Treatment of memory loss with phosphodiesterase inhibitors

Abstract

A method for treating memory loss in a subject is disclosed herein, comprising the step of intranasally administering a phosphodiesterase inhibitor or a salt thereof to the subject by a nasal spray device. Similarly, devices and kits for administering a phosphodiesterase inhibitor or a salt thereof to a subject in need are disclosed herein. The nasal spray devices herein deliver dose units that can be used to treat memory loss and / or cognitive impairment in a subject.

Description

[Technical Field]

[0001] Cross-references to related applications This application claims priority to U.S. Provisional Application No. 63 / 461,360, filed April 24, 2023, which is incorporated herein by reference in its entirety under Section 119 of the U.S. Patent Act. [Overview of the Initiative] [Means for solving the problem]

[0002] summary A method for treating memory loss in a subject requiring treatment for memory loss is disclosed herein, comprising the step of intranasally administering an effective amount of a liquid pharmaceutical composition to the subject by the operation of a nasal spray device. In some embodiments, the liquid pharmaceutical composition may include a phosphodiesterase (PDE) inhibitor or a salt thereof and a pharmaceutically acceptable carrier, excipient, diluent, or any combination thereof. In some embodiments, when the liquid pharmaceutical composition is intranasally administered to the subject by the operation of a nasal spray device, it forms a plume containing a plurality of droplets, the plurality of droplets being approximately 35 μm to approximately 41 μm in diameter. 90 It is characterized by the fact that approximately 90% of the droplets in the plume are D 90 They have a size of less than 10 μm. In some embodiments, memory loss can be treated by the step of administering an effective amount of liquid pharmaceutical composition. In some embodiments, the plurality of droplets may be further characterized in that less than about 7% of the droplets in the plume have a size of less than about 10 μm. In some embodiments, the plurality of droplets have a size of about 21 μm to about 25 μm. 50 It can be further characterized as follows: In some embodiments, about 50% of the droplets in the plume are D 50 It may have a size less than D. In some embodiments, D 50The droplet size may be approximately 23 μm. In some embodiments, the droplet size can be measured by laser diffraction. In some embodiments, the PDE inhibitor or a salt thereof may include apremilast, ciromiralast, crisabolol (AN2728), ibudilast, luteolin, mesembrenone, picramiralast, roflumilast, rolipram, any salt thereof, or any combination thereof. In some embodiments, the composition may include a PDE inhibitor or a salt thereof, including roflumilast or a salt thereof. In some embodiments, the PDE inhibitor or a salt thereof may include theophylline or a salt thereof, cilostazol or a salt thereof, or any combination thereof. In some embodiments, a plume may be formed by the operation of the nasal spray device and lasts for approximately 0.5 seconds to approximately 5 seconds from the start of spraying to the end of spraying. In some embodiments, the pharmaceutically acceptable carrier may include water. In some embodiments, the liquid pharmaceutical composition may further include a viscosity improver. In some embodiments, the viscosity improver may include cellulose. In some embodiments, the liquid pharmaceutical composition may include excipients. In some embodiments, the excipient may include glycerol. In some embodiments, the liquid pharmaceutical composition may further include a preservative. In some embodiments, the action may include an action volume of liquid of about 10 μl to about 200 μl, about 20 μl to about 80 μl, or about 70 μl. In some embodiments, intranasal administration may be once, twice, or three times a day into each nostril. In some embodiments, the plume may cover about 15% to about 50%, or about 10% to about 80%, or about 5% to about 90%, or about 5% to about 100%, of the surface area of ​​the nasal cavity as measured by a nasal cast scan. In some embodiments, the nasal cavity may include the nasal septum, nasal floor, lateral nasal wall, inferior meatus, middle meatus, superior meatus, olfactory cleft, olfactory region, turbinates, or any combination thereof.In some embodiments, the nasal cavity may include the nasal septum, nasal base, lateral walls of the nasal cavity, inferior meatus, middle meatus, superior meatus, olfactory cleft, olfactory region, and turbinates. In some embodiments, the liquid pharmaceutical composition may be a unit dose and may contain about 20 μg to about 2000 μg of a PDE inhibitor or a salt thereof. In some embodiments, memory loss may be due to sleep deprivation. In some embodiments, memory loss may be due to neurodegenerative disorders, old age, concussion, stroke, cancer treatment, hypoxia, head injury, surgery, multiple sclerosis, dementia, post-traumatic stress disorder (PTSD), bipolar disorder, depression, schizophrenia, substance abuse, infection, epilepsy, or nutritional deficiency, or a combination thereof. In some embodiments, the subject prior to the administration step may have reduced levels of cyclic nucleotides in nasal mucus samples derived from the subject compared to the levels of cyclic nucleotides in a control population with normal memory function. In some embodiments, the subject prior to the administration step may have a reduced level of sonic hedgehog in a nasal mucus sample derived from the subject compared to the level of sonic hedgehog in a control population with normal memory function. In some embodiments, the method may further include a step of administering a second therapeutic agent. In some embodiments, the second therapeutic agent may be administered concurrently with or sequentially to the administration step. In some embodiments, the method may further include a step of diagnosing the subject with amnesia. In some embodiments, the subject has been previously diagnosed with amnesia. In some embodiments, the nasal spray device may deliver a plume as a unit dose during operation. In some embodiments, the nasal spray device may contain about 60 to about 300 unit doses, each unit dose may contain about 20 μg to about 2000 μg of a PDE inhibitor or a salt thereof. In some embodiments, the subject may be one that requires it. In some embodiments, the subject may be a human. In some embodiments, the nasal spray device may deliver about 35 mg to about 100 mg of the pharmaceutical composition during operation. In some embodiments, multiple droplets are approximately 11 μm to 14 μm in diameter. 10 It can be further characterized that approximately 10% of the droplets in the plume are D 10has a size less than. In some embodiments, the stroke length of the operation of the nasal spray device can be 4.6 mm, 4.8 mm or 4.9 mm. In some embodiments, the stroke speed of the actuator of the operation of the nasal spray device can be 2 mm / s or 3 mm / s. In some embodiments, the stroke acceleration of the actuator of the operation of the nasal spray device is about 500 mm / s 2 can be. In some embodiments, the nasal spray device can have a nozzle hole size of about 3 μm, about 4 μm or about 5 μm. In some embodiments, the nasal spray device can have about 40 to about 70 nozzle holes, about 45 holes to about 65 nozzle holes or about 60 holes. In some embodiments, the nasal spray device can have a conical angle of about 20 degrees.

[0003] Similarly, a method for treating memory loss in a subject that requires treatment of memory loss, comprising administering a phosphodiesterase (PDE) inhibitor or a salt thereof in a dosage unit containing a therapeutically effective amount of the PDE inhibitor or a salt thereof in a plume during operation, in a liquid pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent, excipient or any combination thereof, using a nasal spray device that delivers the dosage unit, is disclosed herein. In some embodiments, the plume can contain droplets, and (a) less than about 7% of the droplets in the plume have a size less than about 10 μm, and (b) the D of the droplets in the plume is from about 35 μm to about 41 μm 90 and about 90% of the droplets in the plume have a size less than D 90 can have a droplet size distribution characterized by having a size less than.

[0004] Incorporation by reference All publications, patents and patent applications specified herein are hereby incorporated by reference into this specification to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference.

[0005] Novel features of this disclosure are specifically described in the appended claims. A better understanding of the features and advantages of this disclosure can be obtained by referring to the following detailed description illustrating exemplary embodiments utilizing the principles of this disclosure, and the following appended drawings: [Brief explanation of the drawing]

[0006] [Figure 1] Figure 1 shows images of nasal cavity models after spraying with a soft mist nasal spray device, a slow-speed standard nasal spray device, and a standard nasal spray device. Liquid formulations in the spray devices, with and without a cellulose (i.e., carboxymethylcellulose) viscosity improver, were tested. The soft mist nasal spray device deposited a larger amount of the formulation into the olfactory region of the nasal cavity model.

[0007] [Figure 2] Figure 2 shows the nasal spray characteristics of three types of spray devices: a soft mist nasal spray device, a slow-speed standard nasal spray device, and a standard nasal spray device. The soft mist nasal spray device exhibited a spray distribution in which approximately 50% of the particles had a diameter of less than approximately 20 μm, compared to the standard nasal spray (i.e., the standard nasal spray and the slow-speed standard nasal spray) which had sprays containing larger particle sizes.

[0008] [Figure 3] Figure 3 illustrates box plots showing the shot weight (amount released in milligrams (mg)) measured from the soft mist pump device at various operating speeds (1, 2, 3, and 4 millimeters per second (mm / s)) and stroke lengths of 4.6 mm, 4.8 mm, and 4.9 mm.

[0009] [Figure 4]Figure 4 illustrates box plots showing the shot weight (amount delivered in mg) delivered from the soft mist pump device at various operating speeds (1, 2, 3, and 4 millimeters per second (mm / s)) and stroke lengths of 4.6 mm, 4.8 mm, and 4.9 mm.

[0010] [Figure 5] Figure 5 illustrates box plots showing the performance of the plume geometry (plume angle (degrees) and plume width (mm)) at a pattern distance of 60 mm from the soft mist pump device for various operating speeds (1, 2, and 3 millimeters per second (mm / s)) and a stroke length of 4.8 mm.

[0011] [Figure 6] Figure 6 illustrates box plots showing the spray patterns (Dmax (mm), Dmin (mm), ellipticity, and area (mm^2)) at pattern distances of 30 mm and 60 mm from the soft mist pump device for various operating speeds (2 and 3 mm / s) and a stroke length of 4.8 mm.

[0012] [Figure 7-1] Figure 7 illustrates images showing spray patterns at various operating speeds (2 and 3 millimeters per second (mm / s)) and stroke lengths of 4.8 mm, at pattern distances of 30 mm and 60 mm from the soft mist pump device (device 12). [Figure 7-2] Figure 7 illustrates images showing spray patterns at various operating speeds (2 and 3 millimeters per second (mm / s)) and stroke lengths of 4.8 mm, at pattern distances of 30 mm and 60 mm from the soft mist pump device (device 12).

[0013] [Figure 8]Figure 8 illustrates box plots showing the droplet size distribution (% volume < 10 μm; span; D90 value (μm); and D50 value (μm)) at pattern distances of 30 mm and 60 mm from the soft mist pump device, at various operating speeds (2 and 3 mm / s) and a stroke length of 4.8 mm.

[0014] [Figure 9] Figure 9 illustrates box plots showing the performance of the plume geometry (plume angle (degrees) and plume width (mm)) at a pattern distance of 60 mm from the soft mist pump device for various operating speeds (1, 2, and 3 millimeters per second (mm / s)) and stroke lengths of 4.6 and 4.8 mm.

[0015] [Figure 10] Figure 10 illustrates box plots showing the spray pattern (Dmax (mm), Dmin (mm), ellipticity, and area (mm^2)) at a pattern distance of 30 mm from the soft mist pump device for various operating speeds (2 and 3 mm / s) and stroke lengths of 4.6 mm and 4.8 mm.

[0016] [Figure 11] Figure 11 illustrates box plots showing the spray pattern (Dmax (mm), Dmin (mm), ellipticity, and area (mm^2)) at a pattern distance of 60 mm from the soft mist pump device for various operating speeds (2 and 3 mm / s) and stroke lengths of 4.6 mm and 4.8 mm.

[0017] [Figure 12] Figure 12 illustrates box plots showing the droplet size distribution (% volume < 10 μm; span; D90 value (μm); and D50 value (μm)) at a pattern distance of 30 mm from the soft mist pump device for various operating speeds (2 and 3 mm / s) and stroke lengths of 4.6 mm and 4.8 mm.

[0018] [Figure 13] Figure 13 illustrates box plots showing the droplet size distribution (% volume < 10 μm; span; D90 value (μm); and D50 value (μm)) at a pattern distance of 60 mm from the soft mist pump device for various operating speeds (2 and 3 mm / s) and stroke lengths of 4.6 mm and 4.8 mm. [Modes for carrying out the invention]

[0019] Detailed explanation definition Unless otherwise defined, all terms, expressions, and other technical and scientific or specialized terms used herein are intended to have the same meaning as generally understood by those skilled in the art with respect to the claimed subject matter. In some cases, terms that have a generally understood meaning are defined herein for clarity and / or for easy reference, and the inclusion of such definitions herein should not necessarily be construed as representing a substantial difference from the generally understood meaning in the art.

[0020] Throughout this application, various embodiments may be presented in scope form. It should be understood that scope form descriptions are merely for convenience and brevity and should not be interpreted as inflexible limitations on the scope of this disclosure. Therefore, scope descriptions should be considered to specifically disclose all possible sub-scopes and the individual numbers within those scopes. For example, a scope description such as 1-6 should be considered to specifically disclose sub-scopes such as 1-3, 1-4, 1-5, 2-4, 2-6, 3-6, and the individual numbers within those scopes, e.g., 1, 2, 3, 4, 5, and 6. This applies regardless of the width of the scope.

[0021] The singular forms "a," "an," and "the" are used herein to include multiple references unless the context specifically indicates otherwise. Therefore, unless otherwise indicated, the numerical parameters described herein are approximations, which may vary depending on the desired characteristics to be obtained.

[0022] The terms “determining,” “measuring,” “evaluating,” “assessing,” and “analyzing” are often used interchangeably herein and refer to forms of measurement, including determining whether an element may or may not be present (e.g., detection). These terms may include quantitative and qualitative determinations. Assessment may, alternatively, be relative or absolute. “Detecting the presence of” includes determining the amount of something that is present and determining whether it may or may not be present.

[0023] The terms “substantially” or “essentially” refer to a qualitative state that represents the entire or nearly entire range or total extent of the characteristic or feature of interest. In some cases, “substantially” means at least about 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.9%, or 99.99% of the entire range or total extent of the characteristic or feature of interest. In some cases, “substantially” or “essentially” means an amount that can be about 100% of the total amount.

[0024] The term "at least partially" refers to a qualitative state that indicates a partial range or degree of the desired characteristic or feature. In the case of "partial," "at least partially" means at least approximately: 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% of the entire range or degree of the desired characteristic or feature.

[0025] Unless otherwise specified, open terms such as "contain," "containing," "include," and "including" all mean to include or encompass.

[0026] As used herein, the terms “about” or “approximately” mean within an acceptable margin of error for a particular value determined by those skilled in the art, and that the value is within an acceptable margin of error for the method by which it was measured or determined, for example, depending in part on the limits of the measuring system. For example, “about” in the art means plus or minus 10% per practice. Alternatively, “about” means a range of plus or minus 20%, plus or minus 10%, plus or minus 5%, or plus or minus 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term means within one order of magnitude, five times, or two times a given value. Where specific values ​​are described in this application and claims, unless otherwise specified, the term “about” should be assumed to mean within an acceptable margin of error for that particular value. Similarly, where a range and / or subrange of a value is presented, that range and / or subrange may include its endpoints.

[0027] As used herein, the percentages of compounds in a composition are relative to the total weight or total volume of the composition. In some cases, the percentages of components of a composition are relative to the total weight or total volume of the composition.

[0028] The terms “administer,” “give delivery,” and “dosage,” as used herein, refer to methods used to enable the delivery of a compound or its salts or compositions to a desired site of biological action. Delivery may include direct application to affect tissues or areas of the body. The compositions provided herein may be administered by any method. Methods of administration include nasal spray. In some cases, methods of administration may include inhalation, intra-arterial injection, intraventricular injection, intracapsular injection, intramuscular injection, intraorbital injection, intraparenchymal injection, intraperitoneal injection, intraspinal injection, intrathecal injection, intravenous injection, intracardiac injection, stereotactic injection, subcutaneous injection, or any combination thereof. Delivery may include parenteral administration (including intravenous, subcutaneous, intrathecal, intraperitoneal, intramuscular, intravascular, or infusion), oral administration, nasal administration, inhalation administration, intraduodenal administration, and rectal administration. Delivery may include topical administration to external surfaces such as skin (e.g., lotions, creams, gels, liquids, solids, powders, ointments). In some cases, subjects receive an intranasal spray containing the compound without supervision. In some cases, subjects receive an intranasal preparation under the supervision of a healthcare professional (e.g., a physician, nurse, physician's assistant, janitor, hospice staff, etc.). In some cases, a healthcare professional administers the intranasal preparation.

[0029] As used herein, “treating” memory loss includes reducing the frequency or severity of one or more symptoms, preventing one or more symptoms or their underlying causes, eliminating one or more symptoms or their underlying causes, or improving or repairing damage. For example, treating memory loss associated with sleep deprivation may include increasing memory recall in a patient suffering from sleep deprivation-related memory loss.

[0030] "Therapeutic dose" refers to the amount of a compound or a salt thereof, with or without an effective additional agent, that is necessary to achieve the intended purpose. Individual patient requirements may vary. Generally, the dose required to deliver an effective amount of a compound, a salt thereof, or a composition containing one or both will vary depending on the recipient's age, health, physical condition, sex, weight, degree of dysfunction, frequency of treatment, and the nature and extent of memory loss.

[0031] As used herein, "dosage unit" refers to a specific amount of a pharmaceutical composition administered in a single event or in a package. The meaning of the term "dosage unit" is context-specific. For example, for a liquid pharmaceutical composition administered intranasally, the dose unit is the volume of the composition administered in a single event. In the case of a nasal spray, the dose unit is the volume of the composition released with each operation of the nasal spray device.

[0032] "Weight percentage" or "w / w" refers to the ratio of the mass of the specified component to the mass of the total composition (e.g., dosage unit).

[0033] "Plume geometry," or "geometry," when used in relation to plumes, refers to the measured angle of the plume at its origin. Plume geometry can be measured, for example, by two distances from the plume's origin in two side views that are 90° apart. Plume geometry can also be calculated from spray patterns.

[0034] "Spray pattern," "plume ellipticity," or "ellipticity," when used in relation to a plume, refers to the shape and size of the plume at a certain distance from its origin. "Ellipticity" can be measured as the ratio of the maximum diameter to the minimum diameter.

[0035] "D 10 "D 50 "D 90 " and "span" refer to measurements of the droplet or particle size distribution of the plume. In a plume, 10% of the droplets are D10 They have a size less than D 50 They have a size less than D 90 It has a size less than (D). The span is calculated from these numbers using the following formula: span = (D 90 -D 10 ) / D 50 It can be calculated according to D. In some cases, D 10 , D 50 Or D 90 The value may be the average or median from multiple sprays and / or droplets.

[0036] When used in relation to a plume, "total volume" refers to the total volume of all droplets or particles in the plume. For example, a plume with a total volume of 100 μL contains 100 μL of liquid.

[0037] The terms “subject,” “host,” “individual,” and “patient” are used interchangeably herein and refer to animals, usually mammals. Any suitable mammal may be administered the compounds, salts, or compositions described herein or treated by the methods described herein. Non-limiting examples of mammals include humans, non-human primates (e.g., apes, gibbons, chimpanzees, orangutans, monkeys, macaques, etc.), domesticated animals (e.g., dogs and cats), livestock (e.g., horses, cattle, goats, sheep, pigs), and laboratory animals (e.g., mice, rats, rabbits, guinea pigs). Mammals may be of any age or in any developmental stage; for example, a mammal may be a neonatal, infant, adolescent, adult, or fetus (in utero). In some embodiments, the mammal is a human. Humans may be approximately 1, 2, 5, 10, 20, 30, 40, 50, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, or older than approximately 120 years. Humans may be approximately 1, 2, 5, 10, 20, 30, 40, 50, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, or younger than approximately 120 years. In some cases, humans may be under approximately 18 years old. In some cases, humans may be approximately 1 month to 12 months old, approximately 1 year to 20 years old, approximately 15 years to 50 years old, approximately 40 years to 80 years old, or approximately 60 years to 110 years old. In some cases, humans may be older than approximately 18 years old. Mammals such as humans may be male or female. In some embodiments, subjects may have or be suspected of having a disease or condition. Subjects may be patients such as those being treated for amnesia. Subjects may be patients being treated for conditions or diseases such as heart disease, hypertension, atrial fibrillation, stroke, renal failure, liver disease, cancer, diabetes, respiratory disease, asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, lung cancer, cystic fibrosis, coronavirus infection, influenza infection, viral infection, bacterial infection, fungal infection, parasitic infection, pneumonia, pleural effusion, neurodegenerative disease, or any combination thereof. Subjects may be in remission from a condition or disease such as cancer. In some cases, subjects may be healthy.

[0038] As disclosed herein, the term “phosphodiesterase (PDE) inhibitor” means a compound or salt thereof that can inhibit at least part of the function of a phosphodiesterase (PDE) polypeptide, such as PDE1, PDE2, PDE3, PDE4, PDE5, PDE6, PDE7, PDE8, PDE9, PDE10, PDE11 polypeptide or any combination thereof.

[0039] In use herein, references to PDE inhibitors, generally or specifically, include references to any salt, solvate, ester or polymorph of a PDE inhibitor. “Salt” may include pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts may include salts prepared by the reaction of a compound disclosed herein with an inorganic acid, organic acid or inorganic base, such salts being acetates, acrylates, adipines, alginates, aspartates, benzoates, benzenesulfons, bisulfites, bisulfites, bistartrates, bromides, butyrates, butyrates, camphorates, camphor sulfons, capronates, and caprylic acids. Salts, chlorobenzoates, chlorides, citrates, cyclopentanepropionates, decanoates, digluconates, dihydrogen phosphates, dinitrobenzoates, dodecyl sulfates, ethanesulfonates, formate, fumarates, glucoheptanoates, glycerophosphates, glycolates, hemisulfates, heptanoates, hexanoates, hexine-1,6-diates, hydroxybenzoates, γ-hydroxybutyrates, hydrochlorides, hydrobroms, hydroiodides, 2-H Droxyethanesulfonate, iodide ion, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfur This includes salts, 3-phenylpropionate, phosphates, picrates, pivalates, propions, pyrosulfates, pyrophosphates, propiolates, phthalates, phenylacetates, phenylbutyrates, propanesulfonates, salicylates, succinates, sulfates, sulfites, succinates, suberinates, sebacinates, sulfonates, tartrates, thiocyanates, tosylates, undecanoates, and xylenesulfonates.Furthermore, the compounds disclosed herein include, but are not limited to, compounds in free base form, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, Q-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2 These compounds can be prepared as pharmaceutically acceptable salts formed by reacting them with pharmaceutically acceptable inorganic or organic acids, including organic acids such as hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]octa-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. Other acids, such as oxalic acid, are not pharmaceutically acceptable themselves, but can be used to prepare salts that are useful as intermediates in obtaining compounds and / or pharmaceutically acceptable acid addition salts. In some embodiments, compounds disclosed herein that may contain a free acid group may contain a free acid group that reacts with ammonia or a pharmaceutically acceptable organic primary, secondary, or tertiary amine with a suitable base such as a hydroxide, carbonate, bicarbonate, or sulfate of a pharmaceutically acceptable metal cation. Typical alkali salts or alkaline earth salts may include lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, and aluminum salts. Examples of exemplary bases may include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, and N+(C1-4 alkyl)4. Typical organic amines useful for forming base addition salts may include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, and piperazine.It can be understood that the compounds disclosed herein may also include quaternization of any basic nitrogen-containing groups they contain. In some embodiments, such quaternization may yield water-soluble, oil-soluble, or dispersible products. The compounds disclosed herein may be prepared as pharmaceutically acceptable salts formed by either the substitution of an acidic proton present in the parent compound with a metal ion, such as an alkali metal ion, an alkaline earth ion, or an aluminum ion, or by coordination with an organic base. In some embodiments, the base addition salt may also be prepared by reacting the free acid form of the compounds disclosed herein with pharmaceutically acceptable inorganic or organic bases, including, but not limited to, organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, and N-methylglucamine, and inorganic bases such as aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydroxide. Furthermore, salt forms of the disclosed compounds may be prepared using salts of starting materials or intermediates.

[0040] The headings used in this specification are for systematization purposes only and should not be interpreted as limiting the subjects described.

[0041] Overview Methods, compositions, kits, and devices for treating memory loss with phosphodiesterase inhibitors are disclosed herein. In some embodiments, the treatment method may include administering a phosphodiesterase (PDE) inhibitor, a salt thereof, or a combination of PDE inhibitors or salts thereof to a subject by a nasal spray device. The nasal spray device may release dose units into the plume during operation. In some embodiments, the nasal spray device may have a diameter of approximately 38 μm to approximately 49 μm. 90It is configured to release a plume with a value. In some cases, PDE inhibitors may be administered as intranasal formulations. In some cases, PDE inhibitors may inhibit PDE polypeptides and may include roflumilast, its salts, or other PDE4 inhibitors or their salts.

[0042] Phosphodiesterase (PDE) polypeptides and inhibitors PDE inhibitors for treating memory loss are disclosed herein. PDE inhibitors may be selective or non-selective to various phosphodiesterase enzymes. Compositions disclosed herein, such as nasal sprays, comprise a phosphodiesterase inhibitor or a salt thereof and are administered to subjects in need.

[0043] PDE1 (phosphodiesterase type 1) is a known enzyme as a calcium- and calmodulin-dependent phosphodiesterase. Various tissues, including the heart, lungs, and brain, express PDE1. PDE1 can hydrolyze both ribonucleotides and deoxyribonucleotides. The PDE1 enzyme can degrade both cGMP and cAMP. The PDE1 enzyme may play a role in smooth muscle proliferation and cellular signaling pathways.

[0044] The PDE2 polypeptide can reduce aldosterone secretion. Such a reduction may play a significant role in regulating the elevation of intracellular concentrations of cAMP and cGMP in platelets. Several regions of the brain can express PDE2, and rat studies have shown that inhibition of PDE2 may enhance memory. Since PDE2 can be localized to microvessels, particularly venous capillaries and endothelial cells, it may play a role in regulating fluid and cell leakage during inflammatory states. PDE2 may also be a good pharmacological target for pathological conditions such as sepsis, or in more localized inflammatory responses such as thrombin-induced edema formation in the lungs.

[0045] PDE3 family enzymes hydrolyze cAMP and cGMP, suggesting, in a sense, that the in vivo hydrolysis of cAMP may be inhibited by cGMP. The PDE3 family can be distinguished by its ability to be activated by several phosphorylation pathways, including the PKA and PI3K / PKB pathways. PDE3A can be expressed relatively highly in platelets, as well as in cardiomyocytes and oocytes. PDE3B may be the major PDE in adipose tissue, liver and pancreas, as well as in some cardiovascular tissues. Both PDE3A and PDE3B can be highly expressed in vascular smooth muscle cells and are likely to modulate contraction.

[0046] PDE4 polypeptides can regulate the production of pro-inflammatory and anti-inflammatory cytokines, as well as cell proliferation, through the degradation of cAMP. PDE5 polypeptides may be the best known modulators of vascular smooth muscle contraction, and are molecular targets for several frequently advertised drugs used to treat erectile dysfunction and pulmonary hypertension. In the lungs, inhibition of PDE5 can interfere with smooth muscle vasoconstriction, and PDE5 inhibitors are in clinical trials for the treatment of pulmonary hypertension.

[0047] Examples of PDE inhibitors include, for example, Filaminast, Picramilast, Rolipram, Org20241, MCI-154, Loflumilast, Toborinone, Posical, Lixazinone, Zaprinast, Sildenafil, Apremilast, Siromilast, Chrysabolol (AN2728), Ibudilast, Luteolin, Mesembrenone, Pyrazolopyrimidinone, Motapizone, Pimobendan, Zardaverine, Siguazodane, CI-930, EMD53998, Imazodane, Saterinone, Lopurinone hydrochloride, 3-Pyridinecarbonnitrile derivatives, Dembuphylene, Albiphylline, Tolvafiri It may contain doxophylline, theophylline, pentoxophylline, nantherinone, cilostazol, cilostamide, MS857, pyroximon, milrinone, aminone, trafentrin, dipyridamole, papaverine, E4021, thienopyrimidine derivatives, triflusal, ICOS-351, tetrahydropiperazino[1,2-b]beta-carbolin-1,4-dione derivatives, carbolin derivatives, 2-pyrazolin-5-one derivatives, condensed pyridazine derivatives, quinazoline derivatives, anthranilic acid derivatives, imidazoquinazoline derivatives, or salts of any of these.

[0048] PDE inhibitors can be selective PDE inhibitors or nonspecific PDE inhibitors. Selective PDE inhibitors may include PDE1 selective inhibitors, PDE2 selective inhibitors, PDE3 selective inhibitors, PDE4 selective inhibitors, PDE5 selective inhibitors, PDE6 selective inhibitors, PDE7 selective inhibitors, PDE8 selective inhibitors, PDE9 selective inhibitors, PDE10 selective inhibitors, or PDE11 selective inhibitors. In some cases, selective PDE inhibitors may be specific to more than one of PDE1, PDE2, PDE3, PDE4, PDE5, PDE6, PDE7, PDE8, PDE9, PDE10, and PDE11. Nonspecific PDEs may include PDE inhibitors that inhibit at least two, three, four, or five, or more of PDE1, PDE2, PDE3, PDE4, PDE5, PDE6, PDE7, PDE8, PDE9, PDE10, and PDE11.

[0049] PDE inhibitors can inhibit cell apoptosis by inhibiting TNF-alpha, TRAIL, and their metabolites. PDE inhibitors can activate the production and secretion of nitric oxide in all tissues, thereby inducing vasodilation or vasoconstriction in all blood vessels, including peripheral blood vessels (inhibiting intermittent claudication), those of the distal extremities, and the penile region that contributes to penile erection.

[0050] Nonspecific PDE inhibitors may include theophylline, papaverine, caffeine, IBMX (3-isobutyl-1-methylxanthine, aminophylline, doxophiline, cipamphylline, theobromine, pentoxifylline (oxypentiphylline), diprophylline, or salts thereof. Theophylline is a methylxanthine derivative that, when administered as described herein, can be used to treat chemosensory dysfunction, amnesia, or both. In some cases, anti-inflammatory effects may be achieved when theophylline is prescribed or administered at levels that produce systemic levels of theophylline in the blood that are well below levels that would cause side effects. Patients with emphysema and chronic bronchitis may also be relieved by theophylline if their symptoms are partly related to reversible airway narrowing.

[0051] PDE1 selective inhibitors known to date as calcium and calmodulin-dependent phosphodiesterases may include ebrunamenin-14-carboxylate ethyl ester (vinpocetine). In some cases, vinpocetine can be used to induce vasorelaxation in cerebral smooth muscle tissue. In some cases, PDE1 selective inhibitors may include IC86340, amiodarone, lisinopril, 8-methoxymethyl-IBMX, nimodipine, zaprinast, IC224, SCH51866, any salt of these, or any combination thereof. In some cases, PDE1 selective inhibitors may include vinpocetine or a salt thereof.

[0052] PDE2 selective inhibitors may include EHNA (erythro-9-(2-hydroxy-3-nonyl)adenine), 9-(6-phenyl-2-oxohexa-3-yl)-2-(3,4-dimethoxybenzyl)-purine-6-one (PDP), BAY60-7750, or salts of any of these.

[0053] PDE3 selective inhibitors may include enoximon, milrinone (Primacor), amrinone, cilostamide, cilostazol (Pletal), trequinsin, or salts thereof. When administered as described herein, PDE3 inhibitors can induce sympathetic nerve stimulation to increase cardiac inotropy, chronotropy, and dromotropy. When administered as described herein, PDE3 inhibitors can also antagonize platelet aggregation, increase myocardial contractility, and increase vascular and airway smooth muscle relaxation. PDE3A may be a regulator of this process. When administered as described herein, PDE3 inhibitors can effectively prevent aggregation. Cilostazol (Pletal) is approved for the treatment of intermittent claudication. Its mechanism of action may include inhibition of platelet aggregation accompanied by inhibition of smooth muscle proliferation and vasodilation.

[0054] PDE4 selective inhibitors may include mesembrine, rolipram, ibudilast and roflumilast (Daxus), siromilast (Aerflo), or salts of any of these. In some cases, PDE4 selective inhibitors may be administered to treat amnesia. For example, roflumilast or a salt thereof may be administered to treat amnesia. In some cases, PDE4 selective inhibitors may be administered to treat chronic obstructive pulmonary disease. PDE4 selective inhibitors may at least partially suppress the release of inflammatory mediators, such as cytokines, or at least partially inhibit the generation of reactive oxygen species and immune cell infiltration. PDE4 inhibitors may also be used to treat asthma, arthritis, and psoriasis. In some cases, PDE4 selective inhibitors may include apremilast, siromilast, crisabolol (AN2728), ibudilast, luteolin, mesembrenone, picramiralast, roflumilast, rolipram, salts of any of these, or any combination thereof.

[0055] PDE5 selective inhibitors may include sildenafil, tadalafil, vardenafil, udenafil, avanafil, and their salts.

[0056] Additional treatments In some embodiments, the compositions or treatment methods described herein may include one or more additional therapeutic agents. In some embodiments, the compositions described herein may include treatment for a disease such as memory loss. In some cases, the treatment for a disease described herein may include aducanumab, a cholinesterase inhibitor, a glutamate regulator, an orexin receptor antagonist, or any combination thereof. In some cases, the cholinesterase inhibitor may include donepezil, rivastigmine, galantamine, tacrine, a salt of any of these, or any combination thereof. In some cases, the glutamate regulator may include memantine or a salt thereof. In some cases, the orexin receptor antagonist may include suvorexant or a salt thereof. In some embodiments, the treatment for a disease described herein may include riluzole, edaravone, sodium phenylbutyrate, taurursodiol, a salt of any of these, or any combination thereof. In some cases, the treatment for a disease described herein may include tetrabenazine, amantadine, a salt of any of these, or any combination thereof.

[0057] In some embodiments, the compositions described herein may include treatment for Parkinson's disease. In some cases, treatment for Parkinson's disease may be administered by a spray device described herein. In some cases, treatment for Parkinson's disease or another neurological disorder may include amantadine, apomorphine, benserazide, adlogolide, artinicline, benztropine, biperiden, brasofensin, bromocriptine, budipine, cabergoline, dihydroexidine, entacapone, etilevodopa, idazoxane, istradefylline, iometopan, lasabemid, melevodopa, levodopa, carbidopa, carbidopa / levodopa, mofegiline, opicapon, moxylaprine, pergolide, pramipexole, kinerolan, rasagiline, ropinirole, rotigotine, selegiline, safinamide, talipexole, tolcapone, trihexyphenidyl, any salt of these, or any combination thereof.

[0058] In some embodiments, the treatment of the disease described herein may include levodopa. In some cases, levodopa may include co-beneldopa, co-careldopa, a salt of any of these, or any combination thereof. In some embodiments, the treatment of the disease described herein may include a dopamine agonist. In some cases, the dopamine agonist may include pramipexole, ropinirole, rotigotine, apomorphine, a salt of any of these, or any combination thereof. In some embodiments, the treatment of the disease described herein may include an MAO-B inhibitor. In some cases, the MAO-B inhibitor may include rasagiline, selegiline, safinamide, a salt of any of these, or any combination thereof. In some embodiments, the treatment of the disease described herein may include a COMT inhibitor. In some cases, the COMT inhibitor may include entacapone, co-careldopa, and entacapone, opicapone, a salt of any of these, or any combination thereof. In some embodiments, the treatment of the disease described herein may include amantadine or a salt thereof. In some embodiments, the treatment of the disease as described herein may include an anticholinergic agent or a salt thereof. In some cases, the anticholinergic agent may include procyclidine, trihexyphenidyl, benzhexol, a salt of any of these, or any combination thereof.

[0059] In some embodiments, the compositions herein may contain an anticholinergic agent. In some embodiments, the anticholinergic agent may include thioridazine, haloperidol, olanzapine, a salt of any of these, or any combination thereof. In some cases, anticholinergic agents include amitriptyline, atropine, aclidinium, benztropine, chlorpheniramine, chlorpromazine, clomipramine, clozapine, cyclobenzaprine, cyproheptadine, dalifenacin, desipramine, dexchlorpheniramine, dicyclomine, diphenhydramine, doxepin, hydroxyzine, hyosthiamine, imipramine, meclizine, nortriptyline, olanzapine, orphenadrine, oxybutynin, paroxetine, perphenazine, prochlorperazine, promethazine, protriptyline, pseudoephedrine HCl / triprolidine HCl, scopolamine, thioridazine, tolterodine, trifluoperazine, trihexyphenidyl, trimipramine, any salt of these, or any combination thereof. It is possible.

[0060] In some embodiments, the composition may contain luteolin, its salts, or derivatives thereof. In some cases, the composition may contain palmitoylethanolamide, its derivatives, or salts thereof. In some cases, the composition may contain palmitoylethanolamide, its derivatives, or salts thereof, and luteolin, its derivatives, or salts thereof. In some cases, palmitoylethanolamide, its derivatives, or salts thereof and / or luteolin, its derivatives, or salts thereof may constitute an activator in a composition such as a pharmaceutical composition. In some cases, palmitoylethanolamide, its derivatives, or salts thereof, luteolin, its derivatives, or salts thereof may be mixed with a PDE inhibitor or a salt thereof. In some cases, palmitoylethanolamide, its derivatives, or salts thereof, luteolin, its derivatives, or salts thereof, or any combination thereof may be administered by a spray device. In some cases, the PDE inhibitor may contain theophylline or a salt thereof. In some cases, palmitoylethanolamide, its derivatives, or salts thereof, and luteolin, its derivatives, or salts thereof may be mixed with a PDE inhibitor or a salt thereof. In some cases, palmitoylethanolamide, its derivatives or salts thereof, and / or luteolin, its derivatives or salts thereof can be used to treat chemosensory dysfunction, memory loss, or both. In some cases, palmitoylethanolamide, its derivatives or salts thereof, luteolin, its derivatives or salts thereof, PDE inhibitors or salts thereof can each be present independently in therapeutically effective doses to treat chemosensory dysfunction, memory loss, or both. In some cases, PDE inhibitors or salts thereof may be administered intranasally, while palmitoylethanolamide, its derivatives or salts thereof, luteolin, its derivatives or salts thereof, or any combination thereof may be administered orally, for example, in the form of pills, liquids, capsules or tablets.

[0061] In some embodiments, typical doses of palmitoylethanolamide, its derivatives, their salts, luteolin, its derivatives, or their salts may be approximately 1.0 μg to 2000 mg per day, approximately 1.0 μg to 500.0 mg per day, approximately 10 μg to 100.0 mg per day, approximately 10 μg to 10 mg per day, approximately 10 μg to 1.0 mg per day, approximately 10 μg to 500 μg per day, approximately 20 μg to 2000 μg per day, approximately 100 μg to 10,000 μg per day, or approximately 1 μg to 50 μg per day. These dose ranges represent the total daily dose of the active ingredient for a given patient. In some embodiments, the daily dose administered may be approximately less than or equal to: 2000 mg per day, 1000 mg per day, 500 mg per day, 100 mg per day, 10 mg per day, 1.0 mg per day, 500 μg per day, 300 μg per day, 200 μg per day, 100 μg per day, or 50 μg per day. In some embodiments, the daily dose administered may be at least approximately: 2000 mg per day, 1000 mg per day, 500 mg per day, 100 mg per day, 10 mg per day, 1.0 mg per day, 500 μg per day, 300 μg per day, 200 μg per day, 100 μg per day, or 50 μg per day. In some embodiments, based on a per-kilogram basis, the preferred dosage levels of the compound can be approximately 0.001 μg to 10.0 mg per kg of body weight per day, approximately 0.5 μg to 0.5 mg per kg of body weight per day, approximately 1.0 μg to 100 μg per kg of body weight per day, and approximately 2.0 μg to 50 μg per kg of body weight per day.

[0062] Compositions and formulations In some embodiments, the compositions or formulations described herein may include an active ingredient, a carrier, an excipient, a viscosity improver, a diluent, a preservative, an enzyme modulator, a vasoconstrictor, a mucosal adhesive, a humectant, or any combination thereof. In some cases, the carrier, excipient, viscosity improver, diluent, preservative, humectant, enzyme modulator, vasoconstrictor, or mucosal adhesive may be of any pharmaceutically acceptable type thereof. In some embodiments, the compositions or formulations described herein may be liquids. In some cases, the active ingredient may include a PDE inhibitor described herein. For example, the PDE inhibitor may include theophylline or a salt thereof, cilostazol or a salt thereof, roflumilast or a salt thereof, or any combination thereof. In some cases, the carrier may include water. In some cases, the viscosity improver may include cellulose. In some cases, the excipient may include glycerol. In some cases, the compositions or formulations described herein may be delivered by a nasal spray device. In some cases, the compositions described herein may be sterile. In some cases, the compositions described herein may be aseptic.

[0063] In some cases, a formulation or composition may contain an activator such as a PDE inhibitor. In some cases, a composition or formulation may contain an activator in amounts greater than approximately: 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% (by weight / weight) of the whole composition. In some cases, a composition or formulation may contain an activator in amounts less than approximately: 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% (by weight / weight) of the whole composition. In some cases, a composition or formulation may contain an activator in an amount of approximately 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% (by weight / weight) of the total composition. In some cases, a composition or formulation may contain one activator. In some cases, a composition or formulation may contain more than one activator; for example, a composition may contain two, three, four, five or more activators.

[0064] In some embodiments, the composition or formulation may contain excipients. Excipients may include, but are not limited to, water, fluidizers, lubricants, adhesives, surfactants, acidifiers, alkalizing agents, pH adjusters, antimicrobial preservatives, antioxidants, antistatic agents, buffering agents, chelating agents, humectants, or wetting agents. Excipients may also include colorants, coating agents, sweeteners, flavoring agents, and fragrances, or masking agents. The composition and formulation may include or not include a carrier, and may include individual excipients, or optionally a plurality of suitably combined excipients. In some cases, the excipient may include glycerol.

[0065] In some cases, pharmaceutically acceptable excipients include acacia, acesulfame potassium, glacial acetic acid, acetone, tributyl acetylcitrate, triethyl acetylcitrate, agar, albumin, alcohol, alginic acid, aliphatic polyester, alitame, almond oil, alpha-tocopherol, aluminum hydroxide adjuvant, aluminum oxide, aluminum phosphate adjuvant, aluminum stearate, ammonia solution, ammonium alginate, ascorbic acid, ascorbyl palmitate, aspartame, attapulgite, and bentonite. Benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, benzyl benzoate, boric acid, bronopol, butylated hydroxyanisole, butylated hydroxytoluene, butylparaben, calcium alginate, calcium carbonate, dibasic anhydrous calcium phosphate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, calcium stearate, calcium sulfate, canola oil, carbomer, carbon dioxide, calcium carboxymethylcellulose, sodium carboxymethylcellulose, carrageenan, castor oil, hydrogen Castor oil, cellulose (e.g., microcrystalline, powdered, silicified microcrystalline, acetate, acetate phthalate), ceratonia, cetostearyl alcohol, cetrimide, cetyl alcohol, cetylpyridinium chloride, chitosan, chlorhexidine, chlorobutanol, chlorocresol, chlorodifluoroethane, chlorofluorocarbon, chloroxylenol, cholesterol, citric acid monohydrate, colloidal silicon dioxide, colorants, copovidone, corn oil, cottonseed oil, cresol, croscarmellose sodium, crospovidone, cyclodex Trin, cyclomethicone, denatonium benzoate, dextrose, dextrin, dextrose, dibutyl phthalate, dibutyl sebacate, diethanolamine, diethyl phthalate, difluoroethane, dimethicone, dimethyl ether, dimethyl phthalate, dimethyl sulfoxide, dimethylacetamide, disodium edetate, sodium docusate, edetate, erythorbic acid, erythritol, ethyl acetate, ethyl lactate, ethyl maltol, ethyl oleate, ethyl vanillin, ethylcellulose, ethylene glycol palmitostearate,Ethylene vinyl acetate, ethylparaben, fructose, fumaric acid, gelatin, glucose, glycerin, glyceryl behenate, glyceryl monooleate, glyceryl monostearate, glyceryl palmitostearate, glycoflor, guar gum, hectorite, heptafluoropropane, hexetidine, hydrocarbons, hydrochloric acid, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxypropylcellulose, low-substituted hydroxypropyl starch, hypromellose, hypromellose succinate acetate, hypromellose phthalate, honey, imidourea, inulin, iron oxide, isomalt, isopropyl alcohol, myristic acid Isopropyl phosphate, isopropyl palmitate, kaolin, lactic acid, lactitol, anhydrous lactose, lactose monohydrate, spray-dried lactose, lanolin, lanolin alcohol, hydrated lanolin, lauric acid, lecithin, leucine, linoleic acid, macrogol hydroxystearate, aluminum magnesium silicate, magnesium carbonate, magnesium oxide, magnesium silicate, magnesium stearate, magnesium trisilicate, malic acid, maltitol, maltitol solution, maltodextrin, maltol, maltose, mannitol, medium-chain triglycerides, meglumine, menthol, methylcellulose, methylparaben, mineral oil, light mineral oil Mineral oil, lanolin alcohol, monoethanolamine, monosodium glutamate, monothioglycerol, myristic acid, neohesperidin dihydrochalcone, nitrogen, dinitrogen monoxide, octyldodecanol, oleic acid, oleyl alcohol, olive oil, palmitic acid, paraffin, peanut oil, pectin, petrolatum, petrolatum alcohol and lanolin alcohol, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercury acetate, phenylmercury borate, phenylmercury nitrate, phosphoric acid, potassium polaritrate, poloxamer, polycarbophil, polydextrose, polyethylene glycol, polyethylene oxide, polymethacrylate, poly(methyl vinyl ether / maleic anhydride), polyoxyethylene alkyl ether, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester,Polyoxyethylene stearate, polyvinyl acetate phthalate, polyvinyl alcohol, potassium alginate, potassium benzoate, potassium bicarbonate, potassium chloride, potassium citrate, potassium hydroxide, potassium metabisulfite, potassium sorbate, povidone, propionic acid, propyl gallate, propylene carbonate, propylene glycol, propylene glycol alginate, propylparaben, 2-pyrrolidone, raffinose, saccharin, sodium saccharin, saponite, sesame oil, shellac, simethicone, sodium acetate, sodium alginate, sodium ascorbate, sodium benzoate, sodium bicarbonate, sodium borate, sodium chloride, sodium citrate Sodium cyclamate dihydrate, sodium hyaluronate, sodium hydroxide, sodium lactate, sodium lauryl sulfate, sodium metabisulfite, dibasic sodium phosphate, monobasic sodium phosphate, sodium propionate, sodium starch glycolate, sodium stearyl fumarate, sodium sulfite, sorbic acid, sorbitan ester (sorbitan fatty acid ester), sorbitol, soybean oil, starch, starch (e.g., gelatinized, sterilizable corn), stearic acid, stearyl alcohol, sucralose, sucrose, compressed sugar, sugar, powdered sugar, spheroidal sugar, sulfobutyl ether β-cyclodextrin, sulfuric acid, sunflower oil, suppository base, hard fat It may contain fat, talc, tartaric acid, tetrafluoroethane, thaumatin, thimerosal, thymol, titanium dioxide, tragacanth, trehalose, triacetin, tributyl citrate, triethanolamine, triethyl citrate, vanillin, hydrogenated vegetable oil, water, anionic emulsifying waxes, waxes (e.g., carnauba, cetyl ester, microcrystalline, nonionic emulsifying, white, yellow), xanthan gum, xylitol, zein, zinc acetate, zinc stearate, or any combination thereof.

[0066] In some embodiments, the composition or formulation may contain a viscosity improver (e.g., a solution thickener). In some examples, the viscosity improver may contain cellulose. In some cases, the viscosity improver may contain carboxymethylcellulose (CMC), cellulose I, cellulose II, cellulose III, cellulose IV, microcrystalline cellulose (MCC), sodium carboxymethylcellulose (Na CMC), or a combination thereof. In some cases, the viscosity improver may contain cellulose acetate, cellulose triacetate, cellulose propionate, cellulose propionate acetate, cellulose acetate butyrate, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose (HPC), hydroxyethylmethylcellulose, ethylhydroxyethylcellulose, hydroxypropylmethylcellulose, or a combination thereof. In some cases, a composition or formulation may contain viscosity improvers in amounts of approximately 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% (by weight / weight) of the total composition. In some cases, a composition or formulation may contain viscosity improvers in amounts of approximately 0.01% to approximately 10% (by weight / weight) of the total composition. In some cases, a composition or formulation may contain one type of viscosity improver. In some cases, a composition or formulation may contain more than one type of viscosity improver; for example, a composition may contain two, three, four, five, or more types of viscosity improvers.

[0067] In some cases, the viscosity of the intranasal dose unit can affect the residence time in the nasal cavity. In some embodiments, the dose unit has a higher kinematic viscosity than water at the same temperature. In some embodiments, the dose unit can have a kinematic viscosity of 0.5 cSt to 3 cSt at 20°C. For example, the dose unit can have a kinematic viscosity of 0.5 to 2 cSt, 0.5 to 1.5 cSt, 0.5 to 1.25 cSt, 0.5 to 1.1 cSt, 0.5 to 1 cSt, 0.5 to 0.9 cSt, 0.5 to 0.75 cSt, 0.75 to 2 cSt, 0.75 to 1.5 cSt, 0.75 to 1.25 cSt, 0.75 to 1.1 cSt, 0.75 to 1 cSt, 0.75 to 0.9 cSt, and 0.9 to 2 cSt at 20°C. The kinematic viscosity can be St, 0.9-1.5cSt, 0.9-1.25cSt, 0.9-1.1cSt, 0.9-1cSt, 1-2cSt, 1-1.5cSt, 1-1.25cSt, 1-1.1cSt, 1.1-2cSt, 1.1-1.5cSt, 1.1-1.25cSt, 1.25-2cSt, 1.25-1.5cSt, 1.5-2cSt, or 2-3cSt. In some embodiments, the dosage unit has a kinematic viscosity of 0.9-1.25cSt at 20°C. In some embodiments, the dosage unit has a higher kinematic viscosity than water at the same temperature.

[0068] In some embodiments, the composition or formulation may include a carrier. In some cases, the carrier may include water, such as purified water. In some cases, the carrier for the composition or formulation may include, but are not limited to, amino acids, peptides, proteins, non-biopolymers, biopolymers, simple sugars, carbohydrates, gums, inorganic salts, and metal compounds, which may exist alone or in combination. In some embodiments, the pharmaceutically acceptable carrier may include the natural form, the derivatized form, the modified form, or a combination thereof. In some cases, the protein may include, but is not limited to, gelatin or albumin. In some embodiments, sugars that can act as carriers may include, but are not limited to, fructose, galactose, glucose, lactitol, lactose, maltitol, maltose, mannitol, melegitose, myo-inositol, palatinite, raffinose, stachyose, sucrose, trehalose, xylitol, its hydrates, and combinations thereof. In some cases, carbohydrates that can act as carriers include, but are not limited to, starches such as corn starch, potato starch, amylose, amylopectin, pectin, hydroxypropyl starch, carboxymethyl starch, and cross-linked starch. In other embodiments, useful carbohydrates that can act as pharmaceutically acceptable carriers include, but are not limited to, cellulose, crystalline cellulose, microcrystalline cellulose, α-cellulose, methylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose, and cellulose acetate.In some cases, the composition or formulation is approximately: 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49% of the total composition. The carrier can be contained in quantities of 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 97.5%, 98%, 98.5%, 99%, 99.5%, or 99.9% (weight / weight). In some cases, a composition or formulation may contain a carrier in an amount of about 60% to about 99.9% (by weight) of the total composition. In some cases, a composition or formulation may contain one type of carrier. In some cases, a composition or formulation may contain more than one type of carrier; for example, a composition may contain two, three, four, five or more types of carriers. In some cases, the carrier may be a non-aqueous carrier. In some cases, the non-aqueous carrier may contain a solvent, excipient, vehicle, permeation enhancer (also known as a penetration enhancer), or a mixture thereof.

[0069] In some cases, the compositions described herein may be aqueous or non-aqueous formulations. In some cases, the advantages of non-aqueous formulations may be that 1) preservatives may not be necessary, and 2) the solubility of PDE inhibitors such as theophylline in various non-aqueous excipients / vehicles may be potentially higher (for example, the solubility of theophylline in water is about 7-8 mg / mL, compared to 14-15 mg / mL in ethanol), thus potentially leading to a greater drug load in the formulation.

[0070] In some embodiments, the excipients, vehicles (e.g., carriers), or both for non-aqueous formulations (instead of water) may include alkylene glycols, e.g., propylene glycol, butylene glycol, or any combination thereof. In some cases, the excipients, vehicles (e.g., carriers), or both for non-aqueous formulations may include dialkylene glycols (e.g., dipropylene glycol). In some cases, the excipients, vehicles (e.g., carriers), or both for non-aqueous formulations may include polyethylene glycol (PEG) (e.g., PEG400, PEG600, or any combination thereof). In some cases, the excipients, vehicles (e.g., carriers), or both for non-aqueous formulations may include unsaturated fatty alcohols such as palmitrail alcohol, oleyl alcohol, erucyl alcohol, or any combination thereof. In some cases, the excipients, vehicles (e.g., carriers), or both for non-aqueous formulations may include DMSO, Transcutol P (diethylene glycol monoethyl ether), ethanol, acetone, or any combination thereof.

[0071] In some embodiments, the composition or formulation may contain a diluent. In some cases, the diluent may contain an excipient. In some cases, the diluent may contain water, saline solution, buffer solution, sugar, binder, disintegrant, or any combination thereof.

[0072] In some embodiments, the composition or formulation may contain a preservative. In some cases, the preservative may contain an alcohol. In some cases, the preservative may contain phenylethyl alcohol. In some cases, the preservative may contain methylparaben, propylparaben, benzalkonium chloride, phenylcarbinol, potassium sorbate, or a combination thereof. In some cases, the compositions disclosed herein may not contain a preservative. In some cases, the composition or formulation may contain a preservative in an amount of about 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 3%, 4%, or 5% (by weight / weight) of the total composition. In some cases, the composition or formulation may contain a preservative in an amount of about 0.01% to about 10% (by weight / weight) of the total composition. In some cases, a composition or formulation may contain one preservative. In some cases, a composition or formulation may contain more than one preservative; for example, a composition may contain two, three, four, five or more preservatives.

[0073] In some embodiments, the composition or formulation may include a buffering agent. In some cases, the buffering agent may include potassium phosphate, sodium acetate, sodium citrate, sodium phosphate, trisodium citrate, or a combination thereof. In some cases, the composition or formulation may include a pH adjuster such as acetic acid, citric acid, hydrochloric acid, sodium hydroxide, sulfuric acid, or a combination thereof.

[0074] In some embodiments, the pH of the composition or formulation can be 7.1 to 8.5. In some embodiments, the pH can be 7.1 to 7.4. In some embodiments, the pH of the composition or formulation can be 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, or 8.5. In some embodiments, the pH can be at least 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, or 8.5. In some embodiments, the pH of the composition or formulation can be 6 to 7. In some embodiments, the pH of the composition or formulation can be 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, or 7. In some embodiments, the pH of the dose unit can be 7.1 to 8.5. In some embodiments, the pH of the dose unit can be 7.1 to 7.4. In some embodiments, the pH of the dose unit can be 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, or 8.5. In some embodiments, the pH of the dose unit can be at least 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8, 8.1, 8.2, 8.3, 8.4, or 8.5.

[0075] In some embodiments, the composition or formulation may contain glycerol. In some cases, the composition or formulation may contain flavoring and deodorizing agents such as menthol, artificial flavors (e.g., strawberry, fruit flavors, mint flavors), natural flavors, sodium saccharin, sorbitol, or combinations thereof. In some cases, the composition or formulation may contain a fluorescent agent (e.g., fluorophores). Fluorescent agents may be used in nasal cast scans. Some examples of fluorescent dyes include Alexa Fluor 350, Alexa Fluor 405, Alexa Fluor 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 555, Alexa Fluor 561, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 647, Alexa Fluor 660, Alexa Fluor 680, Alexa Fluor 700, Alexa Fluor 750, Bodipy FL, Coumarin, CY3, CY5, Fluorescein (FITC), Oregon Green, Pacific Blue, Pacific Green, Pacific Orange, PE-Cyanine 7, PERCP-Cyanine 5.5, Tetramethylrhodamine (TRITC), and Texas Examples include red, efluor450, efluor506, efluor660, pe-efluor610, percp-efluor710, apc-efluor780, super bright436, super bright600, super bright645, super bright702, super bright780, cyan fluorescent protein (CFP), green fluorescent protein (GFP), red fluorescent protein (RFP), or any combination thereof.

[0076] In some embodiments, the composition or formulation may contain a humectant. In some cases, the humectant may include glycerin, propylene glycol, hexylene glycol, butylene glycol, glyceryl triacetate, vinyl alcohol, neoagarobiose, glycerol, sorbitol, xylitol, maltitol, polydextrose, quillaja, lactic acid, urea, or aloe vera.

[0077] In some embodiments, the compositions disclosed herein are stable in a freezer (e.g., -80°C to about -20°C), a refrigerator (e.g., 4°C), or at room temperature. In some cases, the compositions described herein may be stored in a container, for example, a container containing a pharmaceutical composition for a spray device. In some cases, the container may be glass, plastic, metal, or any solid material. In some cases, the container may be included in a kit. In some cases, when a sealed container containing the compositions described herein is placed in a room atmosphere having about 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, 10°C, 11°C, 12°C, 13°C, 14°C, 15°C, 16°C, 17°C, 18°C, 19°C, 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, or 38°C and a relative humidity of about 50%, or about 40% to 60%, the compositions may retain more than about 40%, 50%, 60%, 70%, 80%, 90%, or 99% of the active ingredient or its salt after 3 months, 6 months, or 12 months, as measured by high-performance liquid chromatography (HPLC).

[0078] In some embodiments, the compositions or formulations described herein may include penetration enhancers. In some cases, the penetration enhancer may be a substance capable of promoting the penetration of a drug into the skin, mucous membranes, nerve sheaths, or through another barrier (e.g., mucosal tissue). In some cases, the penetration enhancer may be at least partially inert, non-toxic, non-irritating, non-allergenic, compatible with drugs and excipients, odorless, tasteless, colorless, or a combination thereof. In some cases, the penetration enhancer may be a fatty acid, alcohol, surfactant, solvent, hydrogen bond acceptor, or any combination thereof. In some cases, the penetration enhancer may include azonem (1-dodecyl azacycloheptan-2-one), dimethyl sulfoxide, dimethylacetamide, dimethylformamide, ethanol, propylene glycol, N-methylpyrrolidone, oleic acid, lauryl alcohol, ketone terpenes, terpenes, sulfoxides, alkanols, organic acids, alcohols, polyols, pyrrolidone, glycols, urea and urea derivatives, enzymes, iminosulfurans, cyclodextrins, fatty acid esters, surfactants, polymers, monoolein, oxalidinone, or any combination thereof. In some cases, the penetration enhancer may include cyclodextrin, sodium hyaluronate, cremophor RH40, chitosan, cyclopentyl adenosine, dextran, or any combination thereof. In some cases, the formulations herein may include enzyme modulators.

[0079] In some embodiments, a composition or formulation may contain a penetration enhancer in an amount of about 0.1% to about 20% (weight-to-weight) (weight / weight) of the total composition. In some cases, a composition or formulation may contain a penetration enhancer in an amount of about 1% to about 10%, 2% to about 8%, 5% to about 15%, 4% to about 12%, or 10% to about 20% (weight / weight) of the total composition. In some cases, a composition or formulation may contain a penetration enhancer in an amount of about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% (weight / weight) of the total composition. In some cases, a composition or formulation may contain one type of penetration enhancer. In some cases, a composition or formulation may contain more than one type of penetration enhancer; for example, a composition or formulation may contain two, three, four, five or more different types of penetration enhancers.

[0080] In some cases, the enzyme modulator may include a p-glycoprotein inhibitor, a CYP450 inhibitor, an acetazolamide inhibitor, or any combination thereof. In some cases, the formulations herein may include a vasoconstrictor. In some cases, the vasoconstrictor may include phenylephrine or a salt thereof. In some cases, the formulations may include a mucosal adhesive. In some cases, the mucosal adhesive may include chitosan, a derivative of chitosan, carboxymethylcellulose, polyacrylic acid, or any combination thereof. In some cases, the formulations herein may include a ciliostatic agent. In some cases, the ciliostatic agent may include chlorbutol, hydroxybenzoate, chlorocresol edetate, phenylmercury acetate, thimerosal, a salt of any of these, or any combination thereof.

[0081] Nasal spray device A device for administering an active ingredient to treat memory loss in subjects such as humans is disclosed herein. In some embodiments, the device can be used to administer a nasal spray to a subject in need. In some embodiments, the device administers a droplet plume in operation. In some cases, the droplet plume may contain a dose unit. For example, a pharmaceutical dose unit can be administered by the device described herein. In some examples, droplets may be referred to as particles. The plume can deliver droplets into the nasal cavity in operation. In some embodiments, the spray may be configured to deposit droplets in the olfactory region of the nasal cavity. The spray devices disclosed herein can release particles in size from about 10 μm to about 20 μm.

[0082] In some embodiments, the nasal spray device delivers a plume as a unit dose during operation. In some cases, the nasal spray device contains about 60 to about 120 unit doses. In some cases, the nasal spray device contains about 60 to about 300 unit doses. In some cases, the nasal spray device contains about 60 to about 240 unit doses. In some cases, the nasal spray device contains about 1 to about 200 unit doses, 10 to about 250 unit doses, 5 to about 50 unit doses, 50 to about 100 unit doses, 20 to about 220 unit doses, about 100 to about 240 unit doses, or about 200 to about 300 unit doses. In some cases, each unit dose may contain about 20 μg to about 4000 μg of a PDE inhibitor or a salt thereof. In some cases, each unit dose may contain about 20 μg to about 2000 μg of a PDE inhibitor or a salt thereof. In some embodiments, the liquid pharmaceutical composition may be administered in the form of a plume from the operation of the device.

[0083] In some embodiments, the nasal spray device may comprise a spray nozzle. In some examples, the spray nozzle may be configured to generate a plume. The spray nozzle can be inserted into the nostril or nose of the target. In some examples, the nasal spray device may comprise one spray nozzle. In some examples, the nasal spray device may comprise multiple spray nozzles to generate a plume; for example, the spray device may comprise two, three, four, five, six, seven, eight, nine, ten, twenty, 30, 40, 50 or more nozzles to generate a plume. In some cases, the spray nozzle may include one or more nozzle holes. In some cases, the spray nozzle may have modified droplet parameters to obtain a droplet size range. In some examples, the droplet size range can increase or decrease the amount of drug deposited in the nasal cavity. In some examples, the droplet size range can increase or decrease the amount of drug coverage in the nasal cavity. In some examples, the droplet size range can increase or decrease the amount of drug in the nasal cavity region. For example, a droplet size range can be obtained in which the majority of the drug is deposited in the olfactory portion of the nasal cavity. In some embodiments, the nasal spray device may include one or more dose units. In some cases, the nasal spray device may include a laser bar having multiple dose units. In some embodiments, the spray device is D 10 , D 50 , D 90 And a plume with span measurements can be emitted. In some cases, droplet or particle size (e.g., D 10 , D 50 Or D 90 The measured value can be determined by a laser diffraction system, such as the Malvern Spraytec system.

[0084] In some embodiments, the spray device may have one or more nozzle holes. The nozzle holes may be located at the end of the spray nozzle, which is inserted into the nose for intranasal administration. In some cases, the spray device may have nozzle hole sizes of approximately 1 μm, 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, 8 μm, 9 μm, or 10 μm. In some cases, the spray device may have nozzle hole sizes of 3 μm. In some cases, the spray device may have nozzle hole sizes of 4 μm. In some cases, the spray device may have nozzle hole sizes of 5 μm. In some cases, the spray device may have approximately 10 to approximately 200 nozzle holes, 10 to approximately 100 nozzle holes, 10 to approximately 60 nozzle holes, 20 to approximately 80 nozzle holes, 30 to approximately 100 nozzle holes, 40 to approximately 70 nozzle holes, 45 to approximately 65 nozzle holes, or 48 to approximately 60 nozzle holes. In some cases, a spray device may have approximately 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, or 75 nozzle holes. In some cases, a spray device may have 60 nozzle holes. In some cases, a spray device may have 48 holes. In some cases, a spray device may have a cone angle for dispensing spray at a given angle. In some cases, the cone angle of the spray device may be approximately 10° to approximately 80°, 10° to approximately 60°, 10° to approximately 40°, 10° to approximately 30°, 15° to approximately 25°, or 20° to approximately 40°.In some cases, the cone angle of the spray device is approximately: 1°, 2°, 3°, 4°, 5°, 6°, 7°, 8°, 9°, 10°, 11°, 12°, 13°, 14°, 15°, 16°, 17°, 18°, 19°, 20°, 21°, 22°, 23°, 24°, 25°, 26°, 27°, 28°, 29°, 30°, 31°, 32°, 33°, 34°, 35°, 36°, 37°, 38°, 39°, 40° It can be 41°, 42°, 43°, 44°, 45°, 46°, 47°, 48°, 49°, 50°, 51°, 52°, 53°, 54°, 55°, 56°, 57°, 58°, 59°, 60°, 61°, 62°, 63°, 64°, 65°, 66°, 67°, 68°, 69°, 70°, 71°, 72°, 73°, 74°, 75°, 76°, 77°, 78°, 79°, or 80°. In some cases, the cone angle of the spray device can be about 20°.

[0085] In one example, the spray device can have 60 nozzle holes with a conical angle of 20° and a size of 4 μm per hole. In another example, the spray device can have 48 nozzle holes with a conical angle of 20° and a size of 5 μm per hole. In yet another example, the spray device can have 60 nozzle holes with a conical angle of 20° and a size of 5 μm per hole. In yet another example, the spray device can have 48 nozzle holes with a conical angle of 20° and a size of 4 μm per hole.

[0086] In some embodiments, a certain volume of dose unit can range from about 25 μL to about 2000 μL. In some embodiments, the spray device described herein may contain single-dose units or multiple-dose units. For example, the spray device described herein may contain multiple-dose spray units. In some cases, the operation of the spray device can dispense a certain volume of dose unit. In some cases, a certain volume of dose unit can range from about 50 μL to about 400 μL. In some cases, a certain volume of dose unit can range from about 20 μL to about 80 μL, 65 μL to about 75 μL, 40 μL to about 300 μL, 60 μL to about 350 μL, 80 μL to about 450 μL, 100 μL to about 600 μL, 250 μL to about 600 μL, 500 μL to about 1 mL, 750 μL to about 1.5 mL, or about 1 mL to about 2 mL. In multiple cases, the dosage units for a given volume are approximately: 20μL, 21μL, 22μL, 23μL, 24μL, 25μL, 26μL, 27μL, 28μL, 29μL, 30μL, 31μL, 32μL, 33μL, 34μL, 35μL, 36μL, 37μL, 38μL, 39μL, 40μL, 41μL, 42μL, 43μL, 44μL, 45μL, 46μL, 47μL, 48μL, 49μL, 50μL, 51μL, 52μL, 53μL, 54μL, 55μL, 56μL, 57μL, 58μL, 59μL, 60μL, 61μL, 62 μL, 63μL, 64μL, 65μL, 66μL, 67μL, 68μL, 69μL, 70μL, 71μL, 72μL, 73μL, 74μL, 75μL, 76μL, 77μL, 78μL, 79μL, 80μL, 81μL, 82μL, 83μL, 84μL, 85μL, 86μL, 87μL, 88μL, 89μL, 90μL, 91μL, 92μL, 93μL, 94μL, 95μL, 96μL, 97μL, 98μL, 99μL, or more than 100μL, less than or equal to these.In some cases, a given volume of dosage is approximately: 100 μL, 110 μL, 120 μL, 130 μL, 140 μL, 150 μL, 160 μL, 170 μL, 180 μL, 190 μL, 200 μL, 210 μL, 220 μL, 230 μL, 240 μL, 250 μL, 260 μL, 270 μL, 280 μL, 290 μL, 300 μL, 310 μL, 320 μL, 330 μL, 340 μL, 350 μL, 360 μL. It may be more than 370 μL, 380 μL, 390 μL, 400 μL, 410 μL, 420 μL, 430 μL, 440 μL, 450 μL, 460 μL, 470 μL, 480 μL, 490 μL, 500 μL, 510 μL, 520 μL, 530 μL, 540 μL, 550 μL, 560 μL, 570 μL, 580 μL, 590 μL or 600 μL, less than or equal to these amounts. In some cases, a dose unit of a certain volume may be more than, less than, or equal to approximately: 600 μL, 700 μL, 800 μL, 900 μL, 1000 μL, 1100 μL, 1200 μL, 1300 μL, 1400 μL, 1500 μL, 1600 μL, 1700 μL, 1800 μL, 1900 μL, or 2000 μL.

[0087] In some embodiments, the dosage unit is defined as follows: (a) less than 3% of the droplets in the plume have a size of less than 10 μm, and (b) less than 15 μm. 10 Therefore, about 10% of the droplets in the plume are D 10 (c) Having a size less than (c) D approximately 15 to approximately 24 μm 50 Therefore, about 50% of the droplets in the plume are D 50 (d) Having a size less than (d) D approximately 30 μm to approximately 50 μm 90 Therefore, about 90% of the droplets in the plume are D 90 (e) having a size less than (D 90 -D 10 ) / D 50 The plume may take the form of a droplet-size distribution characterized by one or more of the calculations performed by the following methods.

[0088] In some embodiments, the dosage unit is defined as follows: (a) less than approximately 1.5% of the droplets in the plume have a size of less than approximately 10 μm, and (b) less than approximately 20 μm. 10 Therefore, about 10% of the droplets in the plume are D 10 (c) Having a size less than (c) D approximately 23 μm to approximately 30 μm 50 Therefore, about 50% of the droplets in the plume are D 50 (d) Having a size less than (d) D approximately 38 μm to approximately 48 μm 90 Therefore, about 90% of the droplets in the plume are D 90 (e) having a size less than (D) and a span of about 0.9 to about 1.4, where this span is (D 90 -D 10 ) / D 50 The plume may take the form of a droplet-size distribution characterized by one or more of the calculations performed by the following methods.

[0089] In some embodiments, the dosage unit is defined as follows: (a) less than 7% of the droplets in the plume have a size of less than 10 μm, and (b) about 11 μm to about 14 μm. 10 Therefore, about 10% of the droplets in the plume are D 10 (c) Having a size less than (c) D approximately 21 to approximately 25 μm 50 Therefore, about 50% of the droplets in the plume are D 50 (d) Having a size less than (d) D approximately 35 μm to approximately 41 μm 90 Therefore, about 90% of the droplets in the plume are D 90 (e) having a size less than (D 90 -D 10 ) / D 50 The plume may be in the form of a droplet-size distribution characterized by one or more of the following: being calculated by

[0090] In some embodiments, the plume may be characterized by less than about 10% of the droplets in the plume having a size of less than about 10 μm. In some embodiments, the plume may be characterized by less than about 9% of the droplets in the plume having a size of less than about 10 μm. In some embodiments, the plume may be characterized by less than about 8% of the droplets in the plume having a size of less than about 10 μm. In some embodiments, the plume may be characterized by less than about 7% of the droplets in the plume having a size of less than about 10 μm. In some embodiments, the plume may be characterized by less than about 6% of the droplets in the plume having a size of less than about 10 μm. In some embodiments, the plume may be characterized by less than about 5% of the droplets in the plume having a size of less than about 10 μm. In some embodiments, the plume may be characterized by less than about 4% of the droplets in the plume having a size of less than about 10 μm. In some embodiments, the plume may be characterized by less than about 3% of the droplets in the plume having a size of less than about 10 μm. In some embodiments, the plume may be characterized by less than about 2% of the droplets in the plume having a size of less than about 10 μm. In some embodiments, the plume may be characterized by less than about 1.5% of the droplets in the plume having a size of less than about 10 μm. In some embodiments, the plume may be characterized by less than about 1% of the droplets in the plume having a size of less than about 10 μm. In some embodiments, the plume droplets can be measured from the total amount of droplets in the plume. In some embodiments, the plume droplets can be measured from the total volume of droplets in the plume. In some embodiments, the plume droplets are less than about 10 μm but greater than about 0.1 μm, 0.01 μm, or 0.001 μm.

[0091] In some embodiments, the plume may be characterized by less than about 10% of the droplets in the plume having a size of less than about 5 μm. In some embodiments, the plume may be characterized by less than about 9% of the droplets in the plume having a size of less than about 5 μm. In some embodiments, the plume may be characterized by less than about 8% of the droplets in the plume having a size of less than about 5 μm. In some embodiments, the plume may be characterized by less than about 7% of the droplets in the plume having a size of less than about 5 μm. In some embodiments, the plume may be characterized by less than about 6% of the droplets in the plume having a size of less than about 5 μm. In some embodiments, the plume may be characterized by less than about 5% of the droplets in the plume having a size of less than about 5 μm. In some embodiments, the plume may be characterized by less than about 4% of the droplets in the plume having a size of less than about 5 μm. In some embodiments, the plume may be characterized by less than about 3% of the droplets in the plume having a size of less than about 5 μm. In some embodiments, the plume may be characterized by less than about 2% of the droplets in the plume having a size of less than about 5 μm. In some embodiments, the plume may be characterized by less than about 1% of the droplets in the plume having a size of less than about 5 μm. In some embodiments, the plume may be characterized by less than about 0.5% of the droplets in the plume having a size of less than about 5 μm. In some embodiments, the plume may be characterized by less than about 0.25% of the droplets in the plume having a size of less than about 5 μm. In some embodiments, the plume may be characterized by substantially all or all of the droplets in the plume being larger than about 5 μm. In some embodiments, the plume droplets can be measured from the total amount of droplets in the plume. In some embodiments, the plume droplets can be measured from the total volume of droplets in the plume. In some embodiments, the plume droplets are less than approximately 5 μm, but larger than approximately 0.1 μm, 0.01 μm, or 0.001 μm.

[0092] In some embodiments, D10 During the bloom, D 10 It contains about 10% droplets with a size of less than 20 μm. In some embodiments, the plume may be less than about 20 μm. 10 It can be characterized by the following. In some embodiments, the plume may be less than about 15 μm. 10 It can be characterized by the following. In some cases, the plume can be about 10 μm to about 20 μm. 10 It can be characterized by the following. In some cases, the plume can be about 8 μm to about 15 μm. 10 It can be characterized by the following. In some cases, the plume can be about 10 μm to about 15 μm. 10 It can be characterized by the following. In some cases, the plume can be about 11 μm to about 14 μm. 10 It can be characterized by the following. In some cases, the plume can be about 12 μm to about 19 μm. 10 It can be characterized by the following. In some cases, the plume can be about 14 μm to about 27 μm. 10 It can be characterized by the following. In some cases, the plume may be approximately 8μm, 9μm, 10μm, 11μm, 12μm, 13μm, 14μm, 15μm, 16μm, 17μm, 18μm, 19μm, 20μm, 21μm, 22μm, 23μm, 24μm, 25μm, 26μm, 27μm, 28μm, 29μm, or 30μm. 10 It can be characterized as follows: In some cases, the plume can be larger than approximately 8μm, 9μm, 10μm, 11μm, 12μm, 13μm, 14μm, 15μm, 16μm, 17μm, 18μm, 19μm, 20μm, 21μm, 22μm, 23μm, 24μm, 25μm, 26μm, 27μm, 28μm, 29μm, or 30μm. 10 It can be characterized by the following.

[0093] In some embodiments, D 50 During the bloom, D 50 It contains approximately 50% droplets with a size of less than 15 μm. In some embodiments, the plume can be about 15 μm to about 24 μm. 50This can be characterized by: In some embodiments, the plume may be about 10 μm to about 20 μm. 50 This can be characterized by: In some embodiments, the plume may be about 20 μm to about 25 μm. 50 It can be characterized by the following. In some embodiments, the plume may be about 21 μm to about 25 μm. 50 It can be characterized by the following. In some embodiments, the plume may be about 21 μm to about 24 μm. 50 This can be characterized by: In some embodiments, the plume may be about 20 μm to about 30 μm. 50 It can be characterized by the following. In some embodiments, the plume may be about 26 μm to about 38 μm. 50 This can be characterized by: In some embodiments, the plume may be about 30 μm to about 40 μm. 50 This can be characterized by: In some embodiments, the plume may be about 23 μm to about 30 μm. 50 In some embodiments, the plume can be approximately 10 μm, 11 μm, 12 μm, 13 μm, 14 μm, 15 μm, 16 μm, 17 μm, 18 μm, 19 μm, 20 μm, 21 μm, 22 μm, 23 μm, 24 μm, 25 μm, 26 μm, 27 μm, 28 μm, 29 μm, 30 μm, 31 μm, 32 μm, 33 μm, 34 μm, 35 μm, 36 μm, 37 μm, 38 μm, 39 μm, and 40 μm. 50 It can be characterized by the following.

[0094] In some embodiments, D 90 During the bloom, D 90 It contains approximately 90% droplets with a size of less than 65 μm. In some embodiments, the plume may be less than 65 μm. 90 It can be characterized by the following. In some embodiments, the plume may be less than about 60 μm. 90 It can be characterized by the following. In some embodiments, the plume may be less than about 50 μm. 90 It can be characterized by the following. In some embodiments, the plume may be less than about 40 μm.90 can be characterized by. In some embodiments, the plume can be less than about 35 μm D 90 can be characterized by. In some embodiments, the plume can be less than about: 60 μm, 59 μm, 58 μm, 57 μm, 56 μm, 55 μm, 54 μm, 53 μm, 52 μm, 51 μm, 50 μm, 49 μm, 48 μm, 47 μm, 46 μm, 47 μm, 46 μm, 45 μm, 44 μm, 43 μm, 42 μm, 41 μm, 40 μm, 39 μm, 38 μm, 37 μm, 36 μm, 35 μm, 34 μm, 33 μm, 32 μm, 31 μm, 30 μm, 29 μm or 28 μm D 90 can be characterized by. In some embodiments, the plume is less than about 35 μm D 90 or less than about 42 μm D 90 can be characterized by. In some embodiments, the plume is less than about 49 μm D 90 can be characterized by. In some embodiments, the plume can be from about 50 μm to about 60 μm D 90 can be characterized by. In some embodiments, the plume can be from about 45 μm to about 55 μm D 90 can be characterized by. In some embodiments, the plume can be from about 30 μm to about 50 μm D 90 can be characterized by. In some embodiments, the plume can be from about 40 μm to about 50 μm D 90 can be characterized by. In some embodiments, the plume can be from about 38 μm to about 49 μm D 90 can be characterized by. In some embodiments, the plume can be from about 37 μm to about 41 μm D 90 can be characterized by. In some embodiments, the plume can be from about 35 μm to about 41 μm D 90 can be characterized by. In some embodiments, the plume can be from about 35 μm to about 45 μm D 90 can be characterized by. In some embodiments, the plume can be from about 45 μm to about 66 μm D 90 can be characterized by. In some embodiments, the plume can be from about 30 μm to about 40 μm D90 It can be characterized by the following. In some embodiments, the plume may be about 25 μm to about 35 μm. 90 In some embodiments, the plume may be approximately 28μm, 29μm, 30μm, 31μm, 32μm, 33μm, 34μm, 35μm, 36μm, 37μm, 38μm, 39μm, 40μm, 41μm, 42μm, 43μm, 44μm, 45μm, 46μm, 47μm, 48μm, 49μm, 50μm, 51μm, 52μm, 53μm, 54μm, 55μm, 56μm, 57μm, 58μm, 59μm, 60μm, 61μm, 62μm, 63μm, 64μm, 65μm, 66μm, 67μm, 68μm, 69μm, or 70μm. 90 It can be characterized by the following.

[0095] In some embodiments, the plume may feature a span that can be about 1 to about 5. In some embodiments, the plume may feature a span that can be about 1 to about 4. In some embodiments, the plume may feature a span that can be about 1 to about 3. In some embodiments, the plume may feature a span that can be about 1 to about 2. In some embodiments, the plume may feature a span that can be about 0.5 to about 1. In some embodiments, the plume may feature a span that can be about 0.5 to about 1.5. In some embodiments, the plume may feature spans that are approximately 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.7, 2.9, 3, 3.25, 3.5, 3.75, 4, 4.5, 5, 5.5, or 6.

[0096] In some embodiments, the plume may be characterized by having an ellipticity of, for example, about 0.5 to about 2. In some embodiments, the plume may be characterized by having an ellipticity of about 0.5 to about 1. In some embodiments, the plume may be characterized by having an ellipticity of about 0.8 to about 1.5. In some embodiments, the plume may be characterized by having an ellipticity of about 1 to about 1.5. In some embodiments, the plume may be characterized by having an ellipticity of about 1 to about 1.2. In some embodiments, the plume may be characterized by having an ellipticity of about 1.1 to about 1.8. In some embodiments, the plume may be characterized by having an ellipticity of about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0.

[0097] In some embodiments, the plume may be characterized by having a geometry (e.g., plume angle) of about 10° to about 90°. In some embodiments, the plume may be characterized by having a geometry of 45° to 75°. In some embodiments, the plume may be characterized by having a geometry of 20° to 45°. In some embodiments, the plume may be characterized by having a geometry of 15° to 40°. In some embodiments, the plume may be characterized by having a geometry of 25° to 40°. In some embodiments, the plume may be characterized by having a geometry of about 10°, 11°, 12°, 13°, 14°, 15°, 16°, 17°, 18°, 19°, 20°, 25°, 30°, 35°, 40°, 45°, 50°, 55°, 60°, 65°, 70°, 75°, 80°, 85°, or 90°.

[0098] In some embodiments, the plume may be characterized by having a plume width of approximately 10 mm to approximately 90 mm. In some embodiments, the plume may be characterized by having a plume width of 45 mm to 75 mm. In some embodiments, the plume may be characterized by having a plume width of 20 mm to 45 mm. In some embodiments, the plume may be characterized by having a plume width of 15 mm to 40 mm. In some embodiments, the plume may be characterized by having a plume width of 25 mm to 40 mm. In some embodiments, the plume may be characterized by having a plume width of approximately 10 mm, 15 mm, 20 mm, 25 mm, 30 mm, 35 mm, 40 mm, 45 mm, 50 mm, 55 mm, 60 mm, 65 mm, 70 mm, 75 mm, 80 mm, 85 mm, or 90 mm.

[0099] In some embodiments, the plume may be characterized by having a plume width of approximately 500 mm to approximately 5 cm. In some embodiments, the plume may be characterized by having a plume width of approximately 1 cm to approximately 3 cm. In some embodiments, the plume may be characterized by having a plume width of approximately 1 cm to approximately 2 cm. In some embodiments, the plume may be characterized by having a plume width of approximately 500 mm, 600 mm, 700 mm, 800 mm, 900 mm, 1 cm, 1.1 cm, 1.2 cm, 1.3 cm, 1.4 cm, 1.5 cm, 1.6 cm, 1.7 cm, 1.8 cm, 1.9 cm, 2 cm, 3 cm, 4 cm, or 5 cm.

[0100] In some embodiments, the plume may be characterized by having a plume length of approximately 500 mm to approximately 10 cm. In some embodiments, the plume may be characterized by having a plume length of approximately 1 cm to approximately 10 cm. In some embodiments, the plume may be characterized by having a plume length of approximately 5 cm to approximately 8 cm. In some embodiments, the plume may be characterized by having a plume width of approximately 500 mm, 1 cm, 2 cm, 3 cm, 4 cm, 5 cm, 6 cm, 6.1 cm, 6.2 cm, 6.3 cm, 6.4 cm, 6.5 cm, 6.6 cm, 6.7 cm, 6.8 cm, 6.9 cm, 7 cm, 7.1 cm, 7.2 cm, 7.3 cm, 7.4 cm, 7.5 cm, 7.6 cm, 7.7 cm, 7.8 cm, 7.9 cm, 8 cm, 9 cm, or 10 cm.

[0101] In some cases, the plume may be characterized by having a maximum spray diameter (Dmax) of approximately 10 mm to 60 mm. In some cases, the plume may be characterized by having a Dmax of approximately 10 mm to 50 mm. In some cases, the plume may be characterized by having a Dmax of approximately 10 mm to 40 mm. In some cases, the plume may be characterized by having a Dmax of approximately 10 mm to 30 mm. In some cases, the plume may be characterized by having a Dmax of approximately 10 mm to 20 mm. In some cases, the plume may be characterized by having a Dmax of approximately 15 mm to 20 mm. In some cases, the plume may be characterized by having a Dmax of approximately 16 mm to 20 mm. In some cases, the plume may be characterized by having a Dmax of approximately 20 mm to 50 mm. In some cases, the plume may be characterized by having a Dmax of approximately 30 mm to 45 mm. In some cases, the plume can be characterized by having a Dmax of approximately 30 mm to 50 mm. In some embodiments, the plume may be characterized by having a Dmax of approximately 10mm, 11mm, 12mm, 13mm, 14mm, 15mm, 16mm, 17mm, 18mm, 19mm, 20mm, 21mm, 22mm, 23mm, 24mm, 25mm, 26mm, 27mm, 28mm, 29mm, 30mm, 31mm, 32mm, 33mm, 34mm, 35mm, 36mm, 37mm, 38mm, 39mm, 40mm, 41mm, 42mm, 43mm, 44mm, 45mm, 46mm, 47mm, 48mm, 49mm, 50mm, 51mm, 52mm, 53mm, 54mm, 55mm, 56mm, 57mm, 58mm, 59mm, or 60mm.

[0102] In some cases, the plume may be characterized by having a minimum spray diameter (Dmin) of approximately 10 mm to 40 mm. In some cases, the plume may be characterized by having a Dmin of approximately 10 mm to 30 mm. In some cases, the plume may be characterized by having a Dmin of approximately 10 mm to 20 mm. In some cases, the plume may be characterized by having a Dmin of approximately 10 mm to 15 mm. In some cases, the plume may be characterized by having a Dmin of approximately 20 mm to 35 mm. In some cases, the plume may be characterized by having a Dmin of approximately 25 mm to 35 mm. In some cases, the plume may be characterized by having a Dmin of approximately 21 mm to 32 mm. In some embodiments, the plume may be characterized by having a Dmin of approximately 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, 20 mm, 21 mm, 22 mm, 23 mm, 24 mm, 25 mm, 26 mm, 27 mm, 28 mm, 29 mm, 30 mm, 31 mm, 32 mm, 33 mm, 34 mm, 35 mm, 36 mm, 37 mm, 38 mm, 39 mm, or 40 mm.

[0103] In some embodiments, the plume is approximately 100 mm 2 ~about 1500mm 2 It can be characterized by having a plume area of ​​500 mm. In some embodiments, the plume is 500 mm 2 ~1200mm 2 It may be characterized by having a plume area of ​​600 mm. In some embodiments, the plume is 600 mm 2 ~1300mm 2 It can be characterized by having a plume area of ​​150 mm. In some embodiments, the plume is 150 mm 2 ~200mm 2 It can be characterized by having a plume area of ​​100 mm. In some embodiments, the plume is 100 mm 2 ~500mm 2 It can be characterized by having a plume area of ​​approximately 100 mm². In some embodiments, the plume is approximately 100 mm².2 , 200mm 2 , 300mm 2 , 400mm 2 , 500mm 2 , 600mm 2 , 700mm 2 , 800mm 2 , 900mm 2 , 1000mm 2 , 1100mm 2 , 1200mm 2 , 1300mm 2 , 1400mm 2 or 1500mm 2 It can be characterized by having a plume area of ​​approximately 100 mm². In some embodiments, the plume is approximately 100 mm². 2 , 200mm 2 , 300mm 2 , 400mm 2 , 500mm 2 , 600mm 2 , 700mm 2 , 800mm 2 , 900mm 2 , 1000mm 2 , 1100mm 2 , 1200mm 2 , 1300mm 2 , 1400mm 2 or 1500mm 2 It can be characterized by having a plume area of ​​approximately 270 mm². In some embodiments, the plume is approximately 270 mm². 2 , 271mm 2 , 272mm 2 , 273mm 2 , 274mm 2 , 275mm 2 , 276mm 2 , 277mm 2 , 278mm 2 , 279mm 2 , 280mm 2 , 281mm 2 , 282mm 2 , 283mm 2 , 284mm 2 , 285mm 2 , 286mm 2 , 287mm2 , 288mm 2 , 289mm 2 , 290mm 2 , 291mm 2 , 292mm 2 , 293mm 2 , 294mm 2 , 295mm 2 , 296mm 2 , 297mm 2 , 298mm 2 , 299mm 2 , 300mm 2 , 301mm 2 , 302mm 2 , 303mm 2 , 304mm 2 , 305mm 2 , 306mm 2 , 307mm 2 , 308mm 2 , 309mm 2 , 310mm 2 , 311mm 2 , 312mm 2 , 313mm 2 , 314mm 2 , 315mm 2 , 316mm 2 , 317mm 2 , 318mm 2 , 319mm 2 or 320mm 2 It can be characterized by having a plume area of ​​[value].

[0104] In some embodiments, the spray device may have an operating time that can range from the start of spraying to the end of spraying. In some cases, the spray device may have an operating time of 0.5 seconds to about 5 seconds. In some cases, the spray device may have an operating time of about 3 seconds. In some cases, the spray device may have an operating time of about 0.5 seconds, 1 second, 1.5 seconds, 2 seconds, 2.5 seconds, 3 seconds, 3.5 seconds, 4 seconds, 4.5 seconds, or about 5 seconds. In some examples, increasing the operating time can increase the amount of spray deposited in the olfactory region.

[0105] In some embodiments, the spray device may have an operating length. In some cases, the operating length may be approximately 4mm, 4.1mm, 4.2mm, 4.3mm, 4.4mm, 4.5mm, 4.6mm, 4.7mm, 4.8mm, 4.9mm, 5mm, 5.1mm, 5.2mm, 5.3mm, 5.4mm, or 5.5mm. In some cases, the operating length may be approximately 4.6mm, 4.8mm, or 4.9mm.

[0106] In some embodiments, the spray device has a spray rate of approximately 100 mm / second. 2 (mm / s 2 ), 200mm / s 2 , 300mm / s 2 , 400mm / s 2 , 500mm / s 2 , 600mm / s 2 , 700mm / s 2 , 800mm / s 2 , 900mm / s 2 or 1000 mm / s 2 It can have an operating stroke acceleration of approximately 500 mm / s². In some cases, the operating stroke acceleration of a spray device is approximately 500 mm / s². 2 It can be done this way.

[0107] In some embodiments, the spray device may have an operating stroke speed of approximately 0.5 mm / second (mm / s), 1 mm / s, 2 mm / s, 3 mm / s, 4 mm / s, 5 mm / s, 6 mm / s, 7 mm / s, 8 mm / s, 9 mm / s, or 10 mm / s. In some cases, the spray device may have an operating stroke speed of approximately 1 mm / s, 2 mm / s, 3 mm / s, or 4 mm / s.

[0108] In some cases, the spray device can have an average holding time of approximately 300 milliseconds (ms), 400 ms, 500 ms, 600 ms, 700 ms, 800 ms, 900 ms, or 1000 ms. In some cases, the spray device can have an average holding time of approximately 684 ms.

[0109] In some cases, a spray device can deliver a certain amount per operation. In some cases, the amount delivered per operation can be approximately: 10 μl, 15 μl, 20 μl, 25 μl, 30 μl, 35 μl, 40 μl, 45 μl, 50 μl, 55 μl, 60 μl, 65 μl, 70 μl, 75 μl, 80 μl, 85 μl, 90 μl, 95 μl, or 100 μl. In some cases, the delivery volume per operation can be approximately: 50 μl, 51 μl, 52 μl, 53 μl, 54 μl, 55 μl, 56 μl, 57 μl, 58 μl, 59 μl, 60 μl, 61 μl, 62 μl, 63 μl, 64 μl, 65 μl, 66 μl, 67 μl, 68 μl, 69 μl, 70 μl, 71 μl, 72 μl, 73 μl, 74 μl, 75 μl, 76 μl, 77 μl, 78 μl, 79 μl, or 80 μl. In some cases, the delivery volume can be approximately: 60 μl to approximately 80 μl, 65 μl to approximately 75 μl, 64 μl to approximately 76 μl, or 63 μl to approximately 73 μl. In some cases, the delivery volume can be approximately 70 μl, or within approximately 10%, 15%, 20%, or 25% of 70 μl.

[0110] In some cases, the spray device can deliver a shot weight per action. In some cases, the delivered shot weight can be approximately: 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg per action. In some cases, the delivered shot weight can be approximately: 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, or 60 mg per action. In some cases, the weight of the delivered shot may be approximately 45 mg, or within approximately 10%, 15%, 20%, or 25% of 45 mg. In some cases, the weight of the delivered shot may be approximately 70 mg, or within approximately 10%, 15%, 20%, or 25% of 70 mg.

[0111] In some cases, the spray device can deliver a measured shot weight per operation. In some cases, the measured shot weight can be approximately: 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg per operation. In some cases, the weighed shot weight may be approximately 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg, 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, or 60mg per action. In some cases, the weighed shot weight may be approximately 45mg, or within approximately 10%, 15%, 20%, or 25% of 45mg. In some cases, the weighed shot weight may be approximately 70mg, or within approximately 10%, 15%, 20%, or 25% of 70mg.

[0112] In some cases, spray devices can be tested by an automated system. In some cases, spray devices can be primed before testing. For example, a spray device may be run several times before testing to ensure that it contains the full dose. In some cases, the characteristics of the spray (e.g., plume) can be determined at a certain distance. In some cases, the characteristics of the plume can be determined at approximately 10 mm, 20 mm, 30 mm, 40 mm, 50 mm, 60 mm, 70 mm, 80 mm, 90 mm, or 100 mm. In some cases, the characteristics of the plume can be determined at approximately 30 mm or approximately 60 mm.

[0113] In some cases, the characteristics of the plume may be derived from a single operation of the spray device. In other cases, the characteristics of the plume may be derived from the average value of multiple operations of the spray device (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or more than 9 operations).

[0114] Treatment method Methods for treating memory loss in humans are disclosed herein. In some embodiments, the treatment method may include the step of administering a nasal spray to a subject in need. In some cases, methods for restoring adequate memory function in a subject with memory loss are disclosed herein. In some cases, the subject with memory loss may have an underlying condition or disease that contributes to the memory loss. In some cases, the subject with memory loss is a healthy subject with no underlying condition or disease that contributes to the memory loss.

[0115] In some cases, memory loss may include memory loss resulting from sleep deprivation (e.g., lack of sleep). In some cases, memory loss may include memory loss resulting from sleep apnea. In some cases, memory loss may result from, or occur between or after, a brain tumor, cancer treatment (e.g., cerebral irradiation, cerebral treatment, chemotherapy or any combination thereof), concussion, head injury, oxygen deprivation to the brain, hypoxia, infection (e.g., central nervous system infection), central nervous system infection, peribrain infection, major surgery, severe illness, surgery (e.g., brain surgery), disease, amnesia, stroke, transient ischemic attack, multiple sclerosis, dementia or any combination thereof. In some cases, memory loss may result from, or occur between or after, a major event, a traumatic event, a stressful event, post-traumatic stress disorder (PTSD), bipolar disorder, depression, mental health disorder, schizophrenia, dementia, hypothyroidism, brain disease, old age (e.g., 65 years of age or older), or any combination thereof. In some cases, memory loss may result from, or occur between or after, a substance abuse, alcohol abuse, illicit drug abuse, drug overuse (e.g., barbiturates), electroconvulsive therapy, epilepsy, Parkinson's disease, Huntington's disease, nutritional deficiencies (e.g., vitamin B1 and / or B12), or any combination thereof. In some cases, head injury may include concussion, skull fracture, intracranial hematoma, closed brain injury, penetrating brain injury, primary brain injury, secondary brain injury, or any combination thereof. In some cases, infections may include Lyme disease, syphilis infection, HIV infection, prion disease, herpes infection (e.g., herpes encephalitis), viral meningitis, bacterial meningitis, neurocysticercosis, progressive multifocal leukoencephalopathy, toxoplasmosis, tropical spastic paraplegia, viral encephalitis, encephalitis, Whipple's disease, parasitic infections, viral infections, bacterial infections, or any combination thereof. In some cases, amnesia may include retrograde amnesia, anterograde amnesia, transient global amnesia, dissociative amnesia, post-traumatic amnesia, drug-induced amnesia, or any combination thereof. In some cases, stroke may include ischemic stroke, hemorrhagic stroke, or both.In some cases, multiple sclerosis can include relapsing multiple sclerosis, primary progressive multiple sclerosis, or secondary progressive multiple sclerosis. In some cases, memory loss can include memory loss resulting from idiopathic Parkinson's disease, familial Parkinson's disease, secondary Parkinsonian syndrome, Parkinsonian dementia (Parkinson's disease dementia), juvenile Parkinson's disease, early-onset Parkinson's disease, drug-induced Parkinsonian syndrome, multiple system atrophy, progressive supranuclear palsy, corticobasal syndrome, corticobasal degeneration, mild cognitive impairment, early-onset dementia, Lewy body dementia (Lewy body dementia), vascular Parkinson's syndrome, normal pressure hydrocephalus, atypical Parkinsonian disorder, amyotrophic spinal lateral sclerosis (ALS), dementia, Huntington's disease, Huntington's disease-like syndrome (HD-like syndrome), limbic-dominant age-related TDP-43 encephalopathy, or any combination thereof. In some cases, dementia may include Alzheimer's disease, vascular dementia, Lewy body dementia, frontotemporal dementia, mixed dementia, mild cognitive impairment, posterior cortical atrophy, primary progressive aphasia, progressive supranuclear palsy, normal pressure hydrocephalus, Creutzfeldt-Jakob disease, or any combination thereof. In some cases, memory loss may not include memory loss caused by dementia. In some cases, memory loss can begin at or around the age of 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or over 100.

[0116] In some cases, methods for restoring cognitive function in a subject are disclosed herein. In some cases, the treatments herein can be used to restore memory, improve memory retention, protect memory, or any combination thereof. In some cases, the treatments herein can be used to improve mental capacity, attention, encoding, memory retrieval, clarity of thought, perception, learning, communication, logical thinking, or any combination thereof. In some cases, the treatments herein can be used to improve cognitive characteristics such as mental capacity, attention, encoding, memory retrieval, perception, learning, communication, logical thinking, or any combination thereof. In some cases, the restoration or improvement of a cognitive characteristic or memory can be determined by comparing the cognitive characteristic or memory of the subject before treatment with the cognitive characteristic or memory of the subject after treatment.

[0117] In some cases, the method may include a step of treating memory loss by administering a therapeutically effective dose of a phosphodiesterase (PDE) inhibitor to the subject. In some cases, the PDE inhibitor may be administered in the form of an intranasal formulation, such as a spray formulated to deposit droplets containing the PDE inhibitor into the nasal cavity. In some cases, the PDE inhibitor may be administered in unit dose form.

[0118] In some embodiments, the nasal spray devices described herein can provide enhanced delivery of therapeutic agents by bypassing the blood-brain barrier (BBB). The therapeutic agents administered herein can travel to the central nervous system (CNS) either by passing through the epithelium of the olfactory region (OR) and traveling along the olfactory nerve to the olfactory bulb, or by traveling along the lateral respiratory region and trigeminal nerve to the pons. In some cases, trigeminal neuron terminals may be found only in the lower region of the epithelium and may not be directly exposed to the nasal cavity. Olfactory neuron cell bodies may be found in the epithelium, and their cilia may reach directly into the nasal cavity. In some cases, the therapeutic agents disclosed herein can be transported to the CNS by intracellular transport mechanisms, such as internalization of the therapeutic agent by neurons in the epithelial region, transport along the axon, and exocytosis within the CNS. In some cases, the therapeutic agents disclosed herein can pass through the epithelium by paracellular transport. In some examples, the therapeutic agents disclosed herein approach the CNS by systemic circulation. In some cases, the therapeutic agents disclosed herein may be transported to the CNS by extracellular transport mechanisms, such as by the movement of the therapeutic agent through fluids in the space through which neurons extend to the CNS.

[0119] In some cases, a method for treating chemosensory dysfunction in subjects requiring treatment for memory loss may include the step of administering a phosphodiesterase (PDE) inhibitor using a nasal spray device that delivers dose units in a plume during operation. In some cases, the dose units may contain a therapeutically effective amount of the PDE inhibitor in a pharmaceutically acceptable carrier, diluent, excipient, or any combination thereof. In some cases, the plume may (a) have a size of less than about 1.5% of droplets in the plume less than about 10 μm, and (b) have a size of about 38 μm to about 49 μm. 90 It can have a droplet size distribution characterized by the following:

[0120] In some cases, a method for treating memory loss in a subject requiring it may include administering to the subject an effective amount of a pharmaceutical composition comprising a phosphodiesterase (PDE) inhibitor and a pharmaceutically acceptable carrier, excipient, diluent, or any combination thereof. In some cases, when the pharmaceutical composition is administered intranasally to a subject by the operation of a nasal spray device containing the liquid pharmaceutical composition, it forms a plume containing multiple droplets, the multiple droplets being approximately 38 μm to approximately 49 μm in diameter. 90 It can be characterized in that approximately 90% of the droplets in the plume are D 90 It has a size less than [size].

[0121] In some cases, a method for treating memory loss in a subject requiring treatment for memory loss may include the step of administering an effective amount of a liquid pharmaceutical composition to the subject. In some cases, the liquid pharmaceutical composition may include a phosphodiesterase (PDE) inhibitor or a salt thereof and a pharmaceutically acceptable carrier, excipient, diluent, or any combination thereof. In some cases, when the liquid pharmaceutical composition is administered intranasally to a subject by the operation of a nasal spray device containing the liquid pharmaceutical composition, it forms a plume containing multiple droplets, characterized by a D90 of about 45 μm to about 66 μm, with about 90% of the droplets in the plume having a size less than D90. In some cases, memory loss may be treated by the administration of an effective amount of the liquid pharmaceutical composition.

[0122] In some cases, the methods or compositions of the Disclosure described herein can be used to treat subjects suffering from memory loss and / or chemical sensitivity. Chemical sensitivity may include loss of smell (anosmia) or reduced sense of smell (hypoesmia). Chemical sensitivity may include loss of taste (anogustasia) or reduced sense of taste (hypoesmia), for example, a reduced ability to taste sweet, sour, bitter, or salty foods. In some cases, chemical sensitivity may include misperception or distortion of smells, tastes, or flavors. For example, chemical sensitivity may cause a person to perceive an unpleasant odor or taste from something that normally tastes or smells pleasant. In some cases, chemical sensitivity may include at least partial: loss of taste, loss of smell, or both. Chemical sensitivity may include impaired taste or smell. In some cases, a disorder of taste or smell may include anosmia, hypoosmia, anosmia, hypogus, osmoticism (distortion of normal smells), spontaneous heterosmia, osmoticism (distortion of normal tastes), paresophagia, or a combination thereof.

[0123] In some embodiments, the compositions herein can be used to treat asthma, diarrhea, motion sickness, gastrointestinal disorders, overactive bladder, urinary incontinence, poisoning, muscle spasms, motion sickness, chronic obstructive pulmonary disease (COPD), hyperhidrosis, or any combination thereof. For example, the anticholinergic agents herein can be used to treat asthma, diarrhea, motion sickness, gastrointestinal disorders, overactive bladder, urinary incontinence, poisoning, muscle spasms, motion sickness, chronic obstructive pulmonary disease (COPD), or hyperhidrosis. In some embodiments, the compositions herein can be used to treat schizophrenia, psychosis, schizoaffective disorder, bipolar disorder, depression, or any combination thereof. In some cases, anticholinergic agents such as thioridazine, haloperidol, olanzapine, or salts of any of these can be used to treat chemosensory dysfunction, amnesia, or both.

[0124] In some cases, the administration of PDE inhibitors described herein can be used to prevent or treat diseases or conditions associated with or caused by viral, bacterial, fungal, parasitic, or any combination thereof. In some cases, the administration of PDE inhibitors described herein can be used to prevent or treat diseases or conditions associated with the nervous system, such as the sensory nervous system, the central nervous system, or the peripheral nervous system. In some cases, viral infections may include coronaviruses. In some cases, viral infections may include influenza viruses. Such diseases and conditions may include, for example, amnesia, anosmia, osmia, osmia, hypoosmia, anosmia, osmoticism, paresthesia, dysosmia, chemosensory dysfunction, cough, fever, malaise, dyspnea, runny nose, sore throat, nasal congestion, or any combination thereof. In some cases, influenza infections may be caused by influenza A, influenza B (e.g., B (Victoria), B (Yamagata)). In some cases, influenza A may include influenza H1N1, H3N2, any mutation of these, or any combination thereof. In some cases, influenza viruses may include one or more mutations. In some cases, coronavirus infections may be caused by alpha coronavirus, beta coronavirus, gamma coronavirus, delta coronavirus, 229E coronavirus, NL63 coronavirus, OC43 coronavirus, HKU1 coronavirus, MERS-CoV, SARS-CoV, SARS-CoV-2, their variant forms, or any combination thereof. In some cases, coronaviruses can cause COVID-19. In some cases, viruses such as coronaviruses or influenza viruses can have mutations.For example, coronavirus or influenza virus is approximately: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 compared to the reference sequence. , contain 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 or more nucleotide mutations. In some cases, coronaviruses or influenza viruses may contain genomes with higher sequence identity or sequence similarity than a reference genome sequence, at approximately 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. In some cases, coronaviruses or influenza viruses may contain genomes with lower sequence identity or similarity than approximately 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% compared to a reference genome sequence. In some cases, the reference sequence may be a reference sequence from the National Center for Biotechnology Information (NCBI).

[0125] Chemical sensitivity may be associated with or related to diseases or conditions such as memory loss, obesity, diabetes, hypertension, malnutrition, or degenerative neurological diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, Huntington's disease-like syndrome (HD-like syndrome), or multiple sclerosis. In some embodiments, chemical sensitivity may be associated with allergies, such as allergic rhinitis. In some cases, the allergy may include drug allergies, food allergies, insect allergies, latex allergies, mold allergies, pet allergies, pollen allergies, or a combination thereof. In some embodiments, chemical sensitivity may be associated with inflammation. In some cases, the inflammation may include sinusitis, mucosal inflammation, rhinosinusitis, nasal polyps, or any combination thereof. In some embodiments, chemical sensitivity may be associated with trauma. In some cases, the trauma may include traumatic brain injury (TBI), head injury, concussion, or any combination thereof.

[0126] In some cases, the PDE inhibitors described herein may be administered to subjects with comorbidities. Such comorbidities include, for example, brain injury, brain disease, hypertension, pulmonary hypertension, congestive heart failure, renal failure, myocardial infarction, stable, unstable and variant (Prinzmetal) angina, atherosclerosis, cardiac edema, heart disease, renal insufficiency, nephrotic edema, hepatic edema, stroke, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, dementia (such as Alzheimer's disease), immunodeficiency, premature birth, Parkinson's disease, multiple sclerosis, dysmenorrhea, benign prostatic hyperplasia (BPH), subvesical urethral obstruction, incontinence, and impaired vascular patency. This may include, for example, post-percutaneous transluminal coronary angioplasty (PTCA), peripheral vascular disease, respiratory disease, bronchitis, emphysema, lung cancer, cystic fibrosis, pneumonia, pleural effusion, allergic rhinitis, glaucoma, malignant diseases and diseases characterized by impaired bowel motility (e.g., irritable bowel syndrome (IBS)), rheumatoid arthritis, bacterial infections, fungal infections, parasitic infections, viral infections, HIV, systemic lupus erythematosus, psoriasis, other autoimmune diseases, Huntington's disease and amyotrophic lateral sclerosis (ALS), or any combination thereof. Treatment of co-existing diseases may be carried out by administering a therapeutically effective amount of the compounds and / or compositions described herein to patients who require it.

[0127] Administration and medication Methods for treating a condition (e.g., memory loss) by administering a PDE inhibitor described herein are disclosed herein. In some cases, administration may include, for example, administering a unit dose form of the PDE inhibitor in a nasal spray. In some embodiments, the method of treatment may include nasal administration by a nasal spray device. Other methods of treatment, just a few examples, include oral administration, transmucosal administration, oral administration, nasal administration, inhalation, parenteral administration, intravenous, subcutaneous, intramuscular, sublingual, transdermal, and rectal administration.

[0128] In some cases, administration may include administration into the nasal cavity. In some embodiments, intranasal administration may include administration to the nasal septum, nasal base, lateral walls of the nasal cavity, inferior nasal meatus, middle nasal meatus, superior nasal meatus, olfactory cleft, olfactory region, nasal conchae, or any combination thereof. In some embodiments, intranasal administration may include administration to the nasal septum, nasal base, lateral walls of the nasal cavity, inferior nasal meatus, middle nasal meatus, superior nasal meatus, olfactory cleft, olfactory region, and nasal conchae. The nasal cavity is the space extending from the nostrils to the nasopharynx. The median boundary is the nasal septum, and the inferior boundary is the nasal base. The lateral boundary includes the lateral walls of the nasal cavity, including the nasal conchae. The space between the nasal conchae and the lateral walls of the nasal cavity, including the inferior nasal meatus, middle nasal meatus, superior nasal meatus, and sphenocrimal recess, exists within the nasal cavity. The superior boundary is defined by the base of the skull, which is formed from the frontal bone, the ethmoid plate of the ethmoid bone, and the sphenoid bone. The olfactory nerve can be seen on the upper surface of the nasal cavity within the olfactory region / olfactory cleft beneath the ethmoid plate. In some embodiments, the nasal cavity may include the superior nasal cavity, olfactory cleft, olfactory epithelium, or any combination thereof. In some cases, the nasal cavity may include squamous epithelial mucosa, olfactory mucosa, respiratory mucosa, or any combination thereof. Administration of the compositions described herein may include administration to any area of ​​the nasal cavity. In some embodiments, the composition may be administered as a spray to at least partially cover the nasal cavity. In some cases, administration may include intranasal application to one or both nostrils.

[0129] In some embodiments, the plume of the nasal spray can cover approximately 5% to approximately 99% of the surface area of ​​the nasal cavity when in operation. In some embodiments, the plume of the nasal spray can cover approximately 10% to approximately 70% of the surface area of ​​the nasal cavity when in operation. In some embodiments, the plume of the nasal spray can cover approximately 15% to approximately 50% of the surface area of ​​the nasal cavity when in operation. In some embodiments, the plume of the nasal spray can cover an area exceeding approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of the surface area of ​​the nasal cavity when in operation. In some embodiments, the plume of the nasal spray, during operation, covers approximately 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, It can cover 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%.

[0130] In some cases, administration may include administration to the sinuses. In some cases, administration may include administration to the ears, eyes, mouth, or a combination thereof. In some cases, the sinuses may include the ethmoid sinus cavity, maxillary sinus cavity, frontal sinus cavity, or sphenoid sinus cavity. In some cases, administration to the sinuses may include administration to the sinus ostium.

[0131] In some embodiments, typical daily intranasal, lingual, pulmonary, topical, or mucosal doses of the active ingredient (e.g., PDE inhibitor) can be approximately 1.0 μg to 2000 mg per day, approximately 1.0 μg to 500.0 mg per day, approximately 10 μg to 100.0 mg per day, approximately 10 μg to 10 mg per day, approximately 10 μg to 1.0 mg per day, approximately 10 μg to 500 μg per day, approximately 20 μg to 2000 μg per day, approximately 100 μg to 10,000 μg per day, or approximately 1 μg to 50 μg per day. These dose ranges represent the total daily dose of the active ingredient for a given patient. In some embodiments, the daily dose administered may be approximately: 2000 mg per day, 1000 mg per day, 500 mg per day, 100 mg per day, 10 mg per day, 9 mg per day, 8 mg per day, 7 mg per day, 6 mg per day, 5 mg per day, 4 mg per day, 3 mg per day, 2 mg per day, 1 mg per day, 500 μg per day, 300 μg per day, 200 μg per day, 100 μg per day, or less than 50 μg per day.In some embodiments, the daily dose administered is at least approximately: 50 μg, 60 μg, 70 μg, 80 μg, 90 μg, 100 μg, 110 μg, 120 μg, 130 μg, 140 μg, 150 μg, 160 μg, 170 μg, 180 μg, 190 μg, 200 μg, 210 μg, 220 μg, 230 μg, 240 μg, 245 μg, 250 μg, 260 μg, 270 μg, 280 μg, 290μg, 300μg, 310μg, 320μg, 330μg, 340μg, 350μg, 360μg, 370μg, 380μg, 390μg, 400μg, 410μg, 420μg, 430μg , 440μg, 445μg, 450μg, 460μg, 470μg, 480μg, 490μg, 500μg, 510μg, 520μg, 530μg, 540μg, 550μg, 560μg, 570μg , 580μg, 590μg, 600μg, 610μg, 620μg, 630μg, 640μg, 650μg, 660μg, 670μg, 680μg, 690μg, 700μg, 710μg, 720μg g, 730μg, 740μg, 750μg, 760μg, 770μg, 780μg, 790μg, 800μg, 810μg, 820μg, 830μg, 840μg, 850μg, 860μg, 870μg g, 880 μg, 890 μg, 900 μg, 910 μg, 920 μg, 930 μg, 940 μg, 950 μg, 960 μg, 970 μg, 980 μg, 990 μg, 1000 μg, 1100 μg, 1120 μg, 1200 μg, 1300 μg, 1400 μg, 1500 μg, 1600 μg, 1700 μg, 1800 μg, 1900 μg or approximately 2000 μg, or may be equal to this.

[0132] In some embodiments, the therapeutically effective dose of the active ingredient delivered by the intranasal device herein may be about half, one-third, one-fourth, one-fifth, one-sixth, one-seventh, one-eighth, one-ninth, or one-tenth, or less, of the dose of the same active ingredient delivered by a standard intranasal spray device. For example, the nasal spray device herein can deliver an active ingredient such as a PDE inhibitor or a salt thereof in a dose of 20 μg, which may be as effective in treating a disease or condition as 50 μg of the same PDE inhibitor or salt thereof delivered by a standard nasal spray device.

[0133] In some embodiments, a typical dose may be per nostril per operation of the spray device, or per nostril per multiple operations of the spray device. In some embodiments, a typical dose may be for nostril doses. In some embodiments, a typical dose may be approximately 1.0 μg to 2000 mg, approximately 1.0 μg to 500.0 mg, approximately 10 μg to 100.0 mg, approximately 10 μg to approximately 10 mg, approximately 0.2 mg to approximately 0.5 mg, approximately 10 μg to 1.0 mg, approximately 10 μg to 500 μg, approximately 20 μg to approximately 2000 μg, approximately 100 μg to approximately 10,000 μg, or approximately 1 μg to 50 μg of the active ingredient (e.g., a PDE inhibitor). In some embodiments, the administered dose can be approximately 2000 mg, 1000 mg, 500 mg, 100 mg, 10 mg, 9 mg, 8 mg, 7 mg, 6 mg, 5 mg, 4 mg, 3 mg, 2 mg, 1 mg, 500 μg, 300 μg, 200 μg, 100 μg, or less than 50 μg of the active ingredient.In some embodiments, the administered dose is at least about 50 μg, 60 μg, 70 μg, 80 μg, 90 μg, 100 μg, 110 μg, 120 μg, 130 μg, 140 μg, 150 μg, 160 μg, 170 μg, 180 μg, 190 μg, 200 μg, 210 μg, 220 μg, 230 μg, 240 μg, 245 μg, 250 μg, 260 μg, 270 μg, 280 μg, 290 μg, 30 μg 0μg, 310μg, 320μg, 330μg, 340μg, 350μg, 360μg, 370μg, 380μg, 390μg, 400μg, 410μg, 420μg, 430μg, 440μg, 4 40μg, 450μg, 460μg, 470μg, 480μg, 490μg, 500μg, 510μg, 520μg, 530μg, 540μg, 550μg, 560μg, 570μg, 580μg, 5 90μg, 600μg, 610μg, 620μg, 630μg, 640μg, 650μg, 660μg, 670μg, 680μg, 690μg, 700μg, 710μg, 720μg, 730μg, 740μg, 750μg, 760μg, 770μg, 780μg, 790μg, 800μg, 810μg, 820μg, 830μg, 840μg, 850μg, 860μg, 870μg, 880μg, The active ingredient may be 890 μg, 900 μg, 910 μg, 920 μg, 930 μg, 940 μg, 950 μg, 960 μg, 970 μg, 980 μg, 990 μg, 1000 μg, 1100 μg, 1120 μg, 1200 μg, 1300 μg, 1400 μg, 1500 μg, 1600 μg, 1700 μg, 1800 μg, 1900 μg, or approximately 2000 μg, or equal to these amounts.

[0134] In some embodiments, based on a per-kilogram basis, preferred dose levels of the compound can be approximately 0.001 μg to approximately 10.0 mg per kg of body weight per day, approximately 0.5 μg to approximately 0.5 mg per kg of body weight per day, approximately 1.0 μg to approximately 100 μg per kg of body weight per day, and approximately 2.0 μg to approximately 50 μg per kg of body weight per day. In some embodiments, preferred dose levels of the active ingredient per kilogram basis can be approximately: 10.0 mg per kg of body weight per day, 1 mg per kg of body weight per day, 500 μg per kg of body weight per day, 100 μg per kg of body weight per day, 10 μg per kg of body weight per day, or less than 1.0 μg per kg of body weight per day. In some embodiments, preferred dose levels of the active ingredient per kilogram can be at least approximately: 10.0 mg per kg of body weight per day, 1 mg per kg of body weight per day, 500 μg per kg of body weight per day, 100 μg per kg of body weight per day, 10 μg per kg of body weight per day, or 1.0 μg per kg of body weight per day.In some embodiments, preferred dose levels of the active ingredient per kilogram are approximately: 0.5 μg per kg of body weight, 1 μg per kg of body weight, 1.5 μg per kg of body weight, 2 μg per kg of body weight, 2.5 μg per kg of body weight, 3 μg per kg of body weight, 3.5 μg per kg of body weight, 4 μg per kg of body weight, 4.5 μg per kg of body weight, 5 μg per kg of body weight, 5.5 μg per kg of body weight, 6 μg per kg of body weight, 6.5 μg per kg of body weight, 7 μg per kg of body weight, 7.5 μg per kg of body weight, 8 μg per kg of body weight, 8.5 μg per kg of body weight, 9 μg per kg of body weight, 9.5 μg per kg of body weight, 10 μg per kg of body weight The amount can be μg, 10.5 μg per kg of body weight, 11 μg per kg of body weight, 11.5 μg per kg of body weight, 12 μg per kg of body weight, 12.5 μg per kg of body weight, 13 μg per kg of body weight, 13.5 μg per kg of body weight, 14 μg per kg of body weight, 14.5 μg per kg of body weight, 15 μg per kg of body weight, 15.5 μg per kg of body weight, 16 μg per kg of body weight, 16.5 μg per kg of body weight, 17 μg per kg of body weight, 17.5 μg per kg of body weight, 18 μg per kg of body weight, 18.5 μg per kg of body weight, 19 μg per kg of body weight, 19.5 μg per kg of body weight, or 20 μg per kg of body weight.

[0135] In some embodiments, one or more PDE inhibitors or salts thereof may be formulated as an intranasal formulation, such as an intranasal spray formulation. In some embodiments, the intranasal formulation may include a nonspecific PDE inhibitor. In some embodiments, the intranasal formulation may include a specific PDE inhibitor. In some embodiments, the PDE inhibitor may include roflumilast or a salt thereof. In some embodiments, the PDE inhibitor may include apremilast, siromilast, crisabolol (AN2728), ibudilast, luteolin, mesembrenone, picramiralast, roflumilast, rolipram, any salt thereof, or any combination thereof. In some embodiments, the intranasal formulation may include a PDE inhibitor selective for a PDE subtype, such as PDE:1, 2, 3, 4, or 5. In some embodiments, the PDE inhibitor may be administered in a range of about 0.001 mg to about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg. In some cases, the dose (e.g., dose units) of a PDE inhibitor may be approximately: 0.001 mg, 0.002 mg, 0.003 mg, 0.004 mg, 0.005 mg, 0.006 mg, 0.007 mg, 0.008 mg, 0.009 mg, 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.1 mg, 0.2 mg, 0.245 mg, 0.25 mg, 0.28 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.12 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg. In some embodiments, the formulation may be in unit dose form. In some embodiments, the formulation may contain a second active ingredient. In some embodiments, the formulation may not contain a second active ingredient. In some cases, the formulation may be a pharmaceutical composition such as an intranasal formulation. In some cases, the composition may be a pharmaceutical composition.

[0136] In some cases, the dose administered may be the same as, or less than, the dose administered to treat a particular disease. Dosage may be once daily, or several times or more times per day. For example, a nasal spray may be administered once or twice daily. In another example, a PDE inhibitor may be administered two, three, four, five, six, seven, eight, nine, ten times, or more times per day. In some cases, doses delivered by one, two, three, four, five, or more actions of a multi-dose nasal spray device into the nostrils may deliver a therapeutically effective amount of the composition disclosed herein. In some cases, the composition may be administered once, two, or three times over a 24-hour period. In some cases, administration of the compositions disclosed herein may be performed at least once, twice, three times, four times, five times, six times, seven times, eight times, nine times, ten times, eleven times, twelve times, thirteen times, fourteen times, fifteen times, sixteen times, seventeen times, eighteen times, nineteen times, twenty times, or twenty-one times per week. In some cases, administration of the compositions disclosed herein may be performed at least once, twice, three times, four times, five times, six times, seven times, eighteen times, nineteen times, ten times, eleven times, twelve times, thirteen times, fourteen times, fifteen times, sixteen times, seventeen times, eighteen times, nineteen times, twenty times, twenty times, twenty-one times, twenty-two times, twenty-two times, twenty-three times, twenty-four times, twenty-five times, twenty-six times, twenty-seven times, twenty-eight times, or twenty-nine times per month. The treatment may be performed 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, or more times. The dose used to treat the subject may produce the desired therapeutic or preventive effect without causing serious side effects.

[0137] The administration of the compositions disclosed herein is for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 days. Treatment may be carried out over a period of 1, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 days or more, either consecutive or non-consecutive days. In some cases, the treatment period can be approximately: 1 to 30 days, 1 to 60 days, 1 to 90 days, 30 to 90 days, 60 to 90 days, 30 to 180 days, 90 to 180 days, or 180 to 360 days.

[0138] Administration of the compositions disclosed herein may be for a treatment period of at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 1 year, at least about 2 years, at least about 3 years, or over a lifetime. Administration may be repeated over the lifetime of the subject, such as once a month or once a year. Administration may be repeated over a substantial portion of the subject's lifetime, such as once a month or once a year for at least about 1 year, 5 years, 10 years, 15 years or longer.

[0139] In some cases, the compositions may be administered as a single dose or as divided doses. In some cases, the compositions described herein may be administered at a first and second time point. In some cases, the compositions may be administered so that the other is administered after the first dose has been given, with a difference in administration time of approximately: 10 seconds, 20 seconds, 30 seconds, 40 seconds, 50 seconds, 60 seconds, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 16 hours, 20 hours, 1 day, 2 days, 4 days, 7 days, 2 weeks, 4 weeks, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year or longer.

[0140] In some embodiments, administration may be carried out over periods of approximately 1 to 8 days, 1 to 5 weeks, 1 month to 12 months, 1 year to 3 years, 3 years to 10 years, 10 years to 50 years, 25 years to 100 years, or 50 years to 130 years. In some embodiments, the composition may be administered as needed, or over periods of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, or longer.

[0141] In some embodiments, administration may be performed within approximately 60 minutes, 45 minutes, 30 minutes, 15 minutes, or 5 minutes before attempting to recall the memory. In some cases, administration may be performed at the time the subject attempts to recall the memory.

[0142] In some embodiments, administration of an effective dose of a PDE inhibitor via intranasal (e.g., spray), tongue, lung, topical, or mucosal administration does not produce detectable blood levels of the PDE inhibitor. In some embodiments, administration of an effective dose of a PDE inhibitor via intranasal, tongue, lung, topical, or mucosal administration produces blood concentrations of the PDE inhibitor that may be approximately 5 mg / dl, 2 mg / dl, 1 mg / dl, 500 μg / dl, 250 μg / dl, 100 μg / dl, 50 μg / dl, 25 μg / dl, 10 μg / dl, 5 μg / dl, or less than 1 μg / dl. In some embodiments, administration of an effective dose of a PDE inhibitor via intranasal, tongue, lung, topical, or mucosal administration results in blood concentrations of the PDE inhibitor that may be higher than approximately 2 mg / dl, 1 mg / dl, 500 μg / dl, 250 μg / dl, 100 μg / dl, 50 μg / dl, 25 μg / dl, 10 μg / dl, 5 μg / dl, or 1 μg / dl.

[0143] In some cases, the compositions described herein may be administered together with one or more additional therapeutic agents. For example, the compositions described herein may be administered together with one, two, three, four, or five, or more, additional therapeutic agents. In another example, a PDE inhibitor may be administered together with a second treatment. In some cases, the second treatment may be administered simultaneously or sequentially. In some cases, the additional treatment may consist of a nasal spray containing a PDE inhibitor.

[0144] In some cases, additional therapeutic agents may include antihistamines, diphenhydramine, chlorpheniramine, cetirizine, desloratadine, fexofenadine, levocetirizine, loratadine, azelastine, olopatadine, ketotifen, olopatadine, pheniramine, decongestants, pseudoephedrine, oxymetazoline, tetrahydrozoline, corticosteroids, budesonide, fluticasone furoate, fluticasone propionate, mometasone, triamcinolone, beclomethasone, ciclesonide, budesonide, fluticasone, mometasone, fluorometholone, loteprednol, prednisone, betamethasone, desonide, hydrocortisone, mometasone, triamcinolone, cromolyn, rhodoxamide, nedocromil, immunotherapy, salts of any of these or any combination thereof. In some cases, the second treatment may include remdesivir, its salts, chloroquine, its salts, lopinavir, its salts, ritonavir, its salts, mornupiravir, its salts, faviravir, its salts, interferon beta, its salts, antivirals, oxygen, or any combination thereof. In some cases, the second treatment may include peramivir, its salts, zanamivir, its salts, oseltamivir phosphate, oseltamivir, its salts, baloxavir marboxil, its salts, or any combination thereof. In some cases, additional therapeutic agents may include nitric oxide, steroids, nonsteroidal anti-inflammatory drugs (NSAIDs), or any combination thereof. In some cases, additional therapeutic agents may include anticholinergics.

[0145] In some cases, anticholinergic agents may include amitriptyline, atropine, aclidinium, benztropine, chlorpheniramine, chlorpromazine, clomipramine, clozapine, cyclobenzaprine, cyproheptadine, dalifenacin, desipramine, dexchlorpheniramine, dicyclomine, diphenhydramine, doxepin, hydroxyzine, hyosthiamine, imipramine, meclizine, nortriptyline, olanzapine, orphenadrine, oxybutynin, paroxetine, perphenazine, prochlorperazine, promethazine, protriptyline, pseudoephedrine HCl / triprolidine HCl, scopolamine, thioridazine, tolterodine, trifluoperazine, trihexylphenidyl, trimipramine, any salt of these, or any combination thereof.

[0146] In some cases, additional therapies may include therapies described herein, such as amantadine, apomorphine, benserazide, adlogolide, artinicline, benztropine, biperiden, brasofensin, bromocriptine, budipine, cabergoline, dihydroexidine, entacapone, etilevodopa, idazoxane, istradefylline, iometopan, lasabemide, melevodopa, levodopa, carbidopa, carbidopa / levodopa, mofegiline, opicapon, moxylaprine, pergolide, pramipexole, kinerolan, rasagiline, ropinirole, rotigotine, selegiline, safinamide, talipexole, tolcapone, trihexyphenidyl, salts of any of these, or any combination thereof. In some cases, additional treatments may include aducanumab, cholinesterase inhibitors, glutamate regulators, orexin receptor antagonists, or any combination thereof. In some cases, additional treatments may include riluzole, edaravone, sodium phenylbutyrate, taurursodiol, tetrabenazine, amantadine, any salt thereof, or any combination thereof.

[0147] Diagnosis and measurement of memory loss and chemical sensitivity. In some cases, a diagnosis may be made to the subject before treatment with a PDE inhibitor (e.g., diagnosed with chemosensory dysfunction and / or amnesia). In some cases, the treatment method may include a step to diagnose amnesia in the subject. In some cases, the diagnosis may include an in vitro assay. In some cases, chemosensory dysfunction and / or amnesia can be diagnosed by detecting threshold levels or lower levels of sonic hedgehog in a human-derived biological sample. In some cases, chemosensory dysfunction and / or amnesia can be diagnosed by threshold levels, lower levels or higher levels of cyclic AMP (cAMP), cyclic GMP (cGMP), IL-10, or a combination thereof in a human-derived biological sample. In some cases, the sample may be a nasal or saliva sample. In some cases, chemosensory dysfunction, amnesia, or both can be diagnosed by detecting threshold levels or lower levels of cyclic nucleotides in a human-derived biological sample. For example, low levels of cyclic nucleotides in a subject's biological sample may suggest that the subject has amnesia. Measurements to detect levels of biomolecules such as cAMP can be completed by ELISA, Western blotting, or some molecular biology assay. In some embodiments, chemosensory dysfunction can be diagnosed by olfactory assays that measure threshold, discrimination, identification, or any combination thereof. In some cases, the diagnosis of chemosensory dysfunction may include detecting a Recognition threshold (RT) score, a Magnitude estimation (ME) score, a Detection threshold (DT) score, a Hedonic (H) score, or a combination thereof, and comparing it to a reference population (e.g., a population without chemosensory dysfunction). The ME score refers to a measure of the subject's ability to determine the intensity of an irritant, such as an odorant or gustatory substance. The RT score refers to a measure of the subject's ability to recognize the identity of an irritant, such as an odorant or gustatory substance.The DT score is a measure of an object's ability to perceive exposure to irritants, such as odorants or taste substances, as pleasant or unpleasant. The H score is a measure of an object's response to irritants, such as odorants or taste substances, as pleasant or unpleasant.

[0148] In some embodiments, cognitive tests may be administered to the subject. In some cases, cognitive tests can measure thinking, memory, language, judgment, learning ability, or any combination thereof. In some cases, cognitive tests may include the Montreal Cognitive Assessment, Mini-Mental State Examination, Mini-Cog, Functional Assessment Questionnaire, Ascertain Dementia8, Neuropsychiatric Inventory Questionnaire, computerized cognitive tests, or any combination thereof. In some cases, the subject may have improved cognitive test scores after administration of the treatment disclosed herein compared to cognitive test scores before administration of the treatment.

[0149] In some embodiments, subjects may experience clinically detectable improvements in memory within approximately 5 minutes to 60 minutes, 1 hour to 24 hours, 1 day to 1 week, 1 week to 6 weeks, 1 week to 4 weeks, 2 weeks to 5 weeks, or 3 weeks to 4 weeks after initiating treatment. In some embodiments, subjects may experience clinically detectable improvements in memory within approximately 1 month to 6 months, 1 month to 4 months, 2 months to 5 months, or 3 months to 4 months after initiating treatment.

[0150] In some embodiments, an olfactory assay may be performed on the subject to measure threshold, discrimination, identification, or any combination thereof. In some examples, the olfactory assay may be performed before, during, or after treatment. In some cases, a threshold assay can be used to determine the lowest concentration of an odorant that can be reliably detected. In some cases, a discrimination assay may be used to assess the subject's ability to distinguish between two or more different odors. In some cases, an identification assay may be used to assess the subject's ability to identify a specific odor. In some cases, olfactory testing can be used to determine the efficacy of a treatment, such as treatment with a nasal spray device containing a PDE inhibitor. For example, an olfactory assay may be completed before and after treatment to determine a measurable change in the subject's chemosensory dysfunction.

[0151] In some embodiments, an olfactory assay may be performed on the subject to measure threshold, discrimination, identification, or any combination thereof. In some examples, the olfactory assay may be performed before, during, or after treatment. In some cases, a threshold assay can be used to determine the lowest concentration of an odorant that can be reliably detected. In some cases, a discrimination assay may be used to assess the subject's ability to distinguish between two or more different odors. In some cases, an identification assay may be used to assess the subject's ability to identify a specific odor. In some cases, olfactory testing can be used to determine the efficacy of a treatment, such as treatment with an implant containing a PDE inhibitor. For example, an olfactory assay may be completed before and after treatment to determine a measurable change in the subject's chemosensory dysfunction.

[0152] In some embodiments, subjects may experience changes in the perception threshold (DT) score, the cognitive threshold (RT) score, or both (e.g., a decrease in the likelihood of effective treatment). In some embodiments, subjects may experience changes in the magnitude estimation (ME) score (e.g., an increase in the likelihood of effective treatment). In some cases, subjects may experience changes in the hedonic (H) score. In some cases, changes in the RT score, ME score, DT score, or H score can be measured by a forced selection, three-stimulation, stepwise-staircase technique using one or more odorants after administration of a PDE inhibitor to the subject. In some cases, one or more odorants include pyridine, nitrobenzene, thiophene, amyl acetate, or a combination thereof. In some cases, changes in the RT score, ME score, DT score, or H score can be measured by a forced selection, three-stimulation, stepwise technique using one or more taste substance test compounds after administration of a PDE inhibitor to the subject. In some cases, one or more taste substances include sodium chloride (NaCl), sucrose, hydrogen chloride (HCl), urea, or a combination thereof.

[0153] In some embodiments, subjects may experience clinically detectable improvement in taste or smell function within approximately 1 to 6 weeks, 1 to 4 weeks, 2 to 5 weeks, or 3 to 4 weeks after initiating treatment. In some embodiments, subjects may experience clinically detectable improvement in taste or smell function within approximately 1 to 6 months, 1 to 4 months, 2 to 5 months, or 3 to 4 months after initiating treatment.

[0154] The Hedgehog signaling pathway is known to be a crucial regulator of animal development, particularly during the later stages of embryogenesis and metamorphosis. Mammals possess three members of the Hedgehog signaling pathway: Sonic Hedgehog (SHH), Desert Hedgehog (DHH), and Indian Hedgehog (IHH). This pathway is associated with the development of certain cancers. Members of the Hedgehog signaling pathway can be used in the diagnosis and treatment of loss and / or distortion of taste or smell, such as hyposmia, osmoticism, anosmia, spontaneous heterosmia, hypogus, gustatory dysfunction, spontaneous paresthesia, and / or anosmia. For example, subjects with chemosensory dysfunction, memory loss, or both may show improved SHH levels compared to pre-treatment levels when treated with PDE inhibitors.

[0155] One or more members of the Hedgehog signaling pathway can be selected from the group consisting of Sonic Hedgehog (SHH), Desert Hedgehog (DHH), and / or Indian Hedgehog (IHH). One or more members of the Hedgehog signaling pathway can be SHH, DHH, IHH, or any combination thereof. Mammalian (e.g., human) hedgehogs can be measured, but it is also intended that non-mammalian hedgehogs can be measured. In some cases, chemosensory dysfunction in a subject can be determined by detecting levels of Sonic Hedgehog (SHH), which may range from approximately 0 pg / mL to approximately 8,500 pg / mL; levels of Indian Hedgehog (IHH), which may range from approximately 0 pg / mL to approximately 1.0 pg / mL; or levels of Desert Hedgehog (DHH), which may range from approximately 0 pg / mL to approximately 5.0 pg / mL; or a combination thereof.

[0156] In some cases, levels of members of the Hedgehog signaling pathway may be lower than those of normal controls in patients exhibiting loss and / or distortion of taste or smell (e.g., hyposmia, osmoticism, anosmia, spontaneous heterosmia, hypogus, osmoticism, spontaneous paresthesia, and / or anosmia). In some cases, levels of members of the Hedgehog signaling pathway may be lower in patients exhibiting memory loss than in patients without memory loss. For example, in patients suffering from loss and / or distortion of taste or smell (e.g., chemosensory dysfunction), SHH levels may vary in some cases to approximately: 0 pg / mL, greater than 0 pg / mL but less than 1 pg / mL, 1 pg / mL to 25 pg / mL, 15 pg / mL to 30 pg / mL, 20 pg / mL to 40 pg / mL; 35 pg / mL to 50 pg / mL; 45 pg / mL to 100 pg / mL; 75 pg / mL to 150 pg / mL, 125 pg / mL to 1 (b) IHH levels are approximately: 0 pg / mL, 900 pg / mL to 2500 pg / mL, 2000 pg / mL to 5000 pg / mL, 4000 pg / mL to 7500 pg / mL, 6000 pg / mL to 10,000 pg / mL, (b) IHH levels are approximately: 0 pg / mL, greater than 0 pg / mL to 0.1 pg / mL, 0.05 pg / mL to 0.15 pg / mL, 0.125 pg / mL to 0.2 pg / mL, 0.15 pg / mL to 0.30 pg / mL, 0.25 pg / mL L~0.5pg / mL, 0.4pg / mL~0.7pg / mL, 0.6pg / mL~0.75pg / mL, 0.725pg / mL~0.9pg / mL, 0.8pg / mL~1.0pg / mL, less than 1.0pg / mL, less than 0.05ng / mL, less than 0.15ng / mL, less than 0.2ng / mL, less than 0.3ng / mL, less than 0.5ng / mL, less than 0.7ng / mL, less than 0.75ng / mL, less than 0.9ng / mL, less than 1.0ng / mL, 1 (c) DHH levels may be less than 0.1 ng / mL, less than 1.5 ng / mL, less than 1.75 ng / mL, less than 2.0 ng / mL, less than 2.25 ng / mL, less than 5.0 ng / mL, less than 6.0 ng / mL, less than 7.0 ng / mL, less than 10.0 ng / mL, or less than 100.0 ng / mL, and (c) DHH levels may be approximately: 0 pg / mL, greater than 0 pg / mL to 0.1 pg / mL, 0.05 pg / mL to 0.15 pg / mL, 0.125 pg / mL to 0.2 pg / mL, 0.15pg / mL~0.30pg / mL, 0.25pg / mL~0.5pg / mL, 0.4pg / mL~0.7pg / mL, 0.6pg / mL~0. 75pg / mL, 0.725pg / mL~0.9pg / mL, 0.8pg / mL~1.0pg / mL, 0.9pg / mL~1.1pg / mL, 1. 0pg / mL~1.3pg / mL, 1.2pg / mL~1.5pg / mL, 1.4pg / mL~2.0pg / mL, 1.9pg / mL~2.5pg / mL, 2.4pg / mL~3.0pg / mL, 2.9pg / mL~3.5pg / mL, 3.4pg / mL~3.8pg / mL, 3.7pg / mL The levels may range from ~3.9 pg / mL, 3.85 pg / mL to 5.0 pg / mL, <5.0 pg / mL, <0.05 ng / mL, <0.15 ng / mL, <0.2 ng / mL, <0.3 ng / mL, <0.5 ng / mL, <0.7 ng / mL, <0.75 ng / mL, <0.9 ng / mL, <1.0 ng / mL, <1.1 ng / mL, <1.5 ng / mL, <1.75 ng / mL, <2.0 ng / mL, <2.25 ng / mL, <5.0 ng / mL, <6.0 ng / mL, <7.0 ng / mL, <10.0 ng / mL, or <100.0 ng / mL). However, since the levels of various members of the Hedgehog signaling pathway vary on a human basis, some inter-patient variability may exist.

[0157] In some embodiments, administration of an effective dose of a PDE inhibitor may increase the levels of SHH, DHH, and / or IHH in saliva and / or nasal mucus in humans by at least about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, or about 50% in humans compared to the SHH, DHH, and / or IHH levels in humans before administration of a therapeutically effective dose of the PDE inhibitor. In some cases, improvements in salivary and / or nasal mucus SHH, DHH, and / or IHH levels are observed after approximately 1 to 10 days, 30 to 90 days, 15 to 45 days, or 30 days of continuous treatment with therapeutically effective doses of PDE inhibitors. In some cases, subjects prior to administration may have reduced levels of sonic hedgehog in nasal mucus samples derived from the subject compared to sonic hedgehog levels in a control population with normal memory function.

[0158] In some embodiments, administration of an effective amount of a PDE inhibitor may increase or decrease biological compounds such as proteins or metabolites. In some embodiments, administration of an effective dose of a PDE inhibitor may improve the levels of cAMP or cGMP in saliva and / or nasal mucus in humans by at least about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, or about 50% compared to the levels of cAMP or cGMP in saliva and / or nasal mucus in humans before administration of a therapeutically effective dose of the PDE inhibitor. In some cases, improvements in salivary and / or nasal mucus cAMP or cGMP levels are observed after continuous treatment with therapeutically effective doses of PDE inhibitors for approximately 1 to 10 days, 30 to 90 days, 15 to 45 days, or 30 days. In some cases, subjects prior to administration may have reduced levels of cyclic nucleotides in nasal mucus samples derived from the subject compared to control populations with normal memory function.

[0159] In some embodiments, administration of an effective dose of a PDE inhibitor may reduce the IL-10 level in saliva and / or nasal mucus in humans by at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, or about 50% compared to the IL-10 level in saliva and / or nasal mucus in humans before administration of a therapeutically effective dose of the PDE inhibitor. In some cases, a decrease in salivary and / or nasal mucus IL-10 levels is observed after approximately 1 to 10 days, 30 to 90 days, 15 to 45 days, or 30 days of continuous treatment with therapeutically effective doses of PDE inhibitors. IL-10 levels can be measured by enzyme-linked immunosorbent assay (ELISA), Western blotting, or other protein assays.

[0160] kit Kits and manufactured products for the use of the therapeutic compositions described herein are also described. In some embodiments, such kits include carriers, packaging, or containers, bottles, tubes, capsules, etc., compartmentalized to contain one or more blister packs. In certain embodiments, the pharmaceutical composition is presented in a pack or dispenser device containing one or more unit dosage forms containing the compounds provided herein. In other embodiments, the pack may contain metal foil or plastic foil, such as a blister pack. In some embodiments, the pack contains capsules, vials, or tubes. In other embodiments, the pack or dispenser device includes instructions for administration. In some embodiments, the dispenser is disposable or single-use, while in other embodiments, the dispenser is reusable. In certain embodiments, the pharmaceutical formulation is pre-loaded into the device. In some embodiments, the kit may include a spray device disclosed herein.

[0161] In other embodiments, the packaging may also be accompanied by a cautionary statement required by a government agency that regulates the manufacture, use, or sale of a drug. This cautionary statement indicates that the drug is approved by the agency for human or veterinary administration. Such a cautionary statement may be, for example, a statement approved by the U.S. Food and Drug Administration for a prescription drug, or a package insert for an approved product. Compositions containing the compounds provided herein, formulated in suitable excipients, diluents, and / or carriers, are also prepared, placed in appropriate containers, and labeled for use in the indicated condition.

[0162] The products provided herein may also include administration devices or dispensing devices. Examples of administration devices include intranasal sprays and inhalers. A pump and / or spray head (e.g., a nozzle) may be provided in the spray and intranasal devices, or the pump and / or spray head may be built into the device. Alternatively, the atomizer may be included with the device or stored inside the device. In some examples, the atomizer may be used with the spray devices disclosed herein.

[0163] Such kits may include identification descriptions or labels relating to the container. In further embodiments, the label is on the surface of the container, and letters, numbers, or other symbols form the label and are attached to, molded, or etched onto the container itself. The label is accompanied by the container, for example, as a package insert, if it is located within a receptacle or carrier that also holds the container. In some embodiments, the label is used to indicate that the contents should be used for a particular therapeutic application. In yet other embodiments, the label also displays instructions regarding the use of the contents, such as in the methods described herein. In some embodiments, a set of instructions may also be included, generally in the form of a package insert. The informational material may include instructions on how to dispense the pharmaceutical composition, including a description of the type of patient to be treated, schedule (e.g., dosage and frequency).

[0164] This disclosure also relates to sets (kits) consisting of separate packs of kits that are frequently assembled for transportation or for the convenience of patients, such as for the weekly, bi-weekly, or monthly supply of medicines.

[0165] Numbered Embodiments Several methods are disclosed herein. Specific exemplary embodiments of these methods are disclosed below. The embodiments below enumerate non-limiting permutations of combinations of features disclosed herein. Other permutations of combinations of features are also contemplated. In particular, each of these numbered embodiments is contemplated independently of the order in which they are enumerated, as dependent on or relating to earlier or subsequent numbered embodiments.

[0166] Embodiment 1 A method for treating memory loss in a subject requiring treatment for memory loss, comprising the step of intranasally administering an effective amount of a liquid pharmaceutical composition to the subject by the operation of a nasal spray device, wherein the liquid pharmaceutical composition is A phosphodiesterase (PDE) inhibitor or a salt thereof, and a pharmaceutically acceptable carrier, excipient, diluent, or any combination thereof, When the liquid pharmaceutical composition is administered intranasally to the target by the operation of the nasal spray device, the liquid pharmaceutical composition forms a plume containing a plurality of droplets. The aforementioned multiple droplets are approximately 45 μm to 66 μm in diameter. 90 It is characterized in that approximately 90% of the droplets in the plume are D 90 A method for treating memory loss, comprising the step of administering an effective amount of the liquid pharmaceutical composition having a size less than the specified size.

[0167] Embodiment 2 The method according to Embodiment 1, further characterized in that less than about 1.5% of the droplets in the plume have a size of less than about 10 μm.

[0168] Embodiment 3 The plurality of droplets are approximately 26 μm to approximately 38 μm in diameter. 50 A further feature is that approximately 50% of the droplets in the plume are D 50 The method according to Embodiment 1, having a size less than [size].

[0169] Embodiment 4 The D 50 The method according to Embodiment 3, wherein the particle size is approximately 32 μm.

[0170] Embodiment 5 The method according to any one of Embodiments 1 to 4, wherein the droplet size is measured by laser diffraction.

[0171] Embodiment 6 The method according to Embodiment 1, wherein the PDE inhibitor or the salt thereof comprises apremilast, siromirlast, crisabolol (AN2728), ibudilast, luteolin, mesembrenone, picramiralast, roflumirlast, rolipram, any salt thereof, or any combination thereof.

[0172] Embodiment 7 The method according to Embodiment 6, comprising the PDE inhibitor comprising roflumilast or a salt thereof, or the salt thereof.

[0173] Embodiment 8 The method according to Embodiment 1, wherein the PDE inhibitor or the salt thereof comprises theophylline or a salt thereof, cilostazol or a salt thereof, or any combination thereof.

[0174] Embodiment 9 The method according to Embodiment 1, wherein the plume formed by the operation of the nasal spray device persists for approximately 0.5 seconds to approximately 5 seconds from the start of spraying to the end of spraying.

[0175] Embodiment 10 The method according to Embodiment 1, wherein the pharmaceutically acceptable carrier contains water.

[0176] Embodiment 11 The method according to Embodiment 1, wherein the liquid pharmaceutical composition further comprises a viscosity improver.

[0177] Embodiment 12: The method according to Embodiment 11, wherein the viscosity improver contains cellulose.

[0178] Embodiment 13 The method according to Embodiment 1, wherein the liquid pharmaceutical composition further comprises an excipient.

[0179] Embodiment 14 The method according to Embodiment 13, wherein the excipient includes glycerol.

[0180] Embodiment 15 The method according to Embodiment 1, wherein the liquid pharmaceutical composition further comprises a preservative.

[0181] Embodiment 16 The method according to Embodiment 1, wherein the operation includes an operating volume of approximately 10 μl to approximately 200 μl, or approximately 20 μl to approximately 80 μl of liquid.

[0182] Embodiment 17 The method according to Embodiment 1, wherein intranasal administration is performed once, twice, or three times a day into each nostril.

[0183] Embodiment 18 The method according to Embodiment 1, wherein the plume covers approximately 15% to approximately 50%, or approximately 10% to approximately 80%, or approximately 5% to approximately 90%, or approximately 5% to approximately 100%, of the surface area of ​​the nasal cavity as measured by a nasal cast scan.

[0184] Embodiment 19 The method according to Embodiment 18, wherein the nasal cavity includes the nasal septum, nasal base, lateral walls of the nasal cavity, inferior nasal meatus, middle nasal meatus, superior nasal meatus, olfactory cleft, olfactory region, nasal turbinates, or any combination thereof.

[0185] Embodiment 20 The method according to Embodiment 18, wherein the nasal cavity includes the nasal septum, nasal base, lateral walls of the nasal cavity, inferior nasal meatus, middle nasal meatus, superior nasal meatus, olfactory cleft, olfactory region, and nasal turbinates.

[0186] Embodiment 21 The method according to Embodiment 1, wherein the liquid pharmaceutical composition contains approximately 20 μg to approximately 2000 μg of the PDE inhibitor or a salt thereof in a unit dose.

[0187] Embodiment 22: The method according to Embodiment 1, wherein the memory loss is caused by sleep deprivation.

[0188] Embodiment 23 The method according to Embodiment 1, wherein the memory loss is caused by neurodegenerative disorder, old age, concussion, stroke, cancer treatment, hypoxia, head injury, surgery, multiple sclerosis, dementia, post-traumatic stress disorder (PTSD), bipolar disorder, depression, schizophrenia, substance abuse, infection, epilepsy or nutritional deficiency or a combination thereof.

[0189] Embodiment 24 The method according to Embodiment 1, wherein the subject prior to the administration step has a reduced level of cyclic nucleotides in a nasal mucus sample derived from the subject compared to the level of cyclic nucleotides in a control population with normal memory function.

[0190] Embodiment 25 The method according to Embodiment 1, wherein the subject prior to the administration step has a reduced level of sonic hedgehog in a nasal mucus sample derived from the subject compared to the level of sonic hedgehog in a control population with normal memory function.

[0191] Embodiment 26: The method according to Embodiment 1, further comprising the step of administering a second therapeutic agent.

[0192] Embodiment 27 The method according to Embodiment 26, wherein the second therapeutic agent is administered simultaneously with or sequentially to the administration step.

[0193] Embodiment 28 The method according to Embodiment 1, further comprising the step of diagnosing the subject with memory loss.

[0194] Embodiment 29 The method according to Embodiment 1, wherein the subject has been previously diagnosed with memory loss.

[0195] Embodiment 30 The method according to Embodiment 1, wherein the nasal spray device delivers the plume as a unit dose during operation.

[0196] Embodiment 31 The method according to Embodiment 1, wherein the nasal spray device contains approximately 60 to approximately 300 unit doses, each unit dose containing approximately 20 μg to approximately 2000 μg of the PDE inhibitor or a salt thereof.

[0197] Embodiment 32: The method according to Embodiment 1, wherein the object is an object that requires it.

[0198] Embodiment 33: The method according to Embodiment 1, wherein the subject is a human.

[0199] Embodiment 34 The method according to Embodiment 1, wherein during operation, the nasal spray device delivers approximately 35 mg to approximately 100 mg of the pharmaceutical composition.

[0200] Embodiment 35 The plurality of droplets are approximately 14 μm to approximately 27 μm in diameter. 10 A further feature is that about 10% of the droplets in the plume are D 10 The method according to Embodiment 1, having a size less than [size].

[0201] Embodiment 36. The method according to Embodiment 1, wherein the stroke length of the operation of the nasal spray device is 4.6 mm, 4.8 mm, or 4.9 mm.

[0202] Embodiment 37. The method according to Embodiment 1, wherein the stroke speed of the actuator of the operation of the nasal spray device is 2 mm / s or 3 mm / s.

[0203] Embodiment 38. The method according to Embodiment 1, wherein the stroke acceleration of the actuator of the operation of the nasal spray device is about 500 mm / s 2 as described in Embodiment 1.

[0204] Embodiment 39. The method according to Embodiment 1, wherein the nasal spray device has a nozzle hole size of about 3 μm, about 4 μm, or about 5 μm.

[0205] Embodiment 40. The method according to Embodiment 1, wherein the nasal spray device has about 45 to about 65 nozzle holes or 60 holes.

[0206] Embodiment 41. The method according to Embodiment 1, wherein the nasal spray device has a conical angle of about 20 degrees.

[0207] Embodiment 42. A method for treating memory loss in a subject requiring treatment for memory loss, comprising administering a phosphodiesterase (PDE) inhibitor or a salt thereof in a dosage unit containing a therapeutically effective amount of the PDE inhibitor or a salt thereof in a plume during operation, in a liquid pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent, excipient, or any combination thereof, using a nasal spray device that delivers the dosage unit, wherein the plume contains droplets, (a) less than about 1.5% of the droplets in the plume have a size less than about 10 μm, and (b) D is about 45 μm to about 66 μm 90 and about 90% of the droplets in the plume have a size less than the D 90 as described above. A method having a droplet size distribution characterized by the following. [Examples]

[0208] (Example 1) Distribution of liquid formulations using various nasal spray devices in a nasal cavity model.

[0209] In a nasal cavity model, the ability of three types of nasal spray devices to deposit liquid formulations was tested. 1 mg / mL of calcein (for fluorescence visualization) was added to a formulation containing theophylline (600 μg / mL) but without a viscosity improver. Furthermore, 1 mg / mL of calcein was added to a separate formulation containing theophylline (600 μg / mL) and a viscosity improver (carboxymethylcellulose). This formulation also contained citrate and sodium hydroxide as buffers, and phenylethyl alcohol as a preservative. Purified water was used as the carrier. The test was conducted at 60% relative humidity. The formulations were tested with three different nasal spray devices: a soft mist nasal spray, a slow-speed standard nasal spray, and a standard nasal spray. The images in Figure 1 show that two operations of the spray device were tested for each image (90 μl liquid spray). Table 1 shows the nasal effective range of the various spray devices in the nasal cavity model. A soft mist nasal spray without viscosity improvers exhibited the maximum effective surface area (approximately 40%) in a nasal cavity model. The soft mist nasal spray targeted the olfactory region and nasal turbinates. Addition of cellulose reduced the covered surface area to approximately 20% of the nasal mucosa. However, the spray concentrated even more in the olfactory region, as shown in Figure 1 and indicated by the oval shape. Furthermore, since the olfactory region is known to affect chemosensory function, this concentration of the soft mist nasal spray in this area was surprising and unexpected compared to standard nasal sprays.

[0210] Table 1 Surface effective range of nasal spray [Table 1]

[0211] (Example 2) Features of 3 types of nasal spray devices

[0212] Theophylline liquid formulation was tested using three types of spray devices: a soft mist nasal spray device, a slow-speed standard nasal spray device, and a standard nasal spray device. The operational data is shown in Figure 2. The left Y-axis represents the cumulative volume (%) of each spray, indicated by an S-shaped curve. The X-axis represents the droplet particle size (μm). The right Y-axis represents the volume frequency (%) of droplet size. The soft mist nasal spray contained approximately 50% droplets with a particle size of less than 20 μm, and virtually no particles larger than 60 μm. The slow-speed standard nasal spray contained approximately 50% droplets with a particle size of less than 30 μm, and the remaining 50% of particles were between approximately 30 μm and 100 μm in size. The standard nasal spray contained approximately 50% droplets with a particle size of less than 60 μm, and the remaining particles were between approximately 60 μm and 200 μm in size. As shown in Figures 1 and 2, the small droplet size of the soft mist nasal spray concentrated the formulation in the olfactory region.

[0213] (Example 3) Theophylline spray formulation

[0214] Table 2 shows two example formulations of theophylline for nasal administration.

[0215] Table 2 - Theophylline preparations [Table 2]

[0216] (Example 4) Treatment of memory loss in the subject

[0217] The subject is admitted to a clinic due to memory loss associated with sleep deprivation. The subject is prescribed a roflumilast composition in a nasal spray device as described herein. The subject administers an effective dose of the nasal spray three times a day into each nostril. The nasal spray is a spray containing D in the range of about 15 μm to about 24 μm 50 and D in the range of about 30 μm to about 50 μm 90 and is characterized in that less than about 3% of the droplets in the spray plume have a size of less than about 10 μm. The subject's memory retention improved after administration of roflumilast.

[0218] (Example 5) Soft Mist Nasal Spray Characteristics

[0219] A Soft Mist nasal spray device was tested to determine the spray characteristics of the Soft Mist nasal spray during operation. Three or six devices were tested using an automated system. The stroke lengths of the operation of the nasal spray device were 4.6 mm, 4.8 mm, and 4.9 mm. The acceleration of the actuator stroke (AS) was about 500 millimeters per second 2 (mm / s 2 ). The AS speed was 1, 2, 3, or 4 millimeters per second (mm / s). The average hold time (i.e., the average amount of time the spray device was depressed) was 684 milliseconds (ms). Each experiment was tested with 3 or 6 dosing shots per AS speed for each device. The devices were prepared with several operations prior to testing. The composition was tested with a formulation containing 2.8 mg / ml theophylline, preservatives (benzalkonium chloride and phenylethyl alcohol), and saline. The spray device had 48 nozzle holes with a size of 4 μm per nozzle hole and a conical angle of 20°. The box-and-whisker graphs of FIGS. 3- / 6 and 8-13 are explained as follows. The box represents the range of the 25th to 75th percentiles. The line within the box is the median (50th percentile). The whiskers are the maximum and minimum values, unless they are considered outliers indicated by asterisks. The whiskers do not indicate that the first quartile is equal to the minimum value and the third quartile is equal to the maximum value.

[0220] The measured shot weight (release amount in mg) is shown in Figure 3. Figure 3 is a box plot showing the shot weight (release amount in milligrams (mg)) measured from the soft mist pump device on the Y axis, with various operating speeds (1, 2, 3, and 4 millimeters per second (mm / s)) on the upper X axis and stroke lengths of 4.6 mm, 4.8 mm, and 4.9 mm shown on the lower X axis. Operating speeds of 2 mm / s and 3 mm / s were within approximately 20% of the target shot weight of 45 mg.

[0221] The delivered shot weight (delivered amount in mg) is shown in Figure 4. Figure 4 is a box plot showing the shot weight (delivered amount in milligrams (mg)) delivered from the soft mist pump device on the Y axis, with various operating speeds (1, 2, 3, and 4 millimeters per second (mm / s)) on the upper X axis and stroke lengths of 4.6 mm, 4.8 mm, and 4.9 mm shown on the lower X axis. Operating speeds of 1 mm / s, 2 mm / s, and 3 mm / s were within approximately 20% of the target shot weight of 45 mg.

[0222] Figure 5 shows the spray plume geometry at a pattern distance of 60 mm. Figure 5 illustrates a box plot showing the performance of the plume geometry (plume angle (degrees) and plume width (mm)) from a soft mist pump device on the Y axis, with various operating speeds (1, 2, and 3 millimeters per second (mm / s)) on the X axis, over a stroke length of 4.8 mm. The plume angle ranged from approximately 15 degrees to approximately 40 degrees. The plume width ranged from approximately 15 mm to approximately 45 mm. For device #11, it was not possible to determine several spray patterns, such as one iteration at 1 mm / s, and for device #13, two iterations at 1 mm / s.

[0223] The performance of the spray patterns at 30 mm and 60 mm is shown in Figure 6. Figure 6 is a box plot showing the spray pattern characteristics Dmax (mm), Dmin (mm), ellipticity, and area (mm^2) on the Y axis, with the upper X axis showing pattern distances of 30 mm and 60 mm, and the lower X axis showing various operating speeds (2 mm / s and 3 mm / s), and a stroke length of 4.8 mm. For a spray distance of 30 mm, Dmax (maximum diameter) was 15-20 mm, Dmin (minimum diameter) was approximately 14 mm, ellipticity was approximately 1.1-1.3, and area was approximately 180-200 mm^2. For a spray distance of 60 mm, Dmax (maximum diameter) was approximately 30-50 mm, Dmin (minimum diameter) was approximately 20-30 mm, ellipticity was approximately 1.1-1.8, and area was approximately 600-1000 mm^2. At 60mm, repeats of device #13 at 2mm / second did not yield a quantifiable pattern.

[0224] Spray patterns at pattern distances of 30 mm and 60 mm are shown in Figure 7. Figure 7 illustrates images showing spray patterns at pattern distances of 30 mm and 60 mm from a soft mist pump device (device 12) at various operating speeds (2 and 3 millimeters per second (mm / s)) and a stroke length of 4.8 mm. In some examples, the spray pattern parameters at 60 mm could not be calculated due to spray dissipation that occurred at 60 mm. The images were captured by the non-collision laser method using a Proveris Sprayview instrument. The non-collision laser method projects a sheet of laser light and generates an image of the concentration of droplets passing through the plane of the laser light.

[0225] The droplet size distribution at pattern distances of 30 mm and 60 mm is shown in Figure 8. Figure 8 is a box plot showing the droplet size distribution (% volume < 10 μm; span; D90 value (μm); and D50 value (μm)) on the Y axis, with the upper X axis showing the pattern distances of 30 mm and 60 mm and the lower X axis showing various operating speeds (2 mm / s and 3 mm / s) at a stroke length of 4.8 mm. For the spray device at 30 mm, % volume < 10 μm is approximately 0.25% to approximately 2%, and the span is approximately 0.8 to approximately 1.6, and D 90 The value is approximately 30-55 μm, D 50 The values ​​were approximately 21-28 μm. For a spray device at 60 mm, % volume < 10 μm was less than approximately 1%, and the span was approximately 0.8-1.2. 90 The value is approximately 40-50 μm, D 50 The value was approximately 26-30 μm.

[0226] The plume geometry at a pattern distance of 60 mm is shown in Figure 9. Figure 9 illustrates box plots showing the performance of the plume geometry (plume angle (degrees) and plume width (mm)) on the Y axis for various operating speeds (1, 2, and 3 millimeters per second (mm / s)) on the lower X axis, with stroke lengths of 4.6 mm and 4.8 mm on the upper X axis. At a stroke length of 4.6 mm, the plume angle was approximately 25–40 degrees and the plume width was approximately 25–40 mm. At a stroke length of 4.8 mm, the plume angle was approximately 15–40 degrees and the plume width was approximately 15–40 mm. In some cases, the spray was not detected at a speed of 1 mm / s.

[0227] The performance of the spray pattern at a pattern distance of 30 mm is shown in Figure 10. Figure 10 is a box plot showing the spray pattern (Dmax (mm), Dmin (mm), ellipticity, and area (mm^2)) on the Y axis, with stroke lengths of 4.6 mm and 4.8 mm on the upper X axis and various operating speeds (2 and 3 mm / s) on the lower X axis. For a stroke length of 4.6 mm, Dmax was approximately 16-20 mm, Dmin was approximately 13-14.5 mm, ellipticity was approximately 1.1-1.4, and area was approximately 170-210 mm^2. For a stroke length of 4.8 mm, Dmax was approximately 16-20 mm, Dmin was approximately 13.5-14.75 mm, ellipticity was approximately 1.1-1.3, and area was approximately 170-210 mm^2.

[0228] The performance of the spray pattern at a pattern distance of 60 mm is shown in Figure 11. Figure 11 is a box plot showing the spray pattern (Dmax (mm), Dmin (mm), ellipticity, and area (mm^2)) on the Y axis, with stroke lengths of 4.6 mm and 4.8 mm on the upper X axis and various operating speeds (2 and 3 mm / s) on the lower X axis. For a stroke length of 4.6 mm, Dmax was approximately 30-45 mm, Dmin was approximately 21-32 mm, ellipticity was approximately 1.1-1.6, and area was approximately 500-1200 mm^2. For a stroke length of 4.8 mm, Dmax was approximately 30-50 mm, Dmin was approximately 24-32 mm, ellipticity was approximately 1.1-1.8, and area was approximately 600-1000 mm^2. In some cases, the spray pattern parameters at 60mm could not be calculated due to spray dissipation at a distance of 60mm.

[0229] The droplet size distribution at a spray distance of 30 mm is shown in Figure 12. Figure 12 illustrates a box plot on the Y axis showing the droplet size distribution (% volume < 10 μm; span; D90 value (μm); and D50 value (μm)) at various operating speeds (2 and 3 mm / s) on the lower X axis, with stroke lengths of 4.6 mm and 4.8 mm on the upper X axis. At a stroke length of 4.6 mm, % volume < 10 μm is approximately 0.5 to 2%, span is approximately 0.8 to 1.6, and D 90 The value is approximately 35-52 μm, D 50 The values ​​were approximately 21-26 μm. For a stroke length of 4.8 mm, the percentage volume < 10 μm was approximately 0.25-1.75%, and the span was approximately 0.8-1.6. 90 The value is approximately 30-55 μm, D 50 The values ​​were approximately 21–27 μm.

[0230] The droplet size distribution at a spray distance of 60 mm is shown in Figure 13. Figure 13 illustrates a box plot on the Y-axis showing the droplet size distribution (% volume < 10 μm; span; D90 value (μm); and D50 value (μm)) at various operating speeds (2 and 3 mm / s) on the lower X-axis, with stroke lengths of 4.6 mm and 4.8 mm on the upper X-axis. At a stroke length of 4.6 mm, % volume < 10 μm is less than 2.5%, span is approximately 0.8 to approximately 1.4, and D 90 The value is approximately 36-63 μm, D 50 The values ​​were approximately 23-34 μm. For a stroke length of 4.8 mm, the % volume < 10 μm was less than approximately 1%, and the span was approximately 0.8-1.1. 90 The value is approximately 40-50 μm, D 50 The value was approximately 25-30 μm.

[0231] A summary of the droplet size distribution is shown in Table 4. Table 4 shows the droplet size distribution by pattern distance or tip distance (30 mm or 60 mm); actuator stroke speed (2 mm / s and 3 mm / s); and stroke length (4.6 mm and 4.8 mm). The mean, standard deviation and coefficient of variation (CV) of the D10 value (μm), D50 value (μm), and D90 value (μm), as well as the percentage volume < 10 μm, percentage volume < 5 μm, and span, are shown for each iteration of the tested device.

[0232] Table 3: Summary of droplet size distribution using soft mist spray devices [Table 3-1] [Table 3-2]

[0233] (Example 6) Treatment of memory loss related to amnesia

[0234] This study aims to treat amnesia-related memory loss in adult human males. The subjects experience difficulty recalling memories from completed daily tasks. The subjects receive a liquid composition containing a PDE4 inhibitor via a nasal spray device described herein. The nasal spray is administered twice daily into each nostril. The subjects' memory improves after 7 days of use of the spray device.

[0235] (Example 7) Measurement of droplet size derived from sprays from devices, including various nozzle designs.

[0236] The average droplet size was determined for several nasal spray devices with various nozzle pore sizes (e.g., 4.0 μm and 5.0 μm), nozzle pore numbers (e.g., 48 and 60), and cone angles (e.g., 5°, 20°, 25°, and 30°), as shown in Table 4. The nozzle pores are located at the tip of the spray nozzle of the spray device. Saline preparations were tested with the devices. Droplet size was determined using a laser diffraction particle size analyzer at a distance of 5 cm from the laser beam. The dosing volume was 200 μl per operation after device preparation. The average droplet size from >20 operations per device is shown in Table 4. The largest droplet size was measured using a 5 μm nozzle pore size, and the cone angle affected the variation in droplet size. Further statistics from the sprays are shown in Table 5, which shows the results for each device per variable (D10, D50, or D90 values). This data shows the total number of sprays, as well as the mean, maximum, and minimum droplet sizes for each variable. Furthermore, the standard error and standard deviation of the mean are presented.

[0237] Table 4: Summary of droplet size distributions from soft mist spray devices with various nozzle sizes, nozzle hole counts, and cone angles. [Table 4]

[0238] Table 5: Statistics on droplet size distribution from soft mist spray devices with various nozzle hole sizes, nozzle hole number variations, and cone angles. [Table 5-1] [Table 5-2]

[0239] (Example 8) Theophylline non-aqueous nasal preparation

[0240] Two non-aqueous theophylline formulations were developed and are shown in Tables 6 and 7. In some cases, the drug concentration in the formulation (e.g., PDE inhibitor) can be as high as 12 mg / mL. This formulation can be used with the nasal spray device described herein. Table 6: Formulation A: 5.7 mg / mL theophylline [Table 6] Table 7: Formulation B: Theophylline 11 mg / mL [Table 7]

[0241] (Example 9) Measurement of droplet size and dosage from a spray device with a nozzle hole size of 5 μm and 60 nozzle holes.

[0242] The average droplet size, spray characteristics, and spray dose were determined for a nasal spray device with a nozzle pore size of 5.0 μm and 60 nozzle pores. The nozzle pores are located at the tip of the spray nozzle of the spray device. A 3.5 mg / ml theophylline formulation was tested with the devices. To determine the dose per action, five spray devices were tested after preparation with a controlled action of 5 kg force, with a maximum possible action time of 2 seconds. The tested dosing volume was 70 μl per action after device preparation. The recorded statistics were from more than 100 actions after preparation, and the results are shown in Table 8. The results show that the delivered dose was consistently around 70 μl, with an average of 70.6 μl, an average minimum of 65.6 μl, and an average maximum of 72.5 μl. Similar results were observed with a 0.9% NaCl solution (average 69.4 μl, average minimum 65.2 μl, and average maximum 71.5 μl), indicating that these values ​​remain constant across various amounts of theophylline. Table 8: Operating dose in μl units delivered [Table 8]

[0243] Droplet size was determined using the Fraunhofer evaluation method with a laser diffraction particle size analyzer for five different spray devices at a velocity of 1.8 mm / s, a distance of 30 mm to the laser axis, a distance of 100 mm to the lens, and a distance of 100 mm to the detector. The average droplet size from three operations per device is shown in Table 9. Table 9 shows the results for each device per variable (D10, D50, D90, V%<10 μm[%], and span value). The minimum D10, D50, and D90 values ​​were 11.7 μm, 21.3 μm, and 35.1 μm, respectively. The maximum D10, D50, and D90 values ​​were 13.5 μm, 24.4 μm, and 40.7 μm, respectively. The average D10, D50, and D90 values ​​were 12.6 μm, 23.1 μm, and 38.8 μm, respectively.

[0244] Table 9: Summary of droplet size distribution using soft mist spray devices [Table 9]

[0245] The spray pattern was determined from multiple trials using five different spray devices at a distance of 60 mm. These results are shown in Table 10. Table 10 shows that the average maximum diameter was 20.7 mm, the average minimum diameter was 18.3 mm, and the average diameter was 19.5 mm. The average area was 298 mm². 2 The mean elliptic ratio was 1.1. Similar results were observed in the 0.9% NaCl solution, indicating that these values ​​remain constant for various amounts of theophylline.

[0246] Table 10: Summary of spray patterns using soft mist spray devices [Table 10-1] [Table 10-2]

[0247] The plume geometry was determined from multiple trials for five different spray devices. These results are shown in Table 11. Table 11 shows that the average spray angle was 14.5 degrees, the average plume width was 1.2 cm, and the average plume length was 7 cm. Similar results were observed for a 0.9% NaCl solution, indicating that these values ​​remain constant with varying amounts of theophylline.

[0248] Table 11: Summary of plume geometry using soft mist spray devices [Table 11]

[0249] While preferred embodiments of the Disclosure are shown and described herein, such embodiments are presented merely as examples. It should be understood that various alternatives to the embodiments of the Disclosure described herein may be used in practicing the Disclosure.

Claims

1. A method for treating memory loss in a subject requiring treatment for memory loss, comprising the step of intranasally administering an effective amount of a liquid pharmaceutical composition to the subject by the operation of a nasal spray device, wherein the liquid pharmaceutical composition is A phosphodiesterase (PDE) inhibitor or a salt thereof, and a pharmaceutically acceptable carrier, excipient, diluent, or any combination thereof, When the liquid pharmaceutical composition is administered intranasally to the target by the operation of the nasal spray device, the liquid pharmaceutical composition forms a plume containing a plurality of droplets. The aforementioned plurality of droplets are approximately 35 μm to approximately 41 μm in diameter. ９０ It is characterized in that approximately 90% of the droplets in the plume are D ９０ A method for treating memory loss, comprising the step of administering an effective amount of the liquid pharmaceutical composition having a size less than the specified size.

2. The method according to claim 1, further characterized in that less than about 7% of the droplets in the plume have a size of less than about 10 μm.

3. The aforementioned plurality of droplets are approximately 21 μm to approximately 25 μm in diameter. ５０ A further feature is that approximately 50% of the droplets in the plume are D ５０ The method according to claim 1, having a size less than [size].

4. The aforementioned D ５０ The method according to claim 3, wherein the thickness is approximately 23 μm.

5. The method according to claim 1, wherein the droplet size is measured by laser diffraction.

6. The method according to claim 1, wherein the PDE inhibitor or the salt thereof comprises apremilast, siromirlast, crisabolol (AN2728), ibudilast, luteolin, mesembrenone, picramiralast, roflumirlast, rolipram, any salt thereof, or any combination thereof.

7. The method according to claim 6, comprising the PDE inhibitor comprising roflumilast or a salt thereof, or the salt thereof.

8. The method according to claim 1, wherein the PDE inhibitor or the salt thereof comprises theophylline or a salt thereof, cilostazol or a salt thereof, or any combination thereof.

9. The method according to claim 1, wherein the plume formed by the operation of the nasal spray device persists for about 0.5 seconds to about 5 seconds from the start of spraying to the end of spraying.

10. The method according to claim 1, wherein the pharmaceutically acceptable carrier comprises water.

11. The method according to claim 1, wherein the liquid pharmaceutical composition further comprises a viscosity improver.

12. The method according to claim 11, wherein the viscosity improver comprises cellulose.

13. The method according to claim 1, wherein the liquid pharmaceutical composition further comprises an excipient.

14. The method according to claim 13, wherein the excipient comprises glycerol.

15. The method according to claim 1, wherein the liquid pharmaceutical composition further comprises a preservative.

16. The method according to claim 1, wherein the operation includes an operating volume of approximately 10 μl to approximately 200 μl, approximately 20 μl to approximately 80 μl, or approximately 70 μl of liquid.

17. The method according to claim 1, wherein intranasal administration is performed once, twice, or three times a day into each nostril.

18. The method according to claim 1, wherein the plume covers about 15% to about 50%, or about 10% to about 80%, or about 5% to about 90%, or about 5% to about 100%, of the surface area of ​​the nasal cavity as measured by a nasal cast scan.

19. The method according to claim 18, wherein the nasal cavity includes the nasal septum, nasal base, lateral walls of the nasal cavity, inferior nasal meatus, middle nasal meatus, superior nasal meatus, olfactory cleft, olfactory region, nasal conchae, or any combination thereof.

20. The method according to claim 18, wherein the nasal cavity includes the nasal septum, nasal base, lateral walls of the nasal cavity, inferior nasal meatus, middle nasal meatus, superior nasal meatus, olfactory cleft, olfactory region, and nasal turbinates.

21. The method according to claim 1, wherein the liquid pharmaceutical composition contains, in a unit dose, about 20 μg to about 2000 μg of the PDE inhibitor or a salt thereof.

22. The method according to claim 1, wherein the memory loss is caused by sleep deprivation.

23. The method according to claim 1, wherein the memory loss is caused by neurodegenerative disorder, old age, concussion, stroke, cancer treatment, hypoxia, head injury, surgery, multiple sclerosis, dementia, post-traumatic stress disorder (PTSD), bipolar disorder, depression, schizophrenia, substance abuse, infection, epilepsy, or nutritional deficiency or a combination thereof.

24. The method according to claim 1, wherein the subject prior to the administration step has a reduced level of cyclic nucleotides in a nasal mucus sample derived from the subject compared to the level of cyclic nucleotides in a control population having normal memory function.

25. The method according to claim 1, wherein the subject prior to the administration step has a reduced level of sonic hedgehog in a nasal mucus sample derived from the subject compared to the level of sonic hedgehog in a control population with normal memory function.

26. The method according to claim 1, further comprising the step of administering a second therapeutic agent.

27. The method according to claim 26, wherein the second therapeutic agent is administered simultaneously with or sequentially to the administration step.

28. The method according to claim 1, further comprising the step of diagnosing the subject with memory loss.

29. The method according to claim 1, wherein the subject has been previously diagnosed with the memory loss.

30. The method according to claim 1, wherein the nasal spray device delivers the plume as a unit dose during operation.

31. The method according to claim 1, wherein the nasal spray device contains approximately 60 to approximately 300 unit doses, each unit dose containing approximately 20 μg to approximately 2000 μg of the PDE inhibitor or a salt thereof.

32. The method according to claim 1, wherein the object is an object that requires it.

33. The method according to claim 1, wherein the subject is a human.

34. The method according to claim 1, wherein during operation, the nasal spray device delivers approximately 35 mg to approximately 100 mg of the pharmaceutical composition.

35. The aforementioned plurality of droplets are approximately 11 μm to approximately 14 μm in diameter. １０ A further feature is that about 10% of the droplets in the plume are D １０ The method according to claim 1, having a size less than [size].

36. The method according to claim 1, wherein the stroke length of the operation of the nasal spray device is 4.6 mm, 4.8 mm, or 4.9 mm.

37. The method according to claim 1, wherein the stroke speed of the actuator for the operation of the nasal spray device is 2 mm / s or 3 mm / s.

38. The stroke acceleration of the actuator for the aforementioned operation of the nasal spray device is approximately 500 mm / s². ２ The method according to claim 1.

39. The method according to claim 1, wherein the nasal spray device has a nozzle hole size of about 3 μm, about 4 μm, or about 5 μm.

40. The method according to claim 1, wherein the nasal spray device has approximately 45 to approximately 65 nozzle holes or 60 holes.

41. The method according to claim 1, wherein the nasal spray device has a cone angle of about 20 degrees.

42. A method for treating memory loss in a subject requiring treatment for memory loss, comprising the step of administering a PDE inhibitor or a salt thereof using a nasal spray device that delivers a dose unit containing a therapeutically effective amount of a phosphodiesterase (PDE) inhibitor or a salt thereof in a plume during operation, in a liquid pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent, excipient or any combination thereof, wherein the plume contains droplets, (a) Less than about 7% of the droplets in the plume have a size of less than about 10 μm, and (b) D of about 35 μm to about 41 μm ９０ and about 90% of the droplets in the plume are less than the D ９０ having a size of A method having a droplet size distribution characterized by the following.

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