Direction-tailored nasal-to-brain drug delivery system

Abstract

A system for the nasal administration of fluid drugs for CNS disease treatment. A nozzle and a base work together to deliver fluid drugs to the brain. The nozzle is generally for single use while the base is generally reusable. The purpose of such a design is to prevent contamination and minimize waste.

Description

[0001] Direction-Tailored Nasal-To-Brain Drug Delivery System

[0002] CONTINUITY

[0003] This application is a PCT Utility Patent Application of Provisional Patent Application number 63 / 689,528, filed on August 30, 2024, and priority is claimed thereto.

[0004] FIELD OF THE PRESENT INVENTION

[0005] The field of the present invention relates generally to drug delivery, and more specifically relates to a nasal drug delivery system that targets the Blood-Brain Barrier.

[0006] BACKGROUND OF THE PRESENT INVENTION

[0007] One of the limiting factors for drugs treating central nervous system (CNS) diseases is their ability to cross the Blood-Brain Barrier (BBB). Over the past few decades, several innovative drug delivery approaches have emerged to overcome the challenges posed by the BBB. One such approach involves delivering drugs via the nasal route to specifically target nasal-to-brain delivery through the olfactory and trigeminal nerve pathways. However, traditional nasal delivery methods target the lower nasal cavity to treat conditions such as allergic rhinitis, sinusitis, and nasal congestion. As a result, standard nasal devices often deposit less than 5% of the active drug in the upper nasal space, where the olfactory mucosal epithelium is located.

[0008] Although there is growing scientific evidence that nasal-to-brain delivery can result in higher concentrations of drugs in the brain, this approach requires careful consideration of the delivery vehicles used. In recent years, several devices (including uni-dosage and multi-dosage) have entered the market for delivering drugs to the upper nasal space where the olfactory mucosa is located. A disadvantage of these devices is that they dispense the drug uniformly in all directions, resulting in inefficient drug delivery to the olfactory mucosa. The device presented here is specifically designed to address these challenges and meet delivery objectives more effectively.

[0009] US Patent No. 8,162,921, granted to Flickinger et al. on April 24, 2012, for a Method and Device for Nasal Irrigation and Drug Delivery presents a method and device for nasal irrigation and drug delivery wherein fluid held in a canister is atomized via a compressed air supply to create particles sized for penetration and retention in the nasal cavity under pressure that is able to stent open the soft tissues of the nose to deliver the resultant mist into the whole of the nasal passages without the need for the patient to create an airstream through inhalation. The device consists of a main canister with a reservoir to hold the fluid, two air outlets and an insert that is placed over the air outlets, the insert having at least one outlet that is larger than the holes in the air outlet and allows the fluid to be atomized and injected directly into the nasal cavity. But unlike the present invention, Flickinger et al.’s device has a different angle of delivery than the present invention. Flickinger et al.’s device has an angle of delivery defined between the angle of the nebulizer and the plane of the front of the user’s face (from the chin to the forehead). Such an angle is not desirable for delivering a drug to the BBB. Additionally, Flickinger et al.’s device has a short nozzle that is not sufficient for drug delivery into the olfactory area. Moreover, Flickinger et al.’s device needs an additional air pressure gauge.

[0010] US Patent No. 10,814,079, granted to Francis et al. on October 27, 2020, for a Device for Nasal Spraying of Fluid Product shows a nasal fluid-spray device having: a reservoir containing at least one dose (D) of fluid; and a dispenser system that, each time the device is actuated, sprays a dose (D) of fluid through a spray orifice, generating a spray that extends axially from the spray orifice. The device further includes a generator system for generating a secondary flow, which generator system is actuated simultaneously with the dispenser system, the secondary flow generator system having a secondary flow channel provided with an outlet orifice, the outlet orifice arranged downstream from the spray orifice, and the secondary flow extending from the outlet orifice along an axis (B) that forms an angle (a) relative to the axis (A) of the spray and that intersects the axis (A), thereby deforming and / or deflecting the spray. Unlike the present invention, though, Francis et al.’s device uses two flows that reflect each other - resulting in a non-linear spray. Thus, with Francis et al.’s device, determining an accurate direction of spray is difficult because the direction of spray varies depending upon how the two flows interact - so accuracy is somewhat lacking with Francis et al.’s invention. Francis et al.’s invention is also somewhat more complex than necessary.

[0011] US Patent Publication No. 2006 / 0118107, published for King on June 8, 2006, for Tubular Nozzles for Use in Systems for Delivering Medicaments describes a system for delivering a pharmaceutical formulation to a patient that includes a container having a pharmaceutical formulation including at least one medicament present therein, a metering assembly in communication with the container, and a tubular nozzle having an inlet configured in size to communicate with the metering assembly, and an outlet for directing the medicament to a patient is disclosed. The tubular nozzle preferably has a defined length and a longitudinal axis that is curvilinear through the defined length of the tubular nozzle. Unlike the present invention, King’s device is concerned with the angle between connected tapered sections. Additionally, King’s device is focused on a tubular nozzle.

[0012] German Patent Publication No. DE2020 / 15009434, published for AP Pharma Atomizadores E Dispensadores Ltda on August 11, 2017, for a Spray Dispenser for Nasal Drugs shows a nasal drug spray dispenser (34) comprising a pressureless bottle (36) for storing medical fluids, particularly drugs and other sterile fluids, a mounting body (38) mounted on top of the bottle (36), and an actuator body

[0013] (40) wherein the bottle (36), mounting body (38) and actuator body (40) are aligned along a longitudinal axis (44), and wherein the actuator body (40) is slidably mounted along the longitudinal axis (44) on the mounting body (38) and movable between an actuation position and a non-actuation position, wherein the spray dispenser (34) comprises an applicator nozzle (98) and an actuation portion (100) for moving the actuation body (40) to the actuation position, characterized in that the applicator nozzle (98) has a nozzle axis (94) inclined with respect to the longitudinal axis (44), the applicator nozzle (98) facing away from the actuating portion (100); as a result of that the dispenser (34) comprises a metering valve (72) and a spray valve (74) actuated by the actuator body, wherein the metering valve (72) is configured to detect a predetermined dosage of the medical fluids to be dispensed upon actuation of the spray dispenser (34) and wherein the spray valve (74) is configured to eject the medical fluids; and in that a) a filter or a filter matrix (110) and a cannula (80) are provided, wherein the filter or the filter matrix (110) between the bottle (36) and the mounting body (38) are arranged and the cannula (80) as a Supply of the medical fluid to be dispensed by the spray dispenser (34) acts, or b) a pouch (116) is provided for storing the medical fluids, wherein the pouch (116) is provided in an interior (118) of the bottle (36), and wherein a neck (120) of the pouch (116) seals with a neck (46) of the bottle (36) is connected. Unlike the present invention, this cited reference refers to an angle of a nozzle as opposed to an angle inside of a channel. Also, this cited reference is notable for not having pressure, unlike the present invention.

[0014] PCT Patent Publication No. WO2022 / 126623, published for WU on June 23, 2022, for a Spray Nozzle Structure of Nasal Spray Bottle describes a spray nozzle structure of a nasal spray bottle, comprising a spray head (51), a connecting plate (52), and a pressing part (53); the spray head (51) and the pressing part (53) are respectively disposed on two opposite surfaces of the connecting plate (52); the spray head (51) passes through a housing (60) which applies a downforce, and can extend into the nasal cavity for spraying; the connecting plate (52) is connected to the inner surface of the housing (60) to form a connection basis for a spray nozzle body (50); the connecting plate (52) is provided with a connecting part (521), a first tube opening (522), and an offset channel (523); the connecting part (521) is adapted to be connected to the inner surface of the housing (60); the first tube opening (522) is communicated with an upper suction tube (31) of a suction member (30); one end of the offset channel (523) is communicated with the first tube opening (522), and the other end of the offset channel (523) is communicated with a spray pipe (510) which passes through the spray head (51); the pressing part (53) is adapted to abut against a compression part (32) of the suction member (30) to transfer the downforce of the housing (60) to the compression part (32), forming a suction action of the suction member (30). The spray nozzle structure changes a spraying path by providing the offset channel (523), shortens the distance between two spray nozzles, and fits the two nasal cavities of the human body, thus supporting simultaneous administration or cleaning of the two nasal cavities. Unlike the present invention, WU’s device focuses on the angle between the nozzle’s exterior top and the nozzle’s exterior bottom - not the inside of the nozzle. Further, WU’s device is designed for nostril cleaning and can only be operated by medical professionals, unlike the present invention.

[0015] US Patent Publication No. 20220032022, published for Gold et al. on February 3, 2022, for a Nasal Drug Delivery System focuses on devices, systems, and methods for treating chronic rhinosinutisits (CRS). The devices can have a guide member defining at least one lumen therethrough. A drug delivery component is advanced through the lumen to deliver a substance to the sino-nasal cavity of a patient. Once the drug delivery component is positioned at the desired area in the sino-nasal cavity, a user actuates the system to deliver the substance to the target area. Actuation of the system delivers the substance to the middle meatus, osteo-meatal complex, or other areas within the sino-nasal cavity of the patient. Unlike the present inventin, Gold et al.’s device has an extendable length nozzle designed for a different purpose then the present invention. Gold et al.’s device is designed for treating chronic rhinosinusitis disease, and unlike the present invention, a flexible nozzle that extends deep inside nostrils may make a patient feel discomfort. SUMMARY OF THE PRESENT INVENTION

[0016] The present invention relates to a device for the nasal administration of fluid drugs for CNS disease treatment. A nozzle and a base work together to deliver fluid drugs to the brain. The nozzle is generally for single use while the base is generally reusable. The purpose of such a design is to prevent contamination and minimize waste.

[0017] The present invention has a nasal drug delivery system with a nozzle inserted into a user’s nostril at an angle that parallels the slope of the users nose vs. the plane of the users face. For example, if the users nose slopes down from the plane of the users face at 30 degrees, then the nozzle is inserted at a 30-degree angle from the plane of the users face; or in other words, parallel to the slope of the users nose. Moreover, if the user’s nose is curved as the users nose slopes away from the users face, the slope at a midpoint between the bridge of the users nose and the tip of the users nose is used for the angle of the nozzle insertion.

[0018] Preferably, the length of the nozzle is roughly 1.2 inches. The tip of nozzle does not spray in linearly. The drug is fired into the nozzle from an upside-down plunger that the user pushes. Alternatively, the drug is fired into the nozzle when user squeezes a base.

[0019] The following brief and detailed descriptions of the drawings are provided to explain possible embodiments of the present invention but are not provided to limit the scope of the present invention as expressed herein this summary section.

[0020] BRIEF DESCRIPTION OF THE DRAWINGS

[0021] The accompanying drawings, which are incorporated herein and form a part of the specification, illustrate the present invention and, together with the description, further serve to explain the principles of the invention and to enable a person skilled in the pertinent art to make and use the invention.

[0022] The present invention will be better understood with reference to the appended drawing sheets, wherein:

[0023] Figure 1 shows how drugs are delivered using the nasal route, specifically though nasal-to-brain delivery, via the olfactory and trigeminal pathways.

[0024] Figure 2A shows the nozzle of the present invention as a cross-section view.

[0025] Figure 2B shows the nozzle of the present invention as a three-dimensional view.

[0026] Figure 3 shows the angle of calculation of the nozzle channel of the present invention.

[0027] Figure 4 shows a syringe-style base of the present invention as a cross-section view.

[0028] Figure 5 shows a scissor-style base of the present invention as a cross-section view.

[0029] Figure 6 shows the drug dispenser with the syringe-style base of the present invention as a cross-section view.

[0030] Figure 7 shows the drug dispenser with the scissor-style base of the present invention as a crosssection view.

[0031] Figure 8 shows the curved channel of the nozzle of the present invention with an angle between the center line of the opening and the center line of the nozzle. Figure 9 shows the present invention with a dual-nozzle syringe-style base.

[0032] Figure 10A shows a view of an alternate embodiment of the nozzle of the present invention, exhibiting clippers configured to connect to slots of the base shown in Figure 10B.

[0033] Figure 10B shows a view of an alternate embodiment of the base of the present invention, exhibiting slots to which the clippers shown in Figure 10A connect.

[0034] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0035] The present specification discloses one or more embodiments that incorporate the features of the invention. The disclosed embodiment(s) merely exemplify the invention. The scope of the invention is not limited to the disclosed embodiment(s).

[0036] References in the specification to “one embodiment,” “an embodiment,” “an example embodiment,” etc., indicate that the embodiment described may include a particular feature, structure, or characteristic, but every embodiment may not necessarily include the particular feature, structure or characteristic. Moreover, such phrases are not necessarily referring to the same embodiment, Further, when a particular feature, structure, or characteristic is described in connection with an embodiment, it is submitted that it is within the knowledge of one skilled in the art to affect such feature, structure, or characteristic in connection with other embodiments whether or not explicitly described.

[0037] The present invention relates to a system for the nasal administration of fluid drugs for CNS disease treatment. As shown in Figure 1, conventionally, nasal drugs are delivered from a device, through the user’s nasal passages, towards the olfactory bulb adjacent to the trigeminal nerve and the nasal epithelium. The present invention improves on how drugs are dispensed to target the nasal epithelium.

[0038] Two parts are provided: One is a nozzle 10 as shown in Figures 2A and 2B, and the other one is a base 20 as shown in Figure 4. The nozzle 10 is only for single use while the base 20 is reusable. The purpose of this design is to prevent contamination and to minimize waste.

[0039] The nozzle 10 has a tapered-circular cylinder 80 with an opening 30 at a top 40 where drug dispensed drug 1 is dispensed from the top 40 of nozzle 10. The tapering of the cylinder 80 leads to appropriate compression of fluid drug as it moves up the cylinder 80 such that it would be atomized when it comes out of the nozzle 10. A curved channel 50 leads to the top 40 of the nozzle 10.

[0040] As shown in Figure 8, there is an angle between a first center line 120 of the opening 30 and the second center line 130 of the nozzle 10, so that the dispensed drug 70 can be better controlled to the targeted region of nasal epithelium. As shown in Figure 8, the curved channel 50 of the nozzle 10 has an angle between the center line (labeled 120 in Figure 8) of the opening 30 and the center of the nozzle 10 (labeled 130 in Figure 8), with the angle shown (in Figure 8, the angle is labeled 170, shown between 120 and 130).

[0041] As shown in Figure 2A, a chamber 90, as shown in Figure 2A, is the place for the fluid drug capsule 70 (not shown), which is sealed when not in use. The curved channel 50 alone cannot guarantee the best result for drug deposition. For this purpose, a guide plate 100 is provided. The user touches the guide plate 100 with the user’s nose (shown in Figure 3) to achieve the desired angle for drug delivery. The very bottom 60 of the nozzle 10 has extended threads 110 that can be assembled with one of the provided bases detailed below. The guide plate 100 is designed for patients with a typical nasal anatomy. For individuals exhibiting unique nasal structures, such as significantly different nostril lengths, some training and corresponding adjustments may be required to achieve ideal results. The curved channel 50 has an angle 170 between the first center line (labeled 120 in Figure 8) and the second center line (labeled 130 in Figure 8), which dispenses drugs more efficiently to the olfactory region of the user. As shown in Figure 3, the shape AB represents the nozzle 10 with a length 1.2 inches. The average nostril length AC is 2.07 inches (52.58 mm), so that BC = AC - AB = 2.07 - 1.2 = 0.87 (inches). The angle <BCE is between 30° to 40°, and for simplicity, we choose the middle value as 35, so that CE = cos(35°) * BC = 0.8192 * 0.87 = 0.7127 (inches). The CE is the height of spray of dispensed drug 1. We are making another assumption that the tip of a user’s nostril and the beginning of the user’s olfactory nerves area as CF = 0.5 (inches). According to literature, the length of the olfactory area is 2.95 inches, and the front one third is the olfactory nerves, so that FG = 2.95 / 3 = 0.983 (inches). We can easily to get BE = Sin(35°) * BC =0.5736* 0.87 = 0.4990 (inches). Hence the range is as follows:

[0042] R = 2*(CF + FG / 2+BE)

[0043] = 2*CF + FG +2*BE =

[0044] = 2* 0.5 + 0.983 + 2*0.4990

[0045] = 2.981 (inches)

[0046] = 0.07571 (meters)

[0047] We can assume that v = Im / s and acceleration of the gravity and g = 9.81 m / s2, then the angle between the spray and horizontal line is as follows:

[0048] 0 = 0.5 * arcsin(gR / v2)

[0049] = 0.5 * arcsin(9.81 * 0.07571)

[0050] = 0.5*arcsin(0.7427)

[0051] = 33°. The spray height is H = v2Sin(20) / g; but the spray heigh needs to be bigger or equal than 0.788; to satisfy this, we need to adjust the initial speed v. according to the angle as follows:

[0052] Hs = sin(66°) / 9.81 m = 0.9135 / 9.81 m = 0.09312 m = 3.666 inches > 0.788 inches.

[0053] So that the angle between the first center line 120 of the opening 30 and the second center line 130 of the nozzle 10 can be calculated as 55° - 33° = 22°. The initial sprayer speed can be adjusted using the Bernoulli principle with the change of the channel diameters.

[0054] The present invention is also concerned with the base 20. The design of the base 20 is different than the current devices on the market. Most of the current devices actuate by pushing down a nozzle, which can easily change the direction of the device and hence impact drug deposit rate. The base 20 of the present invention is shown in two embodiments. One is a syringe style (as shown in Figure 4), which is cylindrical in shape with an opening 30 at the top 40 and threads 110 for connecting the threads 110 of nozzle 10. The bottom part of this base is a plunger 180 (Figure 4) which acts as the actuator. When the plunger 180 is pushed upwards, drug is dispensed.

[0055] The second base embodiment is a rectangular style and works like a scissor (Figure 5). The top side connects with the threads 110 of nozzle 10. In the middle, two bent parts 140 are connected with a pin 150 as shown in Figure 5. Instead of blades like in a scissor, the top of the bent parts 140 has two plates. When the left and right sides are pushed, the two plates press on the drug capsule 70 to dispense the drug fluid.

[0056] Figure 6 and Figure 7 depict the whole device of the present invention with nozzle 10 coupled to the base 20. The placement of the drug capsule 70 is illustrated. The bottom of the drug capsule 70 fits into a tapered cylinder 80, as shown in Figures 6 and 7) and seals the fluid drug inside the capsule while not used. It will open outwards under pressure when the capsule is pressed, thus releasing the fluid drug to the nasal cavity.

[0057] In at least one embodiment of the present invention, a formulation of a small molecule drug suitable for Alzheimer’s disease is applied. Atomized small molecules, or peptide compounds, or other fluid drugs reaching olfactory epithelium - at the roof of the nasal cavity - can be absorbed into the olfactory tract, and readily circumvent the Blood-Brain Barrier (BBB) for disease treatment.

[0058] In another embodiment of the present invention, a formulation of small molecules, or peptide compounds, or other drugs applied to treat Parkinson’s disease can be absorbed into the olfactory tract, and readily circumvent the Blood-Brain Barrier (BBB) for disease treatment.

[0059] In yet another embodiment of the present invention, the two disposable nozzles (labeled 1 in Figure 9) are assembled in a single base device with two syringes or two scissors so that both nasal cavities can be applied with fluid drugs. Figure 9 shows the syringe-style dual-nozzle dispenser, with two nozzles labeled 10 and fluid drug capsules labeled 70. It has a common plunger labeled 180. In such dual-nozzle embodiments, a slot is preferably present in the center of the guide plate 100, allowing the nozzles to slide and adjust the distance between them to accommodate differing shapes and sizes of nostrils.

[0060] It should be noted that additional embodiments of the present invention may exhibit differing options for the connection between the nozzle and the reusable base. The original, screw-type connection 60 as shown in Figure 3 may be changed to a clipper style connection. This design facilitates assembly of the device for the patient as shown in Figures 10A and 10B. In such an embodiment, assembly is achieved when the nozzle 10 is inserted into the base 20 by aligning the clippers 190 with the slots 200 in the base 20, then rotating the base 30-degrees counterclockwise to lock the nozzle 10 in place. Packaging of the present invention is preferably designed for one week of use, and consists of seven nozzles, 14 drug packs (preferably embodied as thin plastic bags fdled with the fluid drug, also referenced as single-use fluid drug capsules), one syringe base, and one copy of instructions. Steps for the use of the device of the present invention by a patient preferably include:

[0061] 1. The patient opening the box and removing one nozzle and a first single-use fluid drug capsule and a second a single-use fluid drug capsule.

[0062] 2. The patient inserting a first single-use fluid drug capsule into the bottom of the nozzle.

[0063] 3. The patient assembling the nozzle with the base by screwing the nozzle to the base tightly, thereby positioning the nozzle at the desired angle.

[0064] 4. Placing the guide plate near the tip of the nose.

[0065] 5. Inserting the nozzle into a first nostril.

[0066] 6. Pushing the actuator, thereby delivering the dose of the drug from the single-use fluid drug capsule to the target area within the first nostril.

[0067] 7. Removing the nozzle from the first nostril.

[0068] 8. Removing the nozzle from the base.

[0069] 9. Removing the first single-use fluid drug capsule from the nozzle.

[0070] 10. Inserting a second single-use fluid drug capsule into the bottom of the nozzle.

[0071] 11. Reassembling the nozzle with the base by screwing the nozzle to the base tightly.

[0072] 12. Placing the guide plate near the tip of the nose.

[0073] 13. Inserting the nozzle into a second nostril. 14. Pushing the actuator, thereby delivering the dose of the drug from the single-use fluid drug capsule to the target area within the second nostril.

[0074] 15. Removing the nozzle from the base.

[0075] 16. Removing the second single-use fluid drug capsule from the nozzle.

[0076] 17. Disposing of the nozzle, the first single-use fluid drug capsule, and the second single-use fluid drug capsule.

[0077] 18. Storing the reusable base for the next use.

[0078] Having illustrated the present invention, it should be understood that various adjustments and versions might be implemented without venturing away from the essence of the present invention. Further, it should be understood that the present invention is not solely limited to the invention as described in the embodiments above, but further comprises any and all embodiments within the scope of this application.

[0079] The foregoing descriptions of specific embodiments of the present invention have been presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the present invention to the precise forms disclosed, and obviously many modifications and variations are possible in light of the above teaching. The exemplary embodiment was chosen and described in order to best explain the principles of the present invention and its practical application, to thereby enable others skilled in the art to best utilize the present invention and various embodiments with various modifications as are suited to the particular use contemplated.

Claims

CLAIMSWe claim:

1. A nasal-to-brain drug delivery device comprising: a disposable nozzle; a single-use fluid drug capsule; and a reusable base.

2. The device as disclosed in Claim 1, wherein said single-use fluid drug capsule contains one of the following: a small molecule, a peptide compound, other fluid drug fomulation, or proteins for CNS disease treatment.

3. The device as disclosed in Claim 1, wherein said disposable nozzle features a curved channel delivering drugs to the upper nasal space where the olfactory mucosal epithelium is located.

4. The device as disclosed in Claim 3, further comprising a nozzle in which the angle between the center line of the opening and center line of nozzle is in the range from 1 to 15 degrees.

5. The device as disclosed in Claim 3, further comprising a nozzle that includes a guide plate to ensure the nasal spray maintains an optimum angle.

6. The device as disclosed in Claim 3, further comprising a nozzle that provides a single dose of drug and can be replaced separately from the device to prevent contamination.

7. The device as disclosed in Claim 3, further comprising a nozzle that features a curved channel with a tapering cylinder that functions as an atomizer of fluid drug delivered into the nasal cavity.

8. The device as disclosed in Claim 3, wherein said disposable nozzle has a chamber for holding said single-use fluid drug capsule; andwherein said drug capsule is sealed when unused and is configured to open up towards a tapered cylinder to be released to the nasal cavity.

9. The device as disclosed in Claim 8, wherein the drug capsule contains at least one of the following: a small molecule, a peptide compound, or other fluid drug formulation for CNS disease treatment.

10. The device as disclosed in Claim 1 comprising a reusable base that provides a syringe configured to apply pressure to the drug capsule.

11. The device as disclosed in Claim 1, wherein said reusable base provides a scissor that applies pressure to the drug capsule.

12. The device as disclosed in Claim 1 comprising two disposable nozzles assembled on a reusable base with two corresponding syringes or scissors which can apply pressure to the two drug capsules, respectively.

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