of PEG are based on a weight average molecular weight (Mw).Exemplary Devices

[0044] The formulations of the instant disclosure can be loaded into the devices disclosed in International Published Application No. WO 2023009154, and U.S. Published Application Nos. 2023 / 0031735, US2021 / 0308393, US2021 / 0338946 and US2020 / 0038594, and selfdispensed by a user in need of relief. Each of the above references are hereby incorporated by reference in their entirety.Though not limited thereto, an exemplary device 100, particularly suitable to dispense the instantly disclosed formulations is shown in FIG. 1. The device 100 is shown as an isometric view and denotes the proximal end 266 and the distal end 268. The nozzle 210 is shown extending from the housing 290 at the proximal end 266 of the housing 290. The proximal end 266 of the nozzle 210 terminates with the atomizer 212. The atomizer 212 comprises the insertion limiter 216 to limit insertion distance. The atomizer 212 may discharge the medication64938-7673-0763, v. 2Attorney Docket No. 1344.0002-1WOvia the one or more apertures 214. The actuation button 300 is shown accessible on the side of the housing 290. Pressing the actuation button 300 once may dispense the first dose of the medication via the atomizer 212. Pressing the actuation button 300 a second time may dispense a second dose of the medication via the atomizer 212. The nozzle cap 310 is shown separated from the housing 290. The locking extension 312 on the nozzle cap 310 may prevent the actuation button 300 from being pressed when in place on the housing 290 when the locking extension 312 mates with the locking aperture 314. The spring cap 296 may cover the housing 290 at the distal end 268 of the housing 290. This device is exemplary, and can be modified based on the teachings of, for example, FIG. 5 (e.g., nozzle depth and bend) and FIG. 7 (e.g., liquid pressure), discussed below.

[0045] Turning now to FIG. 2, the figure shows an isometric view from the side opposite that shown in FIG. 1. The nozzle 210 comprising the atomizer 212, the one or more apertures 214, and the insertion limiter 216 is shown. The upper housing 292 and the lower housing 294 are shown with the actuation button 300 accessible on the upper housing 292. The nozzle cap 310 with the locking extension 312 and the spring cap 296 couple to opposite ends of the device.

[0046] Turning now to FIG. 3, the figure shows an exploded view of the exemplary device 100. Between the upper housing 292 and the lower housing 294 reside the cartridge 202, the plunger 224, the sliding lock 320, and the actuation button 300. The cartridge 202 comprises the nozzle interface 204 that couples to the nozzle 210 and the proximal cartridge aperture 206 through which the medication exits the cartridge 202. The cartridge 202 comprises the distal cartridge aperture 208 which is where the plunger 224 presses in order to force the medication out of the cartridge 202.

[0047] The plunger 224 may move proximally (up in this figure) to dispense the medication. The sliding lock 320 may slide laterally under the influence of the actuation button 300 and the one or more lock springs 322. As the sliding lock 320 slides it may reposition the plunger pin 324 within the lock channel 330. The plunger 224 may move if there is no mechanical interference between the plunger pin 324 and the lock channel 330 or may be prevented from moving if there is mechanical interference between the plunger pin 324 and the lock channel 330. The actuation button 300 may comprise the one or more pivot arms 302 allowing the actuation button 300 to pivot when pressed. The spring cap 296 may removably couple to the upper housing 292 and the lower housing 294 via a threaded interface.74938-7673-0763, v. 2Attorney Docket No. 1344.0002-1WO

[0048] Turning now to FIG. 4, the figure shows a detail view of the nozzle cap 310 illustrating the locking extension 312. Turning now to FIG. 5, the figure shows a detail view of the nozzle 210 illustrating the cartridge interface 218 with the nozzle aperture 220 and the nozzle 210 with the atomizer 212, the one or more apertures 214 and the insertion limiter 216. One or more micropore assemblies disclosed below (e.g., Assemblies I, K, or H) can be provided in fluid communication with the nozzle aperture 220 to serve as the aperture 214 of the device.

[0049] The medication (i.e., an instantly disclosed formulation) can be forced into the nozzle aperture 220 and may emerge from the one or more apertures 214 as a mist or other spray pattern as determined by the nozzle orifice and actuation. The nozzle 210 may be placed into a nostril with the insertion limiter 216 preventing over insertion.

[0050] Turning now to FIG. 6, the figure shows a detail involving the lock channel 330. Note that throughout the description of FIG. 6, the plunger 224 is represented in a stationary position and the plunger pin 324 is represented as moving to the right to various stopping positions. In actuality, the plunger pin 324 is stationed in the horizontal direction and it is the plunger 224 that moves to the left to reposition the plunger pin 324 relative to the plunger 224.

[0051] The lock channel 330 may be a cut-out within the plunger 224. The lock channel 330 may comprise the first offset 332, the second offset 334, the plunger lever 336, and the pin capture channel 338. Initially, the plunger 224 will align with the plunger pin 324 at the first plunger position 280. Specifically, the plunger pin 324 will be located at the first stop position 350 within the first offset 332. As the dispensing spring pushes the plunger 224 to the left, the plunger pin 324 at the first stop position 350 may prevent the plunger 224 from moving.

[0052] When the actuation button is pressed for a first time, the sliding lock may be pushed down and the plunger pin 324 may drop. The plunger 224 may then be free to slide to the left such that the plunger pin 324 is relocated to a subsequent second stop position 352. Movement of the plunger 224 may be stopped when the plunger pin 324 encounters the plunger lever 336. The actuation button may be held down or released immediately. When the actuation button is released, the one or more lock springs may push the sliding lock up, moving the plunger pin 324 to the third stop position 354. Movement of the plunger 224 may be blocked by the plunger pin 324 when the plunger pin 324 is at the third stop position 354. In moving between the first plunger position 280 and the second plunger position 282, the plunger 224 may have caused the first dose to be dispensed.84938-7673-0763, v. 2Attorney Docket No. 1344.0002-1WO

[0053] When the actuation button is pressed for a second time, the sliding lock may be pushed down and the plunger pin 324 may drop. The plunger 224 may press down on the plunger lever 336, causing the plunger lever 336 to flex downward. When the plunger pin 324 is aligned with the pin capture channel 338, the plunger 224 may move to the left again. As the plunger 224 moves to the left, the plunger pin 324 may enter the pin capture channel 338 and may move to the fourth stop position 356. When the plunger pin 324 is within the pin capture channel 338, the plunger pin 324 may be prevented from moving upwards when the actuation button is released. Having the actuation button stuck in the pressed position is an indication that the device is spent. In moving between the second plunger position 282 and the third plunger position 284, the plunger 224 may have caused the second dose to be dispensed. In an alternative embodiment, additional doses may be configured to be dispensed by the addition of additional plunger positions.

[0054] Turning now to FIG. 7, the figure shows detailed views illustrating movement of the plunger 224. Throughout FIG. 7A, FIG. 7B, FIG. 7C, and FIG. 7D the dispensing spring 242 may apply the dispensing force 286 to the plunger 224 such that the dispensing force 286 tends to push the plunger 224 to the left. Whenever the plunger 224 moves to the left, the seal interface 226 may push the seal into the cartridge. FIG. 7A illustrates the plunger 224 in the first plunger position 280. The sliding lock 320 is elevated such that the plunger pin 324 is within the first offset 332 of the lock channel 330. Mechanical interference between the plunger pin 324 and the plunger 224 may prevent the plunger 224 from moving to the left. FIG. 7B illustrates the plunger 224 in the second plunger position 282. The sliding lock 320 has been forced down by a first depression of the actuation button and has lowered the plunger pin 324. With mechanical interference between the plunger pin 324 and the lock channel 330 eliminated, the plunger 224 may be free to move to the left until the plunger pin 324 contacts the plunger lever 336. In moving between the first plunger position 280 and the second plunger position 282, the plunger 224 may have caused the first dose to be dispensed. FIG. 7C illustrates that the actuation button has been released and the one or more lock springs have forced the sliding lock 320 and the plunger pin 324 upwards, positioning the plunger pin 324 within the second offset 334 of the lock channel 330. Mechanical interference between the plunger pin 324 and the lock channel 330 may prevent the plunger 224 from moving to the left. FIG. 7D illustrates the plunger 224 in the third plunger position 284. The sliding lock 320 has been forced down by a second depression of the actuation button and has lowered the plunger pin 324. As the plunger pin 324 is forced downwards, the plunger pin 324 may press94938-7673-0763, v. 2Attorney Docket No. 1344.0002-1WOagainst the top pf the plunger lever 336 and may flex the plunger lever 336 downwards. When the plunger pin 324 is aligned with the pin capture channel 338, the plunger 224 may move to the left to the third plunger position 284. The plunger pin 324 may be vertically trapped within the lock channel 330 at the pin capture channel 338 and may prevent the sliding lock 320 from lifting the actuation button. In moving between the second plunger position 282 and the third plunger position 284, the plunger 224 may have caused the second dose to be dispensed.

[0055] Turning now to FIG. 8, the figure shows a cross-sectional view of the device 100 in an unused state. The plunger 224 may force the seal 222 into the cartridge 202 to dispense the medication when the actuation button 300 is depressed. The actuation button 300 may be accessible through the upper housing 292. When the actuation button 300 is depressed, the actuation button 300 may force the sliding lock 320 and the plunger pin 324 downwards. When the actuation button 300 is released, the one or more spring locks may force the sliding lock 320 and the plunger pin 324 upwards. The downward and upward movement of the plunger pin 324 may allow the plunger 224 to move forward as the plunger pin 324 moves through the lock channel 330 in stages. The nozzle cap 310 may prevent actuation when the nozzle cap 310 is in place on the housing. Specifically, the locking extension 312 of the nozzle cap 310 may press into the lower housing 294 via the locking aperture 314. The locking extension 312 may cause mechanical interference with the sliding lock 320 and may prevent the sliding lock 320 and the plunger pin 324 from moving downwards.

[0056] Turning now to FIG. 9, the figure shows the use of an embodiment of the disclosure where the device is configured to dispense two doses of a medication by action of the user, although this should in no way be considered as limiting as the innovation may be configured to dispense additional doses of medication when required to treat specific conditions. The user 920 may hold the device with the nozzle 210 inserted into the first nostril such that the insertion limiter 216 of the nozzle 210 is pressed against the nostril 924. Applying the actuation force 396 to the actuation button 300 for a first time may result in the aerosol mist 230 being dispensed via the atomizer 212 into the first nostril. The nozzle 210 may be moved to the second nostril and the dispensing force 286 may be applied to press the actuation button 300 a second time to dispense the aerosol mist 230 into the second nostril. The aerosol mist 230 may travel through the nasal cavities until the medication is adjacent to the sphenopalatine ganglion 930 and may thus provide relief.Dosing Amounts104938-7673-0763, v. 2Attorney Docket No. 1344.0002-1WO

[0057] In certain embodiments, the formulation is provided in an amount such that when dispensed by a device, the spray actuation content (SAC) of the API delivered from the device is about 12 mg per spray. In certain embodiments, the spray actuation volume is about 150 pL per spray. In one particular embodiment, the formulation comprises 8% (w / v) lidocaine hydrochloride, and the spray actuation volume is about 150 pL, delivering about 12 mg of lidocaine hydrochloride per spray.

[0058] In certain embodiments, the formulation is administered as a single spray to one nostril. In certain embodiments, the formulation is administered as two sprays, one spray to each nostril. In one particular embodiment, the formulation is administered as two sprays of about 150 pL each, delivering a total of about 24 mg of lidocaine hydrochloride per administration (about 12 mg per nostril).

[0059] In certain embodiments, the total dose of lidocaine hydrochloride administered per treatment is from about 6 mg to about 48 mg. In certain embodiments, the total dose is from about 12 mg to about 36 mg. In certain embodiments, the total dose is from about 18 mg to about 30 mg. In one particular embodiment, the total dose is about 24 mg, administered as two sprays of about 12 mg each.

[0060] In certain embodiments, the spray actuation volume is from about 50 pL to about 300 pL per spray. In certain embodiments, the spray actuation volume is from about 100 pL to about 200 pL per spray. In certain embodiments, the spray actuation volume is from about 125 pL to about 175 pL per spray. In one particular embodiment, the spray actuation volume is about 150 pL per spray.

[0061] In certain embodiments employing the 8% (w / v) lidocaine hydrochloride formulation, the spray actuation content is from about 4 mg to about 24 mg per spray. In certain embodiments, the spray actuation content is from about 8 mg to about 16 mg per spray. In certain embodiments, the spray actuation content is from about 10 mg to about 14 mg per spray. In one particular embodiment, the spray actuation content is about 12 mg per spray.

[0062] In certain embodiments, the formulation may be administered one, two, three, or four times per day. In certain embodiments, the formulation may be administered as needed upon onset of headache pain or migraine symptoms. In certain embodiments, the formulation is administered once at the onset of a migraine attack. In certain embodiments, a second administration may be provided if symptoms persist or return.114938-7673-0763, v. 2Attorney Docket No. 1344.0002-1WO

[0063] In certain embodiments employing a 4% (w / v) lidocaine hydrochloride formulation, the spray actuation content is about 6 mg per spray when the spray actuation volume is about 150 pL. In such embodiments, two sprays deliver a total of about 12 mg of lidocaine hydrochloride per administration.

[0064] While certain illustrative embodiments have been described, it is evident that many alternatives, modifications, permutations and variations will become apparent to those skilled in the art in light of the foregoing description.Example 1 - Permeation in Simulated Nasal Fluid

[0065] To serve as in-vitro tool to differentiate formulations with respect to permeation / residence time, a PermeaPad® bio-mimetic membrane apparatus as shown in FIG.10 was used according to manufacturer’s instruction to assess permeation / residence time of the formulations of Table 2:Table 2. Formulations for Permeation and Droplet Size Distribution Analysis, compounded for 100g scale4938-7673-0763, v. 2Attorney Docket No. 1344.0002-1WO

[0066] Although developed to simulate GI delivery, the PermeaPad® has also found documented use in the literature modeling nasal delivery. See, e.g., Human Lactobacillus Biosurfactants as Natural Excipients for Nasal Drug Delivery of Hydrocortisone, Pharmaceutics 2022, 14, 524. Assessment of permeation of a given formulation over a defined membrane / tissue / cell culture was obtained.

[0067] As shown in FIG. 10, the testing apparatus includes a donor chamber 1000, which includes a port 1002 on a proximal end accessible to the tester and a one part of flat ground joint 1004a at a distal end for engaging the PermeaPad® membrane 1006. The Flat ground joint has a second part 1004b to secure the membrane. Downstream of the membrane, a receptor chamber 1006 provided with a stirbar 1008 collects the permeate and circulate it amongst the chamber, which includes an outlet to a sampling port 1010. The receptor chamber is immersed in a temperature-controlled water jacket 1012 that includes an inlet / outlet 1014a, 1014b to receive a circulating supply of water to control the temperature of the reception chamber.

[0068] Doses of 250 mcl of either 4% or 8% formulation was used along with a control or baseline formulation containing 4% lidocaine without glycerol and PEG400. The results are shown in FIG. 11.

[0069] Remarkably, the addition of glycerol and PEG400 (Formulation F5, 4%, 1100) doubled the permeation rate (y = 0.0082x vs. y = 0.0041x, mg / cm2), as compared to the baseline 4% lidocaine formulation (1104). Also surprisingly, the 8% formulation (Formulation Fl 3, 1102) exhibited an approximately 6.7 times higher flux as compared to the 4% formulation (Formulation F5, 1100). These results indicate that the tested formulations will have increased residence time at the target deposition site in the nose, leading to a prolonged analgesic effect.Example 2 - Stability

[0070] The compositions of Table 7 and Table 8 were prepared and subjected to stability testing under ICH long term (LTC - 25°C / 50% relative humidity) and accelerated (ACC -40°C / 50% relative humidity) conditions.134938-7673-0763, v. 2Attorney Docket No. 1344.0002-1WOTable 7. Composition for 500 ml (-506.5g) scale (8% w / v, lidocaine HC1)144938-7673-0763, v. 2Attorney Docket No. 1344.0002-1WOTable 8. Composition for 500 ml (-506.5g) scale (4% w / v, lidocaine HC1)

[0071] Stability was accessed based on appearance, related substances, DSD and pH. Three-months of observation (ongoing) demonstrated no adverse observations in any of the assessed parameters.

[0072] USP <51> stability testing was also conducted in which five, 10g formulations and control were challenged with 106 CFU of e. coli, pseud, aeruginosa, staph, aureus, Candida albicans, and aspergillus niger. CFUs were evaluated at 7, 14 and 28 days, with generally less than 10 CFU of each inoculated species observed.

[0073] There were no adverse observations in either formulation, all results complying with cat. II of USP<51>. The 8% lidocaine HC1 formulation (Table 2) demonstrated higher bacterial action than the 4% formulation (Table 3), with each formulation showing strong bactericidal activity against each of the tested vectors.4938-7673-0763, v. 2Attorney Docket No. 1344.0002-1WOExample 3 - Nasal Spray Device Optimization for Posterior Nasal Cavity Deposition

[0074] A study was conducted to evaluate nasal spray device design parameters and their role in targeting subregions within the nose, particularly the Posterior Nasal Cavity (PNC).

[0075] A portable nasal delivery device capable of producing aerosolized spray from liquid medication was designed and fabricated. Multiple variants of key aerosolization components were created, including: precision spray orifice (varying pore size, pattern, and angle), nozzle geometry (4 depths and 3 bend angles), and 3 discrete pressurization forces.

[0076] The effect of each design feature on nasal deposition was assessed by spraying the 8% lidocaine formulations of Example 1. Following each spray, the fraction of emitted drug mass was quantified using photometric analysis of particle concentration within four primary regions (Nose, Nasal vestibule, Nasal cavity, Nasopharynx) and three subregions within the PNC (lower, middle, upper). Two commercially available nasal spray devices were also evaluated for comparison.

[0077] The fraction of emitted mass concentrated within the nose was dependent on spray orifice, nozzle length, and nozzle angle (p < 0.05) but not pressurization force. The results are summarized below:<<<4938-7673-0763, v. 2Attorney Docket No. 1344.0002-1WO

[0078] The optimum design combination deposited 96.2% of emitted mass within the Nasal Cavity, while avoiding medication deposition into the nasopharynx (<1%). The same design deposited 47.7% of medication into the PNC, which was significantly higher than commercial devices (Aeropump - 1.7%; Teleflex MAD - 2.3%). The optimized nasal spray device with optimized nozzle geometry and spray orifice delivered 21.3 times more medication to the posterior nasal cavity than commercial nasal atomizers. Spray deposition from a commercial device and the optimum configuration are shown in FIGS. 12 and 13.

[0079] The study demonstrated that drug delivery to the PNC can be achieved with the aqueous formulations of Example 1.

[0080] Drug in Small particle testing was also performed on the selected formulations (i.e., Formulations F5, F6, F12 and F13) using a method based on the FDAs 2003 Nasal Bioavailability / Bioequivalence guideline. This method utilizes cascade impaction to determine the potential inhalable fraction. An NGI impactor was operated at 15 liters per minute in a 5L expansion chamber. FIGS. 14 and 15 depict repeatability results for formulations F5 (FIG. 14) and F13 (FIG. 15) for three different nozzles, n=3 per nozzle. The vast majority of the aerosols for both formulations exhibit a size of less than 8.6 microns, with about 6% of the dose found in stage 2. Also, the vast majority (> 90%) of the dose was deposited in the expansion chamber in the first stage of the NGI, which corresponds to an effective cut-off diameter of 14.1 microns when operated at 15 1pm. The maximum absolute deposition was found to be < 0.5 mg for the size range of 5.4 microns and smaller. Good repeatability was observed with no significant (<10 % RSD) difference observed for intra- and inter-nozzle variation.174938-7673-0763, v. 2Attorney Docket No. 1344.0002-1WOExample 4 - Pharmacokinetic and Tissue Distribution

[0081] The instantly disclosed devices, micropore assemblies and formulations have been developed to locally anesthetize afferent trigeminal sensory fibers within the respiratory epithelium of the posterior nasal cavity via topical mucosal absorption. To achieve this effect, the system has been created to produce a controlled, “soft-mist” plume of medication with aerosolized particles of an ideal size to traverse the posterior nasal cavity while also limiting deposition into the airway. While systemic absorption is expected, a hypothesis to be evaluated here is whether nasal drug delivery with the instantly disclosed devices, micropore assemblies and formulations will result in lower systemic absorption than an equivalent dose of medication delivered from other routes of administration. Thus, achieving the desired clinical effect while further reducing the potential for adverse systemic effects. To inform both device and formulation development, a non-GLP pharmacokinetic (PK) and tissue distribution study was conducted in male Sprague Dawley rats.

[0082] Single dose administration was performed at two nominal dose levels (1.6 mg or 3.2 mg per rat, each corresponding to 4% and 8% lidocaine formulations) via nasal atomized spray (“Nasal Spray”), Nasal drops (instilled into nasal cavity), and IV bolus (Table 9). Twenty-four animals were included in each of the six administration groups (144 total). Based on allometric body surface area (BSA), the selected doses for rats were estimated to be at least 2 times that of equivalent human nasal doses. Both plasma and tissue samples (i.e., liver, lungs, brain, kidneys and spleen) were collected at discrete time intervals (0.5, 1, 2, 4, 8, 12 hrs) and analyzed using a fit for purpose Liquid Chromatography-Mass Spectroscopy method to measure lidocaine.184938-7673-0763, v. 2Attorney Docket No. 1344.0002-1WOTable 9.

[0083] For brevity, a summary of primary PK parameters (C max and AUC last ) for each administration route obtained with the 4% and 8% lidocaine concentrations is presented below in Table 10 and Table 11 respectively. Note, that for IV bolus, CO (back extrapolated) is also included. As, in this case, CO is likely a more appropriate comparison for exposure with the route of administration due to the fast absorption and distribution of lidocaine. Importantly, there were no aberrant clinical signs or safety issues observed during the nasal dosing and subsequent time points.

[0084] At both dose levels, delivery using the instantly disclosed formulations resulted in approximately 1.5 to 2.25 times lower systemic exposure than nasal drops, which, in turn, resulted in 1.7 to 2.5 times lower systemic exposure than IV injection. When using CO of IV bolus injection as a reference, even lower exposures are derived with the present formulations, resulting in approximately 4 to 5.75 times lower exposure than IV. These trends are also reflected in bioavailability (31-35% for NDD vs 56-59% for drops) when compared with the IV bolus route. These findings are in line with previous studies comparing intranasal and IV lidocaine formulations.4938-7673-0763, v. 2Attorney Docket No. 1344.0002-1WOTable 10.Table 11.

[0085] This Example thus supports the hypothesis that nasal delivery results in lower drug exposure (C max and AUC last) than IV bolus for the same administered dose, further increasing the factor of safety when referencing maximum systemic drug exposure limits of previously approved Listed Drugs. Additionally, these data indicate that exposure increases in a dose-proportional manner for both 4% and 8% lidocaine formulations, suggesting interactions are independent of concentration within the tested range (4% or 8% at dose levels of 1.6 mg or 3.2 mg). Finally, the lower bioavailability of the instantly disclosed formulations administered with the instantly disclosed devices relative to nasal drops supports the4938-7673-0763, v. 2Attorney Docket No. 1344.0002-1WOdevelopment thesis that targeted nasal spray delivery can achieve the desired clinical outcome of localized nerve blockade with lower systemic exposure and lower risk of adverse effects compared to standard, non-targeted nasal delivery.Example 5 - Human Administration of Atomized 4% Lidocaine

[0086] SPG block procedures are typically performed with specialized nasal catheters attached to syringes filled with liquid anesthetic; however, evidence has emerged suggesting that symptom relief may be achieved through targeted nasal spray. In a review of intranasal nerve block procedures performed during moderate to severe acute migraine episodes, twenty-five patients (36 unique, migraine instances) received SPG block treatment of lidocaine hydrochloride 4% topical solution delivered via a modified Mucosal Atomizer Device (MAD; commercially available through Teleflex) attached to a 3cc syringe 1617 . All patients (20 female, 5 male) were diagnosed with episodic (>2 per month) or chronic migraine (> 15 per month) and either intolerant, unresponsive, or contraindicated for other forms of headache treatment. The atomizer was modified by removing its accompanying shroud, enabling deeper insertion (4 ±0.5 cm), and including a bend angle of approximately 30° at the mid-point to target medication delivery between the middle and inferior turbinates. The atomizer tip syringe was inserted into the nare with the patient seated upright, and 0.3ml of 4% lidocaine (i.e. the most concentrated solution available without compounding) was sprayed in a short burst while the patient gently inhaled nasally. Outcomes were obtained by clinical chart review, which included patient reported headache severity prior to administration and within 20 minutes following intervention.

[0087] Of the 36 procedures, 31 (88%) patients reported decreased pain, 4 (11.4%) had no perceived change in pain, and 1 patient (2%) had temporary worsening of headache pain. The one patient who experienced a negative outcome had worsening facial and orbital pain 1 hour after administration.

[0088] Although a traditional SPG block’s proposed method of action is anesthetizing the sphenopalatine ganglion via precise delivery of lidocaine to the sphenopalatine fossa, the success of the instant atomizer methods suggests that nerve fibers within the posterior nasal cavity contribute to the analgesic effect. While not being bound by any particular theory, it is believed that these atomizer procedures are anesthetizing afferent trigeminal sensory fibers within the respiratory epithelium of the posterior nasal cavity, rather than the SPG itself. These fibers provide sensory input to the SPG via the posterior superior lateral nasal nerve which lies214938-7673-0763, v. 2Attorney Docket No. 1344.0002-1WOon the middle and superior nasal turbinates and the nasopalatine nerve which lies on the posterior aspect of the nasal septum,. These two nerves, along with the sphenopalatine artery, form the contents of the sphenopalatine foramen.4938-7673-0763, v. 2

Claims

Attorney Docket No. 1344.0002-1WOCLAIMS1. An aqueous formulation for nasal delivery of an anesthetic to the posterior nasal cavity comprising:(a) lidocaine or pharmaceutically acceptable salt thereof;(b) glycerol; and(c) polyethylene glycol at a molecular weight of from about 300 to about 500 daltons.

2. The formulation of claim 1, wherein the lidocaine is between about 3.0% (w / v) to about 9.5% (w / v) of the total weight of the formulation (w / v).

3. The formulation of claim 2, wherein the lidocaine is between about 4% (w / v) to about 8% (w / v) of the formulation.

4. The formulation of claim 3, wherein the lidocaine is 8% (w / v) of the formulation.

5. The formulation of any one of the preceding claims, wherein the lidocaine is lidocaine hydrochloride.

6. The formulation of any one of the preceding claims, wherein the glycerol is from about 0.25% (w / w) to about 15% (w / w) of the total weight of the formulation (w / w).

7. The formulation of any one of the preceding claims, wherein the polyethylene glycol has a molecular weight of about 400 daltons.

8. The formulation of any one of the preceding claims, wherein the polyethylene glycol is from about 2.5% (w / w) to about 20% (w / w) of the total weight of the formulation (w / w).

9. The formulation of any one of the preceding claims, wherein the osmolality of the formulation is from about 1000 to 5000 mOsm / kg.

10. The formulation of any one of the preceding claims, wherein the pH is from about 6 to about 7.234938-7673-0763, v. 2Attorney Docket No. 1344.0002-1WO11. The formulation of any one of the preceding claims, wherein the formulation is provided in an amount, such that when dispensed by a device, the spray actuation content (SAC) of the lidocaine or pharmaceutically acceptable salt thereof delivered from the device is about 12 mg per spray.

12. A method of treating headache pain or disorders in a subject comprising intranasally administering to the subject an effective amount of the formulation of any one of claims 1 to 11.

13. The method of claim 12, wherein the formulation is administered to the posterior nasal cavity.

14. The method of claim 12 or 13, wherein the headache pain or disorder is migraine pain.

15. The method of claim 14, wherein the formulation is administered by the subject after the onset of the migraine.244938-7673-0763, v. 2

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