Improved nasal administration of Parkinson's disease drugs

Abstract

Disclosed herein is a method for treating Parkinson's disease in a subject, comprising administering to the subject a phosphodiesterase inhibitor and a treatment for Parkinson's disease intranasally by a nasal spray device.Disclosed herein is also a device and a kit for administering the composition described herein to a subject in need thereof.The nasal spray device of the present invention delivers a dosage unit that can be used to treat chemosensory dysfunction caused by Parkinson's disease.Disclosed herein is also a treatment for other neurological diseases by a nasal spray device.

Description

[Technical field]

[0001] cross reference This application claims the benefit of U.S. Provisional Application No. 63 / 297,060, filed January 06, 2022, U.S. Provisional Application No. 63 / 404,227, filed September 07, 2022, and U.S. Provisional Application No. 63 / 418,663, filed October 24, 2022, the disclosures of which are incorporated by reference herein in their entireties. Summary of the Invention [Means for solving the problem]

[0002] summary Disclosed herein is a method of treating Parkinson's disease in a subject in need thereof, comprising administering to the subject an effective amount of a liquid pharmaceutical composition, the liquid pharmaceutical composition comprising: a) a phosphodiesterase (PDE) inhibitor or a salt thereof, and b) a pharma- ceutically acceptable carrier, excipient, diluent, or any combination thereof. In some embodiments, the liquid pharmaceutical composition, upon intranasal administration to a subject by actuation of a nasal spray device containing the liquid pharmaceutical composition, forms a plume comprising a plurality of droplets, the plurality of droplets having a D of about 38 μm to about 49 μm. 90 The plume is characterized by approximately 90% of the droplets being D 90 In some embodiments, Parkinson's disease may be treated by administration of an effective amount of the liquid pharmaceutical composition. In some embodiments, the plurality of droplets may be further characterized in that less than about 1.5% of the droplets in the plume have a size of less than about 10 μm. In some embodiments, the plurality of droplets may have a size of less than about 23 μm to about 30 μm. 50 and about 50% of the droplets in the plume have a diameter of D 50 In some embodiments, the size is less than D 50may be about 25 μm. In some embodiments, the droplet size may be measured by laser diffraction. In some embodiments, the PDE inhibitor or salt thereof may include a selective PDE inhibitor, a non-selective PDE inhibitor, or a salt of any of these. In some embodiments, the PDE inhibitor or salt thereof may include theophylline, ibudilast, rolipram, roflumilast, papaverine, a salt of any of these, or any combination thereof. In some embodiments, the plume may be formed by actuation of the nasal spray device and lasts for about 0.5 seconds to about 5 seconds from the start of spray to the end of spray. In some embodiments, the actuation may include an actuation volume of liquid of about 10 μl to about 200 μl or about 20 μl to about 80 μl. In some embodiments, the pharma- ceutically acceptable carrier may include water. In some embodiments, the liquid pharmaceutical composition may further include a viscosity enhancer. In some embodiments, the liquid pharmaceutical composition may further include an excipient. In some embodiments, the liquid pharmaceutical composition may further include a preservative. In some embodiments, intranasal administration can be once, twice, three or four times a day to each nostril. In some embodiments, the plume can cover about: 15% to about 50%, about 10% to about 80%, 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 can include the nasal septum, nasal floor, lateral nasal wall, inferior meatus, middle meatus, superior meatus, olfactory cleft, olfactory region, nasal turbinate or any combination thereof. In some embodiments, the nasal cavity can include the nasal septum, nasal floor, lateral nasal wall, inferior meatus, middle meatus, superior meatus, olfactory cleft, olfactory region and nasal turbinate.In some embodiments, Parkinson's disease can include idiopathic Parkinson's disease, familial Parkinson's disease, secondary Parkinsonism, Parkinson-type dementia (Parkinson's disease dementia), early-onset Parkinson's disease, early-onset Parkinson's disease, drug-induced Parkinsonism, multiple system atrophy, progressive supranuclear palsy, corticobasal syndrome, corticobasal degeneration, essential tremor, dementia with Lewy bodies (Lewy body dementia), vascular Parkinsonism, normal pressure hydrocephalus, atypical Parkinson's disorder, or any combination thereof. In some embodiments, treating Parkinson's disease can include treating symptoms of Parkinson's disease. In some embodiments, the symptoms of Parkinson's disease can include chemosensory disorders, tremors, muscle stiffness, rigid muscles, slow movement, balance disorders, posture disorders, loss of automatic movements, coordination disorders, depression, difficulty swallowing, difficulty chewing, speech disorders, urinary problems, constipation, skin problems, speech changes, writing changes, loss of sleep, difficulty moving, difficulty walking, diminished facial expressivity, dizziness, fainting, or any combination thereof. In some embodiments, the method can further include administration of a second therapeutic agent. In some embodiments, the second therapeutic agent can be administered simultaneously or sequentially. In some embodiments, the second therapeutic agent can include levodopa, carbidopa, entacapone, tolcapone, opicapone, pramipexole, ropinirole, apomorphine, rotigotine, selegiline, rasagiline, safinamide, amantadine, istradefylline, trihexyphenidyl, benztropine, benserazide, any salt thereof, or any combination thereof. In some embodiments, the second therapeutic agent can include levodopa or a salt thereof. In some embodiments, the nasal spray device can deliver a plume as a unit dose upon actuation. In some embodiments, the nasal spray device can include about 60 to about 120 unit doses, each unit dose including about 10 μg to about 2000 μg of a PDE inhibitor or a salt thereof.In some embodiments, the method may further include diagnosing the subject with Parkinson's disease. In some embodiments, the subject has previously been diagnosed with Parkinson's disease. In some embodiments, the subject may be a subject in need thereof. In some embodiments, the subject may be a human. In some embodiments, the nasal spray device, upon actuation, may deliver about 35 mg to about 50 mg of the pharmaceutical composition. In some embodiments, the plurality of droplets may have a diameter of about 14 μm to about 19 μm. 10 can be further characterized, with approximately 10% of the droplets in the plume being D 10 In some embodiments, the stroke length of the actuator of the nasal spray device may be 4.6 mm, 4.8 mm, or 4.9 mm. In some embodiments, the stroke velocity of the actuator of the actuator of the nasal spray device may be 2 mm / s or 3 mm / s. In some embodiments, the stroke acceleration of the actuator of the actuator of the nasal spray device may be about 500 mm / s. 2 In some embodiments, the nasal spray device can have a nozzle orifice 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 orifices, or about 45 orifices to about 65 nozzle orifices. In some embodiments, the nasal spray device can have a cone angle of about 20 degrees.

[0003] Also disclosed is a nasal spray device comprising a PDE inhibitor or a salt thereof, configured to deliver a dosage unit in a plume upon actuation, the dosage unit comprising a therapeutically effective amount of the PDE inhibitor or a salt thereof in a pharma- ceutically acceptable carrier, excipient, diluent, or any combination thereof. In some embodiments, the plume of the nasal spray device has a diameter of about 1.5 mm or less, and a diameter of about 38 mm or less, and a diameter of about 49 mm or less, and a diameter of about 50 mm or less, and a diameter of about 60 mm or less, and a diameter of about 70 mm or less, and a diameter of about 80 mm or less, and a diameter of about 90 mm or less, and a diameter of about 100 mm or less, and a diameter of about 150 mm or less, and a diameter of about 200 mm or less, and a diameter of about 250 mm or less, and a diameter of about 300 mm or less, and a diameter of about 300 mm or less, and a diameter of about 400 mm or less, and a diameter of about 5 ... 90 and about 90% of the droplets in the plume are D 90 The droplets may have a droplet size distribution characterized by having a size less than

[0004] Also disclosed herein is a method of treating Parkinson's disease in a subject in need thereof, comprising administering a PDE inhibitor or salt thereof using a nasal spray device that delivers a dosage unit in a plume upon operation, the PDE inhibitor or salt thereof comprising a therapeutically effective amount in a liquid pharmaceutical composition comprising a pharma- ceutical carrier, diluent, excipient, or any combination thereof. In some embodiments, the plume can include droplets, with a D of about 38 μm to about 49 μm. 90 and about 90% of the droplets in the plume have a droplet size distribution that can be characterized as D 90 has a size less than

[0005] Also disclosed herein is a method of treating Parkinson's disease in a subject in need thereof, comprising administering to the subject an effective amount of a liquid pharmaceutical composition, the liquid pharmaceutical composition comprising a) levodopa or a salt thereof, and b) a pharma- ceutically acceptable carrier, excipient, diluent, or any combination thereof. In some embodiments, the liquid pharmaceutical composition, upon intranasal administration to a subject by actuation of a nasal spray device containing the liquid pharmaceutical composition, forms a plume comprising a plurality of droplets, the plurality of droplets having a D of about 38 μm to about 49 μm. 90 The plume is characterized by approximately 90% of the droplets being D 90 The liquid pharmaceutical composition has a size of less than 100 μm. In some embodiments, Parkinson's disease can be treated by administering an effective amount of the liquid pharmaceutical composition. In some embodiments, the liquid pharmaceutical composition can further include carbidopa, a PDE inhibitor, a salt of any of these, or any combination thereof.

[0006] Also disclosed herein is a method of treating Parkinson's disease in a subject in need thereof, comprising administering to the subject an effective amount of a liquid pharmaceutical composition, the liquid pharmaceutical composition comprising: a) a compound selected from the group consisting of carbidopa, entacapone, tolcapone, opicapone, pramipexole, ropinirole, apomorphine, rotigotine, selegiline, rasagiline, safinamide, amantadine, istradefylline, trihexyphenidyl, benztropine, benserazide, any salt thereof, and any combination thereof, and b) a pharma- ceutically acceptable carrier, excipient, diluent, or any combination thereof. In some embodiments, the liquid pharmaceutical composition, upon intranasal administration to a subject by actuation of a nasal spray device containing the liquid pharmaceutical composition, forms a plume comprising a plurality of droplets, the plurality of droplets having a D of about 38 μm to about 49 μm. 90 The plume is characterized by approximately 90% of the droplets being D 90 In some embodiments, Parkinson's disease can be treated by administration of an effective amount of the pharmaceutical composition.

[0007] Also disclosed herein is a nasal spray device comprising: (i) a compound selected from the group consisting of levodopa, carbidopa, entacapone, tolcapone, opicapone, pramipexole, ropinirole, apomorphine, rotigotine, selegiline, rasagiline, safinamide, amantadine, istradefylline, trihexyphenidyl, benztropine, benserazide, any salt thereof, and any combination thereof; and (ii) a pharma- ceutically acceptable carrier, excipient, diluent, or any combination thereof. In some embodiments, the nasal spray device may be configured to deliver a dosage unit in a plume upon actuation, the plume having a D of about 38 μm to about 49 μm. 90 and about 90% of the droplets in the plume have a droplet size distribution characterized by a droplet size distribution of about 90% of the droplets in the plume having ... 90 has a size less than

[0008] Also disclosed herein is a method of treating a neurological disorder in a subject in need thereof, comprising administering to the subject an effective amount of a liquid pharmaceutical composition, the liquid pharmaceutical composition comprising: a) a compound selected from the group consisting of donepezil, rivastigmine, galantamine, tacrine, memantine, suvorexant, riluzole, edaravone, sodium phenylbutyrate, taurursodiol, tetrabenazine, amantadine, any salt thereof, and any combination thereof, and b) a pharma- ceutically acceptable carrier, excipient, diluent, or any combination thereof. In some embodiments, the pharmaceutical composition, upon intranasal administration to a subject by actuation of a nasal spray device containing the liquid pharmaceutical composition, forms a plume comprising a plurality of droplets, the plurality of droplets having a D of about 38 μm to about 49 μm. 90 The plume is characterized by approximately 90% of the droplets being D 90 The liquid pharmaceutical composition has a size of less than 100 μg / ml. In some embodiments, the neurological disease can be treated by administering an effective amount of the liquid pharmaceutical composition. In some embodiments, the neurological disease can include Alzheimer's disease, amyotrophic lateral sclerosis (ALS), dementia, Huntington's disease, Huntington's disease-like syndrome (HD-like syndrome), or any combination thereof.

[0009] Also disclosed herein is a nasal spray device comprising: (i) a compound selected from the group consisting of donepezil, rivastigmine, galantamine, tacrine, memantine, suvorexant, riluzole, edaravone, sodium phenylbutyrate, taurursodiol, tetrabenazine, any salt thereof, and any combination thereof; and (ii) a pharma- ceutically acceptable carrier, excipient, diluent, or any combination thereof. In some embodiments, the nasal spray device may be configured to deliver a dosage unit in a plume upon actuation, the plume having a D of about 38 μm to about 49 μm. 90 and about 90% of the droplets in the plume have a droplet size distribution characterized by a droplet size distribution of about 90% of the droplets in the plume having ... 90 has a size less than

[0010] Also disclosed herein is a kit that includes the above-described nasal spray device and a container.

[0011] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0012] The novel features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the present disclosure are utilized, and the accompanying drawings, in which: [Brief description of the drawings]

[0013] [Figure 1] Figure 1 shows the images of the nasal model after spraying with soft mist nasal spray device, low speed standard nasal spray device and standard nasal spray device.The liquid formulation in the spray device was tested with and without cellulose (i.e., carboxymethyl cellulose) viscosity enhancer.The soft mist nasal spray device deposited a larger amount of formulation in the olfactory region of the nasal model.

[0014] [Diagram 2] Figure 2 shows the nasal spray characteristics of three spray devices: a soft mist nasal spray device, a low rate standard nasal spray device, and a standard nasal spray device. The soft mist nasal spray device exhibited a spray distribution in which about 50% of the particles were less than about 20 μm in diameter compared to the standard nasal spray (i.e., the standard nasal spray and the low rate standard nasal spray), which had sprays containing larger particle sizes.

[0015] [Diagram 3]FIG. 3 illustrates a box graph showing the metered shot weight (delivery amount in milligrams (mg)) 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.

[0016] [Figure 4] FIG. 4 illustrates a box graph 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.

[0017] [Diagram 5] FIG. 5 illustrates box and whisker plots showing the performance of plume geometry (plume angle (deg) and plume width (mm)) at various operating speeds (1, 2, 3 millimeters per second (mm / s)) and a stroke length of 4.8 mm, at a pattern distance of 60 mm from the soft mist pump device.

[0018] [Figure 6] Figure 6 illustrates box and whisker plots showing the spray patterns (Dmax (mm), Dmin (mm), ellipticity and area (mm^2)) at various operating speeds (2 and 3 mm / s) and stroke length of 4.8 mm, at pattern distances of 30 mm and 60 mm from the soft mist pump device.

[0019] [Figure 7-1] FIG. 7 illustrates images showing spray patterns at various operating speeds (2 and 3 millimeters per second (mm / s)) and a stroke length of 4.8 mm, at pattern distances of 30 mm and 60 mm from the soft mist pump device (device 12). [Figure 7-2]FIG. 7 illustrates images showing spray patterns at various operating speeds (2 and 3 millimeters per second (mm / s)) and a stroke length of 4.8 mm, at pattern distances of 30 mm and 60 mm from the soft mist pump device (device 12).

[0020] [Figure 8] FIG. 8 illustrates box-and-whisker plots showing droplet size distribution (% volume < 10 μm; span; D90 value (μm); and D50 value (μm)) at various operating speeds (2 and 3 mm / s) and stroke lengths of 4.8 mm, and at pattern distances of 30 mm and 60 mm from the soft mist pump device.

[0021] [Figure 9] FIG. 9 illustrates box and whisker plots showing the performance of plume geometry (plume angle (deg) and plume width (mm)) at various operating speeds (1, 2, 3 millimeters per second (mm / s)) and stroke lengths of 4.6 mm and 4.8 mm at a pattern distance of 60 mm from the soft mist pump device.

[0022] [Figure 10] FIG. 10 illustrates box graphs showing the spray patterns (Dmax(mm), Dmin(mm), ellipticity and area(mm^2)) at various operating speeds (2 and 3 mm / s) and stroke lengths of 4.6 mm and 4.8 mm at a pattern distance of 30 mm from the soft mist pump device.

[0023] [Figure 11] FIG. 11 illustrates box graphs showing the spray patterns (Dmax(mm), Dmin(mm), ellipticity and area(mm^2)) at various operating speeds (2 and 3 mm / s) and stroke lengths of 4.6 mm and 4.8 mm at a pattern distance of 60 mm from the soft mist pump device.

[0024] [Figure 12]FIG. 12 illustrates box-and-whisker plots showing droplet size distribution (% volume < 10 μm; span; D90 value (μm); and D50 value (μm)) at various operating speeds (2 and 3 mm / s) and stroke lengths of 4.6 mm and 4.8 mm at a pattern distance of 30 mm from the Soft Mist Pump device.

[0025] [Figure 13] FIG. 13 illustrates box-and-whisker plots showing droplet size distribution (% volume < 10 μm; span; D90 value (μm); and D50 value (μm)) at various operating speeds (2 and 3 mm / s) and stroke lengths of 4.6 mm and 4.8 mm at a pattern distance of 60 mm from the Soft Mist pump device. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0026] Detailed Description definition Unless otherwise defined, all terms of the art, notations, and other technical and scientific terms or terminology used herein are intended to have the same meaning as commonly understood by those skilled in the art of the claimed subject matter. In some cases, terms with commonly understood meanings are defined herein for clarity and / or ease of reference, and the inclusion of such definitions herein should not necessarily be interpreted as representing a substantial difference from what is commonly understood in the art.

[0027] Throughout this application, various embodiments may be described in a range format. It should be understood that the description in range format is merely for convenience and brevity, and should not be construed as an inflexible limitation on the scope of the present disclosure. Thus, the description of a range should be considered to specifically disclose all possible subranges, as well as individual numerical values ​​within that range. For example, the description of a range such as 1-6 should be considered to specifically disclose subranges such as 1-3, 1-4, 1-5, 2-4, 2-6, 3-6, and individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0028] The singular forms "a," "an," and "the" are used herein to include plural references unless the context clearly dictates otherwise. Accordingly, unless indicated to the contrary, the numerical parameters set forth in this application are approximations that may vary depending upon the desired properties sought to be obtained.

[0029] The terms "determining," "measuring," "evaluating," "assessing," "assaying," and "analyzing" are often used interchangeably herein to refer to forms of measurement and include determining whether an element may be present (e.g., detecting). These terms can include quantitative and qualitative determinations. Assessing can alternatively be relative or absolute. "Detecting the presence of" includes determining the amount of something present, as well as determining whether it may be present or absent.

[0030] The terms "substantially" or "essentially" refer to the qualitative state of exhibiting the full or nearly full range or degree of a desired property or characteristic. In some cases, substantially refers to at least about: 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.9%, or 99.99% of the full range or degree of a desired property or characteristic. In some cases, substantially or essentially refers to an amount that can be about 100% of the total amount.

[0031] The term "at least partially" refers to the qualitative condition of exhibiting a partial range or degree of a desired property or characteristic. In some cases, at least partially refers to at least about: 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% of the full range or degree of the desired property or characteristic.

[0032] Unless otherwise indicated, open terms such as "contain," "containing," "include," "including," etc., mean inclusive.

[0033] As used herein, the term "about" or "approximately" means within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which error range depends in part on the method by which the value was measured or determined, for example, on the limitations of the measurement system. For example, "about" means plus or minus 10% per practice in the art. Alternatively, "about" means within 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 an order of magnitude, within 5-fold, or within 2-fold of a value. Where specific values ​​are described in the present application and claims, the term "about" should be assumed to mean within an acceptable error range for the particular value, unless otherwise indicated. Similarly, where ranges and / or subranges of values ​​are presented, the ranges and / or subranges can include the endpoints of the ranges and / or subranges.

[0034] As used herein, the percentage of a compound of a composition is based on the total weight or volume of the composition. In some cases, the percentage of a component of a composition is based on the total weight or volume of the composition.

[0035] The terms "administer", "administering", "administration" and the like, as used herein, refer to methods used to enable delivery of a compound or its salt or composition to a desired site of biological action. Delivery can include direct application to affect a tissue or area of ​​the body. The compositions provided herein can be administered by any method. The method of administration is by nasal spray. In some cases, the method of administration can be by inhalation, intraarterial injection, intraventricular injection, intravesicular injection, intramuscular injection, intraorbital injection, intraparenchymal injection, intraperitoneal injection, intraspinal injection, intrathecal injection, intravenous injection, intraventricular injection, stereotaxic injection, subcutaneous injection, or any combination thereof. Delivery can include parenteral administration (including intravenous, subcutaneous, intrathecal, intraperitoneal, intramuscular, intravascular or infusion), oral administration, nasal administration, inhalation administration, intraduodenal administration, rectal administration. Delivery can include topical administration (lotion, cream, gel, liquid, solid, powder, ointment, etc.) to an external surface such as the skin. In some cases, the subject administers the intranasal spray containing the compound without supervision.In some cases, the subject administers the intranasal formulation under the supervision of a medical professional (e.g., a doctor, a nurse, a medical assistant, a janitor, a hospice worker, etc.).In some cases, a medical professional administers the intranasal formulation.In some cases, a cosmetician administers the intranasal formulation.

[0036] As used herein, "treating" a chemosensory dysfunction includes one or more of the following: 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 ameliorating or repairing damage. For example, treating a chemosensory dysfunction can include increasing smell acuity and taste acuity from a patient suffering from a viral infection, such as a patient with COVID-19 or influenza, and / or causing regression or elimination of the chemosensory dysfunction.

[0037] "Therapeutically effective amount" refers to the amount of a compound or its salt, with or without additional agents, effective to achieve its intended purpose. The required amount of an individual patient may vary. In general, the dosage required to provide an effective amount of a compound, its salt, or a composition containing either or both of them will vary according to the recipient's age, health, physical condition, sex, weight, degree of dysfunction, frequency of treatment, and the nature and extent of dysfunction.

[0038] "Dosage unit" as used herein refers to the individual amount of pharmaceutical composition that is administered in a single event or package.The meaning of the term dosage unit is context specific.For example, the dosage unit for the liquid pharmaceutical composition that is administered intranasally is the volume of the composition that is administered in a single event.In the case of nasal spray, the dosage unit is the volume of the composition that is released during each actuation of the nasal spray device.

[0039] "Weight percentage" or "w / w" refers to the ratio of the weight of a specified component to the weight of the total composition (eg, dosage unit).

[0040] "Plume geometry" or "geometry" when used with respect to a plume means the measurement of the angle of the plume at its origin. Plume geometry can be measured, for example, at two distances from the origin of the plume in two side views at 90° to each other. Plume geometry can also be calculated from the spray pattern.

[0041] "Spray pattern", "plume ellipticity" or "ellipticity", when used in connection with 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.

[0042] "D 10 ", "D 50 ", "D 90 " and "span" are measurements of the droplet or particle size distribution of the plume. In a plume, 10% of the droplets are10 and 50% of the droplets have a size less than D 50 90% of the droplets have a size less than D 90 The span is calculated from these numbers using the following formula: Span = (D 90 -D 10 ) / D 50 In some cases, D 10 , D 50 Or D 90 The value can be an average or median value from multiple sprays and / or droplets.

[0043] "Total volume," when used in connection with a plume, refers to the total volume of all droplets or particles in the plume. For example, a plume having a total volume of 100 μL contains 100 μL of liquid.

[0044] The terms "subject," "host," "individual," and "patient" are used interchangeably herein to refer to an animal, typically a mammal. 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, cows, goats, sheep, pigs), and laboratory animals (e.g., mice, rats, rabbits, guinea pigs). The mammal may be of any age or at any stage of development, for example, the mammal may be a neonate, infant, adolescent, adult, or fetus (in utero). In some embodiments, the mammal is a human. The human may be greater than about: 1, 2, 5, 10, 20, 30, 40, 50, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, or about 120 years old. The human may be less than about: 1, 2, 5, 10, 20, 30, 40, 50, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, or about 120 years old. In some cases, the human may be less than about 18 years old. In some cases, the human may be about 1 month to about 12 months old, about 1 year to about 20 years old, about 15 years to about 50 years old, about 40 years to about 80 years old, or about 60 years to about 110 years old. In some cases, the human may be greater than about 18 years old. The mammal, such as a human, can be male or female. In some embodiments, the subject can have or be suspected of having a disease or condition. The subject can be a patient, such as a patient undergoing treatment for a condition or disease, such as Parkinson's disease. The subject can have a predisposition to the risk of developing a condition or disease, such as Parkinson's disease. The subject can be in remission from a condition or disease, such as a cancer patient. In some examples, the subject can be healthy.

[0045] As disclosed herein, the term "phosphodiesterase (PDE) inhibitor" refers to a compound or salt thereof that can inhibit, at least in part, the function of a phosphodiesterase (PDE) polypeptide, such as a PDE1, PDE2, PDE3, PDE4, PDE5, PDE6, PDE7, PDE8, PDE9, PDE10, PDE11 polypeptide, or any combination thereof.

[0046] As used herein, reference to PDE inhibitors, generally or specifically PDE inhibitors, includes reference to any salt, solvate, ester or polymorph of PDE inhibitor. "Salt" can include pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts can include those salts prepared by reacting the compounds disclosed herein with inorganic acid, organic acid or inorganic base, such as acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bitartrate, bromide, butyrate, butyne-1,4-diacid salt, camphorate, camphorsulfonate, caproate, caprylate, etc. Acid salts, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioxide, hydroxybenzoate, gamma-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxybenzoate, hydroxybenzoate, hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxybenzoate, hydroxybenzoate, hydrochloride, hydrobromide, hydroiodide, 2- ...bromide, hydroiodide, 2-hydroxybenzoate, hydrochloride, hydrobromide, hydrobromide, hydrobromide, hydrobromide, hydrobromide, 2-hydroxybenzoate, hydrobromide, hydrobromide, hydrobromide, hydrobromide, hydrobromide, hydrobromide, 2-hydroxybenzoate, hydrobromide, hydrobromide, hydrobromide, hydrobromide, hydrobromide hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate The salts include, but are not limited to, phenylacetate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate and xylenesulfonate.Additionally, the compounds disclosed herein can be used to dissolve the free base form of the compounds in an aqueous solution of inorganic acids, such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, as well as 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-methylsulfonic acid, 2-methylsulfonic acid, 1 ... The compounds may be prepared as pharma- ceutically acceptable salts by reacting with pharma- ceutically acceptable inorganic or organic acids, including organic acids such as 1,2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-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 sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. Other acids, such as oxalic acid, while not themselves pharma- ceutically acceptable, can be used in the preparation of salts useful as intermediates in obtaining the compounds and / or pharma-ceutically acceptable acid addition salts. In some embodiments, the compounds disclosed herein that can include free acid groups can include free acid groups that react with a suitable base, such as hydroxides, carbonates, bicarbonates, sulfates of pharmaceutically acceptable metal cations, with ammonia, or with pharmaceutically acceptable organic primary, secondary, or tertiary amines. Representative alkali or alkaline earth salts can include lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like. Examples of illustrative bases can include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(C1-4 alkyl)4, and the like. Representative organic amines useful for forming base addition salts can include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like.It can be understood that the compounds disclosed herein can also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, such quaternization can result in water-soluble or oil-soluble or dispersible products. The compounds disclosed herein can be prepared as pharmaceutically acceptable salts formed when the acidic protons present in the parent compound can be replaced by metal ions, such as alkali metal ions, alkaline earth ions or aluminum ions, or coordinated to organic bases. In some embodiments, base addition salts can also be prepared by reacting the compounds disclosed herein in free acid form with pharmaceutically acceptable inorganic or organic bases, including but not limited to organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and inorganic bases such as aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. In addition, salt forms of the disclosed compounds can be prepared using salts of starting materials or intermediates.

[0047] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0048] Overview Disclosed herein are methods, compositions, kits and devices for treating Parkinson's disease with phosphodiesterase inhibitors and other treatments for Parkinson's disease.In some embodiments, the method of treatment can include administering to a subject a phosphodiesterase (PDE) inhibitor, its salt or a combination of PDE inhibitors or their salts by nasal spray device.In some embodiments, the method of treatment can include administering to a subject levodopa, carbidopa, entacapone, tolcapone, opicapone, pramipexole, ropinirole, apomorphine, rotigotine, selegiline, rasagiline, safinamide, amantadine, istradefylline, trihexyphenidyl, benztropine, benserazide, any salt thereof or any combination thereof by nasal spray device.

[0049] The nasal spray device can release the dosage unit in a plume upon actuation. In some embodiments, the nasal spray device has a D of about 20 μm. 50 In some cases, the PDE inhibitor or the therapeutic agent for Parkinson's disease can be administered as an intranasal formulation.In some cases, the PDE inhibitor inhibits PDE polypeptide and can include theophylline or its salt, cilostazol or its salt, roflumilast or its salt, ibudilast or its salt, rolipram or its salt, papaverine or its salt, or any combination thereof.

[0050] Therapeutic Agents Phosphodiesterase (PDE) Polypeptides and Inhibitors Disclosed herein is a PDE inhibitor for treating diseases such as Parkinson's disease.PDE inhibitor can be selective or non-selective for various phosphodiesterase enzymes.Compositions disclosed herein, such as nasal sprays, include phosphodiesterase inhibitors or their salts and are administered to subjects in need thereof.In some cases, the nasal spray device described herein can administer the PDE inhibitor for Parkinson's disease or another neurological disease.

[0051] PDE1 (type 1 phosphodiesterase) is an enzyme known as calcium and calmodulin-dependent phosphodiesterase. Various tissues, such as the heart, lungs, and brain, express PDE1. PDE1 can hydrolyze both ribonucleotides and deoxyribonucleotides. PDE1 enzymes can break down both cGMP and cAMP. PDE1 enzymes can play a role in smooth muscle proliferation and cell signaling pathways.

[0052] PDE2 polypeptide can reduce aldosterone secretion. Such reduction can play an important role in regulating the improvement of intracellular concentrations of cAMP and cGMP in platelets. Some areas of the brain can express PDE2, and rat experiments have shown that inhibition of PDE2 can enhance memory. Since PDE2 can be localized in microvessels, especially venous capillaries and endothelial cells, PDE2 can play a role in regulating fluid and cell leakage during inflammatory conditions. PDE2 can 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.

[0053] The PDE3 family hydrolyzes cAMP and cGMP, but in a way suggests that the hydrolysis of cAMP in vivo may be inhibited by cGMP. The PDE3 family may be distinguished by its ability to be activated by several phosphorylation pathways, including the PKA and PI3K / PKB pathways. PDE3A may be relatively highly expressed in platelets, as well as in cardiac myocytes 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 may be highly expressed in vascular smooth muscle cells, likely modulating contraction. PDE4 polypeptides may regulate the production of pro- and anti-inflammatory cytokines, as well as cell proliferation, through the degradation of cAMP. PDE5 may be a regulator of vascular smooth muscle contraction, best known as the molecular target for several highly promoted drugs used to treat erectile dysfunction and pulmonary hypertension. In the lung, inhibition of PDE5 can interfere with smooth muscle vasoconstriction, and PDE5 inhibitors are in clinical trials for the treatment of pulmonary hypertension.

[0054] Examples of PDE inhibitors are, for example, filaminast, piclamilast, rolipram, Org20241, MCI-154, roflumilast, toborinone, posicar, lixazinone, zaprinast, sildenafil, pyrazolopyrimidinone, motapizone, pimobendan, zardaverine, siguazodan, CI-930, EMD53998, imazodan, saterinone, loprinone hydrochloride, 3-pyridinecarbonitrile derivatives, denbufyllene, albifyline, torbafylline, doxofylline, theophylline, pentoxofylline, In some embodiments, the PDE inhibitor for the treatment of Parkinson's disease can include theophylline, ibudilast, rolipram, roflumilast, papaverine, any salt thereof, or any combination thereof.

[0055] PDE inhibitor can be selective PDE inhibitor or non-specific PDE inhibitor.PDE selective inhibitor can include PDE1 selective inhibitor, PDE2 selective inhibitor, PDE3 selective inhibitor, PDE4 selective inhibitor, PDE5 selective inhibitor, PDE6 selective inhibitor, PDE7 selective inhibitor, PDE8 selective inhibitor, PDE9 selective inhibitor, PDE10 selective inhibitor or PDE11 selective inhibitor.In some cases, selective PDE inhibitor can be specific to more than one of PDE1, PDE2, PDE3, PDE4, PDE5, PDE6, PDE7, PDE8, PDE9, PDE10 and PDE11. Non-specific PDEs can include PDE inhibitors that inhibit at least two, three, four or five, or more of PDE1, PDE2, PDE3, PDE4, PDE, PDE6, PDE7, PDE8, PDE9, PDE10, and PDE11.

[0056] 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 vasorelaxation or vasodilation in all blood vessels, including peripheral blood vessels (inhibiting intermittent claudication), distal limbs, and penile region that contributes to penile erection.

[0057] Nonspecific PDE inhibitors can include theophylline, papaverine, caffeine, IBMX (3-isobutyl-1-methylxanthine, aminophylline, doxofylline, cipamphylline, theobromine, pentoxifylline (oxypentifylline), diprophylline, or a salt of any of these. Theophylline is a methylxanthine derivative that can be used to treat chemosensory dysfunction when administered as described herein. In some cases, an anti-inflammatory effect can be achieved when theophylline is prescribed or administered at a level that results in systemic levels of theophylline in the blood that are well below levels that cause side effects. Patients with emphysema and chronic bronchitis can also be relieved by theophylline when their symptoms are partially related to reversible airway narrowing.

[0058] The PDE1 selective inhibitor previously known as calcium and calmodulin-dependent phosphodiesterase can include eburnamenine-14-carboxylic acid ethyl ester (vinpocetine).In some cases, vinpocetine can be used to induce vasorelaxtion to brain smooth muscle tissue.In some cases, the PDE1 selective inhibitor can include IC86340, amiodarone, lisinopril, 8-methoxymethyl-IBMX, any salt thereof, or any combination thereof.In some cases, the PDE1 selective inhibitor can include vinpocetine or its salt.

[0059] PDE2 selective inhibitors can include EHNA (erythro-9-(2-hydroxy-3-nonyl)adenine), 9-(6-phenyl-2-oxohex-3-yl)-2-(3,4-dimethoxybenzyl)-purin-6-one (PDP), BAY60-7750, or a salt of any of these.

[0060] PDE3 selective inhibitors can include enoximone, milrinone (Primacor), amrinone, cilostamide, cilostazol (Pletal), trequinsin, or any salt thereof. PDE3 inhibitors, when administered as described herein, can produce sympathetic stimulation to increase myocardial inotropy, chronotropy, and dromotropy. PDE3 inhibitors, when administered as described herein, can also antagonize platelet aggregation, increase myocardial contractility, and increase relaxation of vascular and airway smooth muscle. PDE3A can be a regulator of this process. PDE3 inhibitors, when administered as described herein, can effectively prevent aggregation. Cilastazol (Pletal) is approved for the treatment of intermittent claudication. Its mechanism of action includes inhibition of platelet aggregation accompanied by inhibition of smooth muscle proliferation and vasodilation.

[0061] PDE4 selective inhibitors can include mesembrine, rolipram, ibudilast (i.e., neuroprotectant and bronchodilator, which can be used in the treatment of asthma and stroke) and roflumilast (Daxas), cilomilast (Airflo) or any salt thereof.In some cases, PDE4 selective inhibitors can be administered for the treatment of chronic obstructive pulmonary disease.PDE4 selective inhibitors can 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 can also be used to treat asthma, arthritis and psoriasis.

[0062] PDE5 selective inhibitors can include sildenafil, tadalafil, vardenafil, udenafil, avanafil, and salts thereof.

[0063] Additional Therapeutic Agents In some embodiments, the compositions herein can include a treatment for Parkinson's disease. In some cases, the treatment for Parkinson's disease can be administered by a spray device described herein. In some cases, treatment for Parkinson's disease or another neurological disorder can include amantadine, apomorphine, benserazide, androgolide, altinicline, benztropine, biperiden, brasofensine, bromocriptine, budipine, cabergoline, dihydrexidine, entacapone, etilevodopa, idazoxan, istradefylline, iometopane, lazabemide, merevodopa, levodopa, carbidopa, carbidopa / levodopa, mofegiline, opicapone, moxilaprine, pergolide, pramipexole, quinelorane, rasagiline, ropinirole, rotigotine, selegiline, safinamide, talipexole, tolcapone, trihexyphenidyl, any salt thereof, or any combination thereof.

[0064] In some embodiments, the treatment of the disease herein can include levodopa. In some cases, levodopa can include co-beneldopa, co-careldopa, any salt thereof, or any combination thereof. In some embodiments, the treatment of the disease herein can include a dopamine agonist. In some cases, the dopamine agonist can include pramipexole, ropinirole, rotigotine, apomorphine, any salt thereof, or any combination thereof. In some embodiments, the treatment of the disease herein can include an MAO-B inhibitor. In some cases, the MAO-B inhibitor can include rasagiline, selegiline, safinamide, any salt thereof, or any combination thereof. In some embodiments, the treatment of the disease herein can include a COMT inhibitor. In some cases, the COMT inhibitor can include entacapone, co-careldopa and entacapone, opicapone, any salt thereof, or any combination thereof. In some embodiments, the treatment of the disease herein can include amantadine or a salt thereof. In some embodiments, the treatment of the disease herein can include an anticholinergic agent or a salt thereof. In some cases, the anticholinergic agent can include procyclidine, trihexyphenidyl, benzhexol, any salt thereof, or any combination thereof.

[0065] In some embodiments, the compositions herein can include treatments for neurological diseases. In some cases, the neurological diseases can include Alzheimer's disease, amyotrophic lateral sclerosis (ALS), dementia, Huntington's disease, Huntington's disease-like syndrome (HD-like syndrome), or any combination thereof. In some cases, the treatments for diseases herein can include aducanumab, cholinesterase inhibitors, glutamate modulators, orexin receptor antagonists, or any combination thereof. In some cases, the cholinesterase inhibitors can include donepezil, rivastigmine, galantamine, tacrine, any salt thereof, or any combination thereof. In some cases, the glutamate modulators can include memantine or a salt thereof. In some cases, the orexin receptor antagonists can include suvorexant or a salt thereof. In some embodiments, the treatments for diseases herein can include riluzole, edaravone, sodium phenylbutyrate, taurursodiol, any salt thereof, or any combination thereof. In some cases, the treatment of the disease herein may include tetrabenazine, amantadine, any salt thereof, or any combination thereof.

[0066] In some embodiments, the composition can include luteolin, its salts or derivatives thereof. In some cases, the composition can include palmitoylethanolamide, its derivatives or salts thereof. In some cases, the composition can include 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 can constitute the active agent in a composition, such as a pharmaceutical composition. In some cases, palmitoylethanolamide, its derivatives or salts thereof, luteolin, its derivatives or salts thereof can be mixed with a PDE inhibitor or salts thereof. In some cases, palmitoylethanolamide, its derivatives or salts thereof, luteolin, its derivatives or salts thereof, or any combination thereof can be administered by a spray device. In some cases, the PDE inhibitor can include theophylline or salts thereof. In some cases, palmitoylethanolamide, its derivatives or salts thereof, and luteolin, its derivatives or salts thereof can be mixed with a PDE inhibitor or salts thereof. In some cases, palmitoylethanolamide, its derivative or its salt, and / or luteolin, its derivative or its salt can be used to treat chemosensory dysfunction.In some cases, palmitoylethanolamide, its derivative or its salt, luteolin, its derivative or its salt, PDE inhibitor or its salt can be present independently in a therapeutically effective amount to treat chemosensory dysfunction.In some cases, PDE inhibitor or its salt can be administered intranasally, and palmitoylethanolamide, its derivative or its salt, luteolin, its derivative or its salt or any combination thereof can be administered orally, for example, in the form of pill, liquid, capsule or tablet.

[0067] In some embodiments, representative dosages of palmitoylethanolamide, its derivatives, salts thereof, luteolin, its derivatives, or salts thereof can be about 1.0 μg to 2000 mg per day, about 1.0 μg to 500.0 mg per day, about 10 μg to 100.0 mg per day, about 10 μg to about 10 mg per day, about 10 μg to 1.0 mg per day, about 10 μg to 500 μg per day, about 20 μg to about 2000 μg per day, about 100 μg to about 10,000 μg per day, or about 1 μg to 50 μg per day. These dosage ranges represent the total dosage of active ingredient per day for a given patient. In some embodiments, the dose administered per day can be less than or equal to about: 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 dose administered per day can be at least about: 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, on a per kilogram basis, suitable dosage levels of the compound can be from about 0.001 μg / kg to about 10.0 mg / kg of body weight per day, from about 0.5 μg / kg to about 0.5 mg / kg of body weight per day, from about 1.0 μg / kg to about 100 μg / kg of body weight per day, and from about 2.0 μg / kg to about 50 μg / kg of body weight per day.

[0068] Compositions and Formulations In some embodiments, the compositions or formulations described herein can include an active ingredient, a carrier, an excipient, a viscosity enhancer, a diluent, a preservative, an enzyme modulator, a vasoconstrictor, a mucoadhesive, a moisturizer, or any combination thereof. In some cases, the carrier, the excipient, the viscosity enhancer, the diluent, the preservative, the moisturizer, the enzyme modulator, the vasoconstrictor, or the mucoadhesive can be of a pharmaceutically acceptable type. In some cases, the compositions or formulations described herein can be liquid. In some cases, the active ingredient can include a PDE inhibitor described herein. For example, the PDE inhibitor can include theophylline, ibudilast, rolipram, roflumilast, papaverine, any salt thereof, or any combination thereof. In some cases, the carrier can include water. In some cases, the viscosity enhancer can include cellulose. In some cases, the excipient can include glycerol. In some cases, the compositions or formulations described herein can be delivered by a nasal spray device. In some cases, the compositions herein can be sterile. In some cases, the compositions herein can be aseptic.

[0069] In some cases, the formulation or composition can include an active agent, such as a PDE inhibitor. In some cases, the composition or formulation can include the active agent in an amount greater than about: 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% (weight / weight) of the total composition. In some cases, the compositions or formulations may contain the active agent in an amount less than about: 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% (weight / weight) of the total composition. In some cases, the composition or formulation may contain the active agent in an amount of about: 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% (w / w) of the total composition. In some cases, the composition or formulation may contain the active agent in an amount of about 0.01% to about 10% (w / w) of the total composition. In some cases, the composition or formulation can include one active agent. In some cases, the composition or formulation can include more than one active agent, for example, the composition can include two, three, four, five or more active agents.

[0070] In some embodiments, the composition or formulation can include an excipient. The excipient can include, but is not limited to, water, a flow agent, a lubricant, an adhesive, a surfactant, an acidifying agent, an alkalizing agent, a pH adjusting agent, an antimicrobial preservative, an antioxidant, an antistatic agent, a buffering agent, a chelating agent, a moisturizing agent, or a humectant. The excipient can also include a coloring agent, a coating agent, a sweetening agent, a flavoring and fragrance agent, or a masking agent. The composition and formulation can include a therapeutic agent, including an individual excipient, or including multiple excipients, optionally combined in any suitable combination, with or without a carrier. In some cases, the excipient can include glycerol.

[0071] In some cases, the pharma- ceutically acceptable excipient may be acacia, acesulfame potassium, glacial acetic acid, acetone, tributyl acetyl citrate, triethyl acetyl citrate, agar, albumin, alcohol, alginic acid, aliphatic polyesters, 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, bentonite, or the like. Ingredients: benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, benzyl benzoate, boric acid, bronopol, butylated hydroxyanisole, butylated hydroxytoluene, butylparaben, calcium alginate, calcium carbonate, dibasic calcium phosphate anhydrous, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, calcium stearate, calcium sulfate, canola oil, carbomer, carbon dioxide, calcium carboxymethylcellulose, sodium carboxymethylcellulose, carrageenan, castor oil, hydrogenated Ingredients include: silicified 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, chlorofluorocarbons, chloroxylenol, cholesterol, citric acid monohydrate, colloidal silicon dioxide, colorants, copovidone, corn oil, cottonseed oil, cresol, croscarmellose sodium, crospovidone, cyclodex Trimethicone, cyclomethicone, denatonium benzoate, dextrate, dextrin, dextrose, dibutyl phthalate, dibutyl sebacate, diethanolamine, diethyl phthalate, difluoroethane, dimethicone, dimethyl ether, dimethyl phthalate, dimethyl sulfoxide, dimethylacetamide, edetate disodium, docusate sodium, edetic acid, erythorbic acid, erythritol, ethyl acetate, ethyl lactate, ethyl maltol, ethyl oleate, ethyl vanillin, ethyl cellulose, ethylene glycol palmitostearate,Ethylene Vinyl Acetate, Ethyl Paraben, Fructose, Fumaric Acid, Gelatin, Glucose, Glycerin, Glyceryl Behenate, Glyceryl Monooleate, Glyceryl Monostearate, Glyceryl Palmitostearate, Glycofurol, Guar Gum, Hectorite, Heptafluoropropane, Hexetidine, Hydrocarbons, Hydrochloric Acid, Hydroxyethyl Cellulose, Hydroxyethylmethylcellulose, Hydroxypropyl Cellulose, Hydroxypropylcellulose, Low-Substituted Hydroxypropyl Starch, Hypromellose, Hypromellose Acetate Succinate, Hypromellose Phthalate, Honey, Imidurea, Inulin, Iron Oxides, Isomalt, Isopropyl Alcohol, Myristyl Isopropyl phosphate, isopropyl palmitate, kaolin, lactic acid, lactitol, lactose anhydrous, lactose monohydrate, spray dried lactose, lanolin, lanolin alcohol, hydrous lanolin, lauric acid, lecithin, leucine, linoleic acid, macrogol hydroxystearate, magnesium aluminum 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, nitrous oxide, octyldodecanol, oleic acid, oleyl alcohol, olive oil, palmitic acid, paraffin, peanut oil, pectin, petrolatum, petrolatum alcohol and lanolin alcohol, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, phosphoric acid, polacrilin potassium, poloxamer, polycarbophil, polydextrose, polyethylene glycol, polyethylene oxide, polymethacrylate, poly(methyl vinyl ether / maleic anhydride), polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters,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 dihydrate, sodium cyclamate, 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 esters (sorbitan fatty acid esters), sorbitol, soybean oil, starch, starch (e.g., pregelatinized, sterilizable corn), stearic acid, stearyl alcohol, sucralose, sucrose, compressible sugar, sugar, powdered sugar, sugar spheres, sulfobutyl ether b-cyclodextrin, sulfuric acid, sunflower oil, suppository base, hard fat fat), talc, tartaric acid, tetrafluoroethane, thaumatin, thimerosal, thymol, titanium dioxide, tragacanth, trehalose, triacetin, tributyl citrate, triethanolamine, triethyl citrate, vanillin, hydrogenated vegetable oils, water, anionic emulsifying wax, wax (e.g., carnauba, cetyl esters, microcrystalline, nonionic emulsifying, white, yellow), xanthan gum, xylitol, zein, zinc acetate, zinc stearate, or any combination thereof.

[0072] In some embodiments, the composition or formulation can include a viscosity improver. In some examples, the viscosity improver can include cellulose. In some cases, the viscosity improver can include 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 can include cellulose acetate, cellulose triacetate, cellulose propionate, cellulose acetate propionate, cellulose acetate butyrate, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose (HPC), hydroxyethylmethylcellulose, ethylhydroxyethylcellulose, hydroxypropylmethylcellulose, or a combination thereof. In some cases, the composition or formulation may contain a viscosity enhancer 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%, 5%, 6%, 7%, 8%, 9% or 10% (w / w) of the total composition. In some cases, the composition or formulation may contain a viscosity enhancer in an amount of about 0.01% to about 10% (w / w) of the total composition. In some cases, the composition or formulation may contain one viscosity enhancer. In some cases, the composition or formulation may contain more than one viscosity enhancer, for example, the composition may contain two, three, four, five or more viscosity enhancers.

[0073] In some cases, the viscosity of the intranasal dosage unit may affect the residence time in the nasal cavity. In some embodiments, the dosage unit has a kinematic viscosity higher than that of water at the same temperature. In some embodiments, the dosage unit may have a kinematic viscosity of 0.5 cSt to 3 cSt at 20° C. For example, the dosage unit may 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, 0.9 to 2 ... St, 0.9-1.5 cSt, 0.9-1.25 cSt, 0.9-1.1 cSt, 0.9-1 cSt, 1-2 cSt, 1-1.5 cSt, 1-1.25 cSt, 1-1.1 cSt, 1.1-2 cSt, 1.1-1.5 cSt, 1.1-1.25 cSt, 1.25-2 cSt, 1.25-1.5 cSt, 1.5-2 cSt, or 2-3 cSt. In some embodiments, the dosage unit has a kinematic viscosity of 0.9-1.25 cSt at 20° C. In some embodiments, the dosage unit has a kinematic viscosity higher than that of water at the same temperature.

[0074] 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, carriers for compositions or formulations include, but are not limited to, amino acids, peptides, proteins, non-biological polymers, biopolymers, simple sugars, carbohydrates, gums, inorganic salts, and metal compounds, which may be present alone or in combination. In some embodiments, the pharma- ceutically acceptable carrier may include natural forms, derivatized forms, modified forms, or combinations thereof. In some cases, the protein may include, but is not limited to, gelatin or albumin. In some embodiments, sugars that may serve as carriers include, but are not limited to, fructose, galactose, glucose, lactitol, lactose, maltitol, maltose, mannitol, melezitose, myo-inositol, palatinite, raffinose, stachyose, sucrose, trehalose, xylitol, hydrates thereof, and combinations thereof. In some cases, carbohydrates that can serve as carriers include starches, such as, but not limited to, corn starch, potato starch, amylose, amylopectin, pectin, hydroxypropyl starch, carboxymethyl starch, and crosslinked starches. In other embodiments, useful carbohydrates that can serve as pharma- ceutically acceptable carriers include, but are not limited to, cellulose, crystalline cellulose, microcrystalline cellulose, α-cellulose, methylcellulose, hydroxypropylcellulose, carboxymethylcellulose, ethylcellulose, hydroxypropylmethylcellulose, and cellulose acetate.In some cases, the composition or formulation may comprise 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% of the total composition. , 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, the composition or formulation may include a carrier in an amount of about 60% to about 99.9% (w / w) of the total composition. In some cases, the composition or formulation may include one type of carrier. In some cases, the composition or formulation may include more than one type of carrier, for example, the composition may include two, three, four, five or more types of carriers. In some cases, the carrier may include a non-aqueous carrier. In some cases, the non-aqueous carrier may include a solvent, an excipient, a vehicle, a permeation enhancer (also known as a penetration enhancer), or a mixture thereof.

[0075] In some cases, the compositions 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 required, and 2) the drug load in the formulation may be potentially higher since the solubility of PDE inhibitors such as theophylline in various non-aqueous excipients / vehicles is potentially higher (e.g., the solubility of theophylline in water is about 7-8 mg / mL, while in ethanol it is 14-15 mg / mL).

[0076] In some embodiments, the excipient, vehicle (e.g., carrier) or both for non-aqueous formulations (instead of water) can include alkylene glycol, such as propylene glycol, butylene glycol, or any combination thereof. In some cases, the excipient, vehicle (e.g., carrier) or both for non-aqueous formulations can include dialkylene glycol (e.g., dipropylene glycol). In some cases, the excipient, vehicle (e.g., carrier) or both for non-aqueous formulations can include polyethylene glycol (PEG) (e.g., PEG400, PEG600, or any combination thereof). In some cases, the excipient, vehicle (e.g., carrier) or both for non-aqueous formulations can include unsaturated fatty alcohols, such as palmitoleic alcohol, oleyl alcohol, erucyl alcohol, or any combination thereof. In some cases, the excipient, vehicle (e.g., carrier) or both for non-aqueous formulations can include DMSO, Transcutol P (diethylene glycol monoethyl ether), ethanol, acetone, or any combination thereof.

[0077] In some embodiments, the composition or formulation can include a diluent. In some cases, the diluent can include an excipient. In some cases, the diluent can include water, saline, a buffer, a sugar, a binder, a disintegrant, or any combination thereof.

[0078] In some embodiments, the composition or formulation may include a preservative. In some cases, the preservative may include alcohol. In some cases, the preservative may include phenylethyl alcohol. In some cases, the preservative may include methylparaben, propylparaben, benzalkonium chloride, phenylcarbinol, potassium sorbate, or a combination thereof. In some cases, the compositions disclosed herein may be free of preservatives. In some cases, the composition or formulation may include 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% (w / w) of the total composition. In some cases, the composition or formulation may include a preservative in an amount of about 0.01% to about 10% (w / w) of the total composition. In some cases, the composition or formulation can include one preservative. In some cases, the composition or formulation can include more than one preservative, for example, the composition can include two, three, four, five or more preservatives.

[0079] In some embodiments, the composition or formulation can include a buffering agent.In some cases, the buffering agent can include potassium phosphate, sodium acetate, sodium citrate, sodium phosphate, trisodium citrate, or a combination thereof.In some cases, the composition or formulation can include a pH adjusting agent, such as acetic acid, citric acid, hydrochloric acid, sodium hydroxide, sulfuric acid, or a combination thereof.

[0080] 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 dosage unit can be 7.1 to 8.5. In some embodiments, the pH of the dosage unit can be 7.1 to 7.4. In some embodiments, the pH of the dosage 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 dosage 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.

[0081] In some embodiments, the composition or formulation can include glycerol. In some cases, the composition or formulation can include flavoring 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 can include a fluorescent agent (e.g., a fluorophore). The fluorescent agent can be used for nose cast scanning. Some examples of fluorescent agents include alexa fluor350, alexa fluor405, alexa fluor488, alexa fluor532, alexa fluor546, alexa fluor555, alexa fluor561, alexa fluor568, alexa fluor594, alexa fluor647, alexa fluor660, alexa fluor680, alexa fluor700, alexa fluor750, bodipy fl, coumarin, cy3, cy5, fluorescein (FITC), oregon green, pacific blue, pacific green, pacific orange, pe-cyanine 7, percp-cyanine 5.5, tetramethylrhodamine (TRITC), texas 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.

[0082] In some embodiments, the composition or formulation can include a moisturizer. In some cases, the moisturizer can 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.

[0083] 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 can be stored in a container. For example, a container containing a pharmaceutical composition of a spray device. In some cases, the container is glass, plastic, metal, or any solid material. In some cases, the container is included in a kit. In some examples, when a sealed container containing a composition 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 composition can retain about: 40%, 50%, 60%, 70%, 80%, 90% or more than 99% of the active ingredient or a salt thereof after 3 months, 6 months, or 12 months as measured by high performance liquid chromatography (HPLC).

[0084] In some embodiments, the compositions or formulations described herein may include a penetration enhancer. In some cases, the penetration enhancer may be a substance capable of promoting the penetration of a drug into the skin, mucous membrane, nerve sheath, 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 the drug and excipients, odorless, tasteless, colorless, or a combination thereof. In some cases, the penetration enhancer may be a fatty acid, an alcohol, a surfactant, a solvent, a hydrogen bond acceptor, or any combination thereof. In some cases, the penetration enhancer can include azonem (1-dodecylazacycloheptan-2-one), dimethylsulfoxide, dimethylacetamide, dimethylformamide, ethanol, propylene glycol, N-methylpyrrolidone, oleic acid, lauryl alcohol, ketone terpene, terpene, sulfoxide, alkanol, organic acid, alcohol, polyol, pyrrolidone, glycol, urea and urea derivatives, enzyme, iminosulfuran, cyclodextrin, fatty acid ester, surfactant, polymer, monoolein, oxalidinone, or any combination thereof. In some cases, the penetration enhancer can include cyclodextrin, sodium hyaluronate, cremophor RH40, chitosan, cyclopentyladenosine, dextran, or any combination thereof. In some cases, the formulations herein can include enzyme modulators.

[0085] In some embodiments, the composition or formulation may include a penetration enhancer in an amount of about 0.1% to about 20% (weight to weight) (w / w) of the total composition. In some cases, the composition or formulation may include 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% (w / w) of the total composition. In some cases, the composition or formulation may include 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% (w / w) of the total composition. In some cases, a composition or formulation can include one penetration enhancer. In some cases, a composition or formulation can include more than one penetration enhancer, for example, a composition or formulation can include two, three, four, five or more different penetration enhancers.

[0086] In some cases, the enzyme modulator can include a p-glycoprotein inhibitor, a CYP450 inhibitor, an acetazolamide inhibitor, or any combination thereof. In some cases, the formulations herein can include a vasoconstrictor. In some cases, the vasoconstrictor can include phenylephrine or a salt thereof. In some cases, the formulations herein can include a mucoadhesive. In some cases, the mucoadhesive can include chitosan, a derivative of chitosan, carboxymethylcellulose, polyacrylic acid, or any combination thereof. In some cases, the formulations herein can include a ciliostatic. In some cases, the ciliostatic can include chlorbutol, hydroxybenzoate, chlorocresol edetate, phenylmercuric acetate, thiomersal, any salt thereof, or any combination thereof.

[0087] Nasal spray device Disclosed herein is a device for administering an active ingredient for treating chemosensory dysfunction in a subject, such as a human. In some embodiments, the device can be used to administer a nasal spray to a subject in need thereof. In some embodiments, the device administers a plume of droplets upon operation. In some cases, the plume of droplets can include a dosage unit. For example, a pharmaceutical dosage unit can be administered by the device described herein. In some examples, the droplets can be referred to as particles. The plume can deliver the droplets to the nasal cavity upon operation. In some embodiments, the spray can be configured to deposit the droplets in the olfactory portion of the nasal cavity. The spray device disclosed herein can emit particles of about 10 μm to about 20 μm in size.

[0088] In some embodiments, the nasal spray device delivers a plume as a unit dose upon actuation. In some cases, the nasal spray device includes about 60 to about 120 unit doses. In some cases, the nasal spray device includes 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, or about 100 to about 240 unit doses. In some cases, each unit dose can include about 20 μg to about 4000 μg of a PDE inhibitor, a salt thereof, or any active ingredient disclosed herein. In some embodiments, the liquid pharmaceutical composition can be administered in the form of a plume from actuation of the device.

[0089] In some embodiments, the nasal spray device can include a spray nozzle. In some examples, the spray nozzle can be configured to generate a plume. In some examples, the nasal spray device can include one spray nozzle. In some examples, the nasal spray device can include multiple spray nozzles to generate a plume, for example, the spray device can include two, three, four, five, six, seven, eight, nine, ten, twenty, thirty, forty, fifty or more nozzles to generate a plume. In some cases, the spray nozzle can vary 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 coverage of the drug in the nasal cavity. In some examples, the droplet size range can increase or decrease the amount of drug in an area of ​​the nasal cavity. For example, a droplet size range can be obtained that deposits a majority of the drug in the olfactory portion of the nasal cavity. In some embodiments, the nasal spray device can include one or more dosage units. In some cases, the nasal spray device can include a reservoir having multiple dosage units. In some embodiments, the spray device includes a D 10 , D 50 , D 90 and span measurements. In some cases, the droplet or particle size (e.g., D 10 , D 50 Or D 90 The measured value of (p) can be determined by a laser diffraction system, e.g., the Malvern Spraytec system.

[0090] In some embodiments, the spray device can include one or more nozzle holes. In some cases, the spray device can include a nozzle hole size of about: 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 can include a nozzle hole size of 3 μm. In some cases, the spray device can include a nozzle hole size of 4 μm. In some cases, the spray device can include a nozzle hole size of 5 μm. In some cases, the spray device can include about: 10 to about 200 nozzle holes, 10 to about 100 nozzle holes, 10 to about 60 nozzle holes, 20 to about 80 nozzle holes, 30 to about 100 nozzle holes, 40 to about 70 nozzle holes, 45 to about 65 nozzle holes, or 48 holes to about 60 nozzle holes. In some cases, the spray device can have about: 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, the spray device can have 60 nozzle holes. In some cases, the spray device can have 48 holes. In some cases, the spray device can have a cone angle for dispensing the spray at a given angle. In some cases, the cone angle of the spray device can be about: 10° to about 80°, 10° to about 60°, 10° to about 40°, 10° to about 30°, 15° to about 25°, or 20° to about 40°.In some cases, the cone angle of the spray device is 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°, 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°.

[0091] In one example, the spray device can have 60 nozzle holes with a size of 4 μm per hole with a cone angle of 20°. In another example, the spray device can have 48 nozzle holes with a size of 5 μm per hole with a cone angle of 20°. In another example, the spray device can have 60 nozzle holes with a size of 5 μm per hole with a cone angle of 20°. In another example, the spray device can have 48 nozzle holes with a size of 4 μm per hole with a cone angle of 20°.

[0092] In some embodiments, a dosage unit of a volume can be about 25 μL to about 2000 μL. In some embodiments, the spray device herein can include a single dosage unit or can include a multiple dosage unit. For example, the spray device described herein can be a multiple dose spray unit. In some cases, the operation of the spray device can dispense a dosage unit of a volume. In some cases, a dosage unit of a volume can be about 50 μL to about 400 μL. In some cases, a dosage unit of a volume can be about: 20 μL to about 80 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 some cases, a dosage unit of a volume may be about: 20 μL, 21 μL, 22 μL, 23 μL, 24 μL, 25 μL, 26 μL, 27 μL, 28 μL, 29 μL, 30 μL, 31 μL, 32 μL, 33 μL, 34 μL, 35 μL, 36 μL, 37 μL, 38 μL, 39 μL, 40 μL, 41 μL, 42 μL, 43 μL, 44 μL, 45 μL, 46 μL, 47 μL, 48 μL, 49 μL, 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, 80 μL, 81 μL, 82 μL, 83 μL, 84 μL, 85 μL, 86 μL, 87 μL, 88 μL, 89 μL, 90 μL, 91 μL, 92 μL, 93 μL, 94 μL, 95 μL, 96 μL, 97 μL, 98 μL, 99 μL, 100 μL, 101 μL, 10 L, 60μL, 61μL, 62μL, 63μL, 64μL, 65μL, 66μL, 67μL, 68μL, 69μL, 70μL, 71μL, 72μL, 73μL, 74μL, 75μL, 76μL, 77μL, 78μL, 79μL, 80μL, 81μL L, 82 μL, 83 μL, 84 μL, 85 μL, 86 μL, 87 μL, 88 μL, 89 μL, 90 μL, 91 μL, 92 μL, 93 μL, 94 μL, 95 μL, 96 μL, 97 μL, 98 μL, 99 μL, or 100 μL.In some cases, dosage units of a volume are about: 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, 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. In some cases, a dosage unit of a volume can be about: 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.

[0093] In some embodiments, the dosage unit has the following: (a) less than about 3% of the droplets in the plume have a size of less than about 10 μm; (b) a D of less than about 15 μm; 10 and about 10% of the droplets in the plume are D 10 (c) having a size of less than about 15 to about 24 μm D 50 and about 50% of the droplets in the plume are D 50 (d) having a size of about 30 μm to about 50 μm D 90 and about 90% of the droplets in the plume are D 90 and (e) a span of about 1 to about 4, the span being (D 90 -D 10 ) / D 50 The plume may be in the form of a plume having a droplet size distribution characterized by one or more of:

[0094] In some embodiments, the dosage unit satisfies the following: (a) less than about 1.5% of the droplets in the plume have a size of less than about 10 μm; (b) a D of less than about 20 μm; 10 and about 10% of the droplets in the plume are D 10 (c) having a size of less than about 23 μm to about 30 μm D 50 and about 50% of the droplets in the plume are D 50 (d) having a size of about 38 μm to about 48 μm D 90 and about 90% of the droplets in the plume are D 90 and (e) a span of about 0.9 to about 1.4, said span being (D 90 -D 10 ) / D 50 The plume may be in the form of a plume having a droplet size distribution characterized by one or more of:

[0095] In some embodiments, the plume may be characterized by less than about 4% of the droplets in the plume having a size 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 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 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 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 less than about 10 μm. In some embodiments, the plume droplets may be measured from the total amount of droplets in the plume. In some embodiments, the plume droplets may be measured from the total volume of droplets in the plume.

[0096] In some embodiments, the plume may be characterized by less than about 3% of the droplets in the plume having a size 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 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 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 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 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 may be measured from the total amount of droplets in the plume. In some embodiments, the plume droplets may be measured from the total volume of droplets in the plume.

[0097] In some embodiments, D 10 In the plume, D 10 In some embodiments, the plume comprises about 10% of droplets having a size of less than about 20 μm. 10 In some embodiments, the plume may be characterized by a D 10 In some cases, the plume may be characterized by a diameter D that may be about 10 μm to about 20 μm. 10 In some cases, the plume may be characterized by a diameter D that may be about 8 μm to about 15 μm. 10 In some cases, the plume may be characterized by a diameter D that may be about 12 μm to about 19 μm. 10 In some cases, the plume may be characterized as about: 8 μm, 9 μm, 10 μm, 11 μm, 12 μm, 13 μm, 14 μm, 15 μm, 16 μm, 17 μm, 18 μm, 19 μm, or 20 μm. 10In some cases, the plume may be greater than about: 8 μm, 9 μm, 10 μm, 11 μm, 12 μm, 13 μm, 14 μm, 15 μm, 16 μm, 17 μm, 18 μm, 19 μm, or 20 μm D 10 The present invention can be characterized as follows.

[0098] In some embodiments, D 50 In the plume, D 50 In some embodiments, the plume comprises about 50% of droplets having a size of less than about 15 μm to about 24 μm. 50 In some embodiments, the plume may be characterized by a D that may be about 10 μm to about 20 μm. 50 In some embodiments, the plume may be characterized by a D that may be about 20 μm to about 30 μm. 50 In some embodiments, the plume may be characterized by a D that may be about 23 μm to about 30 μm. 50 In some embodiments, the plume can be characterized by a D that can be about: 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, or 33 μm. 50 The present invention can be characterized as follows.

[0099] In some embodiments, D 90 In the plume, D 90 In some embodiments, the plume comprises about 90% of droplets having a size of less than about 65 μm. 90 In some embodiments, the plume may be characterized by a D that may be less than about 60 μm. 90 In some embodiments, the plume may be characterized by a D that may be less than about 50 μm. 90 In some embodiments, the plume may be characterized by a D that may be less than about 40 μm. 90 In some embodiments, the plume may be characterized by a D that may be less than about 35 μm.90 In some embodiments, the plume may be characterized by a D that may 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. 90 In some embodiments, the plume may have a D of less than about 35 μm. 90 or D less than about 42 μm 90 In some embodiments, the plume may have a D of less than about 49 μm. 90 In some embodiments, the plume has a diameter D that can be between about 50 μm and about 60 μm. 90 In some embodiments, the plume may be characterized by a D that may be between about 45 μm and about 55 μm. 90 In some embodiments, the plume may be characterized by a D that may be about 30 μm to about 50 μm. 90 In some embodiments, the plume may be characterized by a D that may be about 40 μm to about 50 μm. 90 In some embodiments, the plume may be characterized by a D that may be between about 38 μm and about 49 μm. 90 In some embodiments, the plume may be characterized by a D that may be about 35 μm to about 45 μm. 90 In some embodiments, the plume may be characterized by a D that may be about 30 μm to about 40 μm. 90 In some embodiments, the plume may be characterized by a D that may be about 25 μm to about 35 μm. 90In some embodiments, the plume may be characterized by a D that can be about: 28 μm, 29 μm, 30 μm, 31 μm, 32 μm, 33 μm, 34 μm, 35 μm, 36 μm, 37 μm, 38 μm, 39 μm, 40 μm, 41 μm, 42 μm, 43 μm, 44 μm, 45 μm, 46 μm, 47 μm, 48 μm, 49 μm, 50 μm, 51 μm, 52 μm, 53 μm, 54 μm, 55 μm, 56 μm, 57 μm, 58 μm, 59 μm, 60 μm, 61 μm, 62 μm, 63 μm, 64 μm, or 65 μm. 90 The present invention can be characterized as follows.

[0100] In some embodiments, the plume may be characterized by a span that may be from about 1 to about 5. In some embodiments, the plume may be characterized by a span that may be from about 1 to about 4. In some embodiments, the plume may be characterized by a span that may be from about 1 to about 3. In some embodiments, the plume may be characterized by a span that may be from about 1 to about 2. In some embodiments, the plume may be characterized by a span that may be from about 0.5 to about 1. In some embodiments, the plume may be characterized by a span that may be from about 0.5 to about 1.5. In some embodiments, the plume can be characterized by a span that can be 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, 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.

[0101] 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 1.1 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.

[0102] 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°, 15°, 20°, 25°, 30°, 35°, 40°, 45°, 50°, 55°, 60°, 65°, 70°, 75°, 80°, 85°, or 90°.

[0103] In some embodiments, the plume may be characterized by having a plume width of about 10 mm to about 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 about: 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.

[0104] In some cases, the plume may be characterized by having a maximum diameter (Dmax) of the spray of about 10 mm to about 60 mm. In some cases, the plume may be characterized by having a Dmax of about 10 mm to about 50 mm. In some cases, the plume may be characterized by having a Dmax of about 10 mm to about 40 mm. In some cases, the plume may be characterized by having a Dmax of about 10 mm to about 30 mm. In some cases, the plume may be characterized by having a Dmax of about 10 mm to about 20 mm. In some cases, the plume may be characterized by having a Dmax of about 15 mm to about 20 mm. In some cases, the plume may be characterized by having a Dmax of about 16 mm to about 20 mm. In some cases, the plume may be characterized by having a Dmax of about 20 mm to about 50 mm. In some cases, the plume may be characterized by having a Dmax of about 30 mm to about 45 mm. In some cases, the plume may be characterized by having a Dmax of about 30 mm to about 50 mm. In some embodiments, the plume may be characterized by having a Dmax of about: 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.

[0105] In some cases, the plume may be characterized by having a minimum diameter of spray (Dmin) of about 10 mm to about 40 mm. In some cases, the plume may be characterized by having a Dmin of about 10 mm to about 30 mm. In some cases, the plume may be characterized by having a Dmin of about 10 mm to about 20 mm. In some cases, the plume may be characterized by having a Dmin of about 10 mm to about 15 mm. In some cases, the plume may be characterized by having a Dmin of about 20 mm to about 35 mm. In some cases, the plume may be characterized by having a Dmin of about 25 mm to about 35 mm. In some cases, the plume may be characterized by having a Dmin of about 21 mm to about 32 mm. In some embodiments, the plume may be characterized by having a Dmin of about: 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, or 40mm.

[0106] In some embodiments, the plume is about 100 mm 2 ~approx. 1500mm 2 In some embodiments, the plume may be characterized by having a plume area of ​​500 mm 2 ~1200mm 2 In some embodiments, the plume may be characterized by having a plume area of ​​600 mm 2 ~1300mm 2 In some embodiments, the plume may be characterized by having a plume area of ​​150 mm 2 ~200mm 2 In some embodiments, the plume may be characterized by having a plume area of ​​100 mm 2 ~500mm 2 In some embodiments, the plume may be characterized by having a plume area of ​​about: 100 mm2 , 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 The plume area may be characterized as having a plume area of

[0107] In some embodiments, the spray device can have an actuation time that can be from the start of spraying to the end of spraying. In some cases, the spray device can have an actuation time of 0.5 seconds to about 5 seconds. In some cases, the spray device can have an actuation time of about 3 seconds. In some cases, the spray device can have an actuation 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 cases, increasing the actuation time can increase the amount of spray deposited in the olfactory region.

[0108] In some embodiments, the spray device can have an operating length. In some cases, the operating length can be about: 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 can be about 4.6mm, 4.8mm, or 4.9mm.

[0109] In some embodiments, the spray device has a spray rate of about: 100 millimeters per second 2 (mm / s 2 ), 200mm / s 2 , 300mm / s 2 , 400mm / s2 , 500mm / s 2 , 600mm / s 2 , 700mm / s 2 , 800mm / s 2 , 900mm / s 2 or 1000mm / s 2 In some cases, the spray device may have an operating stroke acceleration of about 500 mm / s 2 It can be said that:

[0110] In some embodiments, the spray device can have an operating stroke speed of about: 0.5 millimeters per 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 can have an operating stroke speed of about: 1 mm / s, 2 mm / s, 3 mm / s, or 4 mm / s.

[0111] In some cases, the spray device can have an average retention time of about 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 retention time of about 684 ms.

[0112] In some cases, the spray device can deliver a shot weight per actuation. In some cases, the delivered shot weight can be about: 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 actuation. In some cases, the delivered shot weight can be about: 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 actuation. In some cases, the delivered shot weight can be about 45 mg, or can be within about: 10%, 15%, 20%, or 25% of 45 mg.

[0113] In some cases, the spray device can deliver a metered shot weight per actuation. In some cases, the metered shot weight can be about: 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 actuation. In some cases, the metered shot weight can be about: 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 act. In some cases, the metered shot weight can be about 45 mg, or can be within about: 10%, 15%, 20%, or 25% of 45 mg.

[0114] In some cases, the spray device can be tested by an automated system. In some cases, the spray device can be primed before testing. For example, the spray device can be operated several times to ensure that the spray device contains the entire dose before testing. In some cases, the characteristics of the spray (e.g., plume) can be determined at a distance. In some cases, the characteristics of the plume can be determined at about: 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 about 30 mm or about 60 mm.

[0115] Treatment Disclosed herein is a method for treating Parkinson's disease in humans. In some embodiments, the method of treatment can include administering a nasal spray to a subject in need thereof. In some cases, Parkinson's disease can include idiopathic Parkinson's disease, familial Parkinson's disease, secondary Parkinsonism, Parkinson-type dementia (Parkinson's disease dementia), early-onset Parkinson's disease, early-onset Parkinson's disease, drug-induced Parkinsonism, multiple system atrophy, progressive supranuclear palsy, corticobasal syndrome, corticobasal degeneration, essential tremor, dementia with Lewy bodies (Lewy body dementia), vascular parkinsonism, normal pressure hydrocephalus, atypical Parkinson's disorder, or any combination thereof. In some embodiments, disclosed herein is a method for restoring proper chemosensory function in a subject with chemosensory dysfunction caused by Parkinson's disease. In some cases, Parkinson's disease can include chemosensory dysfunction associated with Parkinson's. In some cases, Parkinson's disease can include loss of taste and / or loss of smell associated with Parkinson's.In some cases, the compositions herein are used to treat idiopathic Parkinson's disease, familial Parkinson's disease, secondary Parkinsonism, Parkinson-type dementia (Parkinson's disease dementia), early-onset Parkinson's disease, early-onset Parkinson's disease, drug-induced Parkinsonism, multiple system atrophy, progressive supranuclear palsy, corticobasal syndrome, corticobasal degeneration, essential tremor, dementia with Lewy bodies (Lewy body dementia), vascular Parkinsonism, normal pressure hydrocephalus, atypical Parkinson's disorder, or any combination thereof.

[0116] Also disclosed herein is a method for treating neurological diseases, such as Alzheimer's disease, amyotrophic lateral sclerosis (ALS), dementia, Huntington's disease, Huntington's disease-like syndrome (HD-like syndrome) or any combination thereof.In some cases, the method of treatment can include administering a nasal spray to a subject in need thereof.

[0117] In some cases, the method can include administering to the subject a therapeutically effective amount of a phosphodiesterase (PDE) inhibitor or another therapeutic agent disclosed herein to treat Parkinson's disease or neurological disease.In some cases, the PDE inhibitor or another therapeutic agent can be administered in the form of an intranasal formulation, for example, a spray that is formulated to deposit droplets containing the PDE inhibitor or another therapeutic agent in the nasal cavity.In some cases, the PDE inhibitor or another therapeutic agent can be administered in a formulation in unit dose form.

[0118] In some embodiments, the nasal spray device herein can provide enhanced delivery of therapeutic agents by bypassing the blood-brain barrier (BBB). The therapeutic agents administered herein can travel to the 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 the trigeminal nerve to the pons. In some cases, trigeminal neuron terminals may only be found 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 can 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 at the epithelial site, transport along axons, and exocytosis in the CNS. In some cases, the therapeutic agents disclosed herein can cross the epithelium by paracellular transport. In some examples, the therapeutic agents disclosed herein access the CNS by the systemic circulation. In some cases, the therapeutic agents disclosed herein may be delivered to the CNS by extracellular transport mechanisms, such as by movement of the therapeutic agent through fluids in the spaces where neurons extend to the CNS.

[0119] In some cases, a method of treating Parkinson's disease or a neurological disorder in a subject in need thereof can include administering a PDE inhibitor or another treatment for Parkinson's disease or a neurological disorder using a nasal spray device that delivers a dosage unit in a plume upon operation. In some examples, the dosage unit can include a therapeutically effective amount of a PDE inhibitor or another treatment for Parkinson's disease or a neurological disorder in a pharma- ceutically acceptable carrier, diluent, excipient, or any combination thereof. In some cases, the plume can be characterized by: (a) less than about 1.5% of the droplets in the plume having a size of less than about 10 μm; and (b) a D of about 38 μm to about 49 μm. 90 In some cases, the other treatment can include amantadine, apomorphine, benserazide, adroxylide, altinicline, benztropine, biperiden, prasofensine, bromocriptine, budipine, cabergoline, dihydrexidine, entacapone, etilevodopa, idazoxan, istradefylline, iometopane, lazabemide, merevodopa, levodopa, carbidopa, carbidopa / levodopa, mofegiline, opicapone, moxilaprine, pergolide, pramipexole, quinelorane, rasagiline, ropinirole, rotigotine, selegiline, safinamide, talipexole, tolcapone, trihexyphenidyl, any salt thereof, or any combination thereof.

[0120] In some cases, a method for treating chemosensory dysfunction in a subject in need thereof can include administering to the subject a pharmaceutical composition comprising an effective amount of a phosphodiesterase (PDE) inhibitor and a pharma- ceutically acceptable carrier, excipient, diluent, or any combination thereof. In some cases, a method for treating chemosensory dysfunction in a subject in need thereof can include administering to the subject an effective amount of a pharmaceutical composition comprising a treatment for Parkinson's disease and a pharma- ceutically acceptable carrier, excipient, diluent, or any combination thereof. In some cases, the pharmaceutical composition has a D of about 38 μm to about 49 μm upon intranasal administration to the subject by actuation of a nasal spray device containing the liquid pharmaceutical composition.90 A plume containing a plurality of droplets is formed, and about 90% of the droplets in the plume are D 90 has a size less than

[0121] In some embodiments, the compositions of the present disclosure described herein can be used to treat subjects with neurological disorders, such as Alzheimer's disease, amyotrophic lateral sclerosis (ALS), dementia, Huntington's disease, Huntington's disease-like syndrome (HD-like syndrome), or any combination thereof. In some cases, the dementia can include vascular dementia, dementia with Lewy bodies, Parkinson's disease dementia, mixed dementia, frontotemporal dementia, or any combination thereof. In some cases, the HD-like syndrome can include HDL1, HDL2, HDL3, or HDL4.

[0122] In some cases, the disclosed method or composition described herein can be used to treat Parkinson's disease or neurological disease symptoms.In some cases, Parkinson's disease or neurological disease symptoms can include chemosensory dysfunction (loss of taste and / or smell), tremors, muscle stiffness, muscle rigidity, slowness of movement (bradykinesia), balance disorder, posture disorder, loss of automatism (such as blinking, smiling, or swinging arms when walking), coordination disorder, difficulty swallowing, difficulty chewing, speech disorder, urinary problems, constipation, skin problems, speech change, writing change (e.g., small handwriting), poor sleep, difficulty moving, difficulty walking, masked face (reduced emotional expression), dizziness, fainting, or any combination thereof. In some cases, the speech changes can include a change to soft speech, rapid speech, slurring, hesitating, or any combination thereof. In some cases, the posture disorder can include stooping or hunching. In some cases, the tremor can be in the limbs, hands, fingers, thumbs, arms, legs, jaw, head, or any combination thereof. In some cases, the Parkinson's or neurological disease symptoms can be motor symptoms, such as bradykinesia, stiffness (hypertonia), resting tremor, or any combination thereof. In some cases, the Parkinson's or neurological disease symptoms can be non-motor symptoms. In some cases, symptoms of Parkinson's disease or neurological disorders may include mental decline, difficulty thinking, difficulty understanding, confusion at night, delusions, disorientation, forgetfulness, making up stories, mental confusion, difficulty concentrating, inability to make new memories, inability to do simple calculations, inability to recognize mundane things, anger, apathy, general discontent, mood swings, or any combination thereof. In some cases, symptoms of Parkinson's disease or neurological disorders may include abnormal gait, increased muscle activity, involuntary movements, loss of coordination, muscle loss, muscle spasms, memory loss, delusions, lack of concentration, mental confusion, slowness of activity, difficulty thinking, difficulty understanding, obsessive behavior, fidgeting, irritability, lack of inhibitions, or any combination thereof.In some cases, symptoms of Parkinson's disease or a neurological disorder may include aggression, agitation, difficulty caring for oneself, irritability, meaningless repetition of one's own words, personality changes, restlessness, lack of inhibitions, wandering, getting lost, or any combination thereof.

[0123] In some cases, the disclosed methods or compositions described herein can be used to treat subjects suffering from chemosensory disorders. Chemosensory disorders can include loss of smell (anosmia) or reduced ability to smell (hyposmia). Chemosensory disorders can include loss of taste (ageusia) or reduced ability to taste (hypogeusia), for example, reduced ability to taste sweet, sour, bitter, or salty things. In some cases, chemosensory disorders include misperception or distortion of smell or taste or flavor. For example, chemosensory disorders can cause a person to detect unpleasant odors or tastes from what would normally be a pleasant taste or smell. In some cases, chemosensory dysfunction can include at least partial: loss of taste, loss of smell, or both. Chemosensory dysfunction can include impaired taste or smell. In some cases, taste or smell disorders can include anosmia, hyposmia, anageusia, hypogeusia, dysosmia (distortion of normal smells), parosmia, dysgeusia (distortion of normal tastes), olfactory paresmia, or a combination thereof.

[0124] Chemosensory disorders may involve or be associated with diseases or conditions such as obesity, diabetes, hypertension, malnutrition, or degenerative diseases of the nervous system such as Parkinson's disease, Alzheimer's disease, or multiple sclerosis. In some embodiments, chemosensory disorders may be associated with allergies, such as allergic rhinitis. In some cases, allergies may include drug allergies, food allergies, insect allergies, latex allergies, mold allergies, pet allergies, pollen allergies, or combinations thereof. In some embodiments, chemosensory disorders may be associated with inflammation. In some cases, inflammation may include sinusitis, mucosal inflammation, rhinosinusitis, nasal polyps, or any combination thereof. In some embodiments, chemosensory disorders may be associated with trauma. In some cases, trauma may include traumatic brain injury (TBI), head trauma, concussion, or any combination thereof.

[0125] In some cases, the PDE inhibitor described herein or another treatment for Parkinson's disease or neurological disease can be administered to subjects with co-morbidities.Such co-morbidities include, for example, hypertension, pulmonary hypertension, congestive heart failure, renal failure, myocardial infarction, stable, unstable and variant (Prinzmetal) angina, atherosclerosis, cardiac edema, cardiac disease, renal failure, nephrotic edema, hepatic edema, stroke, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, dementia (including Alzheimer's disease), immunodeficiency, premature birth, Parkinson's disease, multiple sclerosis, dysmenorrhea, benign prostatic hyperplasia (BPH), bladder outlet obstruction, incontinence, conditions with reduced vascular patency, such as , post-percutaneous transluminal coronary angioplasty (post-PTCA), peripheral vascular disease, respiratory disease, bronchitis, emphysema, lung cancer, cystic fibrosis, pneumonia, pleural effusion, allergic rhinitis, glaucoma, malignant disease and diseases characterized by impaired intestinal motility (e.g., irritable bowel syndrome (IBS)), rheumatoid arthritis, bacterial infection, fungal infection, parasitic infection, viral infection, HIV, systemic lupus erythematosus, psoriasis, other autoimmune diseases, Huntington's chorea and amyotrophic lateral sclerosis (ALS), or any combination thereof. Treatment of co-morbidities may be performed by administering to a patient in need thereof a therapeutically effective amount of the compounds and / or compositions described herein.

[0126] Administration and Dosing Disclosed herein is a method of treating a condition (e.g., Parkinson's disease) by administering a PDE inhibitor described herein. Disclosed herein is a method of treating Parkinson's disease by administering a treatment for Parkinson's disease or another neurological disease described herein. In some cases, administration can include administering a PDE inhibitor or another therapeutic agent in a unit dose form, for example, in a nasal spray. In some embodiments, the method of treatment can include nasal administration by a nasal spray device. Other methods of treatment include, by way of example only, oral administration, transmucosal administration, buccal administration, nasal administration, inhalation, parental administration, intravenous administration, subcutaneous administration, intramuscular administration, sublingual administration, transdermal administration and rectal administration.

[0127] In some cases, administration can include administration to the nasal cavity. In some embodiments, administration into the nasal cavity can include administration to the nasal septum, nasal floor, nasal side walls, inferior meatus, middle meatus, superior meatus, olfactory cleft, olfactory region, nasal turbinate, or any combination thereof. In some embodiments, administration into the nasal cavity can include administration to the nasal septum, nasal floor, nasal side walls, inferior meatus, middle meatus, superior meatus, olfactory cleft, olfactory region, and nasal turbinate. The nasal cavity is the space that extends from the nostril to the nasopharynx. The median boundary is the nasal septum, and the inferior boundary is the nasal floor. The lateral boundary includes the nasal side walls, including the nasal turbinate. The space between the nasal turbinate and the nasal side walls, including the inferior meatus, middle meatus, superior meatus, and sphenoethmoid recess, is present in 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 sphenoethmoid bone. The olfactory nerve can be found on the superior surface of the nasal cavity in the olfactory region / olfactory cleft below the ethmoid plate. In some embodiments, the nasal cavity can include the superior nasal cavity, the olfactory cleft, the olfactory epithelium, or any combination thereof. In some cases, the nasal cavity can include squamous epithelial mucosa, the olfactory mucosa, the respiratory mucosa, or any combination thereof. Administration of the compositions described herein can include administration to any region of the nasal cavity. In some embodiments, the compositions can be administered as a spray to at least partially cover the nasal cavity. In some cases, administration can include intranasal application to one or both nostrils.

[0128] In some embodiments, the plume of the nasal spray, when in operation, can cover between about 5% and about 99% of the surface area of ​​the nasal cavity. In some embodiments, the plume of the nasal spray, when in operation, can cover between about 10% and about 70% of the surface area of ​​the nasal cavity. In some embodiments, the plume of the nasal spray, when in operation, can cover between about 15% and about 50% of the surface area of ​​the nasal cavity. In some embodiments, the plume of the nasal spray, when in operation, can cover greater than about: 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. In some embodiments, the plume of the nasal spray, upon actuation, comprises 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%.

[0129] In some cases, administration can include administration to the paranasal sinus. In some cases, administration can include administration to the ear, eye, mouth, or a combination thereof. In some cases, the paranasal sinus can include the ethmoid sinus cavity, the maxillary sinus cavity, the frontal sinus cavity, or the sphenoid sinus cavity. In some cases, administration to the paranasal sinus can include administration to the sinus ostium.

[0130] In some embodiments, a representative daily intranasal, lingual, pulmonary, topical or mucosal dosage may be about 1.0 μg to 2000 mg per day, about 1.0 μg to 500.0 mg per day, about 10 μg to 100.0 mg per day, about 100 mg to 500 mg per day, about 10 mg to 100.0 mg per day, about 50 mg to 100.0 mg per day, about 10 μg to about 10 mg per day, about 10 μg to 1.0 mg per day, about 10 μg to 500 μg per day, about 20 μg to about 2000 μg per day, about 100 μg to about 10,000 μg per day, or about 1 μg to 50 μg per day of active ingredient (e.g., a PDE inhibitor or another therapeutic agent described herein). These ranges of dosage amounts represent the total dosage of active ingredient per day for a given patient. In some embodiments, the dose administered per day can be about: 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 of active ingredient per day.In some embodiments, the dose administered per day 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, 250 μg, 260 μg, 270 μg, 280 μg, 290 μg, g, 300μg, 310μg, 320μg, 330μg, 340μg, 350μg, 360μg, 370μg, 380μg, 390μg, 400μg, 410μg, 420μg, 430μg, 44 0μg, 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, 730μg g, 740μg, 750μg, 760μg, 770μg, 780μg, 790μg, 800μg, 810μg, 820μg, 830μg, 840μg, 850μg, 860μg, 870μg, 88 The amount may be or may be equal to 0 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, 1200 μg, 1300 μg, 1400 μg, 1500 μg, 1600 μg, 1700 μg, 1800 μg, 1900 μg or about 2000 μg of active ingredient. In some embodiments, the dose administered per day may be at least about or equal to: 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, or 25 mg.

[0131] In some embodiments, the therapeutically effective dosage of an active ingredient delivered by an intranasal device herein may be about: 2, 3, 4, 5, 6, 7, 8, 9, or 10 times less than the dosage of the same active ingredient delivered by a standard intranasal spray device. For example, a nasal spray device herein may deliver an active ingredient, such as a PDE inhibitor or salt thereof, at 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.

[0132] In some embodiments, on a kilo basis, suitable dosage levels of the compound may be about 0.001 μg / kg body weight to about 10.0 mg / kg body weight per day, about 0.5 μg / kg body weight to about 0.5 mg / kg body weight per day, about 1.0 μg / kg body weight to about 100 μg / kg body weight per day, and about 2.0 μg / kg body weight to about 50 μg / kg body weight per day. In some embodiments, suitable dosage levels of active ingredient on a per kilo basis may be about: 10.0 mg / kg body weight per day, 1 mg / kg body weight per day, 500 μg / kg body weight per day, 100 μg / kg body weight per day, 10 μg / kg body weight per day, or less than 1.0 μg / kg body weight per day. In some embodiments, suitable dosage levels of active ingredient per kilo basis may be at least about: 10.0 mg / kg body weight per day, 1 mg / kg body weight per day, 500 μg / kg body weight per day, 100 μg / kg body weight per day, 10 μg / kg body weight per day, or 1.0 μg / kg body weight per day of active ingredient.In some embodiments, suitable dosage levels of active ingredient per kilo basis are about: 0.5 μg / kg body weight, 1 μg / kg body weight, 1.5 μg / kg body weight, 2 μg / kg body weight, 2.5 μg / kg body weight, 3 μg / kg body weight, 3.5 μg / kg body weight, 4 μg / kg body weight, 4.5 μg / kg body weight, 5 μg / kg body weight, 5.5 μg / kg body weight, 6 μg / kg body weight, 6.5 μg / kg body weight, 7 μg / kg body weight, 7.5 μg / kg body weight, 8 μg / kg body weight, 8.5 μg / kg body weight, 9 μg / kg body weight, 9.5 μg / kg body weight, It may be 10 μg, 10.5 μg per kg body weight, 11 μg per kg body weight, 11.5 μg per kg body weight, 12 μg per kg body weight, 12.5 μg per kg body weight, 13 μg per kg body weight, 13.5 μg per kg body weight, 14 μg per kg body weight, 14.5 μg per kg body weight, 15 μg per kg body weight, 15.5 μg per kg body weight, 16 μg per kg body weight, 16.5 μg per kg body weight, 17 μg per kg body weight, 17.5 μg per kg body weight, 18 μg per kg body weight, 18.5 μg per kg body weight, 19 μg per kg body weight, 19.5 μg per kg body weight or 20 μg per kg body weight. In some embodiments, suitable dosage levels per kilogram may be about: 100 μg / kg body weight, 150 μg / kg body weight, 200 μg / kg body weight, 250 μg / kg body weight, 300 μg / kg body weight, 350 μg / kg body weight, 400 μg / kg body weight, 450 μg / kg body weight, 500 μg / kg body weight, 550 μg / kg body weight, 600 μg / kg body weight, 650 μg / kg body weight, 700 μg / kg body weight, 750 μg / kg body weight, 800 μg / kg body weight, 850 μg / kg body weight, 900 μg / kg body weight, 950 μg / kg body weight, 1000 μg / kg body weight, 2 mg / kg body weight, 3 mg / kg body weight, or 4 mg / kg body weight.

[0133] In some embodiments, one or more PDE inhibitors or their salts may be formulated in an intranasal formulation, such as an intranasal spray formulation. In some embodiments, the intranasal formulation may include a non-specific PDE inhibitor. In some embodiments, the PDE inhibitor may include theophylline, ibudilast, rolipram, roflumilast, papaverine, any salt thereof, or any combination thereof. In some embodiments, the intranasal formulation may include a PDE inhibitor selective for PDE subtypes, such as PDE:1, 2, 3, 4, or 5. In some embodiments, the PDE inhibitor may be dosed in the 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 dosage (e.g., dosage unit) of the PDE inhibitor can be about: 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, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 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 can be in a unit dosage form. In some embodiments, the formulation may contain a second active ingredient, such as a treatment for Parkinson's disease.

[0134] In some cases, the amount administered may be the same as the amount administered to treat a particular disease, or may be less than the amount administered to treat that particular disease. The dosage may be administered once a day, or several or more times a day. For example, nasal sprays may be administered once a day or twice a day. In another example, the dose of the therapeutic agent disclosed herein may be administered 2, 3, 4, 5, 6, 7, 8, 9, 10 or more times per day. In some cases, the dose delivered by 1, 2, 3, 4, 5 or more actuations of a multi-dose nasal spray device into the nostrils can deliver a therapeutically effective amount of the composition disclosed herein. In some cases, the composition may be administered 1, 2, 3, 4 or 5 or more times in a 24-hour period. In some cases, administration of the compositions disclosed herein may occur at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 times per week. In some cases, administration of the compositions disclosed herein may occur at least 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 times per month. , 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 a subject can produce the desired therapeutic or prophylactic effect without causing serious side effects.

[0135] Administration of the compositions disclosed herein may be 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, 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, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 1 The treatment period may be for a number of consecutive or non-consecutive days, such as 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, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 or more days. In some cases, the treatment period may be about: 1 to about 30 days, 1 to about 60 days, 1 to about 90 days, 30 days to about 90 days, 60 days to about 90 days, 30 days to about 180 days, 90 days to about 180 days, or 180 days to about 360 days.

[0136] The administration of the compositions disclosed herein can be carried out 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 for life. Administration can be carried out repeatedly for the life of the subject, such as once a month or once a year for the life of the subject. Administration can be carried out repeatedly for a substantial part of the life of the subject, such as once a month or once a year for at least about 1 year, 5 years, 10 years, 15 years or more.

[0137] In some cases, the composition can be administered as a single dose or as a divided dose. In some cases, the composition described herein can be administered at a first time point and a second time point. In some cases, the composition can be administered such that the first administration is administered, followed by the other administration at a time interval of about: 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 more.

[0138] In some embodiments, administration may occur for about: 1 day to about 8 days, 1 week to about 5 weeks, 1 month to about 12 months, 1 year to about 3 years, 3 years to about 10 years, 10 years to about 50 years, 25 years to about 100 years, or 50 years to about 130 years. In some embodiments, the composition may be administered as needed or for 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.

[0139] In some embodiments, administration of an effective amount of a PDE inhibitor or treatment for Parkinson's disease or another neurological disease by intranasal (e.g., spray), lingual, pulmonary, topical, or mucosal administration does not result in detectable blood levels of the PDE inhibitor or treatment for Parkinson's disease or another neurological disease. In some embodiments, administration of an effective amount of a PDE inhibitor by intranasal, lingual, pulmonary, topical, or mucosal administration results in a blood concentration of the PDE inhibitor that may be less than about: 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 1 μg / dl. In some embodiments, administration of an effective amount of a PDE inhibitor by intranasal, lingual, pulmonary, topical or mucosal administration results in a blood concentration of the PDE inhibitor that may be about: 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 greater than 1 μg / dl. In some embodiments, administration of an effective amount of a PDE inhibitor by intranasal, lingual, pulmonary, topical or mucosal administration results in a blood concentration of the PDE inhibitor that may be about: 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 greater than 1 μg / dl.

[0140] In some cases, the compositions described herein can be administered with one or more additional therapeutic agents.For example, the compositions described herein can be administered with one, two, three, four or five or more additional therapeutic agents.In another example, the PDE inhibitor can be administered with a second treatment.In some cases, the additional treatment can be administered simultaneously or sequentially.In some cases, the additional treatment can be included in the composition (e.g., nasal spray) that comprises the PDE inhibitor. In some cases, the additional treatment can include a treatment described herein, such as amantadine, apomorphine, benserazide, androgolide, altinicline, benztropine, biperiden, brasofensine, bromocriptine, budipine, cabergoline, dihydrexidine, entacapone, etilevodopa, idazoxan, istradefylline, iometopane, lazabemide, merevodopa, levodopa, carbidopa, carbidopa / levodopa, mofegiline, opicapone, moxilaprine, pergolide, pramipexole, quinelorane, rasagiline, ropinirole, rotigotine, selegiline, safinamide, talipexole, tolcapone, trihexyphenidyl, a salt of any of these, or any combination thereof. In some cases, the additional therapy can include aducanumab, a cholinesterase inhibitor, a glutamate modulator, an orexin receptor antagonist, or any combination thereof. In some cases, the additional therapy can include riluzole, edaravone, sodium phenylbutyrate, taurursodiol, tetrabenazine, amantadine, a salt of any of these, or any combination thereof.

[0141] In some cases, the compositions described herein can be administered with one or more additional therapeutic agents.For example, treatment for Parkinson's disease or another neurological disease can be administered with the second treatment.In some cases, the additional treatment can be administered simultaneously or sequentially.In some cases, the additional treatment can be included in the composition (e.g., nasal spray) that includes the treatment for Parkinson's disease or another neurological disease.In some cases, the additional treatment can be a PDE inhibitor.

[0142] Diagnosing Disease and Measuring Chemosensory Dysfunction In some cases, a subject may be diagnosed (e.g., diagnosed with Parkinson's disease) before treatment with a PDE inhibitor or treatment for Parkinson's disease or another neurological disease. In some cases, the method of treatment may include diagnosing Parkinson's disease in a subject. In some cases, the diagnosis may include an in vitro assay. In some cases, the diagnosis may include a physical examination. In some cases, the diagnosis may include a dopamine transporter (DAT) scan. In some cases, the diagnosis may include a medical imaging technique such as computed tomography (CT), magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), positron emission tomography (PET), or any combination thereof. In some cases, symptoms of Parkinson's disease may be diagnosed, for example, as chemosensory dysfunction. In some cases, the diagnosis may include a blood test, a genetic test, or both.

[0143] In some cases, the subject may be diagnosed with Alzheimer's disease, amyotrophic lateral sclerosis (ALS), dementia, Huntington's disease, or Huntington's disease-like syndrome (HD-like syndrome) prior to treatment with a compound disclosed herein. In some cases, the method of treatment may include diagnosing Alzheimer's disease, amyotrophic lateral sclerosis (ALS), dementia, Huntington's disease, or Huntington's disease-like syndrome (HD-like syndrome) in the subject. In some cases, the diagnosis may include a physical examination, a blood test, a genetic test, or any combination thereof. In some cases, the diagnosis may include a medical imaging technique.

[0144] In some cases, chemosensory dysfunction can be diagnosed by detecting sonic hedgehog at or below a threshold level in a biological sample from a human. In some cases, chemosensory dysfunction can be diagnosed by threshold, lower or higher levels of cyclic AMP (cAMP), cyclic GMP (cGMP), IL-10 or combinations thereof in a biological sample from a human. In some cases, the sample can be a nasal sample or a saliva sample. In some cases, chemosensory dysfunction can be diagnosed by detecting cyclic nucleotide levels at or below a threshold level in a biological sample from a human. For example, low levels of cyclic nucleotides in a biological sample from a subject can suggest that the subject has chemosensory dysfunction. Measurements for detecting the level of a biological substance such as cAMP can be completed by ELISA, Western blot or any molecular biology assay. In some embodiments, chemosensory dysfunction can be diagnosed by an olfactory assay that measures threshold, discrimination, identification or any combination thereof. In some cases, diagnosis of chemosensory dysfunction can 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 with a reference population (e.g., a population without chemosensory dysfunction). ME score refers to a measurement of a subject's ability to determine the intensity of a stimuli, such as an odorant or tastant. RT score refers to a measurement of a subject's ability to recognize the identity of a stimuli, such as an odorant or tastant. DT score refers to a measurement of a subject's ability to recognize exposure to a stimuli, such as an odorant or tastant, as pleasant or unpleasant. H score refers to a measurement of a subject's response to a stimuli, such as an odorant or tastant, as pleasant or unpleasant.

[0145] In some embodiments, the subject may undergo an olfactory assay 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, the threshold assay may be used to determine the lowest concentration of odorant that can be reliably detected. In some cases, the discrimination assay may be used to assess the subject's ability to distinguish between two or more different odors. In some cases, the identification assay may be used to assess the subject's ability to identify a particular odor. In some cases, the olfactory test may be used to determine the efficacy of treatment, such as treatment with a nasal spray device that includes a PDE inhibitor, and / or treatment for Parkinson's disease or another neurological disease. For example, the olfactory assay may be completed before and after treatment to determine measurable changes in the subject's chemosensory dysfunction.

[0146] In some embodiments, the subject may undergo an olfactory assay 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, threshold assays may be used to determine the lowest concentration of odorant that can be reliably detected. In some cases, discrimination assays may be used to assess the subject's ability to distinguish between two or more different odors. In some cases, identification assays may be used to assess the subject's ability to identify a particular odor. In some cases, olfactory testing may be used to determine the efficacy of treatment, such as treatment with an implant that contains a PDE inhibitor. For example, olfactory assays may be completed before and after treatment to determine measurable changes in the subject's chemosensory dysfunction.

[0147] In some embodiments, the method of treatment can include olfactory training (e.g., odor training). In some cases, olfactory training can include repeated stimulation of peripheral olfactory neurons, and can rely on the regenerative capacity of superior olfactory pathway. In some cases, olfactory training can include exposure to 1, 2, 3, 4, 5, 6 or more than 6 different odors. In some cases, olfactory training can include exposure to 1, 2, 3, 4 or more than 4 different odors per day. In some cases, olfactory training can be performed for about: 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 1 year or more than 1 year. In some cases, olfactory training can be performed for about: 7 days to about 21 days, 21 days to about 120 days, 30 days to about 90 days, 1 month to about 5 months, 2 months to about 3 months, 3 months to about 8 months, 6 months to about 1 year, 8 months to about 18 months, or 1 year to about 3 years. In some cases, organic essential oils of lemon, rose, eucalyptus, and clove can be used as various odors for olfactory testing.

[0148] In some embodiments, the subject may experience a change in the detection threshold (DT) score, the recognition threshold (RT) score, or both (e.g., a decrease in response to effective treatment). In some embodiments, the subject may experience a change in the magnitude estimation (ME) score (e.g., an improvement in response to effective treatment). In some cases, the subject may experience a change in the hedonic (H) score. In some cases, the change in the RT score, ME score, DT score, or H score can be measured by a forced-choice, three-stimulus, stepwise-staircase technique using one or more odorants after administering a PDE inhibitor to the subject. In some cases, the one or more odorants include pyridine, nitrobenzene, thiophene, amyl acetate, or a combination thereof. In some cases, the change in the RT score, ME score, DT score, or H score can be measured by a forced-choice, three-stimulus, stepwise-staircase technique using one or more tastant test compounds after administering a PDE inhibitor to the subject. In some cases, the one or more tastant comprises sodium chloride (NaCl), sucrose, hydrogen chloride (HCl), urea, or a combination thereof.

[0149] In some embodiments, a subject may experience a clinically detectable improvement in taste or smell function within about: 1 week to about 6 weeks, 1 week to about 4 weeks, 2 weeks to about 5 weeks, or about 3 weeks to about 4 weeks of initiating treatment. In some embodiments, a subject may experience a clinically detectable improvement in taste or smell function within about: 1 month to about 6 months, 1 month to about 4 months, 2 months to about 5 months, or about 3 months to about 4 months of initiating treatment.

[0150] Hedgehog signaling pathway is known to be a key regulator of animal development, especially during the later stages of embryogenesis and metamorphosis.Mammals have three members of the Hedgehog signaling pathway, namely Sonic Hedgehog (SHH), Desert Hedgehog (DHH) and Indian Hedgehog (IHH).The pathway is related to the development of some cancers.Members of the Hedgehog signaling pathway can be used to diagnose and treat loss and / or distortion of taste or smell, such as hyposmia, anosmia, anosmia, spontaneous parosmia, hypogeusia, dysgeusia, spontaneous dysgeusia and / or anageusia.For example, a subject with chemosensory dysfunction can be treated with a PDE inhibitor to improve SHH levels compared to the levels before treatment.

[0151] The 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). The 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 contemplated that non-mammalian hedgehogs can be measured. In some cases, chemosensory dysfunction in a subject can be determined by detecting a level of Sonic hedgehog (SHH), which can range from about 0 pg / mL to about 8,500 pg / mL, a level of Indian hedgehog (IHH), which can range from about 0 pg / mL to about 1.0 pg / mL, or a level of Desert hedgehog (DHH), which can range from about 0 pg / mL to about 5.0 pg / mL, or a combination thereof.

[0152] In patients exhibiting loss and / or distortion of taste or smell (e.g., hyposmia, dysosmia, anosmia, spontaneous parosmia, hypogeusia, dysgeusia, spontaneous dysgeusia and / or anageusia), levels of members of the Hedgehog signaling pathway may be less than normal controls. For example, in patients suffering from loss and / or distortion of taste or smell (e.g., chemosensory dysfunction), the level of SHH may be in some cases about: 0 pg / mL, greater than 0 pg / mL to 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 1000 pg / mL, 900 pg / mL to 2 (b) the level of IHH may be about: 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 to 0.5 pg / mL, 0.4 pg / mL to 0.7 pg / mL, 0.6 pg / mL to 0.75pg / mL, 0.725pg / mL to 0.9pg / mL, 0.8pg / mL to 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, less than 1.1ng / mL, less than 1.5ng / mL, less than 1.75ng / mL, less than 2.0ng / mL, less than 2.25ng / mL, 5 (c) the level of DHH may be less than about: 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 to 0.5 pg / mL, 0.4 pg / mL to 0.7 pg / mL, 0.6 pg / mL to 0.75 pg / 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~3.9pg / mL, 3.85pg / mL~5.0pg / mL, 5.0pg / mL The Hedgehog signaling pathway may be present in a concentration range of 100-250 ng / mL, 100-250 ng / mL, 100-350 ng / mL, 100-450 ng / mL, 100-500 ng / mL, 100-650 ng / mL, 100-750 ng / mL, 100-850 ng / mL, 100-950 ng / mL, 100-1500 ng / mL, 100-1500 ng / mL, 100-1500 ng / mL, 100-2500 ng / mL, 100-3500 ng / mL, 100-4500 ng / mL, 100-5000 ng / mL, 100-6500 ng / mL, 100-7500 ng / mL, 100-8500 ng / mL, 100-9500 ng / mL, 100-1 ...

[0153] In some embodiments, administration of an effective amount of a PDE inhibitor may increase saliva and / or nasal mucus SHH, DHH and / or IHH levels in a human 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 saliva and / or nasal mucus levels in the human prior to administration of a therapeutically effective amount of a PDE inhibitor. In some cases, improved levels of SHH, DHH and / or IHH in saliva and / or nasal mucus are observed after about: 1 to about 10 days, 30 to about 90 days, 15 to about 45 days, or 30 days of continuous treatment with a therapeutically effective amount of a PDE inhibitor.

[0154] In some embodiments, administration of an effective amount of a PDE inhibitor may increase or decrease a biological compound, such as a protein or metabolite. In some embodiments, administration of an effective amount of a PDE inhibitor may increase saliva and / or nasal mucus cAMP or cGMP levels in a human 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 saliva and / or nasal mucus cAMP or cGMP levels in the human prior to administration of a therapeutically effective amount of a PDE inhibitor. In some cases, enhanced cAMP or cGMP levels in saliva and / or nasal mucus are observed after about: 1 to about 10 days, 30 to about 90 days, 15 to about 45 days, or 30 days of continuous treatment with a therapeutically effective amount of a PDE inhibitor.

[0155] In some embodiments, administration of an effective amount of a PDE inhibitor may reduce saliva and / or nasal mucus IL-10 levels in a human 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 saliva and / or nasal mucus IL-10 levels in the human prior to administration of a therapeutically effective amount of a PDE inhibitor. In some cases, a reduction in IL-10 levels in saliva and / or nasal mucus is observed after about: 1 to about 10 days, 30 to about 90 days, 15 to about 45 days, or 30 days of continuous treatment with a therapeutically effective amount of a PDE inhibitor. IL-10 levels can be measured by enzyme-linked immunoassay (ELISA), Western blot, or other protein measurement assay.

[0156] In some embodiments, the administration of an effective amount of a PDE inhibitor in the form of a liquid spray can improve taste or smell acuity. In some embodiments, the improvement in taste or smell acuity can be at least about: 5%, 10%, 20%, 30%, 40%, 50%, 75% or 100% compared to an untreated state. In some embodiments, taste or smell acuity can be improved to at least about: 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% of the acuity of a normal individual. In some cases, the improvement in taste acuity or olfactory acuity can be measured after about: 10 to about 20 days, 15 to about 30 days, 25 to about 50 days, 1 month to about 6 months, 4 months to 12 months, 6 months to 18 months, or 6 months to about 3 years. In some cases, the improvement in taste acuity or olfactory acuity can be measured after about 30 days. In some embodiments, taste acuity or olfactory acuity can be measured objectively. In some embodiments, taste acuity or olfactory acuity can be measured subjectively. In some cases, olfactory acuity can be measured by detection threshold, recognition threshold, hedonics, magnitude estimation, or any method described herein.

[0157] kit Kits and articles of manufacture are also described for the use of the therapeutic compositions described herein. In some embodiments, such kits include carriers, packaging, or containers, bottles, tubes, capsules, etc., compartmentalized to accommodate one or more blister packs. In certain embodiments, the pharmaceutical compositions are presented in a pack or dispenser device that contains one or more unit dosage forms containing the compounds provided herein. In other embodiments, the pack can contain metal or plastic foils, such as blister packs. In some embodiments, the pack contains capsules, vials, or tubes. In other embodiments, the pack or dispenser device is accompanied by 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 preloaded into the device. In some embodiments, the kit can include a spray device disclosed herein.

[0158] In other embodiments, the package can also be accompanied by a notice required by a government agency that regulates the manufacture, use or sale of pharmaceuticals. This notice states that the drug is approved by the agency for human or veterinary administration. Such notice can be, for example, the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions containing the compounds provided herein formulated in compatible excipients, diluents and / or carriers can also be prepared, placed in appropriate containers, and labeled for the treatment of indicated conditions.

[0159] The product provided herein may also include an administration device or a dispensing device. Examples of administration devices include intranasal sprays and inhalers. Pumps and / or spray heads (e.g., nozzles) may be provided on the spray and intranasal devices, or pumps and / or spray heads may be built into the devices. Alternatively, propellants may be included with the devices or stored inside the devices. In some cases, propellants may be used with the spray devices disclosed herein.

[0160] Such kits may include an identifying description or label on the container. In further embodiments, the label is on the container surface, with letters, numbers or other symbols forming the label and attached, molded or etched into the container itself. The label is associated with the container, for example, as a package insert, when present in 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 still other embodiments, the label also indicates instructions for 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 descriptions of the types of patients that may be treated, schedules (e.g., doses and frequency), etc.

[0161] The present disclosure also relates to sets (kits) of separate packs of kits that are frequently assembled for transportation or for patient convenience, such as weekly, biweekly or monthly supplies of medication.

[0162] Numbered embodiments Some compositions, methods, kits and devices are disclosed herein. Specific exemplary embodiments of these methods, kits and devices are disclosed below. The following embodiments list non-limiting permutations of the combinations of features disclosed herein. Other permutations of the combinations of features are also contemplated. In particular, each of these numbered embodiments is contemplated as dependent on or related to the previous or subsequent numbered embodiments, regardless of the order in which they are listed.

[0163] Embodiment 1. A method of treating Parkinson's disease in a subject in need thereof, comprising administering to the subject an effective amount of a liquid pharmaceutical composition, the liquid pharmaceutical composition comprising: a) a phosphodiesterase (PDE) inhibitor or a salt thereof, and b) a pharma- ceutically acceptable carrier, excipient, diluent, or any combination thereof, wherein the liquid pharmaceutical composition, upon intranasal administration to the subject by actuation of a nasal spray device comprising the liquid pharmaceutical composition, forms a plume comprising a plurality of droplets, the plurality of droplets having a D of about 15 μm to about 24 μm. 50 In the plume, about 50% of the droplets are D 50 wherein Parkinson's disease is treated by administering an effective amount of a liquid pharmaceutical composition having a size of less than 100 μg / ml.

[0164] Embodiment 2. The method of embodiment 1, wherein the plurality of droplets is further characterized in that less than about 3% of the droplets in the plume have a size less than about 10 μm.

[0165] Embodiment 3. A plurality of droplets are formed having a diameter of about 30 μm to about 50 μm. 90 and about 90% of the droplets in the plume are D 90 3. The method of embodiment 1 or 2, wherein the microcapsules have a size of less than 1 mm.

[0166]

[0023] Embodiment 4. The plurality of droplets has a D of less than about 35 μm. 90 or D less than about 42 μm 90 and about 90% of the droplets in the plume are D90 4. The method of embodiment 3, wherein the microcapsules have a size of less than 100 μm.

[0167] Embodiment 5.D 50 The method of any one of embodiments 1-4, wherein the thickness is about 21 μm.

[0168] Embodiment 6. The method of any one of embodiments 1-5, wherein the droplet size is measured by laser diffraction.

[0169] Embodiment 7. The method of any one of embodiments 1-6, wherein the PDE inhibitor or salt thereof comprises a selective PDE inhibitor, a non-selective PDE inhibitor, or a salt of any of these.

[0170] Embodiment 8. The method of any one of embodiments 1-6, wherein the PDE inhibitor or salt thereof comprises theophylline, ibudilast, rolipram, roflumilast, papaverine, any salt thereof, or any combination thereof.

[0171] Embodiment 9. The method of any one of embodiments 1-8, wherein the plume is formed by actuation of the nasal spray device and persists for about 0.5 seconds to about 5 seconds from the start of spray to the end of spray.

[0172] Embodiment 10. The method of embodiment 9, wherein the actuation comprises an actuation volume of liquid of about 10 μl to about 200 μl or about 20 μl to about 80 μl.

[0173] Embodiment 11 The method of any one of embodiments 1-10, wherein the pharma- ceutically acceptable carrier comprises water.

[0174] Embodiment 12. The method of any one of embodiments 1-11, wherein the liquid pharmaceutical composition further comprises a viscosity enhancing agent.

[0175] Embodiment 13. The method of any one of embodiments 1 to 12, wherein the liquid pharmaceutical composition further comprises an excipient.

[0176] Embodiment 14. The method of any one of embodiments 1 to 13, wherein the liquid pharmaceutical composition further comprises a preservative.

[0177] Embodiment 15. The method of any one of embodiments 1-14, wherein the intranasal administration is once, twice, three times, or four times per day to each nostril.

[0178] Embodiment 16. The method of any one of embodiments 1 to 15, wherein the plume covers about: 15% to about 50%, about 10% to about 80%, about 5% to about 90%, or about 5% to about 100% of the surface area of ​​the nasal cavity as measured by a cast scan of the nose.

[0179] Embodiment 17. The method of embodiment 16, wherein the nasal cavity comprises the nasal septum, nasal floor, nasal cavity lateral wall, inferior meatus, middle meatus, superior meatus, olfactory cleft, olfactory region, nasal turbinate, or any combination thereof.

[0180] Embodiment 18. The method of embodiment 16, wherein the nasal cavity includes the nasal septum, nasal floor, nasal lateral walls, inferior meatus, middle meatus, superior meatus, olfactory cleft, olfactory region, and nasal turbinates.

[0181] Embodiment 19. The method of any one of embodiments 1-18, wherein the Parkinson's disease comprises idiopathic Parkinson's disease, familial Parkinson's disease, secondary Parkinsonism, Parkinson-type dementia (Parkinson's disease dementia), early-onset Parkinson's disease, early-onset Parkinson's disease, drug-induced Parkinsonism, multiple system atrophy, progressive supranuclear palsy, corticobasal syndrome, corticobasal degeneration, essential tremor, dementia with Lewy bodies (Lewy body dementia), vascular parkinsonism, normal pressure hydrocephalus, atypical Parkinson's disorder, or any combination thereof.

[0182] Embodiment 20. The method of any one of embodiments 1-19, wherein treating Parkinson's disease comprises treating symptoms of Parkinson's disease, wherein the symptoms of Parkinson's disease comprise chemosensory impairment, tremors, muscle stiffness, muscle rigidity, bradykinesia, balance disorders, posture disorders, loss of motility, coordination disorders, depression, difficulty swallowing, difficulty chewing, speech disorders, urinary problems, constipation, skin problems, speech changes, writing changes, poor sleep, difficulty moving, difficulty walking, reduced emotional expression, dizziness, fainting, or any combination thereof.

[0183] Embodiment 21 The method of any one of embodiments 1-20, further comprising administering a second therapeutic agent.

[0184] Embodiment 22 The method of embodiment 21, wherein a second therapeutic agent is administered simultaneously or sequentially.

[0185] Embodiment 23. The method of embodiment 21, wherein the second therapeutic agent comprises levodopa, carbidopa, entacapone, tolcapone, opicapone, pramipexole, ropinirole, apomorphine, rotigotine, selegiline, rasagiline, safinamide, amantadine, istradefylline, trihexyphenidyl, benztropine, benserazide, a salt of any of these, or any combination thereof.

[0186] Embodiment 24 The method of embodiment 21, wherein the second therapeutic agent comprises levodopa or a salt thereof.

[0187] Embodiment 25 The method of embodiment 1, wherein the nasal spray device delivers the plume as a unit dose upon actuation.

[0188] Embodiment 26. The method of embodiment 1, wherein the nasal spray device comprises about 60 to about 120 unit doses, each unit dose comprising about 10 μg to about 2000 μg of the PDE inhibitor or a salt thereof.

[0189] Embodiment 27. The method of any one of embodiments 1 to 26, further comprising the step of diagnosing the subject with Parkinson's disease.

[0190] Embodiment 28. The method of any one of embodiments 1-26, wherein the subject has previously been diagnosed with Parkinson's disease.

[0191] Embodiment 29. The method of any one of embodiments 1 to 28, wherein the subject is a subject in need thereof.

[0192] Embodiment 30. The method of any one of embodiments 1 to 29, wherein the subject is a human.

[0193] Embodiment 31. A nasal spray device comprising a PDE inhibitor or a salt thereof, wherein the nasal spray device is configured to deliver a dosage unit in a plume upon actuation, the dosage unit comprising a therapeutically effective amount of a PDE inhibitor or a salt thereof in a pharma- ceutically acceptable carrier, excipient, diluent, or any combination thereof, and wherein the plume has (a) less than about 3% of the droplets in the plume having a size of less than about 10 μm, and (b) a D of about 15 to about 24 μm. 50 and about 50% of the droplets in the plume are D 50 16. A nasal spray device having a droplet size distribution characterized by having a size of less than 100 μm.

[0194] Embodiment 32. A kit comprising the nasal spray device of embodiment 31 and a container.

[0195] Embodiment 33. A method of treating Parkinson's disease in a subject in need thereof, comprising administering a PDE inhibitor or salt thereof using a nasal spray device which, upon operation, delivers a dosage unit in a plume, wherein the dosage unit comprises a therapeutically effective amount of a PDE inhibitor or salt thereof in a liquid pharmaceutical composition comprising a pharma- ceutically acceptable carrier, diluent, excipient, or any combination thereof, and wherein the plume comprises droplets having a D of about 15 μm to about 24 μm. 50 and about 50% of the droplets in the plume have a droplet size distribution characterized by D 50 The method has a size less than

[0196] Embodiment 34. A method of treating Parkinson's disease in a subject in need thereof, comprising administering to the subject an effective amount of a liquid pharmaceutical composition, the liquid pharmaceutical composition comprising: a) levodopa or a salt thereof, and b) a pharma- ceutical acceptable carrier, excipient, diluent, or any combination thereof, wherein the pharmaceutical composition, upon intranasal administration to the subject by actuation of a nasal spray device comprising the liquid pharmaceutical composition, forms a plume comprising a plurality of droplets, the plurality of droplets having a D of about 15 μm to about 24 μm. 50 In the plume, about 50% of the droplets are D 50 wherein Parkinson's disease is treated by administering an effective amount of the pharmaceutical composition having a size of less than 100 μg / ml.

[0197] Embodiment 35. The method of embodiment 34, wherein the liquid pharmaceutical composition further comprises carbidopa, a PDE inhibitor, a salt of any of these, or any combination thereof.

[0198] Embodiment 36. A method of treating Parkinson's disease in a subject in need thereof, comprising administering to the subject an effective amount of a liquid pharmaceutical composition, the liquid pharmaceutical composition comprising: a) a compound selected from the group consisting of carbidopa, entacapone, tolcapone, opicapone, pramipexole, ropinirole, apomorphine, rotigotine, selegiline, rasagiline, safinamide, amantadine, istradefylline, trihexyphenidyl, benztropine, benserazide, any salt and any combination thereof, and b) a pharma- ceutically acceptable carrier, excipient, diluent, or any combination thereof, wherein the liquid pharmaceutical composition, upon intranasal administration to the subject by actuation of a nasal spray device comprising the liquid pharmaceutical composition, forms a plume comprising a plurality of droplets, the plurality of droplets having a D of about 15 μm to about 24 μm. 50 In the plume, about 50% of the droplets are D 50 wherein Parkinson's disease is treated by administering an effective amount of a liquid pharmaceutical composition having a size of less than 100 μg / ml.

[0199] Embodiment 37. A nasal spray device comprising: (i) a compound selected from the group consisting of levodopa, carbidopa, entacapone, tolcapone, opicapone, pramipexole, ropinirole, apomorphine, rotigotine, selegiline, rasagiline, safinamide, amantadine, istradefylline, trihexyphenidyl, benztropine, benserazide, a salt of any of these, and any combination thereof; and (ii) a pharma- ceutically acceptable carrier, excipient, diluent, or any combination thereof; wherein the nasal spray device is configured to deliver a dosage unit in a plume upon actuation, and wherein the plume has a D of about 15 μm to about 24 μm. 50 and in the plume, about 50% of the droplets are D 50 A nasal spray device having a size of less than 1.

[0200] Embodiment 38. A method of treating a neurological disorder in a subject in need thereof, comprising administering to the subject an effective amount of a liquid pharmaceutical composition, the liquid pharmaceutical composition comprising: a) a compound selected from the group consisting of donepezil, rivastigmine, galantamine, tacrine, memantine, suvorexant, riluzole, edaravone, sodium phenylbutyrate, taurursodiol, tetrabenazine, amantadine, a salt of any of these, and any combination thereof, and b) a pharma- ceutically acceptable carrier, excipient, diluent, or any combination thereof, wherein the liquid pharmaceutical composition, upon intranasal administration to the subject by actuation of a nasal spray device comprising the liquid pharmaceutical composition, forms a plume comprising a plurality of droplets, the plurality of droplets having a D of about 15 μm to about 24 μm. 50 In the plume, about 50% of the droplets are D 50 wherein the neurological disease is treated by administering an effective amount of a liquid pharmaceutical composition having a size of less than 100 μm.

[0201] Embodiment 39. The method of embodiment 38, wherein the neurological disease comprises Alzheimer's disease, amyotrophic lateral sclerosis (ALS), dementia, Huntington's disease, Huntington's disease-like syndrome (HD-like syndrome), or any combination thereof.

[0202] Embodiment 40. A nasal spray device comprising: (i) a compound selected from the group consisting of donepezil, rivastigmine, galantamine, tacrine, memantine, suvorexant, riluzole, edaravone, sodium phenylbutyrate, taurursodiol, tetrabenazine, a salt of any of these, and any combination thereof; and (ii) a pharma- ceutically acceptable carrier, excipient, diluent, or any combination thereof; wherein the nasal spray device is configured to deliver a dosage unit in a plume upon actuation, and wherein the plume has a D of about 15 μm to about 24 μm. 50 and in the plume, about 50% of the droplets are D 50 A nasal spray device having a size of less than 1. EXAMPLES

[0203] Example 1 Distribution of liquid formulations using various nasal spray devices in a nasal model

[0204] Three types of nasal spray devices were tested for their ability to deposit liquid formulations in the nasal model. 1 mg / mL calcein (for visualization with fluorescence) was added to a formulation containing theophylline (600 μg / mL) and no viscosity enhancer. Additionally, 1 mg / mL calcein was added to a separate formulation containing theophylline (600 μg / mL) and a viscosity enhancer (carboxymethylcellulose). This formulation also contained citric acid and sodium hydroxide as buffering agents, and phenylethyl alcohol as a preservative. Purified water was the carrier. The test was performed at 60% relative humidity. The formulations were tested with three different nasal spray devices: soft mist nasal spray, slow standard nasal spray, and standard nasal spray. The images in Figure 1 show that two acts of the spray device were tested per image (90 μl liquid spray). Table 1 shows the nasal coverage of the various spray devices in the nasal model. The soft mist nasal spray without viscosity enhancer had the greatest surface coverage (about 40%) in the nasal model. The soft mist nasal spray targeted the olfactory region and nasal turbinates. With the addition of cellulose, the surface area covered was reduced to nearly 20% of the nasal mucosa. However, the spray was more concentrated in the olfactory region as shown in FIG. 1 and indicated by the oval shape. Furthermore, the olfactory region is known to affect chemosensory function, so the concentration of this area by the soft mist nasal spray was surprising and unexpected compared to the standard nasal spray.

[0205] [Table 1-1] [Table 1-2]

[0206] Example 2 Nasal spray characteristics of three types of nasal spray devices

[0207] Theophylline liquid formulations were operated using three spray devices: a soft mist nasal spray device, a low rate standard nasal spray device, and a standard nasal spray device. The operating data are shown in FIG. 2. The left Y-axis shows the cumulative volume (%) of each spray, indicated by an sigmoid line. The X-axis shows the particle size (μm) of the droplets. The right Y-axis shows the volume frequency (%) of the droplet size. The soft mist nasal spray had about 50% of the droplets having a particle size of less than 20 μm and had substantially no particles greater than 60 μm in size. The low rate standard nasal spray had about 50% of the droplets having a particle size of less than 30 μm, with the remaining 50% of the particles being between about 30 μm and about 100 μm in size. The standard nasal spray had about 50% of the droplets having a particle size of less than about 60 μm, with the remaining particles being greater than about 60 μm and about 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.

[0208] Example 3 Theophylline spray preparations

[0209] Table 2 shows two exemplary formulations for nasally administered theophylline.

[0210] [Table 2]

[0211] Example 4 Treatment of Parkinson's Disease

[0212] A subject is admitted to a clinic for tremors and muscle stiffness. The subject is diagnosed with Parkinson's disease. The subject is prescribed a rolipram composition in a nasal spray device as described herein. The subject administers an effective dose of the nasal spray to each nostril twice daily. The nasal spray contains a D of about 15 μm to about 24 μm. 50 , D of about 30 μm to about 50 μm 90and wherein less than about 3% of the droplets in the plume of the spray have a size of less than about 10 μm. After administration of the rolipram composition, the subject experienced a reduction in symptoms of Parkinson's disease (e.g., reduced tremors and reduced muscle stiffness).

[0213] Example 5 Treatment of chemosensory dysfunction in patients with Parkinson's disease

[0214] A subject is admitted to a clinic for taste loss associated with Parkinson's disease. The subject is diagnosed with chemosensory dysfunction. The subject is prescribed a theophylline composition in a nasal spray device as described herein. The subject administers an effective dose of the nasal spray to each nostril twice daily. The nasal spray contains a D of about 15 μm to about 24 μm. 50 , D of about 30 μm to about 50 μm 90 wherein less than about 3% of the droplets in the plume of the spray have a size of less than about 10 μm. The subject regains taste sensation after administration of the theophylline composition.

[0215] Example 6 Treatment of Parkinson's Disease

[0216] A subject is admitted to a clinic for bradykinesia and balance disorders. The subject is diagnosed with Parkinson's disease. The subject is prescribed a levodopa composition in a nasal spray device as described herein. The subject administers an effective dose of the nasal spray to each nostril four times daily. The nasal spray contains a D of about 15 μm to about 24 μm. 50 , D of about 30 μm to about 50 μm 90 and wherein less than about 3% of the droplets in the plume of the spray have a size of less than about 10 μm. The subject experienced reduced bradykinesia and improved balance after administration of the levodopa composition.

[0217] Example 7 Treatment of Alzheimer's Disease

[0218] A subject is admitted to a clinic for confusion and inability to concentrate. The subject is diagnosed with Alzheimer's disease. The subject is prescribed a donepezil composition in a nasal spray device as described herein. The subject administers an effective dose of the nasal spray to each nostril three times daily. The nasal spray contains a D 50 , D of about 30 μm to about 50 μm 90 and wherein less than about 3% of the droplets in the plume of the spray have a size of less than about 10 μm. Subjects experienced reduced confusion and improved concentration after administration of the donepezil composition.

[0219] Example 8 Soft Mist Nasal Spray Characteristics

[0220] The soft mist nasal spray device was tested to determine the spray characteristics of the soft mist nasal spray during actuation. An automated system was used to test either three or six devices. The stroke lengths of the actuation of the nasal spray device were 4.6 mm, 4.8 mm, and 4.9 mm. The actuator stroke (AS) acceleration was approximately 500 millimeters per second. 2 (mm / s 2). The AS speeds were 1, 2, 3 or 4 millimeters per second (mm / s). The average hold time (i.e., the average amount of time to depressurize the spray device) was 684 milliseconds (ms). Each experiment was tested with 3 or 6 dose shots per AS speed for each device. The devices were primed with several movements before testing. The compositions were tested with a formulation containing 2.8 mg / ml theophylline, preservatives (benzalkonium chloride and phenylethyl alcohol) and saline. The spray devices had 48 nozzle holes with a size of 4 μm and a cone angle of 20° per nozzle hole. The box and whisker graphs in Figures 3-6 and 8-13 are explained as follows: The boxes are the 25th to 75th percentile range. The line within the box is the median (50th percentile). The whiskers are the maximum and minimum values ​​unless considered outliers, which are indicated by circles. The whiskers do not indicate that the first quartile is equal to the minimum and the third quartile is equal to the maximum.

[0221] The metered shot weights (delivered amount in mg) are shown in Figure 3, which illustrates a box graph showing the metered shot weights (delivered amount in milligrams (mg)) from the soft mist pump device on the Y-axis at various actuation 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. Actuation speeds of 2 mm / s and 3 mm / s were within about 20% of the target shot weight of 45 mg.

[0222] The delivered shot weights (delivered amount in mg) are shown in Figure 4, which illustrates a box graph showing the delivered shot weights (delivered amount in milligrams (mg)) from a soft mist pump device on the Y-axis at various actuation 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. Actuation speeds of 1 mm / s, 2 mm / s and 3 mm / s were within about 20% of the target shot weight of 45 mg.

[0223] The spray plume geometry at a pattern distance of 60 mm is shown in Figure 5. Figure 5 illustrates a box graph showing the performance of plume geometry (plume angle (degrees) and plume width (mm)) from the soft mist pump device on the Y-axis at various operating speeds (1, 2, 3 millimeters per second (mm / s)) on the X-axis at a stroke length of 4.8 mm. The plume angles ranged from about 15 degrees to about 40 degrees. The plume widths ranged from about 15 mm to about 45 mm. Several spray patterns such as 1 iteration at 1 mm / s for device #11, and 2 iterations at 1 mm / s for device #13 could not be determined.

[0224] The spray pattern performance at 30mm and 60mm is shown in Figure 6. Figure 6 illustrates a box graph showing spray pattern characteristics of Dmax (mm), Dmin (mm), ellipticity and area (mm^2) on the Y-axis at various operating speeds (2mm / s and 3mm / s) on the lower X-axis at pattern distances of 30mm and 60mm shown on the upper X-axis with a stroke length of 4.8mm. For the spray distance at 30mm, Dmax (maximum diameter) was about 15-20mm, Dmin (minimum diameter) was about 14mm, ellipticity was about 1.1-1.3, and area was about 180-200mm^2. For the spray distance at 60mm, Dmax (maximum diameter) was about 30-50mm, Dmin (minimum diameter) was about 20-30mm, ellipticity was about 1.1-1.8, and area was about 600-1000mm^2. At 60 mm, repetition of device #13 at 2 mm / sec did not result in a quantifiable pattern.

[0225] The spray patterns at pattern distances of 30 mm and 60 mm are shown in FIG. 7. FIG. 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 cases, the spray pattern parameters at 60 mm could not be calculated due to dissipation of the spray that occurred at 60 mm. Images were captured by a non-colliding laser method on a Proveris Sprayview instrument. The non-colliding laser method projects a sheet of laser light, generating an image of the concentration of droplets passing through the plane of the laser light.

[0226] The droplet size distribution at pattern distances of 30 mm and 60 mm is shown in Figure 8. Figure 8 illustrates a box graph showing droplet size distribution (% volume < 10 μm; span; D90 value (μm); and D50 value (μm)) on the Y axis at various operating speeds (2 mm / s and 3 mm / s) on the lower X axis at pattern distances of 30 mm and 60 mm shown on the upper X axis at a stroke length of 4.8 mm. For the spray device at 30 mm, the % volume < 10 μm is about 0.25% to about 2%, the span is about 0.8 to about 1.6, and the D 90 The value is about 30 to 55 μm, and D 50 The values ​​were about 21 to 28 μm. For the spray device at 60 mm, the % volume <10 μm was less than about 1%, the span was about 0.8 to about 1.2, and D 90 The value is about 40 to 50 μm, D 50 The value was about 26 to 30 μm.

[0227] The plume geometry at a pattern distance of 60 mm is shown in FIG. 9. FIG. 9 illustrates a box graph showing the performance (plume angle (degrees) and plume width (mm)) of the plume geometry on the Y-axis at various operating speeds (1, 2, 3 millimeters per second (mm / s)) on the lower X-axis at 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 about 25-40 degrees and the plume width was about 25-40 mm. At a stroke length of 4.8 mm, the plume angle was about 15-40 degrees and the plume width was about 15-40 mm. In some cases, spray was not detected at a speed of 1 mm / s.

[0228] The spray pattern performance at a pattern distance of 30 mm is shown in FIG. 10. FIG. 10 illustrates a box graph showing the spray pattern (Dmax (mm), Dmin (mm), ellipticity and area (mm^2)) on the Y axis at various operating speeds (2 and 3 mm / s) on the lower X axis at stroke lengths of 4.6 mm and 4.8 mm on the upper X axis. At a stroke length of 4.6 mm, Dmax was about 16-20 mm, Dmin was about 13-14.5 mm, ellipticity was about 1.1-1.4, and area was about 170-210 mm^2. At a stroke length of 4.8 mm, Dmax was about 16-20 mm, Dmin was about 13.5-14.75 mm, ellipticity was about 1.1-1.3, and area was about 170-210 mm^2.

[0229] The spray pattern performance at a pattern distance of 60 mm is shown in FIG. 11. FIG. 11 illustrates a box graph showing the spray pattern (Dmax (mm), Dmin (mm), ellipticity and area (mm^2)) on the Y axis at various operating speeds (2 and 3 mm / s) on the lower X axis at stroke lengths of 4.6 mm and 4.8 mm on the upper X axis. At a stroke length of 4.6 mm, Dmax was about 30-45 mm, Dmin was about 21-32 mm, ellipticity was about 1.1-1.6, and area was about 500-1200 mm^2. At a stroke length of 4.8 mm, Dmax was about 30-50 mm, Dmin was about 24-32 mm, ellipticity was about 1.1-1.8, and area was about 600-1000 mm^2. In some cases, the spray pattern parameters at 60 mm could not be calculated due to dissipation of the spray at the 60 mm distance.

[0230] The droplet size distribution at a spray distance of 30 mm is shown in Figure 12. Figure 12 shows the droplet size distribution (% volume < 10 μm; span; D) on the Y axis at stroke lengths of 4.6 mm and 4.8 mm on the upper X axis and at various operating speeds (2 and 3 mm / s) on the lower X axis. 90 value (μm); and D 50 A box graph showing the volume < 10 μm is about 0.5 to 2%, the span is about 0.8 to about 1.6, and the D 90 The value is about 35 to 52 μm, and D 50 The values ​​were about 21 to 26 μm. At a stroke length of 4.8 mm, the % volume < 10 μm was about 0.25 to 1.75%, the span was about 0.8 to about 1.6, and the D 90 The value is about 30 to 55 μm, and D 50 The values ​​were approximately 21 to 27 μm.

[0231] The droplet size distribution at a spray distance of 60 mm is shown in Figure 13. Figure 13 shows the droplet size distribution (% volume < 10 μm; span; D) on the Y axis at stroke lengths of 4.6 mm and 4.8 mm on the upper X axis and at various operating speeds (2 and 3 mm / s) on the lower X axis. 90 value (μm); and D 50 A box graph showing the percent volume <10 μm is less than 2.5%, the span is about 0.8 to about 1.4, and the D 90 The value is about 36 to 63 μm, and D 50 The values ​​were about 23 to 34 μm. At a stroke length of 4.8 mm, the % volume < 10 μm was less than about 1%, the span was about 0.8 to about 1.1, and the D 90 The value is about 40 to 50 μm, D 50 The value was about 25 to 30 μm.

[0232] A summary of the droplet size distribution is shown in Table 3, which shows the droplet size distribution by pattern 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 D10 value (μm), D50 value (μm), D90 value (μm), percent volume < 10 μm, percent volume < 5 μm and span are shown for the replicates of the tested devices.

[0233] [Table 3]

[0234] Example 9 Treatment of chemosensory dysfunction in Parkinson's disease

[0235] An adult human male subject is treated for chemosensory dysfunction associated with Parkinson's disease. For two years prior to treatment, the subject has no ability to taste or smell. The subject is administered approximately 0.4ml of a liquid composition containing theophylline at a concentration of 3.1mg / ml per day in a nasal spray device as described herein. The subject is administered nasal spray twice a day in each nostril. The subject regains the ability to taste and smell after using the spray device for 7 days.

[0236] Example 10 Non-aqueous nasal formulations of theophylline

[0237] Two non-aqueous theophylline formulations were developed and are shown in Tables 4 and 5. In some cases, the drug concentration (e.g., PDE inhibitor) in the formulation can be as high as 12 mg / mL. The formulations can be used with the nasal spray devices described herein.

[0238] [Table 4]

[0239] [Table 5]

[0240] While preferred embodiments of the present disclosure have been shown and described herein, such embodiments are provided by way of example only, and it should be understood that various alternatives to the embodiments of the disclosure described herein can be employed in practicing the present disclosure.

Claims

1. 1. A liquid pharmaceutical composition for use in the treatment of Parkinson's disease, said liquid pharmaceutical composition comprising: a) a phosphodiesterase (PDE) inhibitor or a salt thereof, and b) a pharmaceutically acceptable carrier, excipient, diluent, or any combination thereof; wherein the liquid pharmaceutical composition, upon intranasal administration to the subject by actuation of a nasal spray device containing the liquid pharmaceutical composition, forms a plume comprising a plurality of droplets, the plurality of droplets having a D of about 35 μm to about 45 μm. ９０ and about 90% of the droplets in the plume are ９０ A liquid pharmaceutical composition characterized in that it has a size of less than 1000 mg / ml.

2. The plurality of droplets have a D of about 20 μm to about 30 μm ５０ and about 50% of the droplets in the plume have a diameter of D ５０ 2. The liquid pharmaceutical composition for use according to claim 1, further characterized in that it has a size of less than 1000 μg / ml.

3. The above D ５０ 3. The liquid pharmaceutical composition for use according to claim 1 or 2, wherein the particle size is about 23 μm.

4. 2. The liquid pharmaceutical composition for use according to claim 1, wherein the droplet size is measured by laser diffraction.

5. 2. The liquid pharmaceutical composition for use according to claim 1, wherein the PDE inhibitor or the salt thereof comprises a selective PDE inhibitor, a non-selective PDE inhibitor, or a salt of any of these, and optionally the PDE inhibitor or the salt thereof comprises theophylline, ibudilast, rolipram, roflumilast, papaverine, or a salt of any of these.

6. 10. The liquid pharmaceutical composition for use according to claim 1, wherein the plume formed by actuation of the nasal spray device lasts for about 0.5 seconds to about 5 seconds from the start of spraying to the end of the spraying.

7. 7. The liquid pharmaceutical composition for use according to claim 6, wherein said actuation comprises an actuation volume of liquid of about 10 μl to about 200 μl or about 20 μl to about 80 μl.

8. 2. The liquid pharmaceutical composition for use according to claim 1, wherein the pharmaceutically acceptable carrier comprises water.

9. The liquid pharmaceutical composition a) viscosity improvers, b) excipients, and / or c) Preservatives 2. The liquid pharmaceutical composition for use according to claim 1, further comprising:

10. 10. The liquid pharmaceutical composition for use according to claim 1, wherein the plume covers: from about 15% to about 50%, from about 10% to about 80%, from about 5% to about 90%, or from about 5% to about 100% of the surface area of ​​the nasal cavity as measured by a nasal cast scan.

11. a) The Parkinson's disease comprises idiopathic Parkinson's disease, familial Parkinson's disease, secondary parkinsonism, Parkinsonian dementia (Parkinson's disease dementia), early-onset Parkinson's disease, early-onset Parkinson's disease, drug-induced parkinsonism, multiple system atrophy, progressive supranuclear palsy, corticobasal syndrome, corticobasal degeneration, essential tremor, dementia with Lewy bodies (dementia with Lewy bodies), vascular parkinsonism, normal pressure hydrocephalus, atypical parkinsonism, or any combination thereof; and / or b) treating Parkinson's disease comprises treating the symptoms of Parkinson's disease, wherein the symptoms of Parkinson's disease comprise chemosensory impairment, tremors, muscle stiffness, muscle rigidity, bradykinesia, balance impairment, posture impairment, loss of motility, coordination impairment, depression, difficulty swallowing, difficulty chewing, speech impairment, urinary problems, constipation, skin problems, speech changes, handwriting changes, poor sleep, difficulty moving, difficulty walking, decreased emotional expression, dizziness, fainting, or any combination thereof; A liquid pharmaceutical composition for use according to claim 1.

12. 10. The liquid pharmaceutical composition for use according to claim 1, further comprising the step of administering a second therapeutic agent, wherein said second therapeutic agent is administered simultaneously with said administration or sequentially.

13. 13. The liquid pharmaceutical composition for use according to claim 12, wherein the second therapeutic agent comprises levodopa, carbidopa, entacapone, tolcapone, opicapone, pramipexole, ropinirole, apomorphine, rotigotine, selegiline, rasagiline, safinamide, amantadine, istradefylline, trihexyphenidyl, benztropine, benserazide, any salt thereof or any combination thereof, optionally wherein the second therapeutic agent comprises levodopa or a salt thereof.

14. 10. The liquid pharmaceutical composition for use according to claim 1, wherein the nasal spray device delivers a plume as a unit dose upon actuation, and optionally the nasal spray device comprises from about 60 to about 120 unit doses, each unit dose comprising from about 10 μg to about 2000 μg of the PDE inhibitor or salt thereof.

15. The plurality of droplets have a D of about 8 μm to about 15 μm. １０ and about 10% of the droplets in the plume have a D １０ 2. The liquid pharmaceutical composition for use according to claim 1, further characterized in that it has a size of less than 1000 μg / ml.

16. The nasal spray device 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. b) the stroke speed of the actuator of the actuation of the nasal spray device is 2 mm / s or 3 mm / s; and / or c) the stroke acceleration of the actuator of said operation of said nasal spray device is about 500 mm / s 2 ; A liquid pharmaceutical composition for use according to claim 1.

17. the nasal spray device a) a nozzle hole size of about 3 μm, about 4 μm, or about 5 μm; and / or b) Approximately 60 nozzle holes 2. The liquid pharmaceutical composition for use according to claim 1, comprising:

Images