Aerosolized lung treatments

Abstract

This document provides methods that can treat and / or prevent pneumothorax. For example, this document provides methods for delivering an aerosolized agent to reduce air leakage at a site in a respiratory tract of patient.

Description

[0001] Attorney Docket No. 07039-2351WO1 / 2020-377

[0002] AEROSOLIZED LUNG TREATMENTS

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS

[0004] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 715,870, filed November 4, 2024. The disclosure of the prior application is considered part of (and is incorporated by reference in) the disclosure of this application.

[0005] BACKGROUND

[0006] 1. Technical Field

[0007] This document relates to methods that can treat and / or prevent pneumothorax. For example, this document relates to methods for supplying an aerosolized agent to reduce air leakage at a site in a respiratory tract of a patient.

[0008] 2. Background Information

[0009] Complications arising from air that leaks from the lung into the pleural space are frequent and are associated with significantly higher hospital resource utilization costs and patient mortality. Airleaks in the lungs occur mainly for 3 reasons: lung surgery, lung biopsies, or lung blebs. Air leaking from the lung into the pleural space can cause a pneumothorax which must be evacuated with a chest tube or pigtail. Some lung airleaks resolve spontaneously after a day or two but many persist for much longer, leading to expensive treatments and hospital stays. There are an estimated 38,000 patients each year in the U.S. that would benefit from an improved treatment for lung airleaks that is more effective, less invasive, and less costly.

[0010] SUMMARY

[0011] This document provides methods that can treat and / or prevent pneumothorax. For example, this document provides methods for supplying an aerosolized agent to reduce air leakage at a site in a respiratory tract of a patient.

[0012] In general, one aspect of this document features a method for reducing air leakage at a site in a respiratory tract of a patient. The method can include, or consist essentially of, creating a negative air pressure in a pleural cavity of the patient and supplying an aerosolized agent into the respiratory’ tract, wherein the negative air pressure in the pleural cavity biases the aerosolized agent to be disposed at the site of Attorney Docket No. 07039-2351WO1 / 2020-377 the air leakage, and wherein accumulation of the aerosolized agent at the site of the air leakage causes occlusion of the site of the air leakage to reduce a rate of the air leakage. The aerosolized agent can be a powder containing a pro-coagulant factor. The pro-coagulant factor can be fibrinogen, albumin, platelet cells, packed red blood cells, or thrombin. The aerosolized agent can be a powder having a particle diameter from about 1 pm to 10 pm. The aerosolized agent can be a powder having a particle diameter of less than 5 pm. The negative air pressure can be created using a chest tube and a vacuum source. The chest tube can create at least -40 cm H2O of suction. The site can be at a lung of the patient. The site at the lung of the patient can be at an alveoli of the lung. The aerosolized agent can be supplied using an endotracheal tube and a ventilator, a nebulizer, a respiratory mask, and / or an inhaler device. The occlusion can be caused by a mechanical obstruction created by the accumulation of the aerosolized agent at the site of the air leakage. The occlusion can be caused by a biological reaction advanced by the accumulation of the aerosolized agent at the site of the air leakage.

[0013] In another aspect, this document features a method of reducing air leakage at a site in the respiratory tract of a patient. The method can include, or consist essentially of, supplying an aerosolized agent into the respiratory7tract, wherein accumulation of the aerosolized agent at the site of the air leakage causes occlusion of the site of the air leakage to reduce a rate of the air leakage. The aerosolized agent can be a powder containing a pro-coagulant factor. The pro-coagulant factor can be fibrinogen, albumin, platelet cells, packed red blood cells, or thrombin. The aerosolized agent can be a powder having a particle diameter from about 1 pm to 10 pm. The aerosolized agent can be a powder having a particle diameter of less than 5 pm. The site can be at a lung of the patient. The site at the lung of the patient can be at an alveoli of the lung. The aerosolized agent can be supplied using an endotracheal tube and a ventilator, a nebulizer, a respiratory7mask, and / or an inhaler device. The occlusion can be caused by a mechanical obstruction created by the accumulation of the aerosolized agent at the site of the air leakage. The occlusion can be caused by a biological reaction advanced by the accumulation of the aerosolized agent at the site of the air leakage.

[0014] Particular embodiments of the subject matter described in this document can be implemented to realize one or more of the following advantages. First, in some embodiments the methods provided herein can be used to supply an aerosolized agent to reduce air leakage at a site in a respiratory7tract of a patient. In some circumstances. Attorney Docket No. 07039-2351WO1 / 2020-377 such methods are less invasive and more precise than current methods for treating lung airleaks. For example, once an airleak has been discovered, current methods sometimes require a patient to return to the operating room for the leak to be resected with staplers or sealed with a surgical glue or pleural patch. In other cases, an airleak may be treated by placing an endobronchial valve via bronchoscope, a procedure requiring sedation. Endobronchial valves typically occlude a segment of lung if not an entire lobe, and not all airleaks are amendable to such treatment. Additional surgeries and procedures to treat airleaks are invasive, expensive, and not always successful. Secondly, unlike some current techniques used for treating airleaks, in some embodiments the methods provided herein to supply an aerosolized agent to reduce air leakage at a site in a respiratory tract can be repeated multiple times, as necessary, to completely treat an airleak. For example, in another current technique used for treating airleaks, if an airleak is noticed during surgery, various surgical glues can be applied to the leak during the surgery'. These glues are somewhat effective; however, once the patient leaves the operating room, the glues cannot be re-applied or adjusted. Because the primary mechanism of action of surgical sealants is as a physical barrier applied over the pleural defect and not within the defect, when the lung is reinflated, the barrier sealant can often become partially or completely detached. In contrast, because the methods described herein are non-invasive and do not require physical access to the site of the airleak, the aerosolized agent can be delivered by the methods described herein as many times as necessary to treat the airleak completely. Thirdly, in some embodiments the methods described herein have a lower potential for causing infection than current methods for treating airleaks. For example, in another current technique used for treating airleaks, blood or fresh frozen plasma can be delivered to the airleak via a chest tube. However, this method introduces fluid into the pleural space which creates the potential for infection. In contrast, because the methods described herein do not introduce fluid into the pleural space, there is a lower potential risk of infection.

[0015] Unless otherwise defined, 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 invention pertains. Although methods and materials similar or equivalent to those described herein can be used to practice the invention, suitable methods and materials are described herein. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In Attorney Docket No. 07039-2351WO1 / 2020-377 case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0016] The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description herein. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.

[0017] DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 is a schematic diagram of patient undergoing treatment of a lung airleak with an aerosolized agent supplied to the site of the airleak in the respiratory tract.

[0019] Figure 2 is a boxplot showing absolute air leak rate values at follow-up time points with comparisons between experimental and control groups.

[0020] Figure 3 is a boxplot showing the percentage of airleak reduction at follow-up time points with comparisons between experimental and control groups.

[0021] Figure 4 is a boxplot showing the changes in airleak rate compared to baseline at follow-up time points with comparisons between experimental and control groups.

[0022] Like reference numbers represent corresponding parts throughout.

[0023] DETAILED DESCRIPTION

[0024] This document provides methods that can treat and / or prevent pneumothorax. For example, this document provides methods for supplying an aerosolized agent to reduce air leakage at a site in a respiratory tract of a patient.

[0025] Pneumothorax (air in the pleural space) caused by a lung airleak can be lifethreatening. A lung airleak is a tissue laceration in the alveoli of the lung where damaged cells release molecules which attract blood components such as platelets, fibrinogen, and thrombin. These components cause hemostasis followed by the other three phases of healing - inflammation, proliferation, and maturation. A major difference, however, is the exceptionally low density of cells in the lung compared to, for example, skin. Since a peripheral parenchymal lung disruption may disrupt few cells, once hemostasis is achieved, the inflammatory phase is quickly withdrawn. What is left, though, is a persistent airleak, with a minimal repair mechanism in place. Attorney Docket No. 07039-2351WO1 / 2020-377

[0026] Resolution of airleaks can occur through a barrier or a biological process. This document provides a solution for lung airleaks based on the same concepts as hemostasis for bleeding vessels. For example, procoagulant cells and proteins bind to the edge of a disrupted vessel and eventually bind together to form a clot and seal the bleeding. As described herein, the delivery of aerosolized procoagulant agents through the airways to the damaged lung alveoli leads to the continuous accumulation of procoagulant agent to occlude an airleak in the lung by, at least in part, reinvigorating the repair response and establishing a scaffold for sealing of the airleak.

[0027] Referring to Figure 1, a patient 10 is undergoing treatment with an aerosolized agent 200 to reduce air leakage at a site in a respiratory tract of the patient 10. In some examples, a site in the respiratory tract of a patient 10 where air leakage is occurring can be an airleak 14 in the patient’s lung 12. For example, an airleak 14 in a patient’s lung 12 can be the result of a tear in the alveoli of the lung 12. A tear in the alveoli of a lung can be caused by any mechanism. For example, a tear in the alveoli of a lung can be the result of a lung surgery, a lung biopsy, or can occur spontaneously from the rupture of a lung bleb. In some embodiments, a site in a respiratory tract of a patient where air leakage is occurring is not in the patient’s lung but at another site in the respiratory tract of a patient (e.g., bronchus).

[0028] An aerosolized agent 200 supplied as described herein disseminates along all of the airways of a respiratory tract of a patient 10; however, a concentrated amount or the majority of the aerosolized agent 200 moves to the site of an airleak 14 in a lung 12 of the patient 10 because this is the area of greatest flow' due to the negative pressure created in the pleural space 16 by the airleak 14. In some embodiments, a chest tube 110 is optionally inserted into a patient 10 and positioned so that a distal end portion of the chest tube 1 10 is in a pleural space 16 near an airleak 14 in a lung 12 of the patient 10. A proximal end portion of a chest tube 110 is connected to a suction source, such as a chest drainage unit (CDU) 100. The connected suction source 100 provides a source of suction that is conveyed through a chest tube 110 that diverts even more of an aerosolized agent 200 to a site of an airleak 14 in a lung 12 of a patient 10 and forms a natural targeted delivery system for the aerosolized agent 200. Such a targeted delivery system minimizes delivery of an aerosolized agent 200 to areas of a respiratory tract that do not need it. In some embodiments, the pressure created by a chest tube 1 10 and a connected suction source 100 can be adjusted, as Attorney Docket No. 07039-2351WO1 / 2020-377 necessary, to divert an aerosolized agent (200) to an airleak 14 in a lung 12 of a patient 10 to treat the airleak. In some embodiments, the pressure created by a chest tube 110 and a connected suction source 100 is -40 cm H2O or greater.

[0029] Any appropriate device can be used to supply an aerosolized agent 200 to a site in a respiratory tract of a patient 10 as described herein. Examples of devices that can be used to supply an aerosolized agent 200 to a site in a respiratory tract of a patient 10 as described herein include, without limitation, an endotracheal tube and a ventilator, a nebulizer, a respiratory mask, and an inhaler device.

[0030] Any appropriate aerosolized agent 200 can be supplied to a site in a respiratory tract of a patient 10 as described herein. In some embodiments, the aerosolized agent 200 can be a powder. For example, the aerosolized agent 200 can be an excipient enhanced growth (EEG) powder. An EEG powder can include a hygroscopic excipient and a dispersion agent. In some embodiments, the EEG powder can further include a drug, such as a pro-coagulation factor, in addition to a hygroscopic excipient and a dispersion agent.

[0031] In some embodiments, an aerosolized agent 200 supplied to a site in a respiratory tract of a patient 10 as described herein can contain a pro-coagulation factor. Examples of pro-coagulation factors that can be contained in an aerosolized agent 200 include, without limitation, fibrinogen, albumin, platelet cells, packed red blood cells, and thrombin. An aerosolized agent 200 containing pro-coagulation factors supplied to a respiratory tract of a patient 10 as described herein can reinvigorate repair response and establish a healing scaffold at a site of air leakage in the respiratory tract. In some embodiments, the pro-coagulation factor must be of an appropriate size such that the molecules can be aerosolized. A non-limiting list of procoagulation factors that can be contained in an aerosolized agent 200 and example dimensions of these factors are provided in Table 1.

[0032] Table 1. Particle size of pro-coagulation factors. Attorney Docket No. 07039-2351WO1 / 2020-377

[0033] In some cases, the particle size of the aerosolized agent 200 supplied to a respiratory tract of a patient 10 as described herein can be a relevant factor. For example, particles of more than 1 pm in diameter are most likely to deposit in the mouth and throat, and particles with a diameter of 5-10 pm deposit more in the airway. Particles smaller than 5 pm in diameter have less mouth-throat deposition and deposit most frequently in the lower airways, making particles of this size more appropriate for pharmaceutical aerosols. In some embodiments, an aerosolized agent 200 supplied to a respiratory tract of a patient 10 as described herein can have a diameter of about 1 pm to about 10 pm. For example, an aerosolized agent 200 supplied to a respiratory tract of a patient 10 as described herein can have a diameter of 5 pm. In some embodiments, the size of the particle can increase during inhalation to maximize lung retention and deposition in the distal airways.

[0034] In some embodiments, the supplying of an aerosolized agent 200 to a site of air leakage 14 in a respiratory' tract of a patient 10 can reduce air leakage at the site. For example, accumulation an aerosolized agent 200 at a site of air leakage in a respiratory tract of a patient 10 can cause occlusion of the site and can reduce the rate of the air leakage. In some embodiments, occlusion of a site of air leakage can be caused by a mechanical obstruction created by an accumulation of an aerosolized agent 200 at the site of the air leakage. In some embodiments, occlusion of a site of air leakage can be caused by a biological reaction advanced by an accumulation of an aerosolized agent 200 at the site of the air leakage. In some embodiments, occlusion of a site of air leakage can be caused by both a mechanical obstruction created by an accumulation of an aerosolized agent 200 at the site of the air leakage and by a biological reaction advanced by an accumulation of an aerosolized agent 200 at the site of the air leakage. Attorney Docket No. 07039-2351WO1 / 2020-377

[0035] EXAMPLES

[0036] Example 1: Aerosolized pro-coagulant agents delivered to the lungs treat air leaks This example investigated the effectiveness of aerosolized pro-coagulant agents for the treatment of airleaks in a lung. The study aimed to determine whether treatment impacted the absolute air leak rate or the change in flow compared to baseline in an airleak. The example also evaluated the treatment effect of aerosolized pro-coagulants over time.

[0037] Materials and Methods

[0038] Study Population

[0039] The study employed a paired design with 14 pigs serving as their own controls. Each pig underwent bilateral thoracotomy and a standardized incision on the lung. One lung was randomly assigned to the experimental group (treatment) while the other lung served as the control group.

[0040] Procedure

[0041] Following induction of general endotracheal anaesthesia, a tracheostomy was performed. A double-lumen endotracheal catheter was inserted under bronchoscopic vision to isolate and independently ventilate each lung.

[0042] Bilateral thoracotomies were subsequently performed through intercostal incisions to access the pleural cavities. A standardized wedge resection of lung tissue was then conducted on each lung to induce airleak. Confirmation of air leakage from both lungs was achieved visually with a bubble test. Chest tubes were placed bilaterally. The thoracotomies were closed in layers. These chest tubes were connected to an airflow meter to measure the rate of air leaking from each lung. Measurements of air leak were taken at several time points: (1) Baseline: Following the incision on the lung before any treatment. (2) Post-treatment: a) Immediately after each aerosol powder administration: Because of aerosolizer size limitations, the powder was administered in thirds (fibrinogen, fibrinogen, thrombin), b) Follow-up: Additional measurements were taken every' 15 minutes following the last posttreatment measurement.

[0043] The airflow meter was very' sensitive and flow readings would vary second to second. Therefore, for each measurement, five readings were obtained and averaged to minimize random error. Percent air leak reduction was calculated as: Attorney Docket No. 07039-2351WO1 / 2020-377

[0044] (% Air Leak Reduction) = [(Post-treatment) - (Baseline)] / (Baseline) x 100%.

[0045] Statistical Analysis

[0046] Continuous variables were summarized with the sample median, minimum, and maximum. Paired Wilcoxon rank sum test for numerical measures were performed to identify the association between air-leak records and experiment-control group. Linear mixed model was used to identify if there was any significant drop of percentage of air-leak reduction over the follow up time points compared to baseline record. Also, boxplots were generated to display the overall trend of outcomes at ordered follow up time points. All statistical tests were two-sided and P-values < 0.05 were considered as statistically significant. Statistical analysis was performed using R Statistical Software (version 4.2.2; R Foundation for Statistical Computing, Vienna, Austria).

[0047] Results

[0048] The baseline airleak rate was very similar between the two groups prior to treatment, but the airleak rate was lower in the experimental group compared to the control at all post-treatment time points (Figure 2). There was a statistically significant difference between the experimental and control groups at the posttreatment result #1 (after all 3 treatments) and #2 (15 minutes later).

[0049] The percent reduction in the airleak rate from baseline was greater in the experimental arm across all time points and was significantly different for 9 of the 19 measurements with a stronger response early in the experiment (Figure 3).

[0050] The change in the airleak rate compared to the baseline was greater in the experimental arm across all time points and was significantly different for the first 4 post-treatment measurements (Figure 4).

[0051] Overall, the experimental group w as statistically different from the control group on absolute values, changes from baseline, and percent reduction from baseline on both the first measurement and overall follow-up time (Tables 2 and 3). The percent reduction in air leak at the first measurement was 66% for the experimental group compared to 3.6% for the control. The control arm had a gradual decrease in the amount of air leak over time. The experimental arm had the biggest reduction in airleak at the first measurement. This reduction diminished over the experiment. In 1 of the 14 experiments the airleak stopped completely. In 4 of the 14 experiments the animal did not survive to the proscribed time point. The animals died of cardiac Attorney Docket No. 07039-2351WO1 / 2020-377 arrest. Although it is not known if the aerosol contributed to the arrest, the veterinary staff suspected that bilateral thoracotomies and lung resection was the primary cause.

[0052] Table 2. Paired Wilcoxon test based on overall follow-up time or key time point.

[0053] Table 3. Linear mixed model to response percentage of air-leak reduction. Attorney Docket No. 07039-2351WO1 / 2020-377

[0054] OTHER EMBODIMENTS

[0055] While this specification contains many specific implementation details, these should not be construed as limitations on the scope of any invention or of what may be claimed, but rather as descriptions of features that may be specific to particular embodiments of particular inventions. Certain features that are described in this specification in the context of separate embodiments can also be implemented in combination in a single embodiment. Conversely, various features that are described in the context of a single embodiment can also be implemented in multiple embodiments separately or in any suitable subcombination. Moreover, although features may be described herein as acting in certain combinations and even initially claimed as such, one or more features from a claimed combination can in some cases be excised from the combination, and the claimed combination may be directed to a subcombination or variation of a subcombination. Attorney Docket No. 07039-2351WO1 / 2020-377

[0056] Similarly, the separation of various system modules and components in the embodiments described herein should not be understood as requiring such separation in all embodiments, and it should be understood that the described program components and systems can generally be integrated together in a single product or packaged into multiple products.

[0057] Particular embodiments of the subject matter have been described. Other embodiments are within the scope of the following claims. For example, the actions recited in the claims can be performed in a different order and still achieve desirable results. As one example, the processes depicted in the accompanying figures do not necessarily require the particular order shown, or sequential order, to achieve desirable results. In certain implementations, multitasking and parallel processing may be advantageous.

Claims

Attorney Docket No. 07039-2351WO1 / 2020-377WHAT IS CLAIMED IS:

1. A method of reducing air leakage at a site in a respiratory7tract of a patient, the method comprising: creating a negative air pressure in a pleural cavity of the patient; and supplying an aerosolized agent into the respiratory7tract, wherein the negative air pressure in the pleural cavity biases the aerosolized agent to be disposed at the site of the air leakage, and wherein accumulation of the aerosolized agent at the site of the air leakage causes occlusion of the site of the air leakage to reduce a rate of the air leakage.

2. The method of claim 1, wherein the aerosolized agent comprises a powder containing a pro-coagulant factor.

3. The method of claim 2, wherein the pro-coagulant factor is selected from the group consisting of fibrinogen, albumin, platelet cells, packed red blood cells, and thrombin.

4. The method of any one of claims 1 -3, wherein the aerosolized agent comprises a powder having a particle diameter from about 1 pm to 10 pm.

5. The method of claim 4. wherein the aerosolized agent comprises a powder having a particle diameter of less than 5 pm.

6. The method of any one of claims 1-5, wherein the negative air pressure is created using a chest tube and a vacuum source.

7. The method of claim 6, wherein the chest tube creates at least -40 cm H2O of suction.

8. The method of any one of claims 1-7, wherein the site is at a lung of the patient.Attorney Docket No. 07039-2351WO1 / 2020-3779. The method of claim 8. wherein the site at the lung of the patient is at an alveoli of the lung.

10. The method of any one of claims 1-9, wherein the aerosolized agent is supplied using an endotracheal tube and a ventilator, a nebulizer, a respiratory' mask, and / or an inhaler device.

11. The method of any one of claims 1-10, wherein the occlusion is caused by a mechanical obstruction created by the accumulation of the aerosolized agent at the site of the air leakage.

12. The method of any one of claims 1-10, wherein the occlusion is caused by a biological reaction advanced by the accumulation of the aerosolized agent at the site of the air leakage.

13. A method of reducing air leakage at a site in the respiratory tract of a patient, the method comprising: supplying an aerosolized agent into the respiratory' tract, wherein accumulation of the aerosolized agent at the site of the air leakage causes occlusion of the site of the air leakage to reduce a rate of the air leakage.

14. The method of claim 13, wherein the aerosolized agent comprises a powder containing a pro-coagulant factor.

15. The method of claim 14, wherein the pro-coagulant factor is selected from the group consisting of fibrinogen, albumin, platelet cells, packed red blood cells, and thrombin.

16. The method of any one of claims 13-15, wherein the aerosolized agent comprises a powder having a particle diameter from about 1 pm to 10 pm.

17. The method of claim 16, wherein the aerosolized agent comprises a powder having a particle diameter of less than 5 pm.Attorney Docket No. 07039-2351WO1 / 2020-37718. The method of any one of claims 13-17, wherein the site is at a lung of the patient.

19. The method of claim 18, wherein the site at the lung of the patient is at an alveoli of the lung.

20. The method of any one of claims 13-19, wherein the aerosolized agent is supplied using an endotracheal tube and a ventilator, a nebulizer, a respiratory mask, and / or an inhaler device.

21. The method of any one of claims 13-20, wherein the occlusion is caused by a mechanical obstruction created by the accumulation of the aerosolized agent at the site of the air leakage.

22. The method of any one of claims 13-21, wherein the occlusion is caused by a biological reaction advanced by the accumulation of the aerosolized agent at the site of the air leakage.

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