CN-121985976-A - Dual density formulation device and method for intranasal drug delivery or sampling

Abstract

The present disclosure describes formulations, methods, and devices for intranasal delivery to a subject. The formulation may form two fluids that are immiscible under intranasal environmental conditions such that when the formulation is delivered to the nasal cavity, the two fluids separate, with the denser fluid of the two fluids settling below the less dense fluid of the two fluids. One or more of the two fluids may accumulate the therapeutic agent or sampling fluid at a selected portion of the nasal cavity, and a denser fluid of the two fluids may increase the residence time of the agent within the nasal cavity. The devices of the present disclosure may provide a convenient and efficient way of intranasal delivery of dual density formulations.

Inventors

• KENNETH OWEN
• JAMES JACKSON
• Alec Lillis
• Timothy Rees

Assignees

• 火箭科学健康公司

Dates

Publication Date

20260505

Application Date

20240925

Priority Date

20230926

Claims (20)

1. 1. A method of focusing a fluid on an olfactory region of a nasal cavity of a subject, the method comprising: a. delivering a formulation to the olfactory region of the nasal cavity, the formulation configured to form: i. Upper fluid, and A lower fluid that is immiscible with the upper fluid under intranasal environmental conditions and has a density greater than that of the upper fluid; Wherein one or more volumes of the formulation delivered to the olfactory region of the nasal cavity each form an upper layer comprising the upper fluid and a lower layer comprising the lower fluid, thereby concentrating the upper fluid at the olfactory region of the nasal cavity.
2. 2. The method of claim 1, wherein the olfactory region comprises olfactory cleavage of the nasal cavity.
3. 3. The method of claim 1, wherein the upper fluid comprises a therapeutic agent.
4. 4. The method of claim 3, wherein the therapeutic agent is preferentially soluble in the upper fluid, and wherein the formulation optionally comprises a second therapeutic agent preferentially soluble in the lower fluid.
5. 5. The method of claim 3, wherein the upper fluid delivers the therapeutic agent to the olfactory region of the nasal cavity and the lower fluid increases residence time of the therapeutic agent within the nasal cavity.
6. 6. The method of claim 3, wherein the upper fluid delivers the therapeutic agent to the olfactory cleft of the nasal cavity and the lower fluid at least partially occludes a lower portion of the olfactory cleft of the nasal cavity.
7. 7. The method of claim 1, wherein the lower fluid comprises a therapeutic agent.
8. 8. The method of claim 1, wherein the upper fluid comprises a first therapeutic agent preferentially soluble in the upper fluid and the lower fluid comprises a second therapeutic agent preferentially soluble in the lower fluid.
9. 9. The method of claim 8, wherein the first therapeutic agent is delivered to an olfactory region of the subject and the second therapeutic agent affects tissue so as to affect absorption of the first therapeutic agent.
10. 10. The method of claim 8, wherein the first therapeutic agent is delivered to an olfactory region of the subject and the second therapeutic agent improves delivery of the first therapeutic agent to the olfactory region.
11. 11. The method of claim 1, wherein the upper fluid comprises a sampling fluid that collects biological material from the olfactory region of the nasal cavity.
12. 12. The method of claim 11, wherein the olfactory region of the nasal cavity is olfactory fissures.
13. 13. The method of claim 11, further comprising analyzing the sampling fluid to evaluate the collected biological material.
14. 14. The method of claim 1, wherein the lower fluid forms a capillary bridge at a lower portion of the nasal cavity that sniffs.
15. 15. The method of claim 14, wherein the capillary bridge contacts opposite sides of an olfactory region of the nasal cavity of the subject and supports a coating of the formulation around the olfactory cleavage.
16. 16. The method of claim 1, wherein the olfactory region of the nasal cavity comprises an underside of a sieve plate of the nasal cavity.
17. 17. The method of claim 1, wherein the upper fluid and the lower fluid are delivered simultaneously.
18. 18. The method of claim 17, wherein the formulation is delivered as a homogeneous formulation that is isolated after delivery.
19. 19. A method of delivering a therapeutic agent to an olfactory region of a nasal cavity of a subject, the method comprising: a. delivering a formulation to the olfactory region of the nasal cavity, the formulation configured to form: i. An upper fluid comprising a therapeutic agent, and A lower fluid that is immiscible with the upper fluid under intranasal environmental conditions and has a density greater than that of the upper fluid; wherein one or more volumes of the formulation delivered to the olfactory region of the nasal cavity each form an upper layer comprising the upper fluid and a lower layer comprising the lower fluid, thereby focusing the upper fluid at the olfactory region of the nasal cavity and delivering the therapeutic agent to the olfactory region of the nasal cavity.
20. 20. A method of collecting biological material from an olfactory region of a subject, the method comprising: a. Delivering a formulation to the olfactory region, the formulation configured to form: i. Upper fluid, and A lower fluid that is immiscible with the upper fluid under intranasal environmental conditions and has a density greater than that of the upper fluid; Wherein one or more volumes of the formulation delivered to the olfactory region of the nasal cavity each form an upper layer comprising the upper fluid and a lower layer comprising the lower fluid, thereby concentrating the upper fluid at the olfactory region, and B. Removing a portion of the formulation and the biological material captured therein, thereby collecting the biological material.

Description

Dual density formulation device and method for intranasal drug delivery or sampling Cross reference The present PCT application claims the benefit of U.S. provisional application No. 63/540,645, filed at 26, 9, 2023, the contents of which are incorporated herein by reference. Background Intranasal drug delivery is an effective route for administering certain drugs, for example, those that act locally in the nasal cavity, or those that are rapidly absorbed into the blood stream through the nasal mucosa. One challenge associated with delivering the composition to the nasal passages of a subject is contacting the target area of the nasal cavity with the therapeutic agent for a sufficient residence time for an effective dose to be administered to the target area. Various formulations and substances such as mucoadhesives may be used for intranasal delivery, but the choice is limited by requirements such as biocompatibility and sufficient solubility of the therapeutic agent in the remainder of the formulation. Variability in the residence time of the formulation within the nasal cavity can hamper dose accuracy and limit safety and efficacy. Otherwise, the residence time of a suitable formulation within the nasal cavity may be insufficient to deliver the therapeutic dose without risking significant wastage of therapeutic material or improper dosage levels. The high cost of multiple therapeutic agents motivates efficient delivery of therapeutic agents and minimization of residual amounts within the delivery device. There is a need for formulations, methods, and devices for intranasal delivery that have optimized residence time of the therapeutic agent or sampling fluid and minimal waste. SUMMARY The inventors appreciate that difficulties in nasal delivery include effective delivery of the therapeutic agent to the target area within the nasal cavity with sufficient residence time for administration of an effective and accurate dose without excessive wastage of the therapeutic agent. For example, certain hydrophobic or water-sensitive therapeutic agents may have a relatively short or variable residence time within the nasal cavity. To overcome such difficulties, the present disclosure provides dual density formulations for intranasal delivery, and methods and devices for delivering the dual density formulations. The formulation may form two fluids that are immiscible under intranasal environmental conditions, wherein an upper fluid or lighter fluid of the fluids is configured to administer a therapeutic dose of the therapeutic agent to a target region of the nasal cavity of the subject, and a lower fluid or denser fluid of the two fluids is configured to increase the residence time of the therapeutic agent within the nasal cavity or to clear residual amounts of the therapeutic agent from the delivery device in order to maximize the efficiency and reproducibility of delivery. In some embodiments, the lower fluid supports the upper fluid, for example, supporting placement of the upper fluid in the desired area for a longer period of time than if the upper fluid was not supported by the lower fluid. In some embodiments, the presence of the denser fluid helps to collect the lighter fluid at a high elevation along the underside of the screen plate. In some embodiments, for example, the denser fluid at least partially blocks the lower portion of the sniffing below the lighter fluid due to its high viscosity and/or strong surface tension, thereby increasing the residence time of the fluid carrying the drug. The volume of dual density formulation delivered to the sniffing may be sufficient to fill or partially fill the sniffing, rather than merely coat the mucosa. A dual density bolus (bolus) may span from one side of the sniffing to the other side of the sniffing. In some embodiments, the lower fluid bridges between the sides of the sniffing so as to suspend the upper fluid within the sniffing. In one aspect is a method of concentrating fluid in an olfactory region of a nasal cavity of a subject, the method comprising delivering a formulation to the olfactory region of the nasal cavity, the formulation configured to form an upper fluid, and a lower fluid that is immiscible with the upper fluid under intranasal environmental conditions and has a density greater than that of the upper fluid, wherein one or more volumes of the formulation delivered to the olfactory region of the nasal cavity each form an upper layer comprising the upper fluid and a lower layer comprising the lower fluid, thereby concentrating the upper fluid in the olfactory region of the nasal cavity. In another aspect is a formulation for intranasal delivery, the formulation configured to form: the nasal device includes an upper fluid, and a lower fluid that is immiscible with the upper fluid under intranasal environmental conditions and has a density greater than that of the upper fluid, wherein under intranasal environmental conditions one or more volumes