JP6945614B2 - Nasal administration - Google Patents

Description

The present invention, in one embodiment, is for a substance in the treatment of pain, including headache (eg, cluster headache and migraine) and neuropathic pain, in particular a drug, particularly a substance that requires rapid onset of action. Regarding nasal administration. The present invention relates to other embodiments relating to nasal administration of carbon dioxide gas or nasal pH regulation as a supplement to therapeutic procedures, such as the treatment of pain.

Referring to FIG. 1 (a), the nasal airway 1 comprises two nasal cavities separated by a septum, which has numerous openings such as sinus ostium 3 and eustachian tube ostium 5 and olfactory cells. And is covered by the nasal mucosa. The nasal airway 1 can reach the nasopharynx 7, the oral cavity 9, and the lower respiratory tract 11, and the nasal airway 1 selectively connects to the anterior region of the nasopharynx 7 and the oral cavity 9 by opening and closing the mesopharyngeal sail 13. The sail 13, often referred to as the soft palate, is indicated by a solid line in the closed position achieved by the application of certain positive pressures to the oral cavity 9, such as the pressure achieved in exhalation through the oral cavity 9. The open position is indicated by a dashed line.

The inventor of the present invention surprisingly brings the substance and at least one gas to the posterior region of the nasal respiratory tract, for example, to a rapid systemic delivery when compared to traditional delivery of equivalent liquid substances. We have found that uptake and rapid reaction rates can be achieved.

The posterior region of the nasal airway is the region behind the nasal flap NV, as shown in FIG. 1 (b). The nasal flap comprises an anterior bone cavity containing inferior turbinate erectile tissue and septal erectile tissue supported by a flexible winged tissue and a solid cartilage septum, respectively (Cole, P (The Respiratory Role of the Upper). Airways, a selective clinical and patheophysiological review. 1993, Mosby-Year Book Inc. ISBN1.55664-390-X)). These components combine to form a dynamic valve that extends over several millimeters, regulates nasal airflow, is stabilized by cartilage and bone, is regulated by voluntary muscles, and is regulated by erectile tissue. The lumen of the nasal flap is the narrowest cross-sectional area between the posterior and anterior regions of the nasal airway, much longer and narrower on the dorsal side than the ventral side, and this lumen is pear-shaped in the bone cavity. It defines a triangular entrance that extends into the area. The nasal flap is covered with transitional epithelium in the anterior part and gradually changes posteriorly to the airway epithelium. The nasal flap and anterior vestibule define approximately the anterior third of the nose.

The posterior region of the nasal airway is covered with ciliated airway epithelium and the olfactory epithelium with nerves extending downward from the olfactory bulb through the lamina cribrosa CP, while the anterior region of the nasal airway is ciliated. It is an area covered with flat epithelium without plaque and transitional epithelium. The olfactory epithelium extends both laterally and centrally to the nasal airways, typically 1.5-2.5 cm downward.

The superior posterior region is the region above the inferior nasal passage IM, as shown in FIG. 1 (b), the opening to the sinus ostium (maxillary sinus, frontal sinus, and ethmoid sinus) in the middle nasal concha, funnel ), The olfactory region, and the region containing the veins that flow into the sinuses that surround the brain, including the upper branch of the trigeminal nerve.

As shown in FIG. 1 (b), the posterior region of the nasal airway is the anterior nasal spine AnS, which is the anterior end of the intermaxillary suture, and the sharp posterior end of the nasal bridge of the hard palate, with the nose and nasopharynx. A virtual lead face located at a location corresponding to a quarter of the distance between the posterior nasal spine PnS, which exhibits a transition between, that is, a distance of about 13 mm to about 14 mm posterior to the anterior nasal spine AnS. VERT1 is of the back of the nose area (Rosenberger, H (Growth and Development of the Naso-Respiratory area in Childhood, PhD Thesis, Laboratory of Anatomy, School of Medicine, Western Reserve University, Presented to the Annual Meeting of the American Laryngological, Rhinological and Otological Society, Charleston, South Carolina, USA, 1934) found that the distance between the anterior nasal spine AnS and the posterior nasal spine PnS was 56 mm in an 18-year-old boy and 53.3 mm in an 18-year-old girl. ). As also shown in FIG. 1 (b), the posterior nasal region is posteriorly bounded by a virtual vertical VERT2 extending through the posterior nasal spine PnS.

Further, as shown in FIG. 1 (b), the upper region of the nasal airway corresponds to one-third of the distance between the nasal airway CP and the nostril bottom NF of the nasal airway and the nasal airway CP, typically. Is the upper part of the nasal airway bordered by the horizontal plane HORIZ located at a height of about 13 to about 19 mm above the bottom of the nostril NF (Zacharek, MA et al (Sagittal and Coronal Divisions of the). Ethmoid Roof: A Radioanatomic Study, AM J Rhinol 2005, Vol 19, pages 348 to 352) defines the distance from the nostril bottom NF to the ethmoid CP as 46 +/- 4 mm). Thus, the upper and posterior regions can include upper and posterior regions that may be bounded by the vertical and horizontal planes VERT1, HORIZ as defined above.

Gas therapies for the treatment of headaches, allergies, asthma, and other conditions, as well as related physiological functions, are described in the following references: Case et al, J Allergy Clin Immunol 121 (1): 105-109 (2008), Vause et al, Headache 47: 1385-1397 (2007), Tzabazis et al, Life Science 87: 36-41 (2010), and Casele et al, Ann Allergy Assma Immunol 107: 364-370. ing.

WO 2001/064280 percutaneously and percutaneously provides carbon dioxide in the form of gas and in the form of capnic solutions (such as carbonated water) for the relief of distress, including musculoskeletal disorders, neuralgia, rhinitis, and other diseases. Discloses methods and devices for transmucosal application.

US Patent Application Publication No. 2011/0046546 discloses devices, methods, and kits for treating symptoms associated with common diseases such as headache, rhinitis, asthma, epilepsy, and neuropathy.

International Publication No. 2001/064280 U.S. Patent Application Publication No. 2011/0046546

Core, P (The Respiratory Role of the Upper Airways, a selective clinical and patheophysiological review.1993, Mosby-YearBook.1993, Mosby-YearBook, Mosby-YearBook, Inc. Rosenberger, H (Growth and Development of the Naso-Respiratory Area in Childhood, PhD Thesis, Laboratory of Anatomy, School of Medicine, Western Reserve University, Presented to the Annual Meeting of the American Laryngological, Rhinological and Otological Society, Charleston, South Carolina , USA, 1934) Zacharek, MA et al (Sagittal and Coronal Dimensions of the Ethmoid Roof: A Radioanatomic Study, AM J Rhinol 2005, Vol 19, pages 348 to 35) Case et al, J Allergy Clin Immunol 121 (1): 105-109 (2008) Vause et al, Headache 47: 1385-1397 (2007) Tzabazis et al, Life Science 87: 36-41 (2010) Case et al, Ann Allergy Asthma Immunol 107: 364-370 (2011)

The inventor of the present invention can result in improved therapeutic treatment by administering a therapeutic substance in combination with control of pH, pressure, and / or NO concentration, such as by supplying gas through the nasal airways. Has found that it can result in a very rapid onset of action of the therapeutic substance.

In one aspect, the present invention is a method of administering a substance to a subject, wherein the substance is administered to the posterior region of the nasal cavity of the subject including the mucous membrane where the trigeminal nerve is distributed, and before the administration of the substance. Provided are methods comprising, stepping on increasing the rate of uptake of the substance by adjusting the pH of the mucosa during or afterwards.

In one embodiment, the pterygopalatine ganglia are further distributed in the mucosa.

In one embodiment, the material is delivered through a nostril that is attached to the nostrils and optionally adhered to the nostrils so that no fluid leaks.

In one embodiment, the substance is delivered through one nostril to one trigeminal nerve of the mucosa.

In one embodiment, the material is delivered to each of the trigeminal nerves sequentially through each nostril to the mucosa.

In one embodiment, the pH is adjusted by delivering at least one gas.

In one embodiment, the at least one gas is optionally delivered in a stream having a concentration of at least 5 vol% of the at least one gas.

In one embodiment, the at least one gas comprises carbon dioxide.

In one embodiment, the pH regulation achieves activity in the V1 branch of the trigeminal nerve.

In one embodiment, the pH regulation is performed during an event in which the parasympathetic effect on the autonomic nervous system is present, making the trigeminal nerve more susceptible to pH regulation and improving substance uptake.

In one embodiment, the pH is lowered in the pH adjustment step.

In one embodiment, the method increases the rate of uptake of the substance by adjusting the pressure in the nasal cavity before, during, or after delivery of the substance. Including further steps to enhance.

In one embodiment, the pressure is at least about 3 kPa and optionally about 3 to about 7 kPa.

In one embodiment, the pressure is regulated by delivering at least one gas.

In one embodiment, the at least one gas is optionally delivered in a stream having a concentration of at least 5 vol% of the at least one gas.

In one embodiment, the at least one gas comprises carbon dioxide.

In one embodiment, the regulation of pressure achieves the activity of the V1 branch of the trigeminal nerve.

In one embodiment, the pressure regulation is performed during an event in which the parasympathetic effect on the autonomic nervous system is present, making the trigeminal nerve more susceptible to pressure regulation and improving substance uptake. ..

In one embodiment, the pressure is increased in the pressure adjusting step.

In one embodiment, the method of uptake of the substance by adjusting the concentration of NO in the nasal cavity before, during, or after delivery of the substance. Includes additional steps to increase speed.

In one embodiment, the concentration of NO is adjusted by delivering at least one gas.

In one embodiment, the at least one gas is optionally delivered in a stream having a concentration of at least 5 vol% of the at least one gas.

In one embodiment, the at least one gas comprises carbon dioxide.

In one embodiment, the regulation of NO concentration achieves the activity of the V1 branch of the trigeminal nerve.

In one embodiment, the concentration of NO is reduced in the NO concentration adjusting step.

In one embodiment, the substance is a substance that does not cross the blood-brain barrier.

In one embodiment, the substance is a triptan. In one embodiment, the substance is sumatriptan.

In one embodiment, the method is a method for the treatment of neurological or CNS disorders.

In one embodiment, the method is a method for the treatment of headaches such as cluster headaches and migraines.

In one embodiment, the method further comprises closing the soft palate of the subject's oropharynx when delivering the substance and / or the at least one gas.

In one embodiment, the method further comprises the step of causing the subject's oropharyngeal soft palate to close by exhaling through the mouthpiece.

In one embodiment, the mouthpiece communicates with the nosepiece so that the exhaled breath from the exhaled breath is delivered through the nosepiece.

In another embodiment, the invention is a method of administering a substance to a subject, wherein the substance is delivered to the posterior region of the nasal cavity of the subject, including the mucous membrane in which the trigeminal nerve is distributed, and before the substance is delivered. Provided are methods that include, step-by-step, increasing the rate of uptake of the substance by adjusting the pressure in the nasal cavity during or after delivery of the substance.

In one embodiment, the pterygopalatine ganglia are further distributed in the mucosa.

In one embodiment, the material is delivered through a nostril that is attached to the nostrils and optionally adhered to the nostrils so that no fluid leaks.

In one embodiment, the substance is delivered through one nostril to one trigeminal nerve of the mucosa.

In one embodiment, the material is delivered to each of the trigeminal nerves sequentially through each nostril to the mucosa.

In one embodiment, the pressure is regulated by delivering at least one gas.

In one embodiment, the at least one gas is optionally delivered in a stream having a concentration of at least 5 vol% of the at least one gas.

In one embodiment, the at least one gas comprises carbon dioxide.

In one embodiment, the regulation of pressure achieves activity in the V1 branch of the trigeminal nerve.

In one embodiment, the pressure regulation is performed during an event in which the parasympathetic effect on the autonomic nervous system is present, making the trigeminal nerve more susceptible to pressure regulation and improving substance uptake. ..

In one embodiment, the pressure is at least about 3 kPa and optionally about 3 to about 7 kPa.

In one embodiment, the pressure is increased in the pressure adjusting step.

In one embodiment, the method of uptake of the substance by adjusting the concentration of NO in the nasal cavity before, during, or after delivery of the substance. Includes additional steps to increase speed.

In one embodiment, the concentration of NO is adjusted by delivering at least one gas.

In one embodiment, the at least one gas is optionally delivered in a stream having a concentration of at least 5 vol% of the at least one gas.

In one embodiment, the at least one gas comprises carbon dioxide.

In one embodiment, the regulation of NO concentration achieves the activity of the V1 branch of the trigeminal nerve.

In one embodiment, the concentration of NO is reduced in the NO concentration adjusting step.

In one embodiment, the substance is a substance that does not cross the blood-brain barrier.

In one embodiment, the substance is a triptan. In one embodiment, the substance is sumatriptan.

In one embodiment, the method is used in the treatment of neurological or CNS disorders. In one embodiment, in the treatment of headaches such as cluster headaches and migraines.

In one embodiment, the method further comprises closing the soft palate of the subject's oropharynx when delivering the substance and / or the at least one gas.

In one embodiment, the method further comprises the step of causing the subject's oropharyngeal soft palate to close by exhaling through the mouthpiece.

In one embodiment, the mouthpiece communicates with the nosepiece so that the exhaled breath from the exhaled breath is delivered through the nosepiece.

In a further embodiment, the invention is a method of administering a substance to a subject, the step of delivering the substance to the posterior region of the nasal cavity of the subject, including the mucosa in which the trigeminal nerve is distributed, and the substance before delivery. Provided are methods that include, step-by-step, increasing the rate of uptake of the substance by adjusting the concentration of NO in the nasal cavity during or after delivery of the substance.

In one embodiment, the pterygopalatine ganglia are further distributed in the mucosa.

In one embodiment, the material is delivered through a nostril that is attached to the nostrils and optionally adhered to the nostrils so that no fluid leaks.

In one embodiment, the substance is delivered through one nostril to one trigeminal nerve of the mucosa.

In one embodiment, the material is delivered to each of the trigeminal nerves sequentially through each nostril to the mucosa.

In one embodiment, the concentration of NO is adjusted by delivering at least one gas.

In one embodiment, the at least one gas is optionally delivered in a stream having a concentration of at least 5 vol% of the at least one gas.

In one embodiment, the at least one gas comprises carbon dioxide.

In one embodiment, the regulation of NO concentration achieves the activity of the V1 branch of the trigeminal nerve.

In one embodiment, the concentration of NO is reduced in the NO concentration adjusting step.

In one embodiment, the method increases the rate of uptake of the substance by adjusting the pH of the mucosa before, during, or after delivery of the substance. Including further steps to enhance.

In one embodiment, the pH is adjusted by delivering at least one gas.

In one embodiment, the at least one gas is optionally delivered in a stream having a concentration of at least 5 vol% of the at least one gas.

In one embodiment, the at least one gas comprises carbon dioxide.

In one embodiment, the pH regulation achieves activity in the V1 branch of the trigeminal nerve.

In one embodiment, the pH regulation is performed during an event in which the parasympathetic effect on the autonomic nervous system is present, making the trigeminal nerve more susceptible to pH regulation and improving substance uptake.

In one embodiment, the pH is lowered in the pH adjustment step.

In one embodiment, the method increases the rate of uptake of the substance by adjusting the pressure in the nasal cavity before, during, or after delivery of the substance. Including further steps to enhance.

In one embodiment, the pressure is at least about 3 kPa and optionally about 3 to about 7 kPa.

In one embodiment, the pressure is regulated by delivering at least one gas.

In one embodiment, the at least one gas is optionally delivered in a stream having a concentration of at least 5 vol% of the at least one gas.

In one embodiment, the at least one gas comprises carbon dioxide.

In one embodiment, the regulation of pressure achieves the activity of the V1 branch of the trigeminal nerve.

In one embodiment, the pressure regulation is performed during an event in which the parasympathetic effect on the autonomic nervous system is present, making the trigeminal nerve more susceptible to pressure regulation and improving substance uptake. ..

In one embodiment, the pressure is increased in the pressure adjusting step.

In one embodiment, the substance is a substance that does not cross the blood-brain barrier.

In one embodiment, the substance is a triptan. In one embodiment, the substance is sumatriptan.

In one embodiment, the method is used in the treatment of neurological or CNS disorders, and in one embodiment, it is used in the treatment of headaches such as cluster headaches and migraines.

In one embodiment, the method further comprises closing the soft palate of the subject's oropharynx when delivering the substance and / or the at least one gas.

In one embodiment, the method further comprises the step of causing the subject's oropharyngeal soft palate to close by exhaling through the mouthpiece.

In one embodiment, the mouthpiece communicates with the nosepiece so that the exhaled breath from the exhaled breath is delivered through the nosepiece.

In a further aspect, the invention is a method of administering a substance to a subject, the step of delivering the substance to the posterior region of the subject's nasal cavity, including the mucous membrane where the trigeminal nerve is distributed, and before delivering the substance. , During delivery of the substance, or after delivery of the substance, the pH of the mucous membrane is adjusted, and before delivery of the substance, during delivery of the substance, or after delivery of the substance. Provided are methods comprising, stepping on increasing the rate of uptake of the substance by adjusting the pressure in the nasal cavity.

In yet another embodiment, the invention is a method of administering a substance to a subject, the step of delivering the substance to the posterior region of the subject's nasal cavity, including the mucous membrane where the trigeminal nerve is distributed, and delivering the substance. Before, during delivery of the substance, or after delivery of the substance, the pH of the mucous membrane was adjusted, and before delivery of the substance, during delivery of the substance, or delivery of the substance. Provided are methods that include, afterwards, stepping up the rate of uptake of the substance by adjusting the concentration of NO in the nasal cavity.

In yet another embodiment, the invention is a method of administering a substance to a subject, the step of delivering the substance to the posterior region of the subject's nasal cavity, including the mucous membrane where the trigeminal nerve is distributed, and delivering the substance. Before, during delivery of the substance, or after delivery of the substance, the pressure in the nasal cavity is adjusted, and before delivery of the substance, during delivery of the substance, or delivery of the substance. Provided are methods that include, afterwards, stepping up the rate of uptake of the substance by adjusting the concentration of NO in the nasal cavity.

In yet another embodiment, the invention is a method of administering a substance to a subject, the step of delivering the substance to the posterior region of the subject's nasal cavity, including the mucous membrane where the trigeminal nerve is distributed, and delivering the substance. Before, during delivery of the substance, or after delivery of the substance, the pH of the mucous membrane was adjusted, and before delivery of the substance, during delivery of the substance, or delivery of the substance. By adjusting the pressure in the nasal cavity afterwards and adjusting the concentration of NO in the nasal cavity before delivery of the substance, during delivery of the substance, or after delivery of the substance, the uptake of the substance can be achieved. Provides methods including, and steps to increase speed.

In a further aspect, the invention provides a substance for the treatment of nerve or CNS disease, which is delivered to the posterior region of the subject's nasal cavity, including the mucosa where the trigeminal nerve is distributed, and the substance is delivered. By adjusting the pH of the mucosa before, during, or after delivery, the rate of uptake of this substance is increased.

In yet another further aspect, the invention provides a substance for the treatment of nerve or CNS disorders, which is delivered to the posterior region of the subject's nasal cavity, including the mucosa where the trigeminal nerve is distributed. By adjusting the pressure in the nasal cavity before, during, or after delivery of the substance, the rate of uptake of this substance is increased.

In yet another embodiment, the invention provides a substance for the treatment of nerve or CNS disorders, which is delivered to the posterior region of the subject's nasal cavity, including the mucosa where the trigeminal nerve is distributed. By adjusting the concentration of NO in the nasal cavity before, during, or after delivery of the substance, the rate of uptake of this substance is increased.

In one embodiment, the substance is a triptan. In one embodiment, the substance is sumatriptan.

In one embodiment, the substance is a substance for the treatment of headaches such as cluster headaches and migraines.

In a further aspect, the invention is a method of administering a substance to a subject, the step of delivering the substance to the subject and the pressure in the nasal cavity before, during, or after delivery of the substance. Provided are methods that include, by adjusting for, the step of increasing the rate of uptake of the substance.

In yet another embodiment, the invention is a method of administering a substance to a subject, in which the substance is delivered to the subject and intranasally before, during, or after delivery of the substance. Provided are methods that include, and include, a step of increasing the rate of uptake of the substance by adjusting the concentration of NO in.

In a further embodiment, the present invention is a method of administering a substance to a subject, wherein the step of delivering the substance to the subject and the trigeminal nerve before, during, or after delivery of the substance. Provided are methods comprising, stepping on increasing the rate of uptake of the substance by adjusting the pH of the distributed mucosa.

In one embodiment, the delivery act is oral, topical, transmucosal, inhalation and / or injection, subcutaneous, nasal, and / or oral.

In a further aspect, the invention is a method of administering a substance to a subject, the step of delivering a first substance causing migraine headaches and the step of delivering a second substance according to any of the disclosed methods. And provide methods including.

According to the present invention, embodiments are directed to methods of treating a patient therapeutically. The method can include administering a therapeutic agent in the first step. The method can further include delivering a therapeutic amount of carbon dioxide or at least one of the pH regulators to a location within the patient's nasal passage in the second step.

Another embodiment is directed to a method for enhancing the therapeutic effect of a drug delivered to a patient. The method can include delivering a stream of fluid to the patient's nasal passage to deliver about 5% to about 6% vol / vol of carbon dioxide to the upper posterior region of the nasal passage. The method can further comprise administering to the patient an amount of said drug.

Yet another embodiment is a method of treating the patient, in which the patient's nostrils are about 5% to about 6 so as to lower the pH of the upper and posterior regions of the nasal passage by at least about 0.1 pH units to bring about a therapeutic effect. Directed to methods involving delivering% vol / vol carbon dioxide.

Further objectives and advantages of the present invention are described in part in the following description and in part are self-evident from the description or can be learned by practicing the present invention. The objects and advantages of the present invention are realized and achieved by the components and combinations detailed in the appended claims.

It should be understood that both the above overall description and the following detailed description are merely examples and description and do not limit the invention as described in the claims.

The accompanying drawings incorporated herein by reference and forming part of this specification, in collaboration with the description, disclose embodiments of the invention that are merely exemplary but useful in explaining the principles of the invention.

It outlines the structure of the upper airways of a human subject. The classification of the nasal cavity according to the embodiment of the present invention is shown. A nasal administration device according to an embodiment of the present invention is shown. A nasal administration device according to an embodiment of the present invention is shown. A nasal administration device according to another embodiment of the present invention is shown. A nasal administration device according to another embodiment of the present invention is shown. The reaction rate in Example 1 is shown. The pharmacokinetic parameters calculated in Example 2 are shown. For Example 2, for nasal sumatriptan powder, 20 mg nasal spray, 100 mg tablets, and 6 mg subcutaneous injection, the sumatriptan plasma concentration-hour profile over a 14 hour sampling period is shown, and the inset is For nasal sumatriptan powder, 20 mg nasal spray, and 100 mg tablets, the sumatriptan plasma concentration-time profile in the first 30 minutes after administration is shown. The main figure in FIG. 6 shows that the mean plasma sumatriptan concentration-time profile is much lower than the profile observed in tablets and injections for both methods of nasal administration. The inset of FIG. 6 shows that in the first 30 minutes after administration, the rate of increase in plasma sumatriptan concentration is faster in sumatriptan powder compared to 20 mg nasal spray or 100 mg tablets. For Example 2, the sumatriptan plasma concentration-time profile at the first 4 hours after administration of the sumatriptan powder by the apparatus of the present invention is shown compared to a 20 mg nasal spray. For Example 2, the results of the pharmacokinetics of sumatriptan in respiratory (breath power) nasal administration of sumatriptan powder are shown compared to 20 mg nasal spray, 100 mg tablets, and 6 mg subcutaneous injection. .. For Example 2, a statistical comparison of plasma sumatriptan pharmacokinetic parameters is shown. For Example 3, a statistical comparison of sumatriptan plasma pharmacokinetic parameters including nitroglycerin (GTN) -induced migraine and healthy subjects is shown. FIG. 11 (a) shows the initial (0-2 minutes) adhesion to each region of the nose for administration by a respiratory force powder dispenser and a traditional nasal spray pump. FIG. 11 (b) shows the initial (0-2 min) horizontal distribution of the nose for respiratory force powder dosing and traditional nasal spray pump dosing. The pharmacokinetic (PK) profile of transnasal sumatriptan from two crossover studies performed by the Breathpower powder device and a commercially available Imitrex sumatriptan nasal spray is shown. One study was conducted in migraine patients during a GTN attack, while the other study was conducted in healthy volunteers. It shows the percentage of patients whose headache was alleviated. It shows pain relief at 2 hours as reported in the insert of the package. For effective drugs and placebo, the pain response rate at 2 hours reported by the study on the package insert is shown. It shows "blind" data from March 2014. It shows pH probes located roughly in the upper and lower regions of the nasal passages. It shows data collected from a pH probe located approximately on the ceiling of the nose and on the same side as the inhaler. It shows data collected from pH probes located approximately 4-5 cm from the ceiling of the nose and the opening of the nostrils. Data for liquid and powder dosing devices are shown. Data on powder administration by sensors located approximately 4-5 cm within the nasal passage at the bottom / center of the nasal passage are shown. Data on powder administration by sensors located approximately 4-5 cm within the nasal passage at the bottom / center of the nasal passage are shown. The data from the prior art literature are shown. The data for the inhalation device described herein are shown. Shows patient demographic data and baseline characteristics (FAS). It shows the distribution of data on inhalers by respiratory force and placebo data. It shows the percentage (FAS) of ^{patient a} whose headache was relieved at the time specified in the procedure up to 120 minutes post-dose ^{and patient b} whose relief was maintained at 24 and 48 hours. It shows the percentage of patients with ^{significant alleviation a} at 120 minutes after administration following treatment with AVP-825 or a placebo device (FAS). It shows the percentage of patients who achieved relief from pain at the end of 120 minutes.

Next, a typical embodiment of the present invention whose examples are shown in the accompanying drawings will be referred to in detail. Wherever possible, the same reference numbers are used to refer to the same or similar parts throughout the drawing.

Typical Distributor Figures 2 (a) and 2 (b) can be operated to deliver powder aerosols Breath Powered ™ powder delivery. device, powder delivery device) is shown.

The breath power (trademark) delivery device includes a housing 15, a capsule containing unit 16 that receives the capsule C, a nosepiece unit 17 that fits in the nasal cavity of the subject, a mouthpiece unit 19 that the subject exhales, and a capsule containing unit 16. It includes a capsule puncture mechanism 20 that can function to prepare the delivery device for operation by puncturing the contained capsule C.

The housing 15 is located at the upper end of the housing 15 in this embodiment and has a first nosepiece opening 21 that receives the nosepiece unit 17 and a housing in this embodiment, as described in more detail herein. It is located on the end wall of the 15 and includes a second lateral opening 22 in which the actuating button 81 of the capsule puncture mechanism 20 extends.

In this embodiment, the capsule containing unit 16 has a housing in this embodiment in order to receive the capsule C housed in the capsule containing member 49 of the nosepiece unit 17, as described in more detail herein. It comprises a capsule containing member 23, which is an elongated upright chamber arranged opposite the nosepiece opening 21 of 15.

In this embodiment, the capsule accommodating member 23 includes an inlet 24 and an outlet 25 for passing airflow, and the outlet 25 defined by the upper downstream end of the capsule accommodating member 23 is the capsule accommodating of the nosepiece unit 17. The member 49 is accommodated, and the capsule accommodating member 49 is configured to fit within the capsule accommodating member 23.

The nosepiece unit 17 includes a main body member 45 configured to fit in the nosepiece opening 21 of the housing 15, a nosepiece 47 extending outward from the main body member 45 so as to fit in the nostril of the subject, and an inside from the main body member 45. Includes a capsule containment member 49 that extends to and accommodates the capsule C having the contents to be brought into the nostrils of the subject. In this embodiment, the capsule C is a hydroxypropyl methylcellulose (HPMC) capsule that contains a particulate matter, such as a powdered substance, and typically a pharmaceutical substance. In other embodiments, the capsule C can be substantially formed with another cellulose derivative such as hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, and carboxymethyl cellulose. In an alternative embodiment, the capsule C can be formed from a gelatin derivative. In one embodiment, the capsule C can be covered with a hydrophobic material such as parylene.

In this embodiment, the nosepiece 47 has a substantially conical outer portion 53 for guiding the nosepiece unit 17 into the nasal cavity of the subject and providing fluid-tight adhesion to the nostrils of the nostrils. , Here a substantially cylindrical portion that brings material to the posterior region of the subject's nasal cavity, in this embodiment the distance between the anterior nasal spine AnS and the posterior nasal spine PnS posterior to the anterior nasal spine AnS. The upper and posterior bordered by a vertical surface located at a position corresponding to a quarter of the above and a horizontal plane located at a height of one-third of the distance between the bottom of the nostril and the nasal plate It has an internal channel 55 that brings it to the area. As mentioned above, the inventor of the present invention, by increasing the amount of powdered material brought to the upper and posterior regions of the nasal cavity, surprisingly, has a much faster effect than traditional nasal administration of liquid substances. I noticed that the expression of was brought about.

In this embodiment, the nosepiece 47 is configured to deliver a significant proportion of the substance to the upper posterior region of the nasal cavity, where it is configured to initially deliver more than 30% of the delivered amount.

In this embodiment, the nosepiece 47 is a fluid with the nostrils of the subject, as disclosed in previous WO 2000/051672 by the applicant of the present application, which is incorporated herein by reference in its entirety. In providing a tight fit that does not leak, provide bidirectional delivery through the subject's nasal airways. However, in another embodiment, the nosepiece 47 does not necessarily provide a tight fit, i.e., nasal delivery, but not necessarily bidirectional delivery.

In this embodiment, the nosepiece 47 is typically a perforated element so that foreign matter, such as a portion of the capsule C that exceeds a predetermined size, does not pass through the nosepiece 47 and enter the nasal cavity of the subject. Alternatively, it includes a trap element 57 which is a mesh element.

The capsule accommodating member 49 includes an elongated flow path 63 that is cylindrical in this embodiment, and an inlet opening 65 that communicates with one end (downstream end) of the flow path 63. The shaft is arranged along the flow path 63 so that it can rotate in the flow path 63 when passed through the 63, and the inlet opening 65 imposes a flow limitation on the airflow driven through the inlet opening 65. At the same time, it functions as a seat for one end (lower end) of the capsule C until the air flow is brought through the flow path 63.

A plurality of capsule containing members 49 (in this embodiment, in this embodiment, a plurality of capsule containing members 49 are provided on the side wall of the capsule containing member 49 so that the capsule C can be punctured at a position spaced apart along the axial length of the capsule C. The first and second) puncture holes 71 and 73 are further provided. In this embodiment, the first (lower) hole 71 is located above the height of the material contained in the capsule C when the lower end of the capsule C is seated in the inlet opening 65 of the flow path 63. The capsule C is positioned so as to be punctured. In this way, the substance contained in the capsule C is not discharged into the flow path 63 until the airflow is released through the flow path 63.

In this embodiment, the nosepiece unit 17 is provided as a replaceable unit that is replaced each time the delivery device is activated. In this embodiment, the nosepiece unit 17 can be packed in an airtight package such as an aluminum foil package.

The mouthpiece unit 19 is gripped by the subject's lips in this embodiment and is exhaled by the subject to provide airflow for transport through the capsule containment unit 16 and an elongated tubular in this embodiment. It is provided with an air chamber 78 for communicating the mouthpiece 77 and the capsule accommodating unit 16.

In this embodiment, the air chamber 78 has a larger volume than the capsule containing member 23 of the capsule containing unit 16, and in one embodiment, has a volume at least twice the volume of the capsule containing member 23.

In this embodiment, the air chamber 78 comprises, at least at its upstream end, a temperature controller 79 formed here as a condenser for cooling the exhaled airflow. This configuration cools the airflow exhaled during exhalation.

In this embodiment, the temperature controller 79 comprises a labyrinth structure. In another embodiment, the temperature controller 79 may be provided by a filter element that can also function as a microbial filter.

In one embodiment, the temperature controller 79 can be provided with means for drying the condensate that collects inside when the delivery device is not in use.

In one embodiment, the air chamber 78 may be removable such that it can be cleaned or replaced.

This configuration has been shown to provide reliable operation of the delivery device in the delivery of material from the capsule C. According to the inventor of the present invention, bringing moist exhaled air directly to the capsule C may prevent the necessary rotation of the capsule C and prevent the proper release of the substance contained in the capsule C. I found out. By preparing cooler air and configuring it to bring such cold air first in the eruption, the required rotation of the capsule C can be seen repeatedly.

The capsule puncture mechanism 20 is supported by an actuating button 81 extending through the lateral opening 22 of the housing 15 and extending in front of the actuating button 81 so that the subject can operate the capsule puncture mechanism 20. When the actuating button 81 is pushed from the retracted position to the protruding position, it is driven through one of the puncture holes 71, 73 on the side wall of the capsule accommodating member 49 to puncture the capsule C (this embodiment). Includes first and second) puncture elements 83, 85.

In this embodiment, the capsule puncture mechanism 20 urges the actuating button 81 outward toward the retracted position in order to return the actuating button 81 to the retracted position after the actuating button 81 is pushed in and the capsule C is punctured. It comprises an elastic element 87 that functions to do so. In this embodiment, the elastic element 87 is formed as an integral part of the actuating button 81, but in other embodiments, it may be provided as a separate element such as a compression spring.

The operation of the sending device is as follows.

First, the delivery device is picked up, the nosepiece unit 17 is inserted into the housing 15, and the subject presses the actuation button 81 of the capsule puncture mechanism 20 to puncture the capsule C housed in the capsule housing member 49.

By pressing the actuating button 81, the capsule C is punctured by the puncture elements 83, 85 at two positions spaced apart along the axial length of the capsule C. In this embodiment, the first lower puncture element 83 functions to puncture the capsule C at a position just above the height of the material contained in the capsule C that is only partially filled. The puncture element 85 above 2 functions to puncture the upper end (distal end) of the capsule C.

Next, the actuating button 81 is released, and the actuating button 81 returns to the retracted position under the urging of the urging element 87. In this way, the delivery device is ready and ready to use.

The subject then inserts the nosepiece 47 into its nasal cavity (at this point, the distal end of the nosepiece 47) until the nosepiece 47 abuts into the nasal passages of the nostrils to achieve a fluid-tight adhesion. Extends about 2 cm into the subject's nostrils) and holds the mouthpiece 77 on its lips.

The subject then begins to exhale through the mouthpiece 47, and this exhalation functions to close the soft palate of the subject's oropharynx and deliver airflow through the subject's nasal airways, with the airflow passing through one nostril. By going around the trailing edge of the nasal septum and exiting the other nostril, bidirectional airflow through the subject's nasal airways is achieved.

When the subject exhales with sufficient force, the capsule C is lifted and rotated from the seat defined by the entrance opening 65 of the capsule containing member 49, and this rotation releases the substance from the capsule C and is exhaled. It functions to carry the airflow and reach the posterior region of the subject's nasal cavity. As the exhalation continues, the capsule C continues to rotate.

Further, in this device, the capsule C is configured to vibrate, which causes ventilation of the nasal airways through the sound transmission pathways provided by the nostril unit 17 inserted into the nostrils, especially in the posterior region of the nasal cavity. Functions to promote. This vibration is thought to contribute to efficacy, as outlined in the discussion below.

This operation of the delivery device can be repeated with a new capsule C. In this embodiment, the entire nosepiece unit 17 is replaced, but in other embodiments, only the capsule accommodating member 49 or the capsule C may be replaced.

The gas can be delivered at a pressure of 2, 3, 4, 5, 6, 7, 8, 9, or 10 kPa.

3 (a) and 3 (b) show a Breathpower ™ liquid delivery device capable of functioning to deliver a powder aerosol.

The delivery device includes a housing 115, a nosepiece 117 that fits in the subject's nasal cavity, a mouthpiece 119 that the subject exhales during use, and a substance supply unit that can be manually operated to bring material into the subject's nasal cavity. With 120, it is possible to bring airflow into the subject's nasal airways as the subject exhales through the mouthpiece 119.

The housing 115 is a substantially elongated tubular portion in this embodiment, and has an opening 123 at one end that projects an operating portion of the substance supply unit 120 (defined by the bottom of the substance containment chamber 151 in this embodiment). The main body member 121 included in the above is provided.

As will be described in more detail later, the housing 115 causes the airflow, which is a form of air ejection in this embodiment, to be brought through the nosepiece 117 at the same time as the operation of the substance supply unit 120. And a valve assembly 125 that communicates with the mouthpiece 119 and is capable of operating between the closed and open states as shown in FIGS. 3 (a) and 3 (b).

The valve assembly 125 includes a main body element 127 and a valve element 129 disposed on the body element 127 so that it can slide between the closed and open positions as shown in FIGS. 3 (a) and 3 (b). To be equipped.

The body element 127 is a tubular portion in this embodiment, which is located downstream of the valve portion 131 in which the valve element 129 is slidably arranged and the valve portion 131, communicates with the nosepiece 117, and in this embodiment. Includes an inward flared front 133 having a tapered portion.

Each of the valve portion 131 and the valve element 129 of the main body element 127 does not communicate when the valve element 129 is in the closed position as shown in FIG. 2 (c), and the valve element as shown in FIG. 2 (d). It is provided with valve openings 137 and 139 that communicate when the 129 is in the open position.

The nosepiece 117 is a body member 141 that defines an outer sealing surface 143 that provides a close fit between the nosepiece 117 and the subject's nasal cavity, and airflow into the subject's nasal airways as the subject exhales through the mouthpiece 119. It comprises an inner delivery channel 145 that selectively communicates with the mouthpiece 119 to selectively bring it, and an outlet unit 147 that is located within the delivery channel 145 and delivers material to the nasal respiratory tract of the subject.

In this embodiment, the outlet unit 147 includes a nozzle 149 to deliver the substance to the subject's nasal airways. In this embodiment, the nozzle 149 is arranged coaxially with the transmission channel 145 in the transmission channel 145.

In a preferred embodiment, the distal end of the exit unit 147 is configured to extend at least about 2 cm, preferably at least about 3 cm, more preferably about 2 cm to about 3 cm into the subject's nasal cavity.

In this embodiment, the substance supply unit 120 is a pump unit including a substance storage chamber 151 and a mechanical delivery pump 153, and the material storage chamber 151 stores a substance and serves as an operation unit of the material supply unit 120 as a housing 115. Protruding from the opening 123 of, the mechanical delivery pump 153 brings a certain amount of material from the material containment chamber 151 to the outlet unit 147, here as an aerosol spray from the nozzle outlet 149 of the outlet unit 147, which is typical here. Can be activated by pushing the substance containment chamber 151 with the subject's finger or thumb.

In this embodiment, the material containment chamber 151 moves with the valve element 129 of the valve assembly 125 to simultaneously bring the operation of the material supply unit 120 and the opening of the valve assembly 125 with the material which is here in the form of a spray. , Here it is connected to the valve element 129 of the valve assembly 125 so as to simultaneously bring airflow as a ejection of air into the subject's nasal cavity.

In this embodiment, the mechanical delivery pump 153 is a liquid delivery pump for delivering a certain amount of material, whereas in another embodiment, the mechanical delivery pump 153 delivers a certain amount of powdered material during operation. It may be a powder delivery pump to bring.

In this embodiment, the substance supply unit 120 is a unit for a plurality of times capable of delivering a fixed amount of a substance a plurality of times in a continuous delivery operation.

Next, the present invention will be described with reference to the following examples (but not limited to these).

The purpose of this study was to study the development of headache relief after administration of sumatriptan. 436 subjects were included in the study population. The procedures in the study were as follows: (i) Nasal administration of 16 mg sumatriptan powder in the Breathpower ™ administration system of the embodiment described above, and (ii) Breathpower ™ administration system without active substance. Oral tablets were administered by orally administering 100 mg of sumatriptan while using the drug.

Headache relief was defined as relief from moderate pain (grade 2) or severe pain (grade 3) to painless (grade 0) or mild pain (grade 1). In the study, in the acute treatment of migraine attacks alone, headache relief 30 minutes after nasal administration of 16 mg sumatriptan was compared to oral administration of 100 mg sumatriptan.

Response rates 30 and 120 minutes after administration in this study are summarized in FIG. As can be seen, the response rate after 30 minutes was 39% with the combination of 100 mg sumatriptan administration and the placebo device. The combination of administration of 16 mg sumatriptan on a Breathpower ™ device with a placebo oral tablet gives a response rate of 67% after 30 minutes.

A possible mechanism for the early onset of sumatriptan action may be due to the ability of carbon dioxide to interfere with sensory nerve activation and the release of calcitonin gene-related peptides (CGRP), carbon dioxide and Drug flow patterns may also play a role. Higher pressures of 3-7 kPa can be exerted through the device of this embodiment, allowing drugs and carbon dioxide to reach the posterior region of the nasal cavity, especially targeting the trigeminal nerve V1. can. A combination of carbon dioxide exposure and mucosal pressure may be effective. Carbon dioxide can counteract the effects of NO and promote the release of CGRP. The pH of the nasal mucosa can also change when exposed to higher carbon dioxide pressures and concentrations.

Other embodiments of the invention will be apparent to those skilled in the art by reviewing the specification and practicing the content disclosed herein. The present specification and examples should be considered as examples only, and the true technical scope and technical idea of the present invention are shown by the following claims.

This example includes a random, open-label, single-dose cross-relative bioavailability study in healthy subjects conducted at one center in the United States. The population under study is determined by the investigator to be healthy and determined by medical history, physical examination, blood chemistry, hematology (including complete blood cell count), urinalysis, biological signals, and electrocardiogram (ECG). Twenty male and female subjects aged 18-55 years without any clinically relevant abnormalities were included. For the subjects, the body mass index (BMI) was 18-32 kg / m ² and the body weight was 50 kg or more. Prior to participation, subjects refrained from alcohol intake for 48 hours prior to each dose of the drug in the study and during the period of restraint, and caffeine / methylxanthine intake for 7 days prior to the study and in the study. They agreed to keep the duration below 300 mg per day and not take it for 24 hours prior to dosing and during restraint. In addition, subjects did not consume foods or beverages containing grapefruit, daidai, or kinin (eg, tonic water) for 72 hours prior to study date-1 after the last pharmacokinetic sample was taken, and poppy seeds during the study. I agreed not to consume foods containing poppy seeds. When subjects were tested for airflow through both nostrils and the ability to close the soft palate (eg, the ability to inflate a balloon), it was possible to use the Breathpower ™ device of this example correctly.

Subjects with a history of migraine headaches or hypersensitivity to any drug containing sumatriptan or any of its components or sulfonamides or allergies were excluded. Subjects donated blood 3 months prior to screening, or suffered significant blood loss (> 500 mL), or within 2 months of completion of the study, if hemoglobin levels were below the normal lower limit at screening. If you plan to donate blood to, you are ineligible. Use of drug-degrading enzyme (CYP-450) inducer 28 days prior to administration, use of drug-degrading enzyme (CYP-450) inhibitor 14 days prior to administration, all monoamine oxidation in 28 days prior to administration Use of enzyme inhibitors, use of any prescription drug / product except hormonal contraceptives in female subjects capable of giving birth, and any over-the-counter non-prescription preparation (in recommended amount) within the first day of study. The use of (excluding ibuprofen and acetaminophen) used in the above was excluded. Pregnant and lactating women were excluded. Allergic rhinitis, septal curvature, polyposis, severe mucosal swelling, nasal ulcers, nasal trauma, or respiratory or known epistaxis due to any other reason, history of chronic epistaxis, current nasopharyngeal disorders, Also, the presence of known soft palate dysfunction was excluded.

The study consisted of 6 visits. At visit 1, the subjects were screened for eligibility. After the physical examination, the subjects were instructed on the use of the Breath Power ™ transmitter of this example. Once it has been demonstrated that the device can be used properly for the subject, the remaining screening procedures (biological signals, ECG recording, blood and urine collection for laboratory tests, testing for alcohol and drug intake, serum, serum. Pregnancy test (female only)) was performed.

Eligible subjects visited the clinic four more times (visits 2-5). At each visit, subjects checked in to the study site the night before dosing and remained at the study site until after the last blood sample was taken to measure sumatriptan levels. Randomization was generated by Celerion Bioanalysis Laboratory in Lincoln, Nebraska, USA. Subjects were randomly assigned to the treatment sequence using the 4x4 Latin square method at the first treatment visit (visit 2). Research procedures include 20 mg sumatriptan powder nasally administered by a Breathpower® device, 20 mg sumatriptan nasal spray (Imitrex® Nasal Spray, GlaxoSmithKline), 100 mg oral tablets (Imitrex®). ) Tablet, GlaxoSmithKline), and 6 mg subcutaneous injection (Imitrex® Injection, GlaxoSmithKline). For each subject, each of these four treatments was performed at approximately the same time at each visit in four separate periods, with a 7-day washout period between the treatments. Subjects were fasted for at least 8 hours prior to dosing and 4 hours after dosing.

In the administration of sumatriptan powder by the Breathpower ™ device, subjects first administered 10 mg to one nostril themselves and then a second 10 mg to the other nostril themselves. For administration by nasal spray, the subject was first instructed on proper administration, and then the subject administered a single dose of 20 mg sumatriptan himself to one nostril. Oral tablets were ingested by the subject with 240 mL of water. For subcutaneous injection, the researcher or nominee injected 6 mg of sumatriptan into the subject's abdomen.

Subjects were revisited at visit 6 for ex-post evaluation 3-10 days after the last blood sampling to measure sumatriptan levels. Safety assessments were based on adverse event (AE) reports, physical examinations, laboratory tests, and measurements of biological signals and ECG.

Blood samples (5 mL) were administered before (time 0) and 2, 5, 10, 15, 20, 25, 30, 45 minutes, 1, 1.5, 2, 3, 4, 6, 8, 10 after administration. , 12, and 14 hours, collected in tubes containing K2EDTA. Plasma moieties were separated by placing the collection tube in a freezer centrifuge (2-8 ° C.) at 1,500 xg for 10 minutes. All plasma samples were cryopreserved at −20 ° C. until sent to a biological analysis facility. Plasma samples were analyzed for sumatriptan using a validated LC-MS / MS method at the Celerion Bioanalysis Laboratory in Lincoln, Nebraska, USA. The lower limit of quantification (LLOQ) was 0.1 ng / mL and all concentrations below LLOQ were treated as 0 for descriptive statistics and calculation of PK parameters. All PK parameters are not available in WinNonlin Professional® Version 5.2 (Mountain View, Calif., USA) and SAS® (Released Version 9.1.3, SAS Institute Inc., Cary, NC, USA). Calculated using the bulkhead method. The calculated PK parameters are shown in FIG.

The sample size was based on practical considerations rather than statistical power. A sample size of 20 subjects was determined to result in at least 5 iterations in each sequence using the 4x4 Latin square method, leading to a robust assessment of PK parameters.

Plasma concentration and PK parameter values were imported into SAS® used for all descriptive statistics calculations. Analysis of variance (ANOVA) of sumatriptan In-transformed PK parameters AUC0-∞, AUC0-t, AUC0-30min, and Cmax was used for treatment comparison. The ANOVA model included sequences, treatments, and durations as fixed effects, with subjects overlapping the sequences as random effects. Sequence effects were tested using subjects (sequences) as error terms at the 5% level of significance. Each ANOVA included a least squares (LS) mean, a difference between the treatment LS means, a standard error, and a 90% confidence interval (CI) calculation for this difference. The LS mean, the difference between the LS means, and 90% CI of each difference were raised to the power of the original scale. The two treatments are considered bioequivalent only if 90% CI of the treatment difference is completely within the acceptable range of 80-125%.

The plasma concentration-time profile of sumatriptan (Fig. 6) is a good indication of the characteristics of each of the four treatments. Total exposure is significantly less in two nasal sumatriptan treatments than in sumatriptan provided by the oral or subcutaneous route. Average plasma concentration-hour profiles up to 4 hours post-dose in the two nasal procedures show distinctly different profiles (FIG. 7) after dosing with the Breathpower ™ device, i.e. the first 30 post-dose. In minutes, sumatriptan powder from Breathpower ™ devices results in a faster increase in plasma sumatriptan concentration and significantly greater exposure compared to nasal sprays of liquid sumatriptan.

An overview of the PK parameters for the four treatments is shown in FIG. For all treatments, the first point tmax value was absent and the mean residual area (defined as AUC% extra) was less than or equal to about 5%. Nasal administration of sumatriptan powder using a Breathpower ™ device resulted in 27% higher peak exposure (Cmax) and 75, despite a 20% less dose than a nasal spray of sumatriptan. It resulted in% more early exposure (AUC 0-15 min). This represents 59% higher peak exposure and 119% higher early exposure, based on dose adjustments. The degree of systemic exposure measured by AUC0-t and AUC0-∞ over 14 hours was similar for Breathpower ™ devices and nasal spray liquid sumatriptan. In contrast, the sumatriptan powder provided by the Breathpower ™ device had significantly lower peak and overall systemic exposure compared to both 100 mg oral tablets and 6 mg subcutaneous injection. Absorption profile curves in both nasal products featured bimodal peaks consistent with the combination of early nasal absorption and subsequent gastrointestinal absorption, but these products did not show the same pattern ( FIG. 7). The early peak was higher with Breathpower ™ administration, while the later peak was higher with nasal spray administration.

The apparent final elimination half-life, located at about 3-4 hours, was comparable for the two nasal procedures and oral tablets, but shorter for subcutaneous injection, about 2 hours.

A statistical comparison of plasma sumatriptan PK parameters using the geometric mean is summarized in FIG. The overall degree of systemic exposure (without dose adjustment) was similar for breathpower ™ administration and nasal spray of sumatriptan powder, but for peak exposure and cumulative exposure in the first 30 minutes after administration. Was about 20% and 52% higher in sumatriptan powder, respectively, which means that more sumatriptan reached the systemic circulation earlier after administration, despite the dose being about 20% lower (16 mg vs. 20 mg). It suggests. For both oral tablets and subcutaneous injections, the peak and overall exposure of sumatriptan powder after nasal administration by the Breathpower ™ device was significantly lower.

Quantitative measurements of residues on the Breathpower ™ device after use showed that the device resulted in 8 ± 0.9 mg (mean ± SD) sumatriptan powder in each nostril (total dose would be 16 mg). It became clear. The degree of systemic exposure over 14 hours was similar for administration of 16 mg sumatriptan powder with Breathpower ™ and 20 mg liquid nasal spray (AUC 0-∞ 64.9 ng · hr / mL vs. 61.1 ng · hr / mL). ), But the sumatriptan powder had a 27% higher peak exposure (Cmax 20.8 ng / mL vs. 16.4 ng / mL), despite a 20% lower dose than the nasal spray. Exposure in the first 30 minutes was 61% higher (AUC 0-30 min was 5.8 ng · hr / mL vs. 3.6 ng · hr / mL). The magnitude of the difference is greater on a basis per milligram. Absorption profiles after standard nasal spray showed bimodal peaks consistent with lower early absorption and subsequent higher absorption. In contrast, the profile after administration with Breathpower ™ showed higher early absorption and lower later absorption.

100 mg oral tablets (Cmax 70.2 ng / mL, AUC 0-∞ 308.8 ng · hr / mL) and 6 mg injections (Cmax 111.6 ng / mL, AUC 0-∞ 128.2 ng · hr / mL) In comparison, the peak and overall exposure of sumatriptan powder after nasal administration with Breathpower ™ was significantly lower.

The PK property of sumatriptan powder in this study is that the initial rise rate of plasma concentration after administration of sumatriptan powder with Breathpower ™ is faster than 20 mg sumatriptan nasal spray or 100 mg oral tablets. showed that.

A comparison of various oral and parenteral formulations of sumatriptan shows that the rate of rise in plasma concentration during the early period of absorption provides a good indication of efficacy, with the clinical efficacy of a 20 mg traditional nasal spray. Explain that it is similar to the clinical effect of 100 mg oral tablets despite the large differences in plasma levels. It can also explain the 60-minute efficacy observed with the Breathpower sumatriptan powder device in patients with migraine headaches.

Assessment of the mean absorption profile for the two forms of nasal administration reveals some important differences. Unlike the range of currently available sumatriptan injectable products that are bioequivalent, the PK profile indicates that these nasal products are not bioequivalent. In liquid nasal sprays, there is a clear mixed pattern with two peaks, with a relatively low nasal absorption followed by a high degree of absorption, which appears to be near gastrointestinal absorption, consistent with most of the dose being swallowed. It suggests that it will continue. In contrast, early peaks are more prominent in sumatriptan powder, suggesting that more portion of the dose is absorbed nasally. As shown in FIG. 8, the difference between Breathpower ™ nasal powder and standard liquid nasal spray is Cmax (20.8 ng / mL pair), even without dose adjustment. 16.4 ng / mL), AUC0-30 (5.8 ng · hr / mL vs. 3.6 ng · hr / mL), and AUC0-15 (2.1 ng · hr / mL vs. 1.2 ng · hr / mL), etc. It is also evident in some of the indicators that characterize the absorption profile of. The time delay to maximum concentration for nasal spray compared to sumatriptan powder ( _{1.5 hours vs. 0.75 hours median t max} ) is also premature nasal administration with Breathpower ™. Consistent with the high rate of absorption. However, the median _tmax must be carefully interpreted in the context of the bimodal absorption profile.

It should be noted that the sumatriptan powder was administered to two nostrils, whereas the nasal spray was administered to one nostril. The effects of liquid sumatriptan nasal spray on both nostrils on pharmacokinetic profiles have already been studied and may not affect the rate or degree of absorption compared to single nostril administration. It has become clear. Therefore, this difference in dosing procedures does not appear to explain the findings in this study.

The amount of sumatriptan powder contained in a pair of drug capsules administered using the Breathpower ™ device was approximately 20 mg. However, the average dose measured was 16 mg, which is 20% less than the 20 mg sumatriptan administered by nasal spray. This further emphasizes the differences in both the rate and degree of absorption seen between the two different nasal administration methods.

Sumatriptan liquid nasal spray has not yet been widely used. This may, in part, reflect a lack of motivation because the perceived significant benefits of nasal spray administration are limited by the inherent inadequacy of nasal spray administration. The difference between nasal and oral administration may not be observable in many patients, given that in many subjects many parts of the drug are absorbed from the gastrointestinal tract. Breathpower ™ administration of sumatriptan powder is typical by distributing the powder to the area beyond the nasal flap, producing an absorption profile with relatively high nasal absorption and low gastrointestinal absorption. Avoid many of the inadequacy of spray administration. The large differences seen in the rate and extent of absorption at the earliest time after treatment may be due to greater absorption through the nasal cavity. Although this study targeted healthy volunteers, the proportionally greater changes towards nasal absorption were more pronounced in the difference between oral and Breathpower ™ administration than in healthy volunteers. It can be especially important in the clinical context of migraine patients who can become. Numerous studies have shown that gastric emptying is slow in patients with migraine headaches, and the risk to the reliability and rate of drug absorption after oral administration in such patients and the risk to the oral PK curve "to the right". It suggests "movement of". Although hypothesized, the rate of rapid rise of blood levels of sumatriptan results in a faster rate of onset or greater efficacy, so administration by Breathpower ™ is faster than oral or nasal sprays. It is important to note that it involves an initial rise rate. A further theoretical advantage for achieving true nasal administration enhanced by positive pressure exhalation is that the drug and carbon dioxide are delivered to the first branch of the trigeminal nerve and the pterygopalatine ganglion of the parasympathetic nerve. ..

The use of injectable or oral triptans may be associated with tolerance and safety concerns. The study revealed that peak and overall systemic exposure with the Breathpower ™ sumatriptan powder device was significantly lower compared to tablets or injections. Less exposure can be translated into a better safety and permissive profile. From this study, there were no systemic side effects, only one subject reported dysgeusia, and breathpower ™ administration of sumatriptan powder was safer and better tolerated by healthy subjects. It became clear that In contrast, 4 subjects experienced fever after subcutaneous injection and each of 3 subjects reported nausea after tablets and injection.

It is concluded that nasal administration of breathpower ™ of sumatriptan powder results in a faster and more efficient absorption profile when compared to nasal sprays and significantly lower exposure levels than tablets or injections.

Figures 10-12 show nitroglycerin compared to the sumatriptan PK parameters of healthy subjects obtained using a Breathpower® (Optinose) delivery device and an Imtrex® nasal spray (GSK). The sumatriptan PK parameters for GTN) -induced migraine are shown.

It is believed that spontaneous changes can result in better absorption and the effect of unilateral delivery to the migraine side. One-sided activation of the trigeminal nerve can alter the nasal mucosa to result in increased nasal absorption and delayed gastrointestinal absorption. Spontaneous activation of the trigeminal nerve allowed more efficient administration of carbon dioxide and made the mucosa more susceptible to pressure. As can be seen from FIG. 10, 7.5 mg brought to the migraine side during a GNT attack in migraine patients resulted in 27% bioavailability. The Cmax for administration on the migraine side is 11, while it is only 9.7 for Imitrex nasal spray. Administration of 7.5 mg to each nostril does not appear to result in higher bioavailability.

Breathpower nasal administration of sumatriptan powder is a more efficient form of drug administration, producing higher peaks and earlier exposure at lower doses compared to nasal sprays, nasal sprays or oral. Produces faster absorption compared to administration. It also results in significantly lower peaks and overall systemic exposure compared to oral tablets or subcutaneous injections.

This study is a double-blind study with a Breathpower ™ device that delivers 20 mg sumatriptan on both sides and a 100 mg sumatriptan tablet. This study is a crossover design in which each subject patient treats headache with their own treatment. Specifically, the patient treated up to 5 headaches with one treatment and then with a crossover up to 5 headaches with the other treatment. In each headache, the patient used the device and took tablets, only one of which was effective. From data on more than 400 unblind headaches so far, the results obtained at 30 minutes for moderate or severe headache (relief of headache 30 minutes after ingestion of the drug) are 54. %.

The literature states that the reaction at 30 minutes from a 100 mg tablet of sumatriptan should be about 9-14%. This indicates that the kinetics seen in the placebo device are much faster than those previously observed with oral tablets alone.

Nasal formulations of dihydroergotamine mesylate (DHE), sumatriptan, zolmitriptan, butorphanol, shibamide, and lidocaine have all been used / studied for the treatment of migraine and / or swarm headache. Cibamid and lidocaine have been administered by nasal droppers to disrupt nerve transmission, and although there is some evidence of clinical efficacy, they are still approved by the U.S. Food and Drug Administration for the treatment of headaches. No. In addition, nerve stimulation of SPG has shown promising results in stopping the progression of cluster headaches, strongly supporting the possibility of topical treatment of nerves accessible through the nasal cavity.

DHE, sumatriptan, zolmitriptan, and butorphanol have been approved for the treatment of migraine headaches and can be administered by patients in the form of traditional nasal sprays. DHE is known to be a highly effective drug when administered intravenously. Unfortunately, the bioavailability of oral administration is less than 1%. However, it has ~ 40% bioavailability in the case of nasal administration and the drug can be used in outpatient situations. In addition to nasal formulations, sumatriptan is available as subcutaneous injections, oral tablets, suppositories, and ready-to-dissolve tablets (outside the United States). In addition to nasal formulations, zolmitriptan is available as oral tablets and fast-dissolving formulations. For both drugs, the nasal prescription is an alternative to the oral prescription, taking the oral drug in the presence of slow onset, less GI absorption during headache from slow motility, and nausea. Introduced to overcome the problem of patient aversion to things.

Both nasal sumatriptan and nasal zolmitriptan have proven superior to counterfeit drugs in providing migraine symptom relief, and nasal zolmitriptan is the same amount of zolmitriptan oral tablets. It has been proven to bring about earlier mitigation compared to. Both result in faster absorption than their respective orally administered tablets. However, none of them have resulted in a significant improvement in overall bioavailability compared to oral.

Traditional nasal sprays of these triptans have a fairly small early peak (due exclusively to absorption in the nasal mucosa) and a subsequent clearer peak (a significant amount of GI absorption of the drug swallowed after bypassing the nose). The absorption pattern of the two peaks having (representing) and is shown. For zolmitriptan, the nose was quantified in the study and revealed to account for about 30% of total absorption. Similar studies have not been performed on sumatriptan nasal sprays, but the pharmacokinetics of sumatriptan liquid nasal sprays have been studied. The approved amount for nasal zolmitriptan is the same as the highest amount for tablets (5 mg), while the approved traditional sumatriptan nasal spray amount range (5, 10). , And 20 mg) is one-fifth that of oral administration (25, 50, and 100 mg). As a result, systemic exposure is significantly lower in the amount range of sumatriptan nasal spray compared to oral formulations, while it is similar or slightly higher in nasal zolmitriptan. The opportunity to result in lower doses is the potential for nasal administration of sumatriptan (against zolmitriptan), as the risk of systemic and GI-related side effects can be reduced by lower systemic exposure compared to oral prescriptions. Emphasize the benefits.

Despite the theoretical benefits of nasal drug administration, there are obstacles to its widespread adoption in the treatment of migraine headaches. For patients, the consequences of improper adhesion to the target mucosa achieved with traditional nasal sprays are considered to be an important factor causing the lack of perceived clinical benefits compared to oral treatment. Future studies have shown that the rate of onset is an important motivation for patients to choose a nasal spray. Moreover, for obvious reasons, other formulations that offer the potential for faster absorption may be preferable to simply increasing the amount of orally administered formulation. Improving the tolerance or safety of oral prescriptions would simply increase the likelihood of choice by the patient if they are accompanied by benefits of core efficacy such as improved rate of onset.

Traditional spray pumps used in nasal sprays have limited adhesion of the drug to the target site beyond a narrow triangular stenosis called the nasal flap located about 2 cm from the entrance to the nostril. The purpose of the narrow nasal flap is to work with the complex and intricate nasal passages to filter and regulate inhaled air, enhance the sense of smell, and optimize fluid retention during gas exchange and exhalation. These important functional features of the nose impose important, often non-negligible, constraints on efficient nasal drug administration.

For example, the expanding convex eruption and high particle velocities radiated from the spray bottle are most likely to hit the walls of the nasal vestibule. Increasing the propulsion of nasal administration also changes the basic anatomical constraints, as the eruption hits the surface it first reached, while "nasal inhalation" exacerbates the problem, as described below. It doesn't mean that. The anterior part of the nasal cavity, the nasal vestibule, is primarily covered with ciliated flat epithelium and is less efficient at absorbing drugs than the ciliated airway epithelium beyond the nasal flap. Due to this inconsistency between the shape of the anterior region of the nose and the eruption, only a small portion of the spray enters past the nasal flap and most of the spray volume remains in the vestibule.

Most of the liquid in the vestibule of the nose can drip or be wiped off. Inhalation through the nose during administration further narrows the nasal flap, and reflexive nasal inhalation to avoid dripping after administration not only further narrows the nasal flap, which is already very narrow on the upper side. It is thought that the slit-shaped deeper nasal passage is already shrunk. This tends to undermine both the intended aiming for a large nasal surface area and the potential benefit of higher adherence, and tends to guide the drug through the nasal flap along the bottom of the nostril to swallow. Has. The taste buds, which detect bitterness located at the base of the tongue, are exposed to the concentrated liquid that causes the intense bitterness often reported in these nasal sprays. Only a smaller percentage of the spray reaches the highly vascular respiratory mucosa, which accounts for the majority of early nasal absorption. Thus, the GI tube contributes more to the amount of drug absorbed than the nose, as a significant portion of the drug provided by traditional nasal sprays is swallowed rather than absorbed by the nose. .. This phenomenon is observed in sumatriptan with bimodal absorption profile after traditional nasal spray administration, with a low early peak appearing to be related to nasal absorption 20 minutes later, followed by 90 minutes. High absorption peak due to GI absorption around.

The predominance of oral absorption following traditional nasal spray administration reduces the intended benefits for nasal administration. That is, the lack of significant differences from oral tablets results in only slightly faster onset of action in some patients, resulting in limited market acceptance of nasal sprays.

In particular, both the sensory and parasympathetic branches of the trigeminal nerve, which are involved in the pathophysiology of migraine and other headaches, stimulate the mucosal surface beyond the nasal flap, where SPG is also located. To the extent that these structures are involved in the pathophysiology of headache, the upper and posterior parts of the nasal cavity are considered interesting targets for current and future drug interventions, but are not effectively reached by standard nasal sprays. It is possible.

A comprehensive review of adhesion patterns for nasal drops and spray pumps has led to the conclusion that traditional delivery devices are not optimal for delivery to the respiratory mucosa beyond the nasal flap. Several techniques that attempt to improve the delivery of traditional spray pump drugs have been proposed and tested for many years, but are generally impractical, suboptimal, or repetitive nasal administration studies in humans. Has not yet been proved in. Efforts to optimize traditional nasal sprays by improving the way they are used have also been unrewarded, and studies have tested seven different head and body positions using traditional nasal sprays. It was concluded that "there is no best way".

The breath-powered bidirectional delivery mechanism described herein is feasible in simple devices without the cost or complexity of electromechanical machines and overcomes a number of drawbacks of traditional nasal administration. Such devices can be used to deliver both liquid and powdered agents. This concept of nasal administration consists of a device comprising a flexible mouthpiece and a molded sealed nosepiece. It utilizes a unique aspect of nasal structure and physiology to improve the degree and reproducibility of drug delivery to the target site in the nose beyond the nasal flap while avoiding the risk of lung inhalation. Designed.

In one movement, the user slides the molded nostril into one nostril to create close contact with the nasal tissue, inserts the mouthpiece between the open lips, takes a deep breath, and puts the lips into the mouthpiece. Close around the mouth and then exhale strongly into the mouthpiece. Mouth exhalation to the device creates positive pressure in the oropharynx, which naturally lifts and brings the soft palate into close contact, completely separating the nasal cavity from the oral cavity. Due to the close contact of the nosepiece, airflow and dynamic positive pressure are transmitted by the device to the nasal cavity, inflating the nasal flap and narrow slit passages. The pressure in the nasal cavity, which is slightly lower than the driving pressure in the mouth due to the resistance of the device and the nasal passages, balances with the pressure across the soft palate, largely avoiding excessive lifting of soft tissue. This generally maintains the opening of the communication path between the two nostrils located behind the nasal septum at the back of the nasal cavity, allowing exhaled breath to escape from the opposite nostril while relieving excessive pressure in the nasal cavity. to enable.

A dedicated multi-use breathpower powder device with a reusable device body and a disposable nosepiece has been developed for use in patients with migraine headaches. 11 mg sumatriptan powder is placed in standard respiratory capsules and provided to the patient in a disposable nosepiece capsule chamber. There can be a small airflow entrance at the bottom of the room and a larger opening at the top. Prior to use of the device, a new nosepiece can be fitted to the top of the device and the capsule can be punctured by pressing a button on the device body. In exhalation to the device, the punctured capsule can vibrate and / or rotate with exhaled breath, releasing the powder into the air stream. The nasal cavity before the drug particles are carried backwards by the expansive flow of physiologically warmed air into one nostril past the nasal flap and the air reverses its path and escapes forward through the other nostril. Can adhere widely over the entire position in the back of the nostril.

Numerous studies assessing differences in anthropometry between individuals were performed to result in the proper design of the device to accommodate differences in individual nostril size and distance and angle between the mouth and nose. Ease of use and clinical trials have shown that the design is well accepted in terms of comfort and ease of use.

The scintigraphy techniques used in decades to investigate nasal adhesions of liquid and powder formulations in vivo are relatively crude and reliable patterns of adhesion and elimination per nasal region. Does not allow absolute or relative quantification. An improved system has been introduced that allows reliable quantification of the attachment of radiolabeled particles per nasal region in subjects, clinically comparing traditional nasal spray devices with breath power devices for both liquid and powdered drugs. Used in adhesion tests.

In a recent study, a Tc99m-labeled lactose powder was provided by a breath power powder device. Capsule filling and particle size profiles similar to sumatriptan powder are used. To measure the difference in adhesion, the nose was divided into three horizontal parts, a vertical dividing line was placed on the head of the inferior turbinate, and the radiation count inside each part was quantified after administration. ..

Breathpower powdering devices show more extensive attachment in areas where the nasal mucosa is covered by ciliated airway epithelium, especially in the upper posterior and middle posterior areas, but also in the upper anterior and middle anterior areas. In the nasal vestibule, there was less adhesion and significantly more initial adhesion to the upper posterior region beyond the nasal flap compared to conventional spray administration (~ 54% vs. 16%) (Fig. 11a). In contrast, in liquid sprays, most of the dose adhered to a limited area of the lower nose (~ 60% vs. ~ 17%) (FIGS. 11a, 11b).

Region-by-region analysis of adhesion and elimination shows that the Breathpower powder device results in extensive exposure to the highly vascularized respiratory mucosa beyond the nasal flap, especially improving delivery to the central and upper regions of the nasal cavity. , Clearly shows. This is reasonably expected to lead to faster and more pronounced drug absorption than is achieved with standard nasal spray administration for the appropriate drug. This difference is reflected in the improvement of PK and ultimately in the improvement of efficacy, so it should be possible to measure objectively. Such studies are now being conducted to evaluate the outcome of administration of sumatriptan in this manner.

Two studies evaluated the PK of sumatriptan administered by a breath power device. Twelve patients were treated with either subcutaneous (SC) injected sumatriptan or sumatriptan powder provided by a breath power device prior to an attack with nitroglycerin (GTN attack), which is known to cause migraines. This was a crossover study in patients with migraine headaches. A second study larger than 40, sumatriptan powder (15 mg dose shared between nasal passages) administered by a breath power device, 20 mg sumatriptan nasal spray (one nasal passage), 100 mg sumatriptan tablets. , And a 4-way crossover study in healthy volunteers compared to 6 mg sumatriptan SC injection. In both studies, there was a bimodal absorption pattern representing early nasal absorption and subsequent GI absorption for breath power administration (Fig. 12). The early peaks observed in both studies were more prominent than the peaks observed in standard nasal sprays (measured in the second study), except for more efficient and rapid systemic absorption in breath power devices. It is shown together with the PK parameter of (Fig. 12). Also, absorption occurs earlier than with tablet administration, but peak and total systemic exposure is significantly lower than with either oral tablets or subcutaneous injection.

The nasal peaks of sumatriptan powder are very similar in two PK studies, one in migraine patients and one in healthy volunteers, occurring early in both populations. However, the later peak, which appears to represent exclusively GI absorption, is significantly smaller in studies performed in migraine patients during a GTN attack (Fig. 12). This may reflect slower and lesser GI absorption due to the autonomic dysfunction observed in migraine patients, which is further emphasized during the attack.

It should be noted that the sumatriptan powder was distributed to the two nostrils, while the nasal spray was administered to only one nostril. The effect of splitting the dose of liquid spray between the nostrils on the PK profile has already been investigated and revealed that it does not improve the rate or degree of absorption compared to administration to a single nostril. ing. Therefore, this difference in the method of administration does not appear to explain the findings in PK studies of healthy subjects.

When reviewing pharmacokinetic data, it is important to remember that the total amount of sumatriptan administered by the breath power delivery device is 20-25% less than a 20 mg liquid spray of sumatriptan. By increasing nasal absorption with breath power administration, the proportion of sumatriptan that bypasses the nose is lower compared to sumatriptan spray, and the dose is split between the two nostrils (Fig. 12). Lower doses, wider nasal distribution, and significantly altered clearance patterns after breathpower administration (note that the soft palate is usually substantially closed at the time of administration) reach the taste buds located at the base of the tongue. It is thought that the amount and concentration of the drug are further reduced to reduce the intensity of bitterness perception. The results show that the increased attachment to the nose produced by the breath power device is actually linked to pharmacokinetic benefits.

Increased early absorption can provide benefits for improved efficacy, especially faster onset of pain relief, and lower doses improve tolerance or safety. It is reasonable to make a hypothesis that it can be done. The ability to prevent migraine attacks in studies with GTN attacks, combined with findings in similar EEG records after SC and Breathpower powder administration, has clinically significant potential despite much lower blood levels. Suggests an advantage. These findings provided the rationale for advancing to a randomized placebo-controlled study with a breath-powered sumatriptan delivery device.

In a first placebo-controlled parallel group 3-group study in acute migraine (117 patients in total), two doses of sumatriptan powder were administered with a breathpower device and combined with a "placebo" control group using a dummy device. Compared. Rapid onset of pain relief was observed with both effective doses, and the degree of early pain relief was similar to historical data for SC injections despite much less systemic exposure. Also, significant benefits were observed for pain relief at 120 minutes at both doses, and the higher dose was selected for further development. The higher dose resulted in a 60% (P <.01) response to 44% with placebo at 2 hours, 60 minutes (74% vs. 38%, P <.01) and 30 minutes (P <.01). It resulted in a high early response rate at 54% vs. 31%; NS).

A Phase III placebo-controlled parallel group 2-group study in 212 patients was recently performed on sumatriptan powder administered by a breath power device. As discussed and shown below, at 2 hours post-dose, a significant proportion of patients faced pain relief (68% vs. 45%, P <.01) and the high value of triptan treatment compared to placebo. .. However, again the most striking result was the rapid onset of pain relief with a significantly higher response rate (42% vs. 27%, P <.05) at 30 minutes. This is particularly noteworthy in light of the very low doses of triptans. The reported adverse events were predominantly mild and transient and were largely confined to the site of administration. It was concluded that breathpower administration of nasal sumatriptan powder is effective, safe, shows good tolerability and can provide a rapid onset of pain relief in adults with acute migraine. rice field.

[Example 5 (a)]
The purpose of the study is to compare the efficacy and safety of breathpower sumatriptan powder with placebo in the treatment of patients with moderate to severe migraine headaches. Patients taking oral triptans generally mention slow onset of action, inadequate pain relief, and side effects as reasons for dissatisfaction, and nausea or vomiting can also be a barrier to use. The side effects known as "triptan action" are most often associated with formulations and dosages that produce higher plasma concentrations. In a small study, the low dose sumatriptan powder provided by the breath power device produced a headache relief rate close to the rate already reported for injection, without associated side effects.

Single dose, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Patients had a history of migraines for more than a year prior to participation, with more than one day and less than 15 days complaining of headaches per month. Patients were randomized to a breath power device containing either 20 mg sumatriptan powder (15 mg released) or placebo. Patients treated seizures that reached moderate or severe intensity and recorded symptoms at the planned time.

The results are roughly shown in FIG. Specifically, 223 patients were treated (112 with sumatriptan powder, 111 with placebo). The average age was 42 years and 85% were female. The main result was that at 120 minutes, 68% of patients in the sumatriptan powder group reported pain relief, compared with 45% in the placebo group (p <.01). The pain relief curves were separated early and became statistically significant at 30 minutes (42% vs. 27%; p <.05). At 120 minutes, 37% of patients receiving sumatriptan powder reported complete relief, compared with 17% (p <.01) of placebo, patients who reported meaningful relief. Was 45% (p <.001) with respect to 70%. Of the patients whose pain was relieved at 120 minutes, 65% had sumatriptan powder and 53% had placebo (ns), and pain relief continued even at 24 hours. Significant reductions in nausea, noise phobia, and photophobia have been reported. In both groups, the differences between the groups were not statistically significant. Systemic adverse events have only been reported in one patient. Only patients reported slight and temporary hand and head tingling. The most common (> 5%) AEs reported were product taste (22%), nasal discomfort (13%), and rhinitis (6%), all of which were temporary and generally mild. ..

This study also found that breath-powered devices that administer small amounts of sumatriptan powder produce early headache relief in a large proportion of patients compared to historical rates in placebo and oral treatment, resulting in a high rate of headache relief. It is a repetition of the previous discovery that causes. Treatment was well tolerated and there were few systemic adverse events.

Comparison of these results with published data shows that the rate of onset of pain relief is much faster than oral treatment, approaching the rate achieved with SC injection, but systemic exposure is significantly lower and therefore concomitant. It suggests that the risk of adverse events is significantly lower.

Interesting high placebo response rates have been observed in each clinical trial with Breathpower administration. In these trials, control patients used the same breath power delivery device as the effective patients, rather than undergoing "no treatment". Note that the high response in these "placebo" patients may be due to chance, long-term tendency, or other factors, but there are also potential explanations directly related to the use of breath power devices. That is interesting.

During normal breathing, there is minimal sympathy of air in the narrow area above the nose. A breath power delivery device that contains about 5-6% carbon dioxide, has a flow rate of about 30 L / min or more, lasts for about 2 to about 3 seconds, and sends a large amount of exhaled air that enters the narrow part of the upper part of the nose. Specific aerodynamics have been reported at 100% carbon dioxide administration (although this carbon dioxide administration is performed for a short duration, at low flow rates (10 mL / s) and at low doses). It is possible to bring about the same therapeutic effect as the therapeutic effect. In the breath power device of the present invention, vibrating capsules and airflow can significantly enhance air exchange in the narrow part of the upper part of the nose, as partially observed in response to humming and pulsating nebulizers. Presumed. In addition, the hypothesis that the potential positive effects achieved by positive barometric pressure, the rapid vibrations produced by capsule rattling, and the elimination of NO can all play a role in migraine relief. There is a reason to stand. One or more of these device-related mechanisms and other device-related mechanisms may contribute to the high response rate of the placebo group in breathpower-administered trials in migraine patients.

The deep attachment of the nasal cavity with respect to breath power administration allows for the wider potential of the drug to the trigeminal-distributed tissue and SPG, which can be beneficial in the treatment of various headache disorders. The aerodynamic properties of the device itself can provide different mechanisms of action and / or synergies.

In addition to its potential in neutralizing or preventing migraines, cluster headaches and trigeminal headaches include, for example, triptans, DHE, lidocaine, nonsteroidal anti-inflammatory drugs (NSAIDs), topical corticosteroids, and potential. It represents a target indication of the possibility of administration of a number of new or current agents, such as CGRP antagonists, alone or in combination. There is a major unmet need to improve current equipment to optimize administration for treatment specifically intended to target the region closest to SPG for optimal efficacy. Can be done. Other potential signs include chronic migraine headaches in which very small daily doses of triptans or other agents in this manner can provide adequate receptor inhibition and reduce the number of acute attacks. .. Even topical steroids can be beneficial as a single or postoperative adjuvant therapy in cluster headaches or headaches due to sinusitis.

Nasal administration of the drug has long been a route of administration known to be useful in the treatment of headaches and other diseases. However, typical methods of nasal administration are relatively successful in delivering the drug to the posterior / upper region of the nasal cavity where the drug can be widely, rapidly and efficiently absorbed and other benefits can be effectively produced. There is little effect. Therefore, the promise of nasal drug administration has not been fully realized. In vivo human gamma attachment studies with a breath power device demonstrate that the mechanism of this novel device can result in significantly improved nasal drug attachment patterns. A pharmacokinetic study to assess the outcome of this improved adhesion was performed following the administration of a small amount of sumatriptan powder, and this improved administration was performed on the nasal mucosa when compared to standard nasal sprays. It has been shown to be associated with increased absorption rates and efficiencies as well as reduced rates of GI absorption. In repeated clinical trials, small doses of sumatriptan breathpower administration resulted in a significant response rate and early pain relief similar to SC injection rather than other forms of administration, but orally or SC. It has now been shown that the exposure is much lower than the treatment with. This new form of nasal administration can provide some interesting treatment options for the treatment of various headache disorders in the future.

In another example, administration of a nominal 20 mg sumatriptan dry powder using a Breathpower ™ Deliverer (BPPSIT) was found to result in 16 mg nasally. This means that the total exposure to sumatriptan in this device is a total milligram dose less than tablets, nasal sprays, or injections. However, direct comparative pharmacokinetic studies have shown that 16 mg BPPSIT powder treatment produces higher peak concentrations (Cmax ng / mL) than 20 mg conventional liquid sumatriptan nasal spray (20.8 mg vs. 20.8 mg). 16.4 mg, no dose adjustment). Both nasal formulations produce significantly lower peak concentrations (Cmax ng / mL) than sumatriptan tablets (100 mg tablets = 70.2.6 mg) or subcutaneous injections (6 mg = 111.6 mg). Similarly, total drug exposure measured by the area below the curve (AUC 0 ng ^* hr / mL) is also compared to 100 mg tablets (308.8 mg) or injections (128.2 mg) in nasal formulations. Much less (BPPSIT = 64.9 mg, traditional sumatriptan liquid nasal spray = 61.1 mg, no dose adjustment). The sumatriptan powder administered by BPPSIT is not bioequivalent to any sumatriptan product tested. In particular, the pharmacokinetics of BPPSIT showed a faster and more efficient absorption pattern compared to traditional liquid nasal sprays, with 20% less drug administered but liquid sumatriptan at AUC 0-15 minutes. 1.2 for nasal sprays vs. 2.1 for BPPSIT, AUC 0-30 minutes is 3.6 for conventional sprays vs. 5.8 for BPPSIT, i.e. early It should be noted that plasma exposure is even greater than the 60% increase.

A Phase 2 randomized controlled trial of BPPSIT, published in 2010, included 117 adult subjects with temporary migraines. There are three groups: a group of 10 mg sumatriptan powder, a group of 20 mg sumatriptan powder, and a placebo. All treatment groups, including placebo, used a breath-powered bidirectional device. Similar to the Phase 3 study described below, subjects were instructed to take action when migraine headaches were moderate or severe. Phase 3 studies used only nominal 20 mg doses that resulted in 16 mg nasal as described above, and therefore only those data were examined.

In a Phase 2 study, pain relief at 2 hours occurred in 57% of 20 mg subjects and 25% of placebo subjects (P <.05). Headache relief at 2 hours, defined as the transition from moderate to severe headache to none or mild headache, was fairly high and statistically significant, 80% for 20 mg and 44% for placebo. Both doses were statistically separated from placebo for headache relief up to 60 minutes. The most frequent treatment-related adverse event was the metallic flavor that occurred in 13% of the 20 mg subjects.

In a Phase 3 defined central study of BPPSIT 20 mg, the TARGET study, there were 223 randomized subjects (112 were BPPSIT, 111 were placebo-filled devices) to be treated. The primary index of outcome was headache relief in 2 hours that occurred in 67.6% of subjects in the BPPSIT group and 45.2% of subjects in the placebo group (P <.01). For headache relief, BPPSIT reached a statistically significant distance from placebo earlier than in the Phase 2 trial, a time of 30 minutes (41.7% vs. 26.9%; P <.05). Pain relief at 2 hours occurred in 34% of subjects for BPPSIT, compared to 17% for placebo (P <.01).

Adverse events that occurred above 5% included abnormal taste (22%), nasal discomfort (13%), and rhinitis (6%). Both were temporary and generally minor. No serious adverse events occurred in the central study.

There are some issues that are worth investigating in the BPPSIT data. They include the difference in efficacy between Phase 2 and Phase 3 studies, overall efficacy, early response, and placebo response and therapeutic effect (TG). The data from Phase 2 was remarkable, with about 80% rating headache relief at 2 hours, but in Phase 3, the number at 2 hours was not so high, about 67%. Closer to the upper end of the traditional triptan range, the figure at 30 minutes was 42%, significantly higher than the values reported for oral treatment and various injectable triptans. This can probably be explained simply by the number of subjects in Phase 3 which is more than double that of Phase 2. There are numerous cases in which clinicians change their drug ratings from Phases 2 to 3 due to the differences in results that become apparent with a larger number of subjects (N). The smaller the number of subjects, the more likely the results will be at the mercy of random variation.

However, the reaction rate may actually be higher in BPPSIT, and one possibility is that the device is the reason. That is, perhaps a higher response occurs when sumatriptan powder is delivered high up in the nose near the lateral edge that abuts the pterygopalatine canal, which includes the pterygopalatine ganglion and the superior bifurcation of the trigeminal nerve. The potential action of triptans on these key structures for migraines and cluster headaches may deserve further investigation.

Headache relief at 2 hours is considered to be clinically important for patients, although it is a standard primary outcome variable in most Phase 3 migraine trials because it is the only time point. It does not provide information about the early effects that can be achieved. In BPPSIT, the reaction at 30 minutes ranged from 42% to 49%. This is a high response rate at this early point in time. Data from a randomized, controlled, prescribed trial included in the Food and Drug Administration-approved prescription information for almost all approved triptans provides a graphic of pooled efficacy data explaining the headache response. Examination of these graphics shows that the headache response at 30 minutes with sumatriptan injection is in the range of 50%, while the pain relief at 30 minutes is 10-20% in the oral formulation. It is clear that it is 20-30% in conventional nasal spray formulations. These data suggest that the early response rate of BPPSIT can approach the early response rate observed in injection compared to the early response rate reported in other non-injection dosage forms.

It is interesting to note that such a small actual dose of 16 mg can have near-injection efficacy at an early stage and can be comparable to a 6-fold dose tablet at 2 hours. In general, comparable efficacy at low exposures is attractive when considering the potential for adverse events.

Further scrutiny of the BPPSIT Phase 3 trial shows that the placebo rate appears to be fairly high, with headache relief of 45.2% at 2 hours and still high at 44% in the Phase 2 trial. In contrast, in a paper by Ryan and his colleagues summarizing two Phase 3 trials of traditional sumatriptan liquid nasal spray, the rate of headache relief at 2 hours of placebo was 29 and 35%. Is. There is a tendency for placebo rates to gradually increase over time in triptan randomized controlled trials. For example, in the study used to approve oral sumatriptan tablets, the placebo response rate was 17%. Increased placebo response rates, including the absence of triptan inexperienced patients with concomitant elevated patient expectations for triptans, and changes in the study population when the patient background pool is affected by the wide availability of triptans. There are numerous hypotheses to explain.

In the case of BPPSIT, the device itself may be responsible for the high placebo response rate. Many researchers are aware of higher placebo rates in the context of device testing. As one group of researchers states, "the placebo / anti-placebo response to sham treatment with the device is similar to that previously reported for long-term drug treatment." For the high placebo response rate in the Phase 3 trial, one possibility was the novelty and use of the device itself.

The technical reason for the high placebo response may be that the rate of severe headache at baseline was significantly lower at 17% in this Phase 3 trial. In previous triptan studies, the rate of severe headaches is typically higher. Fewer intense baseline assessments compared to moderate baseline assessments are expected to result in a higher placebo response in view of standard assessment measures and analytical methods.

It is possible that the placebo group provided effective treatment. The placebo in the BPPSIT test was treatment with an OPTINOSE device (carbon dioxide pressure and lactose powder). Although this could clearly be considered a fake treatment, there is in fact literature on the beneficial effects of carbon dioxide on migraines. In a preliminary study available only in the form of a summary, Spierings and colleagues found that continuous carbon dioxide infusion for the acute treatment of temporary migraines was highly statistically significant compared to placebo. It was found to result in a response of pain relief (25.0% vs. 4.8%) (P = .006) at 2 hours.

That is, carbon dioxide is probably part of the pain regulation system. Vause and colleagues commented on their findings in 2007-cultured rat trigeminal ganglion cells: "Culturing major trigeminal ganglion cultures at pH 6.0 or 5.5 is a calcitonin gene-related peptide (CGRP). It has been shown to greatly stimulate liberation, ... carbon dioxide treatment of cultured tissues under isothermal conditions ... greatly stimulates KCI, capsaitin, and nitrogen oxide on the secretion of CGRP. Suppression, carbon dioxide treatment under isothermal conditions ... results in a decrease, ... an increase in intracellular calcium via capsaitin, but carbon dioxide suppresses sensory nerve activation and thus nerves. It provides the first evidence of a unique regulatory mechanism by suppressing the release of peptides. " Furthermore, the observed inhibitory effect of CGRP secretion on carbon dioxide is thought to include regulation of calcium channel activity and changes in intracellular pH.

Therefore, the carbon dioxide "placebo" of BPPSIT may provide some degree of treatment, i.e. it may not be a true placebo reaction. The fact that both Phase 2 and Phase 3 studies showed high placebo response rates of 44-45% suggests this possibility. However, there is precedent for the high placebo rate in new triptan administration trials. In a test of tablets that can be dissolved in the mouth of the first rizatriptan, the placebo rate was 47%. The unknown concentration of carbon dioxide in the Spierings device compared to BPPSIT limits the opportunity to further investigate this possibility at this time.

A further issue to consider in the BPPSIT Phase 3 data is the issue of TG, which is defined as the difference obtained when the response in placebo is subtracted from the response in active drug. For headache relief at 2 hours with 20 mg, the TG in Phase 2 was 36 and in Phase 3 it was 22. This second TG appears to be firstly located at the lower end for the triptan. In fact, the TGs of the two BPPSITs would appear to be comparable to the TGs in sumatriptan liquid nasal spray if the use of TGs is selected in the study (more on this later). The TGs in five trials of traditional sumatriptan liquid nasal spray were 25, 25, 29, 35, and 36.

Sheftell and colleagues evaluated whether the conversion of triptan efficacy data to TG would be useful. The intent of TG is to reveal the true effect of a drug despite changes in placebo. Surprisingly, it was found that TG correlates more strongly with placebo reactions than with effective drugs. It should be noted that TG should not be used to compare triptans and that treatment of migraine headaches can only be compared by using well-designed one-on-one studies, not by meta-analysis.

For analytical purposes, this issue was reviewed and compared for headache relief at 2 hours as reported in the package insert of the study on responses to effective and placebo drugs (FIGS. 14 and 15). According to TG's theory, the response rate of an effective drug to a placebo must have a better positive correlation than the correlation between the effective drugs. For TG to be a useful concept in the interpretation of migraine studies, the response observed in treatment with an effective drug must fluctuate in proportion to the response rate in the placebo observed.

However, perhaps unlike other applications of the concept of TG, it is clear that the response rate in placebo varies widely but has little or no effect on response rate in effective agents. Data on triptans show that there is a large variability in response to placebo between studies on a given drug, as seen on the X-axis of FIG. At a given effective treatment, the response rate at an effective drug is much less variable between studies, as seen as a relatively flat line on the Y-axis of FIG. 15 across the rate for placebo. There is no noteworthy correlation between the reactions observed in the placebo and effective drug groups. In the studies drawn, the effective drug: placebo R2 = 0.02.

The response rate at an effective drug better reflects the true therapeutic effect than TG, which does not appear to be a useful idea in migraine headaches, but as stated in 2001, a well-designed pair. One study remains the basis for comparison. As already mentioned, the headache relief rate in BPPSIT seems to be historically consistent with other triptan treatments at 2 hours and probably historically in injectable sumatriptan at 30 minutes. It may be reasonable to say that it approaches the response rate reported in. This rapid onset can be important for patients, especially those who require rapid onset as already mentioned. Again, it should be noted that this reaction is achieved at doses as low as 16 mg. Again, this suggests the potential for desirable safety and tolerability when compared to higher dose treatments, but contributes to the possible efficacy of the unique activity of the intranasal device or drug. It also emphasizes interesting questions about.

Acute treatment of migraine requires the needs of individual patients to be investigated by drugs and prescriptions. In particular, nausea and response, quick time to peak intensity, and in fact all of the common gastroparesis in migraine patients require various parenteral formulations for the treatment of seizures. As generic triptans become available, attempts are being made to use them in new formulations. The novel BPPSIT provides at least an improvement in pharmacokinetics compared to traditional liquid nasal sumatriptan sprays.

The device used for drug administration in this breath-powered nasal sumatriptan uses the natural nasal structure to close the soft palate and advance a small amount of powdered sumatriptan upward in the nasal cavity on one side. This technique can reduce adverse events and improve efficacy.

Creating a new dosing system for known and effective migraine medications is certainly a valuable endeavor. The clinical role of fast-acting parenteral nasal formulations, as already mentioned, is that tablets are destined to fail, namely those in nausea and vomiting situations, central sensitization, migraine, And the time to remedy of migraine is too short for the patient to respond to the tablet in view of the unpredictable and slow absorption profile of the oral drug. Further studies should reveal whether this new system will provide the predicted benefits in rate and efficacy of expression clinically with fewer adverse events than previous parenteral formulations. be.

In another study, the results of nasal pH measurements during Breathpower ™ Bi-Directional ™ administration were analyzed. In some embodiments, these data can be considered as a viable and available method for confirming "device effect" in vivo. However, measurement of NO and carbon dioxide levels in the nose is typically not feasible because it requires constant suction of air from the nose and is thought to alter the flow pattern.

A set of data contains blinded one-to-one (H2H) results. They generally show a high response rate in blinded data, i.e. migraine reduction from severe / moderate migraine to mild migraine or migraine relief, and after unblinding at 30 minutes. A potential scenario suggests one or more "device effects".

If you add the highest placebo rate (31%) at 30 minutes for 16 mg to the highest effective response rate (13%) at 30 minutes for 100 tablets of sumatriptan, the total is 30 minutes. At that point it will be 44%. This data suggests a response rate of 70% for 16 mg of the nose with placebo tablets at 30 minutes, which is extremely high. For 174 severe seizures, 95% improved at 30 minutes. Again, this is a very high response rate for both treatment options (at least 90% response).

There were 1556 seizures for "blind" data. Of these, only reaction data at 30 minutes is shown. 713 seizures were mild seizures at the time of treatment, 669 seizures were moderate seizures at the time of treatment, and 174 seizures were severe seizures at the time of treatment. For mild seizures, 117 (16.4%) resolved at 30 minutes. For moderate seizures, 288 (43%) were mild seizures and 101 (15.1%) were resolved. Regarding severe seizures, 77 (44.3%) had moderate seizures, 65 (37.4%) had mild seizures, and 22 (12.6%) were resolved. For all seizures, 1 point improvement was 43% and pain relief was 15.4%. For moderate / severe seizures (n = 843), 57% achieved mild seizures / resolution and 14.6% achieved pain relief. These results are summarized in FIG.

We revisited some physiological aspects of the bidirectional flow pattern. In general, such a flow pattern results in exposure of exhaled carbon dioxide to the nasal mucosa in the range of about 5-5% carbon dioxide. In addition, pH can change locally in the nasal mucosa (Djupesland, 2014). Removal of NO from the upper part of the nose (Djupesland, 1999) can also occur and positive pressure can be applied to the nasal mucosa (Valsalva and pain relief). In addition, the oscillating airflow can facilitate gas exchange from narrow slit passages and caves. Humming and other publications describe nasal NOs, vibrating meshes, and pulsed nebulizers.

There are several possible explanations for the potential device effects described above. Evidence of such effects comes from the high rate of placebo observed even at early time points in Phase 2 and Phase 3 trials. Blinded H2H data also suggest "further device effects".

One hypothesis is to bidirectionally deliver exhaled breath containing about 5-6% carbon dioxide, with very low flow rates of 100% carbon dioxide (see Capnia data) or low flow rates of 15-45%. It results in the exposure of carbon dioxide to the nasal mucosa similar to the low flow delivery of carbon dioxide (Schusterman, 2003). In Capnia's Phase 2 Migraine Study (Spierings, 2008), carbon dioxide was used for migraine headaches with a minimum of 3.5 minutes of rest, 45 seconds of rest in the first 2 hours, and 90 seconds of up to 7 dosing cycles (up to 7 dosing cycles). It was passively delivered at 10 ml / sec over 900 ml) or 5 x 15 (1050 ml). This was roughly equivalent to 10 ml of carbon dioxide per second. Significant dilution of carbon dioxide is expected due to open nasal as well as nasal inhalation or exhalation that can occur during administration.

Passive administration of Capnia's AR study (Casale, 2008) included administering gas to the subject twice nasally at a flow rate of 10 mL / s for 60 seconds, with a total dose of approximately 1200 mL. there were. Administrations were administered to alternating nostrils, separated by intervals of less than 5 minutes. Subjects avoided inhaling gas by breathing through the mouth, allowing gas to flow into one nostril, through the nose and nasal passages, and out through the other nostril. The flow rate was also 10 ml of carbon dioxide per second. Significant dilution of carbon dioxide is expected due to open nasal as well as nasal inhalation or exhalation that can occur during administration.

In addition, Shusterman's 2003 paper describes 5 l / min 15% x 3 seconds synchronized with inhalation. This equals 250 ml x 0.15 = 37.5 ml of carbon dioxide, ie 12.5 ml per second. By comparison, Breathpower Bi-Directional administration (Djupesland, 2014) resulted in 5% carbon dioxide at 30 l / min for 3 seconds, ie 500 ml / sec at about 5-6% carbon dioxide, 25-30 ml. 75-90 ml at / sec or 3 seconds. In summary, carbon dioxide has been shown to be effective in migraines (Phase 2 of Capnia) and carbon dioxide has been shown to be effective in allergic rhinitis (Phase 2 of Capnia). Carbon dioxide is also thought to act on the trigeminal nerve by locally lowering the pH of the mucosa, causing intercellular events that desensitize the nerve. In addition, carbon dioxide delivered to the nose can cause pH changes in the nasal mucosa (Shuterman, 2003).

It was determined that it might be possible to detect nasal pH changes with a small probe following Bi-Dir treatment. As mentioned above, aerodynamic effects, exposure to about 5-6% carbon dioxide in exhaled breath, NO removal, and pressure can be considered.

Carbon dioxide functions by changing the pH in migraines (and AR) (Capnia, CA). A recent publication from 2013 states that the release of CGRP from the trigeminal sensory fibers during stimulation (carbon dioxide) inhibits the response of olfactory receptor neurons to odor. A paper by Vause and Spierings states that "the results from this study provide first evidence of a unique regulatory mechanism by carbon dioxide suppressing sensory nerve activation and thus suppressing neuropeptide release." Says. Furthermore, the inhibitory effect of CGRP secretion observed on carbon dioxide is thought to include regulation of calcium channel activity and changes in intracellular pH.

It is the change in intracellular pH that achieves the effect, and it is believed that to a large extent extracellular pH change is buffered by the secretion of nasal mucus. However, recent studies and studies by Shusterman (2003) have reliably detected small changes in nasal pH indicators with probes inserted into the nasal passages with diameters between 1.5 and 2 millimeters. .. These probes have been used to measure esophageal and chamber pH and can be directly coupled to software that provides detailed curves (see examples below). Carbon dioxide concentrations above 15% appear to be required to see changes in nasal pH. This means that even if the concentration in the exhaled breath actually reaches the level of 5-6% in bidirectional administration, no change can be seen at this concentration of 5-6% in the exhaled breath. ing. However, 15% carbon dioxide is probably delivered to the nose in a way that is significantly diluted. A carbon dioxide probe is placed 4 cm into the nose along the bottom of the nose, and carbon dioxide is inhaled into the anterior part of the nose by a cannula at a flow rate of 5 L / min in a 3 second pulse (approximately 0%). It was administered synchronously with (carbon dioxide). The cannula placed in one nostril was non-obstructive. Therefore, the inhalation flow can be significantly higher than 5 L / min through one nostril, and 15% carbon dioxide may be significantly diluted in the mucus location around the pH probe. be. According to the above assessment, the mixing and dilution of carbon dioxide will be much more pronounced and rapid than in the case of the sensory region after breathpower Bi-Directional administration. Changes in carbon dioxide and related extracellular pH may, of course, become apparent to be too small to be detected by a pH probe, but the only way to detect them is by testing.

In some embodiments, monitoring equipment (Medtronic, Minnesota, see attached data sheet) or similar equipment can be used for "look and see" experiments. For example, some probes are reusable and others are disposable. After inserting a 1.8 mm probe into the area of the sense of smell under endoscopic control, the pH during periods of non-breathing and normal slow breathing and during the Bi-Directional supply of air. Can be used to measure. In addition, lactose and sumatriptan can be administered simultaneously to observe changes or trends. Such data can explain the "placebo" effect or prove how authentic the effect is and not the placebo.

Previous literature describes rats with hypersensitivity olfactory receptors capable of sensing or squeezing carbon dioxide concentrations as low as 1-3%. This sensitive aspect of carbon dioxide detection depends on the activity of carbonic anhydrases that catalyze the synthesis of carbonic acid and the like. The resulting acidification causes activity in a small population of sensory receptor neurons located in the most dorsal recesses of the olfactory epithelium.

In humans, such sensitive detection of carbon dioxide does not exist, and carbon dioxide has no odor to humans. However, at higher carbon dioxide concentrations, trigeminal nerve fibers are also activated by acidification. Importantly, the protons that give rise to trigeminal activity are not released in the mucus or interstitial fluid of the sense of smell, but in the axonal protoplasm of the trigeminal nerve fibers. Recently, studies of TRPA1 channel gating in trigeminal ganglion neurons have revealed that channels are opened by intracellular acidification (Wang et al., 2010).

Since carbon dioxide can easily diffuse across the plasma membrane, the carbonic amphydrase reaction inside the sensory endings can cause a decrease in intrafiber pH. The exact degree of this intracellular acidification has not yet been measured, and the intracellular concentration of carbonic anhydrase is unknown. However, given the small accessible volume within the fiber, acidification is expected to be more emphasized in the fiber compared to the surrounding fluid, which has a much larger volume.

In human subjects, Shusterman (2003) had an extracellular pH during carbon dioxide stimulation similar to that used in this study (5 L / min, duration of 3 seconds, 20% carbon dioxide). Acidification of nasal mucosal pH was measured by electrodes. The extracellular pH drops by 0.05-0.1 pH units from the basal level of ~ 7.4, and the effect of carbon dioxide is in the middle of each carbon dioxide pulse. These small drops in extracellular pH reflect the efficient pH buffering of extracellular media. The advantage of carbon dioxide detection by intracellular acidification is that the carbon dioxide inside the axonal protoplasm can cause larger pH changes. With respect to extracellular media, trigeminal nerve fibers appear to act as carbon dioxide electrodes rather than as pH electrodes, regardless of the volume and pH buffering capacity of the surrounding fluid.

Recent studies suggest that humans can perceive carbon dioxide levels of about 5-6% CO, even if humans do not have high sensitivity to carbon dioxide. In addition, the nasal mucosa can be more sensitive in the anterior part of the nose.

One or more factors can influence the reaction data described above obtained from bidirectional administration. One hypothesis is that the specific airflow and pressure characteristics achieved by performing bidirectional administration are the high placebo effect seen in previous studies and when the placebo was combined with 100 mg sumatriptan tablets. Provides another advantage that can at least partially explain the high response that will be seen at 30 minutes. One or more factors can have an effect, and these factors are expected to likely include pressure, NO removal from the nose, or exposure to about 6% of exhaled carbon dioxide. Of these factors, carbon dioxide can have the greatest impact.

Carbon dioxide is known to have effects on migraines and allergic rhinitis, which may be achieved by small changes in local pH. Previous studies have shown that exposure to 5 L / min of carbon dioxide at both 15% and 45% concentrations causes a decrease in mucosal pH by 0.1 to 0.2 pH units. Studies suggest that such small pH changes can affect the trigeminal nerve and alter the sensitivity and conductivity of the trigeminal nerve. Other studies suggest that it may affect the release of CGRP, and thus the pain of migraines.

Measurement of nasal pH during Bi-Directional administration with both a powder delivery device and a liquid delivery device gave unexpected results. Bidirectional air flow through both powder and liquid devices without the release of any substance is repetitive and generally reproducible (data can vary depending on sensor position) pH in the range of 0.1 to 0.2 pH units. Caused a decline. This data is similar to what was observed in the 3 second eruption of 15% and 45% carbon dioxide. In these studies, the sensor was placed at the bottom of the nose. Further measurements with sensors near the bottom of the nose and the ceiling of the nose were also performed. In many cases, a greater "drop" is observed when the sensor is placed closer to the ceiling than the floor of the nose.

Achievement of carbon dioxide concentration in the upper part of the nose when carbon dioxide is brought to the nasal floor at very low flow rates of carbon dioxide, at least partially based on the previous measurements of NO, as in the above hypothesis. And it takes time to rise. Even at high concentrations of about 45% to about 100%, it may take more time to result in a 10 second pulse to achieve the 6% achieved with Bi-Directional administration. This can explain the above-mentioned "device effect".

It should be noted that a "lowering" of pH in a direct response to Bi-Directional administration can be detected. This data provides a scientific and logical explanation for some of the high placebo effects and response rates. In the 30-minute early moderate to severe migraine response rate in the one-to-one study described above, 57% of "blind" seizures were reduced from moderate / severe to slight or none at 30 minutes. rice field. This data was unexpected, regardless of the distribution between the two treatment groups. It seems even more impressive that 95% of the seizures rated as severe were alleviated to moderate, minor, or none at 30 minutes.

The data described herein provide support for the device effect hypothesis. Measurements in both powder and liquid formulations provide similar data. Therefore, the Bi-Directional method, rather than the specific device, appears to have greater curing. It is worth noting that carbon dioxide also has an effect on allergic rhinitis.

Nasal pH measurements were performed using a 1.6 mm pH sensor called Digitrapper pH and software called AccuView. Digitrapper and software are provided by WinMed of Norway. In some embodiments, one or more probes can be arranged as roughly shown in FIG. The probe can be placed in either nasal passage.

Data showing pH as a function of expiratory flow by a sensor probe placed on the same side towards the ceiling of the nose using a powder device is shown in FIG. Data showing pH as a function of exhaled flow using a liquid and powder device is shown in FIG. 19, where the pH sensor is located approximately 4-5 cm from the opening of the nostrils towards the ceiling of the nose. There is. FIG. 20 shows data showing pH as a function of exhaled flow with respect to the powder device, with the sensor located approximately 4-5 cm in the nose at the nasal floor and mid-range. FIG. 21 shows additional data showing pH as a function of expiratory flow, again with the sensor located approximately 4-5 cm in the nose at the nasal floor and mid-range.

Shusterman (2003) brought a 3-second pulse of normal air (0%) as well as 15% and 45% carbon dioxide to the nose. The pH sensor was placed along the nasal floor. The sampling frequency was 10 times per second (10 Hz). Data from this study is shown in FIG. For comparison, this data compared mouth breathing, gentle nasal breathing, and gentle nasal breathing prior to breath power Bi-Directional administration with powder and liquid devices. The sensor was placed approximately 4-5 cm in the right nostril and the inhaler was inserted into the left nostril. Data on this method is shown in FIG.

In summary, Breathpower ™ Bi-Directional ™ administration systems and methods have been calculated to show conical effects in migraine and allergic rhinitis (Capnia-Casale 2008 and Spierings). It provides a higher delivery of carbon dioxide per second compared to the 100% carbon dioxide provided in 2008). Breath Power ™ Bi-Directional ™ is a pH level in the direct reaction to exhaled breath through the device when both 15% and 45% carbon dioxide is delivered in pulses of 3 seconds at 1 minute intervals. It also shows a similar decline. These results show that the nature of Breathpower ™ Bi-Directional ™ treatment is similar to that when the 100% administration used in the study was effective in migraine and persistent allergic rhinitis. It suggests that exposure to can be produced. The effects of these carbon dioxide effects of Breath Power ™ Bi-Directional ™ can be exerted on the trigeminal nerve and mast cells during treatments with positive pressure, high flow rates and altered flow patterns. Can be used in combination with improved airflow entering the nose, vibrating effects of the dosing device, removal of nitrogen oxides, and increased exposure to carbon dioxide.

A Phase 2 study with low-dose sumatriptan powder using a palatal closure Breathpower ™ device produced headache relief that approached previously reported levels at injection, but without a triptan effect. Further studies were designed to evaluate the efficacy and safety of this form of administration when compared to placebo in patients with moderate to severe acute migraine. These studies were performed in Phase 3, other-centered, randomized, double-blind, placebo-controlled, single-dose, patients experiencing migraine headaches 1-8 times / month in the 12 months prior to screening. Included administration, parallel group studies. Each patient has a single, moderate or severe migraine headache, a breath power device containing 11 mg sumatriptan powder so that the total dose is 22 mg, or an equivalent device loaded with placebo. Treatment was with either two doses (one for each nostril). The following efficacy results were measured.
Headache response (pain assessed as mild or none) at 120 minutes (major) and at multiple time points up to 120 minutes.
Complete pain relief at multiple time points up to 120 minutes (freedom from headache pain).
Time to significant relief (patient report of interpretation of headache pain response).
Clinical helplessness and migraine-related symptoms (photophobia, phonophobia, nausea, and vomiting).
Use of paramedics.
Duration of response / duration of pain relief (effective for headache at 120 minutes / pain disappears completely, no recurrence or use of paramedics until 24 and 48 hours after administration).

A total of 223 patients (mean age 42 years; 85% female) were treated (112 were sumatriptan powder; 111 were placebo). Demographic data and baseline characteristics of patients are shown in FIG.

The headache response (major outcome) at 120 minutes was 68% vs. 45% (P <.01). The headache response curve split early and became statistically significant at 30 minutes (42% vs. 27%; P <.05). In general, this form of administration was statistically superior to placebo for complete alleviation and sustained response and remained at 24 and 48 hours. Relief was also seen in asthenia and migraine-related symptoms.

The results are shown in FIG. In general, complete pain relief (120 minutes) was 37% vs. 17% (P <.01), and meaningful relief (120 minutes) was 70% vs. 45% (P <.001). The duration of the reaction was 44% vs. 24% (P <.01) at 24 hours and 34% vs. 20% (P = .01) at 48 hours. The duration of pain relief was 28% vs. 12% (P = .005) at 24 hours and 20% vs. 9% (P = .02) at 48 hours. In addition, reductions in nausea, phonophobia, and photophobia were reported in both groups (not significant for placebo). Patients in need of paramedics were significantly more likely to use placebo than in this dosage form (52% vs. 37%; P = .02).

Regarding the primary endpoint, 68% of patients who used this dosage form reported relief of headache 120 minutes after administration, compared with 45% when using a placebo device (P <.01; FIG. 26). Headache relief in this dosage form was achieved early and was statistically significant compared to placebo at 30 minutes (42% vs. 27%, P <.05; FIG. 26). Patients who felt meaningful relief at the end of 120 minutes (Fig. 27-120 minutes after administration felt significant relief after treatment with this dosage form or placebo device, consistent with the results on the headache relief scale. Patients (FAS) and patients who felt complete pain relief (Percentage of patients who achieved pain relief at the end of FIGS. 28-120 (FAS)) were compared to placebo. It was significantly more common in patients who used this dosage form. Patients who felt sustained headache relief at 24 and 48 hours were more likely to use this dosage form than the placebo device (FIG. 26). Patients who maintained pain relief at 24 hours without the need for paramedics were more likely (28%) (P. <.01). The number of patients in need of paramedics was significantly lower in patients using this dosage form than in placebo devices (37% vs. 52%, P <.05). The clinical disability score was significantly improved in patients treated with this dosage form compared to placebo, including between 45 and 120 minutes (P <.05). The incidence of migraine-related symptoms was significantly reduced at the end of 120 minutes (form vs. placebo device: nausea 19% vs 21%, vomiting 2% vs 0%, phonophobia 48% vs 60%, Phonophobia 32% vs. 44%). These reductions have not reached significant levels between groups.

There were few systemic side effects (AEs) and nothing was reported except for one patient. The AE, known as the "triptan effect," is associated with formulations and doses that produce high plasma drug concentrations. There was also minimal triptan perception. Specifically, there was no chest tightness and only one patient reported mild temporary paresthesia. The most common (> 5%) AEs reported were product taste (22%), nasal discomfort (13%), and rhinitis (6%).

Unlike traditional nasal sprays, this dosage form uses a novel breath power device to deliver powdered sumatriptan deep into the nasal structure where rapid absorption is possible. This deep region is also the region of great distribution of nerves by the trigeminal and olfactory nerves, which theoretically provides a direct effect or potential for nasal-to-brain transport. The breath power device locally delivers carbon dioxide and removes nitrogen oxide (NO). This effect may also contribute to the placebo response seen in this study. The high placebo response may also be associated with the neurochemical effects of carbon dioxide delivery and / or NO removal at the trigeminal nerve endings in the nasal cavity. NO is known to stimulate the release of CGRP from the trigeminal neurons, an important mediator in the pathophysiology of migraine, while carbon dioxide suppresses the release of CGRP and regulates migraine. Can be beneficial in.

In conclusion, treatment with this form of administration results in agile and persistent migraine relief compared to placebo devices with minimal triptan perception. These data are consistent with the results from the previous Phase 2 study, suggesting that this dosage form can provide an important therapeutic and viable option in the treatment of acute migraine.

In the examples and studies presented above, carbon dioxide is intended to provide a mechanism for providing and / or enhancing therapeutic or pharmacokinetic effects and / or for adjusting the pH of the region within the nasal passages. Explained. Carbon dioxide can react in the nasal passages and lower the pH. As mentioned above, the resulting concentration of carbon dioxide may be in the range of about 5-5% vol / vol. In other embodiments, the therapeutic amount of carbon dioxide can include carbon dioxide greater than about 1% vol / vol and carbon dioxide less than about 10% vol / vol.

Gases or fluids other than carbon dioxide can be used to provide pH regulation, for example increasing the pH. Also, one or more solid substances, with or without carbon dioxide or other gases or fluids, can be used to regulate pH in the nasal passages. For example, fine particulate matter can be used to regulate the pH of the extracellular environment surrounding tissues in the nasal passages.

In some embodiments, the pH regulator can include acid or basic gases or buffers. Also, the pH regulator can form part of a prescription that is included with the therapeutic agent, or it can form part of a prescription that is separate from the therapeutic agent. The pH adjusting material value can adjust the pH by a known amount. A known amount can be determined based on the requirements of an individual or group of individuals, a therapeutic agent, a group of agents, or the expected behavior of one or more agents. Known amounts may range from about 0.01 to about 0.5 pH units, or about 0.1 to about 0.2 pH units.

Various mechanisms can be used to create airflows containing pH regulators by aerosolization or other methods. For example, powders of pH regulators can be combined with therapeutic agents in capsules or blister packs. In another embodiment, one or more separate capsules or blister packs are placed near, upstream, or downstream of the therapeutic agent to provide pH adjustment before, simultaneously, or after air delivery of the therapeutic agent. can do. Mechanical, electrical, or chemical vibration mechanisms can also be used to release pH regulators.

In a 3-month sham-controlled study of 109 patients with chronic nasal sinusitis with nasal polyps, administration of fluticasone (400 μg, twice daily) with a Breathpower ™ liquid drug delivery device was well tolerated. It was reported to produce significant reductions in both symptoms and overall polyp score.

Notably compared to expectations for standard nasal spray administration, complete removal of polyps was reported after 3 months in nearly 20% of subjects. The proportion of subjects with improved total polyp scores was significantly higher in this dosage form compared to placebo at 4, 8, and 12 weeks (22% vs. 7%, p = 0.011, respectively). 43% vs. 7%, P <0.001, and 57% vs. 9%, P <0.001). Despite the relatively low baseline polyp score, after 12 weeks, the total polyp score decreased significantly from 2.8 to 1.8 in the effective treatment group, while the polyp score was slightly lower in the placebo group. There was a significant increase (-0.98 vs. +0.23, P <0.001).

Peak nasal inhalation flow (PNIF) gradually increased during treatment with this dosage form (p <0.001). The combined symptom score, nasal obstruction, discomfort, rhinitis symptoms, and odor sensory effects were all significantly improved.

A very large progressive therapeutic effect of this dosage form was observed regardless of the baseline polyp score. Previous sinus surgery did not affect efficacy. This is because, in addition to complete removal of polyps in many patients with small polyps, the improved adherence to the target location achieved by the Breathpower ™ transmitter leads to true clinical benefits, perhaps surgical. It suggests that the need for surgery can be reduced.

A small placebo-control study (N = 20) was performed in patients with postoperative refractory CRS without polyps using the same drug-device combination product as in Example 10 with objective indicators and awareness. There was a clinically significant improvement in both symptoms.

Endoscopic scores for edema showed marked and progressive improvement (12 weeks (median): this dosage form was -4.0, whereas placebo was -1.0, p = 0. 015).

Peak nasal inhalation flow (PNIF) was significantly increased during treatment with this dosage form when compared to placebo (4 weeks: p = 0.006; 8 weeks: p = 0.03). After 12 weeks, the MRI score of the group receiving this dosage form improved relative to baseline (p = 0.039), with no significant tendency seen for placebo.

The nasal RSOM-31 subscale was also significantly improved in treatment with this dosage form (4 weeks: p = 0.009; 8 weeks: p = 0.016, 12 weeks: NS). Smell sensations, nasal discomfort, and combination scores were all significantly improved (p <0.05). Among other things, this is the condition demonstrated by a number of recent negative placebo-controlled studies. In this context, in addition to comparison with historical data in similar patient populations, Breathpower Bi-Directional administration is superior in clinical practice for deep nasal adhesion (in this case, to the middle nasal meatus). It also suggests that it can produce improved reach) and thus improve clinical response.

With respect to administration of fluticasone, the inventor of the present invention can provide a significantly higher dose of 400 μg or 800 μg twice daily compared to 200 μg daily, but with significantly improved bioavailability. It was made clear that it did not.

As mentioned above, the present invention provides a method of treating a patient. The treatment can include one or more steps, the first step can include administration of a therapeutic agent. The second step can include bringing carbon dioxide or a pH regulator to one or more areas of the nasal passages, as described above. The order of these steps is interchangeable, so the second step may occur before the first step. It is also believed that both steps or additional steps may occur at the same time.

As mentioned above, the effects of carbon dioxide, especially on pH and NO concentrations, as well as the high pressure on the trigeminal and pterygopalatine ganglia produced by the intranasal device, are more prevalent, especially in the oral tablet group. It is assumed to result in a high overall response rate.

Finally, the invention is described in various embodiments and can be modified in a number of different ways without departing from the technical scope of the invention as defined by the appended claims. You can understand. For example, although the present invention has been exemplified with respect to sumatriptan, the present invention presents the present invention with other triptans such as lisatriptan, naratriptan, eletriptan, flovatriptan, and solmitriptan, as well as caffeine, fentanyl, oxycodon, hydromorphone, It can be understood that it also applies to many other analgesics such as morphine, codein, ketobemidone, cocaine, and other analgesics such as dihydroergotamine mesylate, ergonovine maleate, and ergotamine including ergotamine tartrate, which have triptans in general. Will. The present invention also applies to benzodiazepines such as midazolam. Furthermore, the present invention also applies to non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, indomethacin, diclofenac, and ketoprofen.

Furthermore, the present invention also relates to proteins and peptides, in particular having a molecular weight of greater than 1000 g / mol, typically having very low oral bioavailability, often less than 1%. Applies. Specific examples include insulin (including analogs and derivatives), desmopressin, and calcitonin. Furthermore, the present invention also applies to powder vaccines, immunostimulants, and immunostimulants. In summary, the present invention applies with respect to the following broad definitions of molecules.

Small molecules (<1000) with relatively rapid nasal absorption and high nasal BA, such as fentanyl, midazolam, and oxycodone. The present invention exhibits a much faster CNS effect compared to prior art nasal administration systems, which are differences between arterial and venous concentrations where arterial absorption is approximately 25% to 50% greater than venous absorption, animals. "Reflux" transport that can occur in the cavernous sinuses and carotid arteries that must pass through the BBB, which has been shown to grow by about 25%, and direct N2B that can occur along the olfactory and trigeminal nerves. May be due to transport (Einer-Jensen, Net al, Pharmacol. Toxicol., 87 (6]), 2000, pages 276 to 278, Einer-Jensen, Net al, Exp. Brain Res. , 130 (2), 2000, pages 216 to 220, and Dale, O et al, International Midazolam: a comparison of artery devices in human veins, J.P. However, N2B transport and clinical effects by the trigeminal nerve are not always reflected in traditional PK profiles.

Small and medium sized molecules with relatively low BA, such as sumatriptan and zolmitriptan. For the sumatriptan powders of the present invention, sumatriptan does not pass through the BBB relatively well, but studies in animals suggest that sumatriptan may be delivered directly to the brain by a direct N2B mechanism (Gladstone, J.). P, Newer formulas of triptans: Advances in migraine treatment, Drugs, 63, 2003, pages 2285 to 2305). The present invention results in an increase in absorption, which is especially important when rapid absorption and rapid onset of action are desired. The present invention exhibits a faster CNS effect, which can result in direct N2B uptake, possible "reflux" transport to the cavernous sinus and carotid artery where molecules can pass through the BBB, and the olfactory and trigeminal nerves. It may be due to the direct N2B transport that can occur along.

Nasal BA is low, typically about 3-15%, and oral BA is very low due to degradation in the GI tract, typically less than 1%, large molecules such as peptides and proteins (> 1000) ). The present invention is highly suited for the administration of peptides and proteins in the supply of powder formulations, where the powder can not only provide improved nasal absorption, but also have improved stability. For these substances, it is hypothesized that there may be dedicated transport mechanisms along the olfactory and trigeminal nerves to direct brain structures that are not CSF-mediated. Therefore, measurements from CSF may not indicate the presence of an active substance, but recent studies (Thorne, RG et al, Delivery of insulin-like growth factor-l to the rat brain and spinal cord alcohol). Substantial effects can be present in the brain and can produce clinical effects, as illustrated in and trigeminal patheways following intraadminal administration, Neuroscience, 127 (2), 2004 pages 481 to 496).

Although the principles of the invention have been described herein with reference to exemplary embodiments for a particular application, it should be understood that the invention is not limited thereto. Those skilled in the art, in view of the teachings presented herein, have come up with further improvements, applications, embodiments, and equivalents, all of which are within the technical scope of the embodiments described herein. You can do it. Therefore, the present invention should not be considered to be limited by the above description.

Claims (15)

A therapeutic agent containing fluticasone for the therapeutic treatment of chronic nasal sinusitis with or without nasal polyps in a patient.
In the first step, the therapeutic agent is delivered and administered in an amount of 100 μg to 400 μg by a delivery device including a mouthpiece and a nosepiece, and is administered.
In the second step, the mouthpiece is placed in the patient's mouth, the nosepiece is placed in the patient's first nostril, and a flow of fluid exiting the nosepiece is generated in the first nostril. As the patient exhales into the mouthpiece, a therapeutic amount of carbon dioxide is delivered to a first location within the patient's first nostril.
The carbon dioxide lowers the pH of the nasal mucosa at the first position inside the first nasal passage of the patient.
A therapeutic agent, wherein the first step is performed before or at the same time as the second step. The therapeutic agent according to claim 1, wherein the first step is performed before the second step. The therapeutic agent according to claim 1, wherein the first step is performed at the same time as the second step. The therapeutic agent according to claim 1, wherein the position comprises an upper posterior region of the nasal passage. Before notated Ruchikazon is in the form of a flop propionate fluticasone, is administered as a liquid aerosol, optionally, therapeutic agent according to請Motomeko 1. The therapeutic agent according to claim 1, wherein the therapeutic agent is delivered in an amount of 100 μg, optionally twice a day. The therapeutic agent according to claim 1, wherein the therapeutic agent is delivered in an amount of 200 μg, optionally twice a day. The therapeutic agent according to claim 1, wherein the therapeutic agent is delivered in an amount of 400 μg, optionally twice a day. The therapeutic agent according to claim 1, wherein the second step lowers the pH at the position by an amount in the range of about 0.01 to about 0.5 pH units. The therapeutic agent according to claim 9, wherein the amount is in the range of about 0.1 to about 0.2 pH unit. The therapeutic agent according to claim 1, further comprising controlling the flow of the fluid to lower the pH at the position in the second step. The therapeutic agent according to claim 11, wherein controlling the flow of the fluid comprises controlling at least one of the duration, flow rate, pressure, and composition of the flow of the fluid. The therapeutic agent according to claim 12, wherein the duration of the fluid flow is controlled to be in the range of about 2 to about 3 seconds. 13. The therapeutic agent of claim 13, comprising controlling the flow rate of the fluid flow to at least 10 L / min, optionally at least 20 L / min, and optionally at least 30 L / min. In the second step, the patient exhales into the mouthpiece so that the nosepiece is placed in the patient's second nostril and a second fluid flow out of the nosepiece is generated. Delivers a therapeutic amount of carbon dioxide to a second location inside the second nostril.
The therapeutic agent according to claim 1, wherein the carbon dioxide lowers the pH of the nasal mucosa at the second position inside the second nasal passage of the patient.

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