Breathing-driven nasal devices and methods for treating traumatic brain injury (TBI) including cerebral concussion

Abstract

The present invention relates to a one-way blower or breath-driven nasal device providing a unique dual flow for propelling a pharmaceutical substance into the nasal cavity, preferably into the upper nasal cavity and into the olfactory region and the trigeminal mucosa, for rapid diffusion into the brain for the treatment of nasal and / or central nervous system ("CNS") injuries, diseases or disorders, and for the treatment of nasal and / or central nervous system ("CNS") injuries, diseases or disorders. The present invention relates to brain injury, in particular brain injury including cerebral concussion (e.g., traumatic brain injury ("TBI")), and methods related to nasal treatments therewith. Respiratory driven nasal devices are disclosed for delivering a tight or restricted concentrated plume of drug substance to a targeted site deep in the nasal cavity, bypassing the blood brain barrier (i.e., olfactory nerve) to provide concentrated drug substance for direct absorption by the brain. The restricted plume of the drug substance ejected from the nasal device by breathing of the patient is narrow in the vertical direction, similar to the diameter of the inner chamber in which the drug substance is stored. By creating such a narrow or restricted plume, higher concentrations of drug substances can be deposited at deeper nasal targeting sites. The breath-driven nasal device of the present invention achieves this unique advantage by using a novel double elongate double-walled tube chamber consisting of an outer hollow chamber and an inner chamber wherein the inner chamber is stabilized in the outer chamber by preferably two, three or more ribs. More specifically, the breath-driven nasal device simultaneously blows air through both chambers at the same force rate using the patient's own breath. When the blown air exits from the two chambers, propulsion air from the outer tube chamber encloses the drug substance propelled from the inner tube chamber in the blown air, forcing the drug substance to exit vertically in a tight or restricted concentrated plume shape, whereby the drug substance can be released from the outer tube chamber as compared to the drug substance exiting a conical fan-out plume shape of a single hollow chamber. And the drug substances with higher concentration reach the targeted nasal part (as shown in Figure 44-45). This unique feature allows the pharmaceutical substances to more effectively treat brain diseases or injuries without or to minimize systemic or blood brain barrier ("BBB") issues. According to the invention, air is blown through the two inner drug chambers by utilizing natural respiration of a patient, so that drug substances are pushed into the deep part of the nasal cavity from the inner drug substance chambers to reach a targeted part and bypass the BBB, and possibility is provided for better treatment of central nervous system diseases, such as traumatic brain injury, including cerebral concussion, migraine, epilepsy, insomnia and postoperative pain, and the treatment effect is good. The latter is typically relieved by opioids.

Description

[0001] Related U.S. Provisional Applications

[0002] This U.S. patent utility model application claims priority to U.S. Provisional Application Serial No. 63 / 257,117 filed on October 19, 2021, the entire contents of which are incorporated herein by reference as if fully set forth herein. Technical Field

[0003] The present invention relates to a unidirectional insufflator or breath-actuated nasal device providing a unique dual airflow for propelling a drug substance into the nasal cavity, preferably deep into the upper nasal cavity and into the olfactory region and trigeminal mucosa for rapid diffusion into the brain to treat nasal and / or central nervous system ("CNS") injuries, diseases or disorders, particularly brain injuries including concussions (e.g., traumatic brain injury ("TBI")), and methods of nasal treatment using the same. Background Art

[0004] The non-invasive nature of intranasal drug delivery makes it an attractive option for local and systemic delivery of therapeutics. See FDA. Content updated as of: April 28, 2021. How computational analysis of 3D mucociliary clearance models can help predict drug absorption and develop more universal nasal drug products. https: / / www.fda.gov / drugs / regulatory-science- research-and-education / how-computational-analysis-3d-mucociliary-clearance- model-can-help-predict-drug-uptake-and-lead-more (“FDA, April 28, 2021”). The nasal mucosa is unlike other mucous membranes and is easily accessible. FDA, April 28, 2021. Intranasal drug delivery avoids gastrointestinal degradation and first-pass hepatic metabolism of drugs. FDA, April 28, 2021. See also Bitter C, Suter-Zimmermann K, Surber C.: Nasal drug delivery in humans. Karger Publishers, Topical Applications and the Mucosa .Pages 20-35(2011).

[0005] Drugs designed to hit targets within the nasal cavity are often trapped in the highly viscous gel layer, which reduces their effectiveness. FDA, April 28, 2021. Although the drug is trapped, soluble drugs dissolve in the mucus layer, diffuse through the gel and sol layers, and are ultimately absorbed by the highly vascularized nasal epithelial cells. FDA, April 28, 2021. This process within the nasal cavity is believed to allow the drug to enter the body through the bloodstream without losing effectiveness. FDA, April 28, 2021.

[0006] For most nasal delivery purposes, extensive distribution of the drug on the mucosal surface appears to be acceptable for drugs intended for local action or systemic absorption. See, e.g., Vidgren MT, Kublik H.: Nasal delivery systems and their effect on deposition and absorption. Adv Drug Deliv Rev. 29:157–77(1998). See also Djupesland, PG: Nasal drug delivery devices: characteristics and performance in clinical perspective—a review. Drug Deliv.and Transl.Res. 3:42–62 (2013). However, for chronic sinusitis and nasal polyposis, targeted delivery to the middle and upper nasal passages where the sinus openings are located and nasal polyps originate is beneficial. See Laube B.: Devices for aerosol delivery to treat sinusitis. J Aerosol Med. 20(Suppl):5–18.43(2007); and Aggrawal R, Cardozo A, Homer JJ.: The assessment of topicalnasal drug distribution. Clin Otolaryngol. 29:201–5(2004). See also Djupesland, PG: Nasal drug delivery devices: characteristics and performance in clinical perspective—a review. Drug Deliv.and Transl.Res. 3:42–62(2013).

[0007] Despite this, there is still interest in the industry to develop products that target the blood-brain barrier (BBB) ​​to rapidly deliver drugs to the central nervous system, including the brain. Pardeshi CV, Belgamwar VS.: Direct nose to brain drug delivery via integrated nerve pathways bypassing the blood–brain barrier: an excellent platform for brain targeting. Expert opinion on drug delivery10(7):957-72. (2013). See also FDA, April 28, 2021. Unfortunately, the latest FDA guidance on nasal devices appears to be primarily directed toward mechanical liquid spray pumps and pressurized metered-dose inhalers for local action. FDA 2003. Draft guidance for industry from the U.S. FDA. Bioavailability and bioequivalence studies for nasal aerosols and nasal sprays. Bethesda. http: / / www.fda.gov / cder / guidance / index.htm. April 2003. See also Djupesland, PG: Nasal drug delivery devices: characteristics and performance in a clinical perspective—a review. Drug Deliv. and Transl. Res. 3:42–62 (2013) (“FDA 2003 guidance”). See also Djupesland, PG: Nasal drug delivery devices: characteristics and performance in a clinical perspective—a review. Drug Deliv.and Transl.Res. 3:42–62 (2013). The FDA guidance does not provide guidance for breath-actuated or breath-propelled nasal devices for nasal use to deliver drug substances to the brain for the treatment of brain injury or disease. FDA 2003 Guidance. See also Djupesland, PG: Nasal drug delivery devices: characteristics and performance in a clinical perspective—a review. Drug Deliv.and Transl.Res. 3:42–62(2013).

[0008] Unlike nasal drug substances that are widely distributed in the nasal cavity for local action or systemic absorption, drug substances for "nose-to-brain" (NTB) delivery face unique challenges. NTB drug delivery requires more targeted delivery to the upper nasal portion located deep in the nasal cavity to deposit onto the olfactory area and olfactory nerves, which is critical for NTB drug delivery and effective brain treatment. Djupesland, PG: Nasal drug delivery devices: characteristics and performance in a clinical perspective—a review. Drug Deliv.and Transl.Res. 3:42–62(2013).

[0009] However, recent animal data suggest that some amount of drug substance may be delivered along and across the branches of the first and second divisions of the trigeminal nerve, which innervate most, if not all, of the mucosa in and outside the nasal valvular region. Johnson HJ et al: Trigeminal pathways deliver a low molecular weight drug from the nose to the brain and orofacial structures. Mol Pharm. (3):884–93(2010). See also Djupesland, PG: Nasal drug delivery devices: characteristics and performance in clinical perspective—a review. Drug Deliv. and Transl. Res. 3:42–62 (2013). Johnson HJ et al. thus suggest that a combination of targeted delivery to the olfactory region and widespread distribution to the mucosa innervated by the trigeminal nerve may be the optimal approach for NTB delivery and effective brain treatment of drug substances. Djupesland, PG: Nasal drug delivery devices: characteristics and performance in a clinical perspective—a review. Drug Deliv.and Transl.Res. 3:42–62(2013).

[0010] The central nervous system (CNS) includes the brain, brainstem, and spinal cord. The CNS is separated from the outside world by several membranes that both cushion and protect the brain, brainstem, and spinal cord. For example, membranes that form the blood-brain barrier (BBB) ​​protect the brain from certain components of the blood. The blood-cerebrospinal fluid barrier (BCSFB) protects the rest of the CNS from many chemicals and microorganisms. Thus, two barrier systems in the brain form the BBB, the brain microvascular endothelium and the choroid plexus epithelium (BCSFB). In addition to the BBB, the brain is surrounded by the arachnoid epithelial barrier, forming the subarachnoid space.

[0011] Drug transport from blood to cerebrospinal fluid (CSF) is regulated by the choroid plexus or BCSFB. Drug transport from blood to interstitial fluid (ISF) is regulated by the brain microvascular endothelium or BBB. See WM Pardridge: Drug transport in brain via the cerebrospinal fluid. Fluids Barriers CNS. 8:7(2011).

[0012] The human brain does not have a lymphatic system. However, the human brain secretes more than 500 ml of cerebrospinal fluid every day. CSF is secreted in the choroid plexus or BCSFB. CSF fills the cranial and spinal subarachnoid spaces and the cavities of the four ventricles. See WM Pardridge: Drug transport in brain via the cerebrospinal fluid. Fluids Barriers CNS. 8:7(2011). The cerebral ventricles are a network of communicating cavities filled with CSF and located within the brain parenchyma. The ventricular system includes the two lateral ventricles, the third ventricle, the cerebral aqueduct, and the fourth ventricle. The choroid plexus, located in the ventricles, secretes CSF, which then fills the ventricles and subarachnoid space through a cycle of continuous production and reabsorption. See https: / / emedicine.medscape.com / article / 1923254-overview#:~:text=Overview-,Overview, (see%20the%20images%20below).

[0013] CSF flows over the surface of the brain and spinal cord. CSF is rapidly absorbed into the systemic circulation. As mentioned above, the choroid plexus forms the blood-CSF barrier, and this barrier is functionally distinct from the brain microvascular endothelium that forms the blood-brain barrier. Almost all noncellular material in the blood is distributed into the CSF, and drug entry into the CSF is not an indicator of drug delivery across the blood-brain barrier. Drugs injected into the CSF rapidly enter the bloodstream via bulk flow but have difficulty penetrating brain tissue due to diffusion limitations. See WM Pardridge: Drug transport in brain via the cerebrospinal fluid. Fluids Barriers CNS.8:7(2011).

[0014] Traditional methods of delivering compounds to the CNS are generally invasive. For example, certain compounds (such as epidural steroid injections (ESI), facet joint injections, hardware injections, sacroiliac (SI) joint injections, and lower extremity differential injections) are injected directly through the protective membrane into the CNS. However, spinal injections are not trivial and are generally not practical for most compounds.

[0015] Another example of delivering compounds to the CNS is pumps implanted within the skull, such as intracerebroventricular (ICV) pumps, which can deliver a variety of compounds to the brain. However, implantation of such pumps requires brain surgery, which can cause a variety of serious complications. Despite this, ICV or intracerebroventricular devices have been widely used to treat central nervous system (CNS) disorders in children and adults. Due to the limited permeability of the blood-brain barrier, CNS diseases often require direct infusion of drugs into the brain to achieve meaningful therapeutic effects. It is generally believed that the clinical use and complications of ICV drug delivery have resulted in device-related complications with a non-infectious complication rate of up to 33% and an infectious complication rate of up to 27%. The reason for these poor safety outcomes may be the lack of consensus among practitioners on best practices for the use of the devices. See Slavc I. et al: Best practices for the use of ICV drug delivery devices. Molecular Genetics and Metabolism .124(3):184-188(2018).

[0016] Current brain research focuses on enhancing drug delivery to the brain through various formulations. Traditional methods for improving brain absorption of compounds include (1) mucoadhesive formulations; 2) penetration enhancers; 3) liposomes; 4) vasoconstrictors; and 5) nanoparticles. Examples of various compounds with enhanced formulations include various cytokines, such as tumor necrosis factor, interleukin, and interferon discussed in U.S. Patent No. 6,991,785, and growth and differentiation factor-5 (GDF-5) and related proteins discussed in U.S. Publication No. 20100074959.

[0017] Targeting drugs to the central nervous system (CNS) is a challenging task. A large number of drugs, including biotech products, are candidates for the treatment of CNS diseases, but drug delivery across the BBB is a difficult problem for brain targeting. A limitation in treating brain tumors is that less than 1% of most systemically administered therapeutics cross the BBB. Delivery of small molecules across the BBB is the exception rather than the rule, with 98% of small molecules unable to cross the BBB. See, e.g., Pardride, WM: The blood-brain barrier: bottleneck in brain drug development. NeuroRx .2(1):3-14 (January 2005), in which Pardride concluded that approximately 100% of large molecule drugs or genes cannot cross the BBB. According to Pardride, the BBB allows small (less than about 500 Da) lipophilic molecules in the blood to enter the CNS from the bloodstream and prevents many larger therapeutic agents from reaching the brain to treat CNS disorders such as, but not limited to, Parkinson's disease, Alzheimer's disease, depression, stroke, and epilepsy. Pardride, WM: The blood-brain barrier: bottleneck in brain drug development. NeuroRx .2(1):3-14 (January 2005). See also Chapman, CD et al.: Intranasal Treatment of the Central Nervous System Dysfunction in Humans. Pharm.Res .30:2475-2484(2013).

[0018] Diseases including autism, lysosomal storage disorders, fragile X syndrome, ataxia, and blindness are serious conditions with few effective treatments. In many of these cases, the underlying genes for the disease are known, but BBB delivery is a rate-limiting problem in gene therapy or enzyme replacement therapy, and no treatments have been developed. Drug delivery of therapeutic compounds such as proteins presents several challenges due to their instability, high rates of enzyme metabolism, low gastrointestinal absorption, rapid renal elimination, and potential immunogenicity. Pardride, WM: The blood-brain barrier: bottleneck in brain drug development. NeuroRx .2(1):3-14(January 2005).

[0019] Pardridge believes that "…despite its importance to the neurotherapeutic mission, insufficient attention has been paid to the BBB by both academic and industry programs in neuroscience, and minimal efforts have been made to develop solutions to BBB problems, which, combined with minimal delivery of the BBB in most potential CNS drugs, has foreshadowed the current state of neurotherapeutics, where there are few effective treatments for most CNS disorders." Pardridge, WM: The blood-brain barrier: bottleneck in brain drug development. NeuroRx .2(1):3-14 (January 2005). See also FDA 2003 guidance.

[0020] According to Chapman, CD, et al., intranasal delivery is emerging as a non-invasive option for delivering drugs to the CNS with minimal peripheral exposure. Chapman, CD, et al.: Intranasal Treatment of the Central Nervous System Dysfunction in Humans. Pharm.Res .30:2475-2484 (2013). See also FDA, April 28, 2021; Trevino, JT et al.: Non-Invasive Strategies for Nose-to-Brain Drug Delivery. J Clin Trials .10(7):439.(2020); and Dhakar,RC et al.: Nasal Drug Delivery: Success Through Integrated Device Development. J.DrugDeliv.Ther.1(1):2-7(2011). Chapman, CD et al. suggested that intranasal delivery could facilitate the delivery of large and / or charged therapeutics that are unable to effectively cross the blood-brain barrier (BBB). Therefore, Chapman, CD et al. concluded that intranasal delivery is emerging as an effective method of drug delivery for a variety of growth factors, hormones, neuropeptides, and therapeutics (including insulin, oxytocin, orexin, and even stem cells) and is a promising therapeutic strategy for the treatment of CNS diseases such as obesity, Alzheimer's disease, Parkinson's disease, Huntington's disease, depression, anxiety, autism spectrum disorder, epileptic seizures, drug addiction, eating disorders, and stroke. Chapman, CD et al.: Intranasal Treatment of the Central Nervous System Dysfunction in Humans. Pharm.Res .30:2475-2484(2013).

[0021] However, intranasal drug delivery has traditionally focused on the distribution of drug solutions as a mist delivered topically to the nasal epithelium. Due to the easy access to the vascular bed in the nasal cavity, nasal drug delivery has focused on delivering drugs topically to the nasal cavity or directly to the bloodstream.

[0022] There is a real need for a nasal insufflator that can deliver drugs to the upper nasal cavity, thereby avoiding BBB issues and achieving direct nose-to-brain or NTB delivery to effectively treat brain injuries and disorders. Certain existing nasal drug delivery devices do not adequately push the drug out of the device or concentrate the drug for effective targeting and treatment. Inconsistent propulsion of a steady flow of drug concentration is also far from optimal. In addition, the plume produced by such existing devices is too wide and too dispersed for effective NTB delivery. Certain existing nasal drug devices rely on circumferential velocity to propel the drug to the olfactory epithelium. Traditional circumferential devices result in a low percentage of drug substance deposited on the olfactory epithelium. The circumferential component in the aerosol plume tends to result in a wider spray plume with a portion of the aerosol particles targeted to the lateral nasal cavity in the lower nasal cavity.

[0023] Therefore, there is a real clinical need for improved nasal insufflators and mechanisms to effectively target and centrally deposit the desired drug substance within the brain, brainstem, and / or spinal cord and to improve clinical presentation and efficacy in the treatment of CNS and brain injuries and disorders such as TBI, especially concussion. Summary of the invention

[0024] The present invention overcomes the above-mentioned shortcomings and deficiencies of the prior art nasal insufflator technology through the discovery of a novel one-way insufflator or breath-actuated nasal device and method that provides a unique dual airflow for propelling drug substances into the nasal cavity, preferably deep into the upper nasal cavity, for effective targeted delivery to the olfactory region, and distribution into the mucosa innervated by the trigeminal nerve with high drug substance concentrations for rapid diffusion to the brain for the treatment of nasal and / or central nervous system ("CNS") injuries, diseases or disorders (particularly brain injuries), including traumatic brain injuries ("TBI"), particularly concussions.

[0025] The novel one-way insufflator or breath-actuated nasal device and delivery method of the present invention utilizes a novel double-walled dispensing system (i.e., a double-walled tube configuration) and natural nasal anatomy and features to improve nasal delivery of drug substances in the form of fine particles, liquids, suspensions, gels, etc., without causing pulmonary or gastric deposition or first-pass liver metabolism of the drug substance, thereby improving nasal therapeutic efficacy. The novel one-way insufflator or breath-actuated nasal device is preferably a disposable, single-use device for single-dose delivery of a single drug substance or for single-dose delivery of two or more drug substances. The novel one-way insufflator or breath-actuated nasal device of the present invention is both hygienic and can provide uniquely effective and accurate dosing of drug substances for effective nasal treatment of local, systemic and CNS injuries, diseases or disorders.

[0026] The novel one-way insufflator or breath-actuated nasal device of the present invention is highly intuitive and simple to use and utilizes the natural nasal reflex to insufflate a dry powder or liquid dose deep into the nasal cavity for effective targeted delivery to the olfactory region and distribution into the mucosa innervated by the trigeminal nerve with a high drug substance concentration for rapid diffusion into the brain. For ease of illustration, a subject using the device of the present invention fits the nose guard on one end of the device tightly into one nostril and then inserts or places the mouthpiece on the other end of the device into the mouth between the lips. When the subject exhales the blown air through the inserted or placed mouthpiece, overcoming the resistance created by the device, the nasal reflex that automatically closes the soft palate is activated, thereby closing the oral and nasal airways of the subject. Thus, the blown drug substance loaded into the device is pushed out of the nose guard, exits in the unique dual airflow created by the dual-walled dispensing system of the novel device, and is transported and retained deep into the nasal cavity for delivery of the retained drug substance to the superior nasal membranes and trigeminal mucosa in the olfactory region for direct diffusion into the brain within a few minutes after the device is used. Once the subject completes the puffing maneuver to deliver the dose to the nasal cavity, the subject's nasal reflex naturally subsides and the subject's oral and nasal airways reopen.

[0027] While any effective insufflation rate is contemplated by the present invention, an insufflation rate of about 40 liters per minute at a pressure of at least about 40 cm H2O or greater appears to be more suitable for effective operation of the novel one-way insufflator or breath-actuated nasal device of the present invention.

[0028] It is therefore an object of the present invention to provide a novel one-way insufflator or breath-actuated nasal device for treating local, systemic and CNS injuries, diseases and disorders, particularly TBI and more particularly concussion, by using a novel and unique dual airflow combination to push highly concentrated drug substances deep into the nasal cavity, deposit and distribute throughout the olfactory region, to the mucosa innervated by the trigeminal nerve, and diffuse directly into the brain, thereby uniquely avoiding systemic and BBB issues. If so selected, the novel one-way insufflator or breath-actuated nasal device can also deposit drug substances in the nasal cavity for local and systemic application of the same or different drug substances. These objects are achieved by the novel and unique double-walled dispensing system configured in the novel one-way insufflator or breath-actuated nasal device of the present invention.

[0029] Generally speaking, the one-way insufflator or breath-actuated nasal device of the present invention comprises a one-way valve mouthpiece at one end and a nose guard at the other end, which are fluidly connected by a bellows to deliver a loaded drug substance into the deep nasal cavity by oral pressure, blow through the one-way valve mouthpiece, and cause the drug substance to exit the nose guard in a vertical, slightly tight, narrow or restricted concentrated plume through the novel double-walled drug substance technology for delivering high drug substance concentrations to targeted sites deep in the nasal cavity and distributed throughout the olfactory area and into the mucosa innervated by the trigeminal nerve, and diffuse from there into the brain. When the nose guard is snugly inserted into one of a person's nostrils and the person blows into the one-way valve mouthpiece, delivery of the drug substance (for example, in the form of dry powder, liquid, suspension or gel) occurs, and the breathing closes the person's limbal membrane (soft palate) and allows the pressurized air flow to pass through the one-way valve mouthpiece, and then through the novel double-walled dispensing system of the present invention, the drug substance with a high drug concentration is uniquely brought into the deep upper nasal cavity in a vertical, slightly tight or restricted and narrow concentrated plume shape at the outlet of the nose guard for effective distribution in the olfactory area and the mucosa innervated by the trigeminal nerve, and from there directly diffuses into the brain.

[0030] More specifically, if Figure 1-2 and Figure 9-10 As shown, the one-way insufflator or breath-driven nasal device 10 of the present invention includes a nose protector 20, a double-walled dispensing system 30, a mesh disk 40 for placing a drug 200 (not shown), a first tube connector 60, a bellows 80, a second tube connector 70, a ridge connector 110, and a one-way valve mouthpiece 100 having a one-way valve 50 (not shown) installed in a bottom portion 103, which guides airflow in one direction and prevents reverse airflow direction, so that when the one-way insufflator or breath-driven nasal device 10 is used and the sealing cover 150 (i.e., the top cover) is removed and the user blows air through the one-way valve mouthpiece 100, the first airflow direction indicating band 160 and the second airflow direction indicating band 170 push the drug 200 (not shown) placed on the mesh disk 40 out of the nose protector 20.

[0031] like Figure 9-10 As further shown, the top portion 31 of the double wall dispensing system 30 is press fit through the bottom 26 of the through hole 24 of the nose guard 20 and is placed against the nose guard seat 22 located near the top 25 of the through hole 24 of the nose guard 20. The bottom portion 32 of the double wall dispensing system 30 is press fit into the first top hollow collar 65 of the first tube connector 60 to form a tight seal therebetween. The mesh plate 40 is inserted and positioned on top of the first seat 61, which is positioned at the bottom of the first top hollow collar 65 of the first tube connector 60. The first bottom hollow neck 66 of the first tube connector 60 is press fit into the first hollow hoop 81 of the bellows 80 to form a tight seal therebetween. The second bottom hollow neck 76 of the second tube connector 70 is press fit into the second hollow hoop 82 of the bellows 80 to form a tight seal therebetween. The bottom portion 102 of the one-way valve mouthpiece 100 is press-fit into the second top hollow collar 75 of the second tube connector 70 until it rests on the second seat 71 of the second tube connector 70 to form a tight seal therebetween.

[0032] Therefore, if Figure 9-10 As further shown, the one-way valve 50 (not shown) installed in the bottom portion 103 of the one-way valve mouthpiece 100 guides the air flow in one direction (preventing reverse air flow direction) through (a) the conduit 101 in the one-way valve mouthpiece 100, (b) the second bottom hollow neck 76 of the second tube connector 70, (c) the bellows 80, (d) the first bottom hollow neck 66 of the first tube connector 60 and the mesh disk 40 located on the first seat 61 in the first tube connector 60, and (e) the inner and outer hollow chambers 33a and 33b of the double-walled dispensing system 30, which generates a novel inner and outer airflow, wherein the drug substance 200 is concentrated in the inner airflow and pushed by the inner airflow. The inner airflow is surrounded by the outer airflow, and when the drug substance leaves the top portion 31 of the inner hollow chamber 33a and the top 25 of the through hole 24 (not shown) of the nose protector 20, the drug substance 200 is concentrated in the inner airflow, so that when driven by breathing, the drug substance 200 is propelled by the novel one-way insufflator or the breath-driven nasal device 10 in the novel and unique dual airflow to form a vertical, slightly tight or restricted and narrow high drug concentration concentrated plume (i.e., the inner airflow), which penetrates deep into the upper nasal cavity for effective distribution to the olfactory area and the mucosa innervated by the trigeminal nerve, and diffuses directly therefrom into the brain through the air blown out by the novel one-way insufflator or the breath-driven nasal device 10.

[0033] like Figure 7-8As shown, the bridge 110 connects one side 131 of the novel one-way insufflator or breath-driven nasal device 10 (including the one-way valve mouthpiece 100 and the second tube connector 70) to the other side 131 of the novel one-way insufflator or breath-driven nasal device 10 (including the nose guard 20, the double-walled dispensing system 30, the mesh disk 40 and the first tube connector 60) to maintain the breath-driven insufflator or breath-driven nasal device 10 of the present invention in a "U-shaped" configuration 140. The bridge 110 includes a bridge connector 110 sandwiched between a first hollow ring 122 and a second hollow ring 123, and is used to slide on the first hollow hoop 81 and the second hollow hoop 82 of the bellows 80. See Figure 15-16 and Figure 18-19 .

[0034] Alternatively, if Figure 13-14 As shown, the bridge connector 110 is fixed to the one-way insufflator or breath-driven nasal device 10, as depicted in front view 135 with a nose guard side 130 and a one-way valve mouthpiece side 131, which can be designed with perforations or score lines 124 or any other configuration to allow the bridge 110 to be broken and separated into two separate parts when the sides 130 and 131 of the breath-driven insufflator or breath-driven nasal device 10 need to be oriented or adjusted at different angles for use (such as for a concussion patient or to assist a second person who is unable to apply the necessary blowing force to provide sufficient airflow on their own), thereby effectively pushing the drug substance out of the one-way insufflator or breath-driven nasal device 10 of the present invention to effectively treat concussion with the drug substance, such as Fig.12 shown.

[0035] The double wall dispensing system 30 (i.e., double wall tube configuration) is a novel and unique delivery system for delivering one or more drug substances into the nasal cavity. The double wall dispensing system 30 includes a top portion 31 and a bottom portion 32 and two hollow chambers 33, an inner hollow chamber 33a and an outer hollow chamber 33b. When the breath-actuated insufflator or breath-actuated nasal device 10 of the present invention is propelled by breath, the drug substance 200 is propelled through the hollow inner chamber 33a. The hollow outer chamber 33b surrounding the hollow inner chamber 33a is divided into two, three, four or more independent chambers 34 by rib walls 35. Preferably, but not necessarily, the hollow outer chamber 33b is divided into three independent chambers 34. In addition to providing multiple hollow chambers 34, the rib walls 35 give integrity, structure and strength to the double wall dispensing system 30 and support the double wall dispensing system.

[0036] Although the present invention contemplates that the dual chamber 34 (i.e., a double-walled tube configuration) consisting of the inner hollow chamber 33a and the outer hollow chamber 33b of the double-walled dispensing system 30 can have any suitable dimensions required to effectively achieve the purposes of the present invention, preferably, the inner hollow chamber 33a can accommodate up to about 120 mg or more and any amount of dry powder or other forms of drug substances in between, and its outer wall diameter 331 can range from (for example) about 3 mm to about 7 mm or more or less, its inner wall diameter 332 can range from about 2 mm to about 5 mm or more or less, and the outer wall diameter 333 can range from (for example) about 9 mm to about 13 mm or more or less, and its inner wall diameter 334 can range from about 7 mm to about 12 mm or more or less.

[0037] Preferably, and by way of example, Fig.29 As shown, the present invention contemplates an inner hollow chamber 33a having an outer wall 331 diameter of about 5 mm and an inner wall 332 diameter of about 3 mm, thereby forming an inner gap 37 of about 3 mm in diameter for the inner hollow chamber 33a. While these exemplary diameter dimensions produce an inner gap 37 of about 3 mm between the outer wall 333 of the inner hollow chamber 33a and the inner wall 334 of the outer hollow chamber 33b, the present invention also contemplates inner hollow chambers 33a designed with inner gaps 37 having diameters of up to about 1 mm to about 4 mm or more. Thus, according to the present invention, and preferably, the diameter of the inner gap 37 can range from about 1 mm to about 4 mm or more, including inner gaps 37 having diameters of about 1 mm, about 1.5 mm, about 2 mm, about 2.5 mm, about 3 mm, about 3.5 mm, and about 4 mm, and dimensions therebetween, such that the nose guard 20 has dimensions that allow the size of the nose guard 20 to fit snugly into any size of nostrils as previously discussed herein.

[0038] Although the thickness of the outer wall 331 and the inner wall 332 of the inner hollow chamber 33a and the outer wall 333 and the inner wall 334 of the outer hollow chamber 33b can have any suitable thickness, preferably, the actual thickness of the walls 331, 332 and 333, 334 of the double-walled dispensing system 30 (i.e., double-walled tube configuration) is about 2 mm.

[0039] In order to load the powdered, spray-dried form of the drug substance 200 into the novel one-way insufflator or breath-actuated nasal device 10 of the present invention, a sterile funnel (not shown) is used to specifically load the powdered drug substance 200 into the inner hollow chamber 33a of the double-walled dispensing system 30. Figure 9-10 and Fig.23As shown, the mesh disk 40 located on the bottom end portion 32 of the inner hollow chamber 33a and the first seat 61 of the first tube connector is the first part that the loaded powdered drug substance 200 encounters and will rest on once fully loaded. Since the pore size of the mesh disk 40 is smaller than the particle size of the powdered drug substance, the powdered drug substance cannot fall through the mesh disk 40. However, the holes throughout the mesh disk 40 allow the blown air flow to penetrate upward and through the mesh disk 40 to carry and propel the powdered drug substance 200 through the inner hollow chamber 33a of the double-walled dispensing system 30 (i.e., the double-walled tube configuration), as well as the top 25 of the through hole 24, and out of the nose guard 20, deep into the nasal cavity. It should be understood that if liquids, suspensions, gels, etc. are loaded into the double-walled dispensing system 30 (i.e., the double-walled tube configuration), a different mesh disk 40 may be required to ensure that leakage or seepage is prevented.

[0040] Preferably, the powdered, spray-dried drug substance 200 has a particle size distribution predominantly in the range of about 1 μm to about 10 μm or greater. In one embodiment, the powdered, spray-dried drug substance 200 contains a drug, particularly a drug for treating nasal conditions. Despite the preferred particle size, the present invention contemplates any effective particle size distribution of the powdered, spray-dried drug substance that achieves the purposes of the present invention, including larger particles or smaller fractions of larger particles, typically in the range of about 10 μm to about 30 μm, and preferably in the range of about 20 μm to about 30 μm.

[0041] Now let's see how to operate. Fig.11 and Fig.12 As shown, when a person blows or exhales through the mouthpiece 100 of the one-way insufflator or breath-actuated nasal device 10 of the present invention, the blown airflow flows through the two hollow chambers 33a and 33b of the double-walled dispensing system 30 (i.e., the double-walled tube configuration), and simultaneously and with substantially the same force, the drug substance loaded into the inner hollow chamber 33a is expelled from the nose guard 20. The pressure of the airflow exiting from the outer hollow chamber 33b surrounds the airflow loaded with a high drug substance concentration exiting from the inner hollow chamber 33a, forcing the drug-loaded airflow to travel, at least initially, in a vertical, slightly tight or restricted and narrow, concentrated plume, carrying the high drug substance concentration into the deepest part of the upper nasal cavity, i.e., the olfactory area and the nerves and mucosa innervated by the trigeminal nerve, so as to diffuse directly into the brain therefrom. Thus, the novel double-walled drug system 30 (i.e., double-walled tube configuration) uniquely and surprisingly delivers high concentrations of drug substance to targeted olfactory areas and even to mucosal membranes innervated by the trigeminal nerve for direct diffusion into the brain to effectively treat CNS injuries, diseases and / or disorders, including the brain, brainstem and spinal cord, particularly TBI, especially concussion.

[0042] While it should now be understood that the unique design of the one-way insufflator or breath-actuated nasal device 10 of the present invention uniquely deposits and delivers drug into the olfactory region and trigeminal mucosa for direct diffusion into the brain, the initial flow pattern of the exiting drug substance-laden airstream may be somewhat fanned, resulting in some drug substance being deposited in other portions of the nasal cavity. It should also be further understood that while it is preferred that only the drug substance 200 be loaded into the inner hollow chamber 33a, different or identical drug substances may also be loaded into two or more separate chambers 34 of the outer hollow chamber 33b for deposition of drug substance throughout the nasal cavity to treat both the CNS and nasal cavity and other nasal conditions that are treated by nasal administration.

[0043] Thus, the present invention is particularly suitable for treating local, systemic and CNS injuries and / or disorders. However, it should be understood that the one-way insufflator or breath-actuated nasal device 10 of the present invention is preferably a single-use, disposable device, specifically designed for treating TBI, preferably treating mild, moderate and severe TBI, more preferably, mild to moderate TBI, even more preferably mild TBI, and most preferably, concussion. Examples of drug substances suitable for use in combination with the one-way insufflator or breath-actuated nasal device 10 are C-20 steroid compounds in dry powder, spray-dried form, as disclosed and described in U.S. Patent Publication No. 2016 / 0168190 entitled “C-20steroid compounds, compositions and uses thereof” and WO 2016 / 044559A1 entitled “C-20steroid compounds, compositions and uses thereof to treat traumatic brain injury (TBI), including concussions”, each of which is incorporated herein by reference in its entirety as if fully set forth herein. A preferred C-20 steroid compound contemplated by the present invention is ent-19-norprogesterone in dry powder, spray-dried form. The molecular formula of Ent-19-norprogesterone is C 20 H 28 O2, with a molar mass of 300.435 g / mol. One chemical name for ent-19-norprogesterone is ent-19-norpregn-4-ene-3,20-dione. The chemical structure of ent-19-norprogesterone is as follows:

[0044]

[0045] ENT-19-Norprogesterone is a fully synthetic, non-naturally occurring neurosteroid. In preclinical studies, ENT-19-Norprogesterone has been shown to have equal or superior neuroprotective effects compared to related neurosteroids. Animal models of concussion have shown that ENT-19-Norprogesterone reduces behavioral pathology associated with symptoms of brain injury, such as memory impairment, anxiety, and motor / sensory performance. In addition, ENT-19-Norprogesterone is lipophilic and can easily cross the blood-brain barrier, rapidly eliminating or at least reducing swelling, oxidative stress, and inflammation in the brain during the healing process of TBI (e.g., concussion), attempting to restore normal blood flow and heal damaged or affected brain and / or other tissues.

[0046] When ent-19-norprogesterone is the drug substance of choice for treating TBI, especially concussion, according to the present invention, the inner hollow chamber 33a is preferably pre-loaded with about 100 mg of the drug substance ent-19-norprogesterone, wherein the ent-19-norprogesterone drug substance includes about 8 mg, and the pharmaceutically acceptable excipient hydroxypropyl-β-cyclodextrin includes about 92 mg. The 19-norprogesterone formulation is preferably in dry powder, spray-dried form, and can be administered up to four or more times a day according to a prescribed treatment regimen for a necessary period of time to treat (for example) patients suffering from TBI, especially concussion. To pre-load the inner hollow chamber 33a of the double-walled dispensing system 30 of the one-way insufflator or breath-driven nasal device 10 of the present invention with the ent-19-norprogesterone drug substance, the concussion or TBI victim inserts the nose guard 20 into one nasal vestibule or nostril until it fits tightly, and then inserts the mouthpiece 100 between his / her lips. Once the one-way insufflator or breath-actuated nasal device 10 of the present invention is properly installed in the nostrils and between the lips of a concussion or TBI victim, the concussion or TBI victim inhales / exhales through the mouthpiece 100: (a) to close the limbal membrane or soft palate to isolate the nasal cavity, preventing the ent-19-norprogesterone drug substance from being inhaled or entering the digestive system, thereby reducing systemic side effects; (b) to push the ent-19-norprogesterone drug substance in the inner hollow chamber 33a out of the nose guard 20 with sufficient airflow force and pressure to deposit and distribute the concentrated ent-19-norprogesterone drug substance throughout the olfactory area and trigeminal mucosa for direct diffusion into the brain, thereby effectively treating concussion or TBI within a few minutes after nasal administration. Importantly, the one-way valve mouthpiece 100 prevents reverse airflow, and the closed soft palate will retain the concentrated ent-19-norprogesterone drug in the nasal cavity, causing it to adhere to the upper nasal membrane for direct diffusion into the brain through the olfactory nerve and trigeminal mucosa.

[0047] This highly advantageous and unique nasal delivery is achieved by the novel double-walled dispensing system 30 (i.e., double-walled tube configuration) of the one-way insufflator or breath-actuated nasal device 10 of the present invention by using the following unique dual airflow combination: (i) a first airflow carrying the ent-19-norprogesterone drug substance discharged from the inner hollow chamber 33a, and (ii) a second airflow discharged simultaneously from the outer hollow chamber 33b, generating an airflow pressure around the first exhaust airflow so that the first exhaust airflow is initially formed and travels in a vertical, slightly tight or confined and narrow concentrated plume, which drives the concentrated drug substance (e.g., ent-19-norprogesterone drug substance) to the targeted olfactory area, including the olfactory nerves and trigeminal nerve mucosa, for direct diffusion into the brain and effective treatment of concussion or TBI within minutes after nasal administration.

[0048] Although the one-way insufflator or breath-actuated nasal device 10 of the present invention is simple in structure, the operation of the device does enable effective delivery of drug substances, particularly powders containing drug substances, to the posterior region of the nasal airway, because the powdered drug substance is delivered to the deep nasal cavity in a one-way manner and the airflow into the nasal cavity is through the same opening, that is, each nostril and the closed posterior region of each nasal cavity act as a pressure reflective surface, allowing the exhaled air to fully reach the posterior region of each nasal cavity, deposited in the olfactory region and trigeminal mucosa, and quickly diffuse into the brain for the treatment of nasal and / or CNS injuries, diseases or disorders, particularly brain injuries, such as TBI, including concussion. In addition, when providing a short burst of airflow to one of the nasal cavities, it is now possible to achieve a continuous one-way airflow of highly concentrated powdered drug substances deep in the nasal cavity, which is believed to be necessary for the effective delivery of powdered drug substances to the posterior region of the nasal airway for deposition in the olfactory region and trigeminal mucosa and rapid diffusion into the brain.

[0049] As contemplated by the present invention, any suitable material may be used for the various portions or components of the one-way insufflator or breath-actuated nasal device 10 of the present invention, with VESTAMID ML21 being the material of choice for plastic portions, such as the double-walled dispensing system 30 and tube connectors 60 and 70. ABS is an exemplary material for the mouthpiece 100 and the one-way valve 50 (not shown). PTFE is an exemplary material for the bellows 80. Silicone HD-150A is an exemplary material for the nose guard 20, the bridge 110, and the sealing cap 150 (i.e., the top cap).

[0050] According to one embodiment of the present invention, the length of the double wall dispensing system 30 (i.e., the double wall tube configuration) is about 2.00 inches, and the length of the bellows is about 4 inches. The overall length of this exemplary device is about 8 inches. When in the U-shaped configuration, the maximum length of this device from the bottom of the corrugated material to the top of the nose guard 20 is about 4 inches, and the width is about 2.2 inches. From a side view, the width of the corrugated material is about 0.45 inches, and the widest width of the nose guard 20 is about 0.75 inches, as shown in FIG. Fig.38 As shown, the widest width of the one-way valve mouthpiece 100 is about 0.5 inches.

[0051] It should be further understood that the above summary of the present invention is not intended to limit or describe every possible embodiment or embodiment of the present invention, but rather contemplates these possible embodiments and embodiments. However, this specification does illustrate illustrative embodiments. In many places throughout the specification, guidance is provided by examples, which can be used in various combinations. In each case, the examples are only representative groups and should not be interpreted as exclusive examples. BRIEF DESCRIPTION OF THE DRAWINGS

[0052] The structure, operation and advantages of the present invention will become more apparent from the following description considered in conjunction with the accompanying drawings, in which:

[0053] Figure 1 is a front assembled elevation view 135 of a one-way insufflator or breath-actuated nasal device 10 according to an embodiment of the present invention;

[0054] Figure 2 is a rear elevational view 136 of the back assembly of a one-way insufflator or breath-actuated nasal device 10 according to an embodiment of the present invention;

[0055] Figure 3 is a top view 850 of a bellows 80 according to an embodiment of the present invention, showing a corrugated middle portion 85 and a bridge 110;

[0056] Figure 4 is a bottom view 860 of a bellows 80 showing a corrugated middle portion 85 according to an embodiment of the present invention;

[0057] Figure 5 is an assembled bottom view of the nose guard side 130 of a one-way insufflator or breath-actuated nasal device according to an embodiment of the present invention;

[0058] Figure 6 is an assembled bottom view of a one-way valve mouthpiece side 131 of a one-way insufflator or breath-actuated nasal device according to an embodiment of the present invention;

[0059] Figure 7is a bottom view of the right mouthpiece assembly of a one-way insufflator or breath-actuated nasal device according to an embodiment of the present invention;

[0060] Figure 8 is a bottom view of the left mouthpiece assembly of a one-way insufflator or breath-actuated nasal device according to an embodiment of the present invention;

[0061] Fig. 9 is an unassembled front view of the right mouthpiece of a one-way insufflator or breath-actuated nasal device according to an embodiment of the present invention;

[0062] Fig.10 is an unassembled front view of the left mouthpiece of a one-way insufflator or breath-actuated nasal device according to an embodiment of the present invention;

[0063] Fig.11 The embodiment of the present invention is schematically described. Figure 1-2 and Figure 4-8 A one-way insufflator or breath-actuated nasal device is inserted into the nasal cavity of the subject for operation;

[0064] Fig.12 The following schematically describes an embodiment of the present invention. Fig.13 and Fig.14 The nasal guard of the alternative embodiment of the one-way insufflator or breath-actuated nasal device shown is inserted into the nasal cavity of a first subject to be treated with a pharmaceutical substance, and the nasal guard is inserted into the nasal cavity of the first subject to be treated with a pharmaceutical substance. Fig.13 and Fig.14 The mouthpiece of the alternative embodiment shown is inserted between the lips of a second subject for use as Fig.13 and Fig.14 The operation of the alternative embodiment is shown to be performed by a second subject;

[0065] Fig.13 is a front right mouthpiece assembly elevation view of an alternative embodiment of a one-way insufflator or breath-actuated nasal device herein according to an embodiment of the present invention, wherein the bridge is designed with perforations or score lines for disconnecting the bridge;

[0066] Fig.14 is a front right mouthpiece assembly elevation view of an alternative embodiment of a one-way insufflator or breath-actuated nasal device herein according to an embodiment of the present invention, wherein the bridge is broken in two at a perforation line or score line for breaking the bridge, such as Fig.13 As shown;

[0067] Fig.15 Schematically depicting the assembly of the bridge 110 to the bellows 80 according to an embodiment of the present invention;

[0068] Fig.16 schematically depicts a perspective view of a bridge 110 and a bellows 80 assembled in accordance with an embodiment of the present invention;

[0069] Fig.17 Schematically depicts a front view of a bridge 110 and a bellows 80 assembled in accordance with an embodiment of the present invention;

[0070] Fig.18 The embodiment of the present invention schematically describes the assembly of the first pipe connector 60 and the second pipe connector 70 to the corrugated pipe 80 assembled with the bridge 110, as shown in FIG. Fig.16 and Fig.17 As shown;

[0071] Fig.19 The perspective view schematically illustrates a first pipe connector 60 and a second pipe connector 70 assembled to a corrugated pipe 80 assembled with a bridge 110 according to an embodiment of the present invention. Fig.16 and Fig.17 As shown;

[0072] Fig. 20 schematically depicts a cross-sectional view of a pipe connector according to an embodiment of the present invention;

[0073] Fig.21 The embodiment of the present invention schematically describes the insertion of the mesh tray 40 into the first pipe connector 60, wherein the first pipe connector 60 and the second pipe connector 70 are assembled to the corrugated pipe 80 assembled with the bridge 110, as shown in FIG. Fig.16 and Fig.17 As shown;

[0074] Fig. 22 The double-walled dispensing system 30 (i.e., a double-walled tube configuration) is schematically described as being inserted into a first tube connector 60 according to an embodiment of the present invention, wherein a mesh disk 40 is inserted into the first tube connector 60, and the first tube connector 60 and the second tube connector 70 are assembled to a corrugated tube 80 assembled with a bridge 110, as shown in FIG. Fig.16 , 17 , 19 and 21;

[0075] Fig.23 Schematically depicts an exploded cross-sectional view of a first tube connector 60 assembled according to an embodiment of the present invention, wherein the mesh disk 40 and the double-walled dispensing system 30 (i.e., a double-walled tube configuration) are assembled within the first tube connector 60, and the mesh disk 40 is located on a first seat 61 of the first tube connector 60, and a first top hollow collar 65 of the first tube connector 60 is press-fit into a first hollow ferrule 81 of a corrugated tube 80;

[0076] Fig.24The top portion 31 of the double-walled dispensing system 30 (i.e., the double-walled tube configuration) is schematically described as being inserted into the bottom 26 of the through hole 24 of the nose protector 20 according to an embodiment of the present invention, wherein the mesh disk 40 is assembled into the first tube connector 60, and the first tube connector 60 and the second tube connector 70 are assembled to the corrugated tube 80 assembled with the bridge 110, as shown in FIG. Fig.16 , 17 , 19, 21 and 22;

[0077] Fig.25 Schematically depicting a front view of a nose guard 20, a first tube connector 60, a mesh tray 40 (not shown), a double-wall dispensing system 30 (i.e., a double-wall tube configuration), a first tube connector 60 and a second tube connector 70, a bridge 110, and a bellows 80 assembled in accordance with an embodiment of the present invention;

[0078] Fig.26 Schematically depicting the placement of the sealing cap 150 and the sealing cap plug 151 into the top portion 25 (not shown) of the through hole 24 (not shown) above the nose guard 20, the first tube connector 60, the mesh tray 40 (not shown), the double-walled dispensing system 30 (i.e., the double-walled tube configuration), the first tube connector 60 and the second tube connector 70, the bridge 110, and the bellows 80 of the assembled nose guard 20 according to an embodiment of the present invention;

[0079] Fig. 27 Schematically depicts an exploded cross-sectional view of a nose guard 20 according to an embodiment of the present invention, wherein a double-wall dispensing system 30 (i.e., a double-wall tube) is inserted through the through hole 24 of the nose guard 20, a top portion 31 of the double-wall dispensing system 30 (i.e., a double-wall tube configuration) is abutted against a nose guard seat 22 of the nose guard 20, and a sealing cap 150 is positioned above the nose guard 20, and a nose guard rod 151 is inserted through the top 25 of the nose guard 20 and into the through hole 24;

[0080] Fig.28 Schematically depicting the insertion of the bottom portion 102 of the one-way valve mouthpiece 100 into the double-wall dispensing system 30 (i.e., double-walled tube) into the second top hollow collar 75 of the second tube connector 70, the assembled sealing cap 150, the nose guard 20, the first tube connector 60, the mesh tray 40 (not shown), the double-walled dispensing system 30 (i.e., double-walled tube configuration), the first tube connector 60 and the second tube connector 70, the bridge 110 and the bellows 80 according to an embodiment of the present invention;

[0081] Fig.29It is an exploded cross-sectional view of an inner hollow chamber 33a having an outer wall 331 and an inner wall 332 and an outer hollow chamber 33b having an outer wall 333 and an inner wall 334 of a double-wall dispensing system 30 (i.e., a double-wall tube configuration), describing a size tube diameter, wherein the outer hollow chamber 33b has an outer wall 333 diameter of 11 mm and an inner wall 334 diameter of 9 mm, and the inner hollow chamber 33a has an outer wall 331 diameter of 6 mm and an inner wall 332 diameter of 4 mm, has an internal gap 36 of 1.5 mm, and the inner hollow chamber 33a has an inner diameter of 4 mm. Illustrations of alternative size tube diameters are as follows: (a) an outer hollow chamber 33b having an outer wall 333 diameter of 10 mm and an inner wall 334 diameter of 8 mm, and an inner hollow chamber 33a having an outer wall 331 diameter of 6 mm and an inner wall 332 diameter of 4 mm, with an internal gap 36 of 1 mm, and the inner hollow chamber 33a having an inner diameter of 4 mm; (b) an outer hollow chamber 33b having an outer wall 333 diameter of 11 mm and an inner wall 334 diameter of 9 mm, and an outer hollow chamber 33a having an outer wall 331 diameter of 5 mm. and an inner hollow chamber 33a having an inner wall 332 diameter of 3 mm, having an inner gap 36 of 2 mm, and the inner hollow chamber 33a having an inner diameter of 3 mm; and (c) an outer hollow chamber 33b having an outer wall 333 diameter of 13 mm and an inner wall 334 diameter of 11 mm, and an inner hollow chamber 33a having an outer wall 331 diameter of 5 mm and an inner wall 332 diameter of 3 mm, having an inner gap 36 of 3 mm, and the inner hollow chamber 33a having an inner diameter of 3 mm according to various embodiments of the present invention;

[0082] Fig.30 is a perspective view of a double-walled dispensing system 30 (i.e., a double-walled tube configuration), a bottom end portion 32, an internal gap 36, and two hollow chambers 33 (i.e., an inner hollow chamber 33a and an outer hollow chamber 33b) according to an embodiment of the present invention, wherein the outer hollow chamber 33b is divided into three independent chambers 34 by a rib wall 35;

[0083] Fig.31 is a cross-sectional view of a double-walled dispensing system 30 (i.e., a double-walled tube configuration) according to an embodiment of the present invention, Fig. 9 , 10 , 19 and 30;

[0084] Fig.32 3 is a cross-sectional view along line A of a double-walled dispensing system 30 (i.e., a double-walled tube configuration) according to an embodiment of the present invention. Fig. 9 , 10 , 19, 30 and 31;

[0085] Fig.33 : is a cross-sectional view along line A of a pipe connector 60 or 70 according to an embodiment of the present invention, Fig. 9 , 10, 18, 23 and 31;

[0086] Fig.34 is a cross-sectional view of a pipe connector 60 or 70 according to an embodiment of the present invention, Fig. 9 , 10 , 18, 23 and 31;

[0087] Fig.35 2 is a cross-sectional view of the nose protector 20 according to an embodiment of the present invention along line A, showing the top 25 of the through hole 24, as shown in FIG. Fig. 9 , 10 , 24, 25 and 27;

[0088] Fig.36 An alternative cross-sectional view of a nose guard 20 is schematically depicted according to an embodiment of the present invention, showing the through hole 24 and the top 25 and bottom 26 of the nose guard holder 22, as shown in FIG. Fig. 9 , 10 , 24, 25, 27 and 35;

[0089] Fig.37 Schematically depicts an assembly view of a one-way insufflator or breath-actuated nasal device 10 according to an embodiment of the present invention, showing a one-way valve mouthpiece 100, a first airflow directing strip 160, a first tube connector 60, a bellows 80, a bridge 110, a second tube connector 70, a second airflow directing strip 170, a double-walled dispensing system 30, and a nose guard 20;

[0090] Fig.36 Schematically depicts an alternative one-way valve mouthpiece 131 of a one-way insufflator or breath-actuated nasal device 10 nose guard assembled according to an embodiment of the present invention, as shown in FIG. Figure 6 As shown;

[0091] Fig.39 Schematically depicts an unassembled view of a sealing cap 150 (i.e., a top plug), a nose protector 20, a one-way valve double-wall dispensing system 30 (i.e., a double-wall tube configuration), a mesh tray 40, and an alternative connector 180 for connecting the one-way double-wall dispensing system 30 (i.e., a double-wall tube and a corrugated tube 80) according to an embodiment of the present invention;

[0092] Fig.40 Schematically depicts an alternative cross-sectional view of the assembly of a sealing cap 150 (i.e., a top plug), a nose guard 20, a one-way valve double-wall dispensing system 30 (i.e., a double-wall tube configuration), and an alternative connector 180 according to an embodiment of the present invention, as shown in FIG. Fig.39 As shown;

[0093] Fig.41Schematically depicts an assembled front view of a nose guard 20, a double-wall dispensing system 30 (i.e., a double-wall tube configuration), an alternative connector 180, a bellows 80, and the nose guard 20 according to an embodiment of the present invention;

[0094] Fig.42 schematically depicts a top view of a tray packaged with twenty one-way insufflators or breath-actuated nasal fully assembled devices, wherein twenty such devices are positioned in two rows of five pairs of such devices each row, wherein each pair of devices shows two such devices positioned in an interlocked position relative to one another, in accordance with an embodiment of the present invention;

[0095] Fig.43 schematically depicts a side plan view of a tray packaged with twenty one-way insufflators or breath-actuated nasal fully assembled devices with exposed inner longitudinal walls, wherein twenty such devices are positioned in two rows of five pairs of such devices each row, wherein each pair of devices shows two such devices positioned in an interlocked position relative to each other, in accordance with an embodiment of the present invention;

[0096] Fig.44 A screenshot depicting a comparison of the width of a lactose powder spray between a single tube configuration and a double wall dispensing system 30 of the present invention (i.e., a double wall tube configuration) according to an embodiment of the present invention, wherein the inner diameter of the inner tube of the double tube is about 4 mm and the gap between the inner and outer tubes of the double tube is 1.5 mm or 1 mm for the single tube configuration compared to a baseline (i.e., a single tube configuration);

[0097] Fig.45 A screenshot depicting a comparison of the width of a lactose powder spray between a single tube configuration and a double wall dispensing system 30 of the present invention (i.e., a double wall tube configuration) according to an embodiment of the present invention, wherein the inner diameter of the inner tube of the double tube is about 3 mm compared to the baseline (i.e., the single tube configuration), and the gap between the inner and outer tubes of the double tube is 2 mm or 3 mm for the single tube configuration;

[0098] Fig.46 is a screenshot of a single tube configuration with a baseline of 3 mm after lactose powder spraying, showing significant accumulation or buildup of lactose powder on the inner wall after spraying;

[0099] Fig.47 is a screenshot of a single tube configuration with a baseline of 4 mm after lactose powder spraying, showing significant accumulation or buildup of lactose powder on the inner wall after spraying;

[0100] Fig.48 is a screen shot of a double-walled dispensing system 30 (i.e., a double-walled tube configuration) according to an embodiment of the present invention, and Fig.45 Compared to the single tube configuration shown, there is a 1 mm gap after lactose powder spraying, showing that there is almost no lactose powder accumulation or accumulation on the inner wall 332 of the inner hollow chamber 33a after powder spraying;

[0101] Fig.49 is a screen shot of a double-walled dispensing system 30 (i.e., a double-walled tube configuration) according to an embodiment of the present invention, and Fig.45 Compared to the single tube configuration shown, there is a 1.5 mm gap after lactose powder spraying, showing that there is almost no lactose powder accumulation or accumulation on the inner wall 332 of the inner hollow chamber 33a after powder spraying;

[0102] Fig.50 is a screen shot of a double-walled dispensing system 30 (i.e., a double-walled tube configuration) according to an embodiment of the present invention, and Fig.45 Compared to the single tube configuration shown, there is a 2 mm gap after lactose powder spraying, showing that there is almost no lactose powder accumulation or accumulation on the inner wall 332 of the inner hollow chamber 33a after powder spraying; and

[0103] Fig.51 is a screen shot of a double wall dispensing system 30 (i.e., a double wall tube configuration), and Fig.45 Compared to the single tube configuration shown, there is a 3 mm gap after lactose powder spraying, showing that there is almost no lactose powder accumulation or accumulation on the inner wall 332 of the inner hollow chamber 33a after powder spraying. DETAILED DESCRIPTION

[0104] The present disclosure may be more readily understood with reference to the following detailed description and drawings of the desired embodiments.In the following specification and claims, reference will be made to a number of terms which shall be defined to have the following meanings.

[0105] Although for the sake of clarity, specific terms are used in the following description, these terms refer only to the specific structures of the embodiments selected for illustration in the drawings, and are not intended to define or limit the scope of the present disclosure. In the drawings and the following description, it should be understood that the same number marks refer to components with the same functions.

[0106] The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0107] As used herein and in the claims, the term "comprising" means that the specified elements or steps are essential, but other elements or steps may also be added, present, contained or included. Therefore, the term "comprising" as used herein and in the claims is synonymous with "including," "containing," "containing," or "characterized by," and is therefore an inclusive or open claim and does not exclude additional, unrecited elements or steps. The term "comprising" should be interpreted as including the term "consisting of," i.e., only the specified components / steps are allowed to be present.

[0108] As used herein and in the claims herein, the term "consisting essentially of" necessarily includes the recited elements or steps, but also includes unrecited elements or steps that do not materially affect the basic and material characteristics of the claimed subject matter, whether that subject matter be a composition, compound, formulation, process or method.

[0109] The term "consisting of" as used herein and in the claims excludes any elements or steps not explicitly recited and is thus a closed claim.

[0110] Numerical values ​​should be construed to include those values ​​which are the same when rounded to the same number of significant figures and those values ​​which differ from the stated value by less than the experimental error found in determining the value using routine measurement techniques of the type described herein.

[0111] All ranges disclosed herein are inclusive of the recited endpoints and are independently combinable (e.g., a range of "2 mg to 10 mg" includes the endpoints 2 mg and 10 mg and all intermediate values). The ranges and endpoints of any values ​​disclosed herein are not limited to the exact ranges or values; their lack of exactness is sufficient to include values ​​approximating these ranges and / or values.

[0112] The modifier "about" used in conjunction with a quantity includes the stated value and has the meaning dictated by the context. When used in the context of a range, the modifier "about" should also be considered to disclose the range defined by the absolute values ​​of the two endpoints. For example, a range of "from about 2 to about 10" also discloses a range of "from 2 to 10". The term "about" can refer to an indicated number plus or minus no more than 10% in an applicable or appropriate context. For example, "about 10%" can mean a range of 9% to 11%, and "about 1" can mean 0.9-1.1.

[0113] As used herein, a "composition" can be a single drug or a combination drug (fixed dose combination) that combines at least two formulations as discussed below in a single dose. In another embodiment, a "composition" can include a combination of drugs or agents that are each administered or formulated separately or simultaneously. Similarly, treatment can include administering a composition as a fixed dose drug or agent combination to a patient, or it can include administering two or more separate agents or drugs to a patient, for example, at respective dosage strengths or amounts together, substantially together, simultaneously, or in a predetermined order, frequency, and time.

[0114] The actual dosage level of the selective drug substance may vary so as to achieve an effective and safe therapeutic response for a particular patient. The phrase "therapeutically effective amount" or "effective amount" refers to a sufficient amount of the drug substance to treat an injury, disease or disorder at a reasonable benefit / risk ratio applicable to any medical treatment. However, it should be understood that the total daily dosage of the drug substance disclosed herein will be determined by the attending physician or other medical provider within the scope of reasonable medical judgment. If necessary, the daily effective dose can be divided into multiple doses for administration; therefore, a single dose of the drug substance may contain an amount or a submultiple thereof constituting the daily dose. The specific therapeutically effective dosage level for any particular patient will depend on a variety of factors, including the injury, disease or disorder being treated and the severity of the injury, disease or disorder; the patient's medical history, age, weight, general health, the patient's sex and diet, the time of administration, the route of administration, the duration of treatment, other medications the patient is taking, etc. Usually a single administration is sufficient to produce a therapeutic effect, but in order to ensure a sustained long-term response, it is expected that multiple administrations will be used over a considerable period of time.

[0115] Thus, the present invention provides a one-way insufflator or breath-actuated nasal device 10 for delivering a drug substance in powder or liquid form to the nasal airway of a subject, the device comprising: a closure unit for closing the oropharyngeal membrane of the subject; and a double-walled drug system 30 providing a dual airflow for delivering a vertical, slightly tight and narrow or restricted concentrated plume airflow entraining the drug substance to one of the nostrils of the subject under a driving pressure driven by breath to drive the restricted and concentrated plume deep into the nasal cavity for targeting the olfactory area including the olfactory nerve and trigeminal mucosa, directly diffusing into the brain to effectively treat nasal and / or CNS injuries, diseases or disorders, particularly TBI, especially concussion, within minutes of nasal administration, wherein the one-way insufflator or breath-actuated nasal device 10 of the present invention comprises a nose guard 20, the nose guard comprising an outlet through which the breath-actuated airflow is delivered to one nostril to provide a fluid tight seal between the nose guard 20 and one nostril.

[0116] More specifically, the one-way insufflator or breath-actuated nasal device 10 of the present invention includes a nose guard 20, a one-way valve mouthpiece 100, a bellows 80, and a device for propelling a dual airflow, such as a double-walled dispensing system 30 (i.e., a double-walled tube configuration), for propelling a first airflow carrying a powdered drug substance and a second airflow surrounding the first airflow to propel a highly concentrated powdered drug substance deep into the nasal cavity, e.g. Figure 1 and Figure 2 shown.

[0117] More specifically, the one-way insufflator or breath-actuated nasal device 10 of the present invention includes a nose guard 20, a double-walled dispensing system 30 (i.e., a double-walled tube configuration), a mesh disk 40, a first tube connector 60, a bellows 80, a second tube connector 70, and a one-way valve mouthpiece 100, as shown in FIG. Figure 1-2 and Figure 7-10 shown.

[0118] The nose guard 20 is conical and is provided with a through hole 24 and an inner collar 26. When the double-walled dispensing system 30 (i.e., a double-walled tube configuration) is fully inserted into the hole 24 of the nose guard 20, the top portion 31 of the double-walled dispensing system 30 rests against the inner collar, as shown in FIG. Figure 9-10 and Figure 23-24 As shown. The nose guard 20 can be made of any material suitable for the intended use of the nose guard 20. Figure 1 , 9 -10, 13-14 and Figure 26-28 As shown, a sealing cap 150 (ie, a top cap) can be inserted into the top 25 of the hole 24 to seal the nose protector 20.

[0119] The double-walled dispensing system 30 is a novel and unique system for delivering one or more drug substances into the nasal cavity and is an important aspect of the present invention. The double-walled dispensing system 30 (i.e., a double-walled tube configuration) is preferably extruded and includes a top portion 31 and a bottom portion 32 and two hollow chambers 33, an inner hollow chamber 33a and an outer hollow chamber 33b. The hollow inner chamber 33a contains a drug substance 200 (not shown). The hollow outer chamber 33b surrounding the hollow inner chamber 33a is divided into two, three, four or more independent chambers 34 by a rib wall 35. Preferably, the hollow outer chamber 33b is divided into three independent chambers 34. See, for example, Figure 30-32 .

[0120] The bridge 110 connects the one-way valve mouthpiece side 131 including the one-way valve mouthpiece 100 and the second tube connector 70 to the nose guard side 130 including the nose guard 20, the double-walled dispensing system 30 (i.e., the double-walled tube configuration), the mesh disk 40, the first tube connector 60, and the bellows 80 to maintain the breath-actuated insufflator or breath-actuated nasal device 10 of the present invention in a constant "U-shaped" configuration 140. The bridge 120 includes a bridge 121 sandwiched between two hollow rings 122 and 123, respectively, for sliding on a first hollow hoop 81 and a second hollow hoop 82 having a corrugated curled middle portion 80, respectively, as shown in FIG. Figure 1-4 and 7-12, 16-17-19, 21-22, 24-26 and 28.

[0121] Alternatively, the bridge 120 may be designed with perforations or score lines 124 or any other configuration to allow the bridge 120 to be broken in two when it is necessary to straighten the sides 130 and 131 of the device for use by a second person who is assisting, for example, a concussed patient who is unable to exert the necessary blowing force on his own to provide sufficient airflow for effectively pushing the drug substance out of the one-way insufflator or breath-actuated nasal device 10 of the present invention, thereby effectively treating the concussion with the drug substance. See Fig.13 and Fig.14 .

[0122] The double-walled dispensing system 30 (i.e., a double-walled tube configuration) is a novel and unique system for delivering one or more drug substances into the nasal cavity and is an important aspect of the present invention. The double-walled dispensing system 30 (i.e., a double-walled tube configuration) includes a top portion 31 and a bottom portion 32 and two hollow chambers 33, an inner hollow chamber 33a and an outer hollow chamber 33b. The hollow inner chamber 33a contains the drug substance 200. The hollow outer chamber 33b surrounding the hollow inner chamber 33a is divided into two, three, four or more independent chambers 34 by a rib wall 35. Preferably, the hollow outer chamber 33b is divided into three independent chambers 34. See, for example, Figure 29-32 .

[0123] The first and second pipe connectors 60 and 70 are provided with a first top hollow collar 65 and a second top hollow collar 75, respectively, for being inserted into the first hollow collar 81 and the second hollow collar 82, respectively, of the corrugated tube 80. However, before the first top hollow collar 65 and the second top hollow collar 75 are inserted into the corresponding first hollow collar 81 and the second hollow collar 82 of the corrugated tube 80, the first hollow ring 122 and the second hollow ring 123 of the bridge 110 are respectively slid over the first hollow collar 81 and the second hollow collar 82 to create a U-shaped configuration 140. See FIG. Figure 16-17 .

[0124] As previously described, in order to load the powdered form, particularly the spray-dried form, of the drug substance 200 into the novel one-way insufflator or breath-actuated nasal device 10 of the present invention, a sterile funnel (not shown) is used to specifically load the powdered drug substance 200 into the inner hollow chamber 33a of the double-walled dispensing system 30 (double-walled tube configuration). The mesh disk 40 located at the bottom end portion 32 of the inner hollow chamber 33a, the top 66 of the first tube connector 60, is the first part that the loaded powdered drug substance 200 encounters and rests on once fully loaded. Since the pore size of the mesh disk 40 is smaller than the particle size of the powdered drug substance, the powdered drug substance cannot fall through the mesh disk 40. However, the holes throughout the mesh disk 40 allow the blown airflow to penetrate upward and through the mesh disk 40 to carry and propel the powdered drug substance 200 from the inner hollow chamber 33a out of the nose guard 20 and into the nasal cavity.

[0125] For example Figure 1 As shown, the mesh disk 40 can be made of a variety of different material options. For example, the mesh disk 40 can be made of PET material. Different materials and mesh sizes can be used for different applications. For example, a liquid can be used and a PTFE hydrophobic membrane can be used to contain the dose (depending on its chemical nature of course). An example of a material contemplated for use in the mesh disk 40 of the present invention is SEFAR MEDIFAB 07-135 / 40 158cm, product number: 3A07-0135-158-00. An example of a mesh disk 40 of a specific size is made of SEFAR MEDIFAB 07-135 / 40 158cm, product number: 3A07-0135-158-00 material, which is intended for use in accordance with the present invention, and is a mesh disk 40 having a diameter of about 0.411, a thickness of about 0.004 inches to about 0.012 inches or more, and a surface roughness of about 125μin.

[0126] Preferably, the powdered, spray-dried drug substance 200 has a particle size distribution primarily in the range of about 1 μm to about 10 μm. In one embodiment, the powdered, spray-dried drug substance contains a drug, particularly a drug for treating nasal conditions. Despite the preferred particle size, the present invention contemplates a particle size distribution of the powdered, spray-dried drug substance, including larger particles or smaller fractions of larger particles, generally in the range of about 10 μm to about 30 μm, and preferably in the range of about 20 μm to about 30 μm.

[0127] By nesting the inner hollow chamber 33a containing the powdered, spray-dried drug substance 200 (not shown) within the unobstructed larger outer hollow chamber 33b, such as Figure 1-2 , 7- and Fig.30 As shown, the double-walled dispensing system 30 (i.e., a double-walled tube configuration) will allow the unmedicated airflow to engage the side walls of the nasal cavity while allowing the airflow carrying the powdered, spray-dried drug substance 200 to flow in the center of the unmedicated airflow to reach a targeted destination deep in the nasal cavity with minimal loss of the drug substance 200.

[0128] Figure 48-51 This benefit is illustrated in that after spraying powder through the inner hollow chamber 33a, almost no dry powder is accumulated on the inner wall 332 of the inner hollow chamber 33a of the double-walled dispensing system 30 (i.e., the double-walled tube configuration) (compared to Fig.46 A large amount of dry powder is accumulated on the inner wall of a single tube structure with a 3mm or 4mm baseline, and a large amount of dry powder is accumulated on the inner wall of a single tube structure with a mm baseline, Fig.47 ), and both tubes are almost opaque after powder spraying through a single tube structure. Figure 48-51As shown, the inner wall 332 of the inner hollow chamber 33a of the double-wall dispensing system 30 (i.e., double-wall tube configuration) has 1 mm gap, 1.5 mm gap, 2 mm gap and 3 mm gap respectively. After powder is sprayed through the inner hollow chamber 33a, there is slight powder spreading and very little powder accumulation, which indicates that more dry powder reaches the targeted destination.

[0129] like Figure 1-2 , 9-10 and 28, the one-way valve mouthpiece 100 includes a conduit 101 passing through a top portion 102 and a bottom portion 103, respectively. A one-way valve (not shown) is provided in the bottom portion 103 for guiding the blown air into the bellows 80 and preventing reverse airflow. The one-way valve mouthpiece 100 is designed to be inserted into the second collar 75 of the second tube connector 70, and when the one-way valve mouthpiece 100 is fully press-fitted into the second collar 75 of the second tube connector 70, the bottom portion 103 abuts against the collar. An example of a one-way valve mouthpiece 100 contemplated by the present invention is the Crosstex Safe-Flo TM Adapter, M1020ADAP Check Valve Mouthpiece, made by Crosstex International. Safe-Flo TM The adapter is designed with a unique built-in check valve to provide a physical barrier to prevent backflow.

[0130] The degree of curvature of the bellows 80 allows the nose guard sides 130 and 131 to form a U-shaped configuration 140, such as Figure 1-2 , 7-8, 13, 11, 13 and 37. The corrugated middle portion 85 of the bellows 80 has first and second top ends 811 and 821 for receiving the first bottom hollow neck 66 of the first tube connector 60 and the second bottom hollow neck 76 of the second tube connector 70, respectively, to further assemble the one-way insufflator or breath-actuated nasal device 10 of the present invention, as shown in FIG. Fig.15 and 18 shown.

[0131] Figure 1 It is a front assembled elevation view 135 of the one-way insufflator or breath-actuated nasal device 10.

[0132] Figure 2 It is an elevated rear view 136 of the back assembly of the one-way insufflator or breath-actuated nasal device 10.

[0133] Figure 3 is a top view 850 of the bellows 80 showing the corrugated mid-section 85 and the bridge 110 .

[0134] Figure 4 is a bottom view 860 of the bellows 80 showing the corrugated middle portion 85 .

[0135] Figure 5It is an assembled bottom view of the nose guard side 130 of the one-way insufflator or breath-actuated nasal device 10.

[0136] Figure 6 It is an assembled bottom view of the one-way valve mouthpiece side 131 of the one-way insufflator or breath-actuated nasal device 10.

[0137] Figure 7 It is a bottom view of the right mouthpiece assembly of the one-way insufflator or breath-actuated nasal device 10.

[0138] Figure 8 It is a bottom view of the left mouthpiece assembly of the one-way insufflator or breath-actuated nasal device 10.

[0139] Fig. 9 It is a front unassembled view of the right mouthpiece of the one-way insufflator or breath-actuated nasal device 10.

[0140] Fig.10 It is a front unassembled view of the left mouthpiece of the one-way insufflator or breath-actuated nasal device 10.

[0141] Fig.11 Describes how Figure 1-2 The one-way insufflator or breath-actuated nasal device 10 shown in Figures 4-8 is inserted into the nasal cavity of a subject for operation.

[0142] Fig.12 Describes Fig.13 and Fig.14 The nasal guard 20 of the one-way insufflator or breath-actuated nasal device 10 is shown inserted into the nasal cavity of a first subject to be treated with a drug substance 200 (not shown) and as shown in FIG. Fig.13 and Fig.14 The one-way valve mouthpiece 100 is shown inserted between the lips of a second subject for operation of an alternative embodiment by the second subject, such as Fig.13 and Fig.14 shown.

[0143] Fig.13 It is a front elevation view of the right mouthpiece assembly of a one-way insufflator or breath-actuated nasal device 10, wherein the bridge 110 is designed with a perforation or score line 142 for breaking the bridge 110 into two parts.

[0144] Fig.14 is a front elevation view of the right mouthpiece assembly of a one-way insufflator or breath-actuated nasal device 10, wherein the bridge 110 is broken into two parts at a perforation or score line 142 for breaking the bridge 110 into two separate parts, such as Fig.13 shown.

[0145] Fig.15 The assembly of the bridge 110 to the bellows 80 is described.

[0146] Fig.16 A perspective view of the bridge 110 and the bellows 80 in an assembled configuration is depicted.

[0147] Fig.17 A front view of the bridge 110 and bellows 80 is depicted in an assembled configuration.

[0148] Fig.18 The first pipe connector 60 and the second pipe connector 70 are assembled to the corrugated pipe 80 assembled with the bridge 110, as shown in FIG. Fig.16 and Fig.17 shown.

[0149] Fig.19 A perspective view depicting the assembly of the first pipe connector 60 and the second pipe connector 70 to the corrugated tube 80 assembled with the bridge 110 is shown. Fig.16 and Fig.17 shown.

[0150] Fig. 20 Cross-sectional views of tube connectors 60 and 70 are depicted.

[0151] Fig.21 The mesh tray 40 is inserted into the first pipe connector 60, wherein the first pipe connector 60 and the second pipe connector 70 are assembled to the corrugated pipe 80 assembled with the bridge 110, as shown in FIG. Fig.16 and Fig.17 shown.

[0152] Fig. 22 The double-walled dispensing system 30 (i.e., double-walled tube configuration) is inserted into the first tube connector 60, wherein the mesh disk 40 is inserted into the first tube connector 60, and the first tube connector 60 and the second tube connector 70 are assembled to the corrugated tube 80 assembled with the bridge 110, as shown in FIG. Fig.16 , 17 , 19 and 21.

[0153] Fig.23 An exploded sectional view of the assembled first tube connector 60 is described, wherein the mesh disk 40 and the double-wall dispensing system 30 (i.e., a double-wall tube configuration) are assembled within the first tube connector 60, and the mesh disk 40 is located on the first seat 61 of the first tube connector 60, and the first top hollow collar 65 of the first tube connector 60 is press-fit into the first hollow hoop 81 of the corrugated tube 80.

[0154] Fig.24 The top portion 31 of the double-walled dispensing system 30 (i.e., the double-walled tube configuration) is inserted into the bottom 26 of the through hole 24 of the nose guard 20, wherein the mesh disk 40 is assembled into the first tube connector 60, and the first tube connector 60 and the second tube connector 70 are assembled to the corrugated tube 80 assembled with the bridge 110, as shown in FIG. Fig.16 , 17 , 19, 21 and 22.

[0155] Fig.25 A front view of the assembled nose guard 20, first tube connector 60, mesh tray 40 (not shown), double wall dispensing system 30 (ie, double wall tube configuration), first tube connector 60 and second tube connector 70, bridge 110, and bellows 80 is depicted.

[0156] Fig.26 The sealing cover 150 and the sealing cover plug 151 are described as being placed into the top 25 (not shown) of the through hole 24 (not shown), above the nose protector 20, the first tube connector 60, the mesh disk 40 (not shown), the double-wall dispensing system 30 (i.e., the double-wall tube configuration), the first tube connector 60 and the second tube connector 70, the bridge 110 and the bellows 80 of the assembled nose protector 20.

[0157] Fig. 27 An exploded sectional view of the nose protector 20 is described, wherein a double-wall dispensing system 30 (i.e., a double-wall tube) is inserted through the through hole 24 of the nose protector 20, the top portion 31 of the double-wall dispensing system 30 (i.e., the double-wall tube configuration) is close to the nose protector seat 22 of the nose protector 20, and the sealing cover 150 is located above the nose protector 20, and the nose protector rod 151 is inserted through the top 25 of the nose protector 20 and enters the through hole 24.

[0158] Fig.28 The invention describes inserting the bottom portion 102 of the one-way valve mouthpiece 100 into the double-wall dispensing system 30 (i.e., double-wall tube) into the second top hollow collar 75 of the second tube connector 70, and assembling the sealing cap 150, the nose protector 20, the first tube connector 60, the mesh disk 40 (not shown), the double-wall dispensing system 30 (i.e., double-wall tube configuration), the first tube connector 60 and the second tube connector 70, the bridge 110 and the bellows 80.

[0159] Fig.29It is an exploded cross-sectional view of an inner hollow chamber 33a having an outer wall 331 and an inner wall 332 and an outer hollow chamber 33b having an outer wall 333 and an inner wall 334 of a double-wall dispensing system 30 (i.e., a double-wall tube configuration), describing a size tube diameter, wherein the outer hollow chamber 33b has an outer wall 333 diameter of 11 mm and an inner wall 334 diameter of 9 mm, and the inner hollow chamber 33a has an outer wall 331 diameter of 6 mm and an inner wall 332 diameter of 4 mm, has an internal gap 36 of 1.5 mm, and the inner hollow chamber 33a has an inner diameter of 4 mm. The illustration of alternative size tube diameters is as follows: (a) an outer hollow chamber 33b having an outer wall 333 diameter of 10 mm and an inner wall 334 diameter of 8 mm, and an inner hollow chamber 33a having an outer wall 331 diameter of 6 mm and an inner wall 332 diameter of 4 mm, with an internal gap 36 of 1 mm, and the inner hollow chamber 33a having an inner diameter of 4 mm; (b) an outer hollow chamber 33b having an outer wall 333 diameter of 11 mm and an inner wall 334 diameter of 9 mm, and an outer hollow chamber 33a having an outer wall 331 diameter of 6 mm and an inner wall 332 diameter of 4 mm, with an internal gap 36 of 1 mm, and the inner hollow chamber 33a having an inner diameter of 4 mm. An inner hollow chamber 33a having a wall 331 diameter of 3 mm and an inner wall 332 diameter of 3 mm, having an internal gap 36 of 2 mm, and the inner hollow chamber 33a has an inner diameter of 3 mm; and (c) an outer hollow chamber 33b having an outer wall 333 diameter of 13 mm and an inner wall 334 diameter of 11 mm, and an inner hollow chamber 33a having an outer wall 331 diameter of 5 mm and an inner wall 332 diameter of 3 mm, having an internal gap 36 of 3 mm, and the inner hollow chamber 33a has an inner diameter of 3 mm.

[0160] Fig.30 It is a view of a double-wall dispensing system 30 (i.e., a double-wall tube configuration), a bottom end portion 32, an internal gap 36, and two hollow chambers 33 (i.e., an inner hollow chamber 33a and an outer hollow chamber 33b), wherein the outer hollow chamber 33b is divided into three independent chambers 34 by a rib wall 35.

[0161] Fig.31 is a cross-sectional view of a double-walled dispensing system 30 (i.e., a double-walled tube configuration), as shown Fig. 9 , 10 , 19 and 30.

[0162] Fig.32 is a cross-sectional view of the double-walled dispensing system 30 (i.e., double-walled tube configuration) along line A, as shown Fig. 9 , 10 , 19, 30 and 31.

[0163] Fig.33 is a cross-sectional view of the pipe connector 60 or 70 along line A, as shown Fig. 9 , 10 , 18, 23 and 31.

[0164] Fig.34is a cross-sectional view of the pipe connector 60 or 70, as shown Fig. 9 , 10 , 18, 23 and 31.

[0165] Fig.35 2 is a cross-sectional view of the nose guard 20 along line A, showing the top 25 of the through hole 24, as shown in FIG. Fig. 9 , 10 , 24, 25 and 27.

[0166] Fig.36 An alternative cross-sectional view of the nose guard 20 is depicted, showing the through hole 24 and the top 25 and bottom 26 of the nose guard mount 22, as shown in FIG. Fig. 9 , 10 , 24, 25, 27 and 35.

[0167] Fig.37 An assembly diagram of a one-way insufflator or breath-actuated nasal device 10 is depicted showing a one-way valve mouthpiece 100, a first airflow directing strip 160, a first tube connector 60, a bellows 80, a bridge 110, a second tube connector 70, a second airflow directing strip 170, a double-walled dispensing system 30, and a nose guard 20.

[0168] Fig.36 An alternative one-way valve mouthpiece 131 of an assembled one-way insufflator or breath-actuated nasal device 10 nose guard is described, such as Figure 6 shown.

[0169] Fig.39 An unassembled view of a sealing cap 150 (i.e., a top plug), a nose protector 20, a one-way valve double-wall dispensing system 30 (i.e., a double-wall tube configuration), a mesh disk 40, and an alternative connector 180 for connecting the one-way double-wall dispensing system 30 (i.e., a double-wall tube and a bellows 80) is described.

[0170] Fig.40 Describes an alternative cross-sectional view of the assembly of the sealing cap 150 (ie, the top plug), the nose guard 20, the one-way valve double-walled dispensing system 30 (ie, the double-walled tube configuration) and the alternative connector 180, as shown in FIG. Fig.39 As shown;

[0171] Fig.41 An assembled front view of the nose guard 20, double wall dispensing system 30 (ie, double wall tube configuration), alternative connector 180, bellows 80, and nose guard 20 are depicted.

[0172] Fig.42 Depicted is a top view of a tray packaged with twenty one-way insufflators or breath-actuated nasal fully assembled devices, wherein twenty such devices 10 are positioned in two rows of five pairs of such devices each row, wherein each pair of devices shows two such devices positioned in an interlocked position relative to each other.

[0173] Fig.43 Depicted is a side plan view of a tray packed with twenty one-way insufflators or breath-actuated nasal fully assembled devices with exposed inner longitudinal walls, wherein twenty such devices 10 are positioned in two rows of five pairs of such devices each row, wherein each pair of devices shows two such devices positioned in an interlocked position relative to each other.

[0174] Fig.44 Screen shots comparing the width of the lactose powder spray between a single tube configuration and a double-walled dispensing system 30 of the present invention (i.e., a double-walled tube configuration) are depicted, wherein the inner diameter of the inner tube of the double tube is approximately 4 mm and the gap between the inner and outer tubes of the double tube is 1.5 mm or 1 mm for the single tube configuration.

[0175] Fig.45 Screen shots comparing the width of the lactose powder spray between a single tube configuration and the double-walled dispensing system 30 of the present invention (i.e., a double-walled tube configuration) are depicted, wherein the inner diameter of the inner tube of the double tube is approximately 3 mm and the gap between the inner and outer tubes of the double tube is 2 mm or 3 mm.

[0176] like Fig.44 and 45 As shown, when comparing the powder spray width at the same height, the powder spray width of the double-walled dispensing system 30 (i.e., the double-walled tube configuration) having an inner hollow chamber 33a with an inner diameter of 4 mm and 3 mm, respectively, remains more concentrated than the baseline single-tube configuration. In other words, the baseline single-tube configuration spreads wider and faster than the double-walled dispensing system 30 (i.e., the double-walled tube configuration). These results demonstrate that the double-walled dispensing system 30 (i.e., the double-walled tube configuration) can allow the drug substance 200 (not shown) to potentially reach deeper into the nasal cavity, rather than being accumulated on the wall of the nasal cavity. In addition, compared with Figure 44-45 It is believed that the 3 mm ID device 30 can disperse the spray powder at a lower height and reach a lower maximum height compared to the 4 mm ID device 30, so the double-walled dispensing system 30 (i.e., double-walled tube configuration) of the present invention is preferably configured with an inner hollow chamber 33a having an inner diameter of about 4 mm ID or greater.

[0177] Fig.46 Screen shot depicting a single tube configuration with a baseline of 3 mm after lactose powder spray, showing the Fig.45 Compared to the single tube configuration shown, there is significant buildup or accumulation of lactose powder on the inner wall after powder spraying.

[0178] Fig.47 Screen shot depicting a single tube configuration with a baseline of 4 mm after lactose powder spray, showing the Fig.45 Compared to the single tube configuration shown, there is significant buildup or accumulation of lactose powder on the inner wall after powder spraying.

[0179] Fig.48 Screen shot depicting a double wall dispensing system 30 (i.e., a double wall tube configuration) and Fig.45 Compared to the single tube configuration shown, there is a 1 mm gap after lactose powder spraying, showing that there is almost no lactose powder accumulation or accumulation on the inner wall 332 of the inner hollow chamber 33a after powder spraying.

[0180] Fig.49 Screen shot depicting a double wall dispensing system 30 (i.e., a double wall tube configuration) and Fig.45 Compared to the single tube configuration shown, there is a 1.5 mm gap after lactose powder spraying, showing that there is almost no lactose powder accumulation or accumulation on the inner wall 332 of the inner hollow chamber 33a after powder spraying.

[0181] Fig.50 Screen shot depicting a double wall dispensing system 30 (i.e., a double wall tube configuration) and Fig.45 Compared to the single tube configuration shown, there is a 2 mm gap after lactose powder spraying, showing that there is almost no lactose powder accumulation or accumulation on the inner wall 332 of the inner hollow chamber 33a after powder spraying.

[0182] Fig.51 Screen shot depicting a double wall dispensing system 30 (i.e., a double wall tube configuration) and Fig.45 Compared to the single tube configuration shown, there is a 3 mm gap after lactose powder spraying, showing that there is almost no lactose powder accumulation or accumulation on the inner wall 332 of the inner hollow chamber 33a after powder spraying.

[0183] It should be understood that the various component connections described herein are all airtight connections to ensure that the blown air flow does not escape and travels in a harmonious single direction.

[0184] It should be further understood that the top 25 of the through hole 24 of the nose protector 20 and the top 102 of the hole 101 of the one-way valve mouthpiece 100 can be sealed with any effective sealing device, respectively, to seal the nose protector 20 and the one-way valve mouthpiece 100 from the influence of external air or other pollutants and moisture, such as, when the size is suitable, the top plug 150 designed to seal the top 25 of the through hole 24 of the nose protector 20 and the top portion 102 of the conduit 101. The present invention also contemplates other suitable sealing devices that can be used as an alternative to the top plug 150, such as sealing using induction foil or shrink wrap, as long as the purpose of the present invention is achieved and does not violate.

[0185] In a preferred embodiment, when the substance is in solid form (eg, powder), the present invention contemplates the use of a filter or desiccant if high humidity poses a problem for solid administration.

[0186] The drug substance 200 may be a single compound or a mixture of compounds, and the compounds may be in any suitable form, such as powder form, solution, suspension, gel, etc.

[0187] The drug substance 200 may be any suitable substance for delivery to humans or, in some cases, animals. The drug substance 200 may be used for delivery to act deep within the nasal cavity, to diffuse directly into the brain, and / or to act locally or systemically for treatments that may require nasal administration of the drug substance 200. Thus, the drug substance 200 may be used for systemic delivery to act in areas away from the nasal airways.

[0188] Preferably, drug substance 200 is for delivery to the olfactory region and trigeminal mucosa for rapid diffusion into the brain for treatment of nasal and / or CNS injuries, diseases or disorders, particularly brain injuries such as TBI (mild, moderate and / or severe), including concussion.

[0189] The drug substance 200 may have a beneficial medical effect, which may include a diagnostic effect, a therapeutic effect, a healing effect, a systemic effect, and / or a preventive effect, etc. Preferably, the drug substance 200 has a therapeutic or healing effect.

[0190] Preferably, the drug substance 200 is a pharmaceutical. The drug may be mixed with any suitable carrier, diluent, excipient or adjuvant to form a pharmaceutical composition.

[0191] There are many nasal conditions that require treatment. One such condition is known as traumatic brain injury, i.e. mild, moderate and severe TBI, including concussion. Another such condition is nasal inflammation, specifically rhinitis, which can be allergic or non-allergic and is often associated with infection and interferes with normal nasal function. For example, allergic and non-allergic inflammation of the nasal airways typically affects 10% to 20% of the population, with the most common symptoms including nasal congestion, tearing, watery mucus, sneezing and itching. It is important to understand that nasal congestion impedes nasal breathing and promotes mouth breathing, leading to snoring and sleep disturbances. Worryingly, the incidence of such allergic and non-allergic inflammatory diseases is increasing. Other nasal diseases include nasal polyps arising from the paranasal sinuses, adenoid hypertrophy, secretory otitis media, sinus disease and decreased sense of smell.

[0192] In the treatment of certain nasal conditions, local administration is preferred, particularly in cases where the distribution of high concentrations of the drug substance in the nasal mucosa, especially in the olfactory region, and in the mucosa innervated by the trigeminal nerve for rapid diffusion to the brain is the primary pathological pathway, such as in the treatment or alleviation of CNS damage, disease or disorder. In fact, local administration is advantageous in minimizing the side effects that may occur with systemic administration. Commonly locally delivered pharmaceutical compositions include decongestants, antihistamines, cromoglycates, steroids (including C-20 steroids) and antibiotics.

[0193] Nowadays, more and more adults and children rely on medications to relieve symptoms associated with nasal diseases. Among the known anti-inflammatory drugs, topical steroids have been shown to be effective for nasal congestion. Local decongestants have also been suggested to relieve nasal congestion. Although there is some controversy, the use of topical decongestants, steroids, and antimicrobial agents has also been proposed for the treatment of hypertrophic adenoids and chronic secretory otitis media. In addition, local application of drugs has been used to treat or at least relieve the symptoms of inflammation in the anterior nasopharynx, paranasal sinuses, and Eustachian tubes.

[0194] In addition, an increasing number of drugs are now delivered systemically via the nasal route, which provides a good administration route for local, systemic and CNS delivery of drugs, such as steroids (including C-20 steroids), hormones (e.g., oxytocin), and anti-migraine compositions, because the high blood flow and large surface area of ​​the nasal mucosa advantageously provide rapid systemic absorption.

[0195] Preferably, the pharmaceutical composition is used to treat any one or more of the above-mentioned conditions. For example, the pharmaceutical composition can be used to treat any allergic and non-allergic inflammatory diseases.

[0196] Typical pharmaceutical compositions for nasal administration according to the present invention include, but are not limited to, steroids (e.g., C-20 steroids), antihistamines, cromoglycates, anti-allergic drugs, anti-inflammatory drugs, anti-leukotrienes, prolactin (e.g., oxytocin), and anti-migraine drugs.

[0197] By discovering novel unidirectional insufflators or breath-actuated nasal devices and methods, more optimized, selectable nasal delivery of a broad spectrum of drug substances and nasal insufflators technology are achieved, thereby improving the effectiveness of topical drugs in preferably treating CNS injuries, diseases or disorders, especially TBI, and most preferably concussion.

[0198] It should be understood that any references, documents, patents, patent publications, etc., including articles and websites, cited or disclosed herein are incorporated by reference in their entirety, as if fully set forth herein.

[0199] The present disclosure has been described with reference to example embodiments. Other persons skilled in the art may modify and alter the above detailed description upon reading and understanding it. The present disclosure should be interpreted as including all such modifications and alterations within the scope of the appended claims or their equivalents.

[0200] Figure legend

[0201] One-way insufflator or breath-actuated nasal device 10

[0202] Nose guard 20

[0203] Nose guard holder 22

[0204] Through hole 24

[0205] Top 25

[0206] Bottom 26

[0207] Double wall dispensing system 30, i.e. double wall tube configuration

[0208] Top section 31

[0209] Bottom part 32

[0210] Two hollow chambers 33

[0211] Inner hollow chamber 33a

[0212] Outer wall 331

[0213] Inner wall 332

[0214] Outer hollow chamber 33b

[0215] Outer wall 333

[0216] Inner wall 334

[0217] Independent chamber 34

[0218] Rib 35

[0219] Internal clearance 36

[0220] Netdisk40

[0221] One-way valve 50 (not shown)

[0222] First pipe connector 60

[0223] The first 61

[0224] First top hollow collar 65

[0225] First bottom hollow neck 66

[0226] Second pipe connector 70

[0227] The second building 71

[0228] Second top hollow collar 75

[0229] Second bottom hollow neck 76

[0230] Bellows 80

[0231] The first hollow hoop 81

[0232] First Top 811

[0233] Second hollow ferrule 82

[0234] Second top 821

[0235] Corrugated middle part 85

[0236] Top view 850

[0237] Bottom View 860

[0238] One-way valve mouthpiece 100

[0239] Catheter 101

[0240] Top section 102

[0241] Bottom part 103

[0242] Bridge 110

[0243] Bridge 121

[0244] The first hollow ring 122

[0245] The second hollow ring 123

[0246] Perforated or scored lines 124

[0247] Nose guard side 130

[0248] One-way valve mouth side 131

[0249] Front view of a one-way insufflator or breath-actuated nasal device 135

[0250] Rear view of a one-way insufflator or breath-actuated nasal device 136

[0251] Drug substance 200 (not shown)

[0252] U-shaped configuration 140

[0253] Sealing cover 150, i.e. top cover

[0254] Sealing plug 151

[0255] First airflow direction indicating tape 160

[0256] Second airflow direction indication tape 170

[0257] Replacement connector 180

Claims

1. A novel unidirectional breath-actuated nasal device for providing dual airflow to push a drug substance into the nasal cavity when the drug substance is loaded into the device, for targeted delivery to the olfactory area with high drug substance concentration for rapid diffusion into the brain, for treatment of local or systemic nasal and / or central nervous system ("CNS") injuries, diseases or disorders, comprising: (a) a mouthpiece, for a subject to blow air into the device; (b) a nasal protector for pushing the drug substance into the nasal cavity of the subject; (c) a flexible, curled middle portion sandwiched between the mouthpiece and the nose guard; as well as (d) A double-walled dispensing system, comprising a first hollow device loaded with the drug substance to generate a first airflow, and a second hollow device surrounding the first hollow device, so that when a subject blows air through the mouthpiece and into the device, the first hollow device and the second hollow device provide dual airflows in parallel, the dual airflows comprising (i) a first airflow carrying the drug substance discharged from the first hollow device, and (ii) a second airflow discharged from the second hollow device to generate an airflow pressure around the first discharged airflow, so that the first discharged airflow is formed and initially travels as a vertical, slightly tight and narrow or restricted concentrated plume, driving the concentrated drug substance to the targeted olfactory area for direct diffusion into the brain for effective treatment.

2. The device of claim 1, wherein the drug substance is deposited into the upper nasal cavity.

3. The device of claim 1, wherein the drug substance is distributed into mucosa innervated by the trigeminal nerve.

4. The device of claim 1, wherein the CNS injury is a brain injury.

5. The device of claim 1, wherein the brain injury is a traumatic brain injury ("TBI").

6. The device of claim 1, wherein the TBI is mild TBI, moderate TBI, or severe TBI.

7. The device of claim 4, wherein the brain injury is a concussion.

8. The device according to any one of claims 1, wherein the drug substance is ent-19-norprogesterone.

9. The device according to any one of claims 2, wherein the drug substance is ent-19-norprogesterone.

10. The device according to any one of claims 3, wherein the drug substance is ent-19-norprogesterone.

11. The device according to any one of claims 4, wherein the drug substance is ent-19-norprogesterone.

12. The device according to any one of claims 5, wherein the drug substance is ent-19-norprogesterone.

13. The device according to any one of claims 6, wherein the drug substance is ent-19-norprogesterone.

14. The device according to any one of claims 7, wherein the drug substance is ent-19-norprogesterone.

15. A method for treating a local or systemic nasal injury, disorder or disease or a CNS injury, disorder or disease in a subject in need of such treatment, the method comprising: (a) using a device according to claim 1 to deliver a therapeutically effective concentrated amount of a drug substance to the olfactory region of a subject for rapid diffusion into the brain to treat the local or systemic nasal injury, disorder or disease and / or CNS injury, disease or disorder.

16. The method of claim 9, wherein the concentrated drug substance is deposited into the upper nasal cavity.

17. The method of claim 9, wherein the concentrated drug substance is distributed into the mucosa innervated by the trigeminal nerve.

18. The method of claim 9, wherein the CNS injury is a brain injury.

19. The method of claim 9, wherein the brain injury is traumatic brain injury ("TBI").

20. The method of claim 9, wherein the TBI is mild TBI, moderate TBI, or severe TBI.

21. The method of claim 12, wherein the brain injury is a concussion.

22. The method of claim 9, wherein the drug substance is ent-19-norprogesterone.

23. The method of claim 10, wherein the drug substance is ent-19-norprogesterone.

24. The method of claim 11, wherein the drug substance is ent-19-norprogesterone.

25. The method of claim 12, wherein the drug substance is ent-19-norprogesterone.

26. The method of claim 13, wherein the drug substance is ent-19-norprogesterone.

27. The method of claim 12, wherein the drug substance is ent-19-norprogesterone.

28. The method of claim 13, wherein the drug substance is ent-19-norprogesterone.

29. The method of claim 14, wherein the drug substance is ent-19-norprogesterone.

30. The method of claim 15, wherein the drug substance is ent-19-norprogesterone.

31. The method of claim 16, wherein the drug substance is ent-19-norprogesterone.

32. The method of claim 17, wherein the drug substance is ent-19-norprogesterone.

33. The method of claim 18, wherein the drug substance is ent-19-norprogesterone.

34. The method of claim 19, wherein the drug substance is ent-19-norprogesterone.

35. The method of claim 20, wherein the drug substance is ent-19-norprogesterone.

36. The method of claim 21, wherein the drug substance is ent-19-norprogesterone.

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