Treatment of chemical sensory impairment caused by coronavirus infection

Abstract

To provide treatment of chemosensory dysfunction from a coronavirus infection.SOLUTION: Disclosed herein are methods of treating a taste and smell disorder caused by a viral infection in a subject, comprising administering to the subject a phosphodiesterase inhibitor. Also disclosed herein are methods of treating taste and smell loss from COVID-19 by administering a phosphodiesterase inhibitor to a subject in need thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 62 / 994,172, filed on 24 March 2020, and U.S. Provisional Patent Application No. 63 / 006,489, filed on 7 April 2020, each of which is incorporated herein by reference in whole.

[0002] Built-in by reference All publications, patents, and patent applications referenced herein are incorporated by reference to the same extent as each individual publication, patent, or patent application is specifically and individually indicated as being invoked by reference. To the extent that any publication, patent, or patent application incorporated by reference conflicts with any disclosure contained herein, this Specified is intended to supersede and / or take precedence over any such conflicting material. [Overview of the project] [Means for solving the problem]

[0003] Disclosed herein are methods for treating chemosensory impairment in humans, which may arise at least partially from or during or after a coronavirus infection. In some embodiments, the method may include administering a therapeutically effective amount of a phosphodiesterase (PDE) inhibitor or a pharmaceutically acceptable salt thereof to a human for the treatment of chemosensory impairment. In some embodiments, (i) the coronavirus may include SARS-CoV-2 or a variant thereof, (ii) the PDE inhibitor or a pharmaceutically acceptable salt thereof may be administered in a unit-dose formulation, or (iii) any combination thereof. In some embodiments, a therapeutically effective amount of a PDE inhibitor or a pharmaceutically acceptable salt thereof may be formulated as a liquid formulation, a solid formulation, or a gel formulation. In some embodiments, the PDE inhibitor or a pharmaceutically acceptable salt thereof may be formulated as a liquid formulation, and administration may include the application of the liquid formulation as a nasal irrigation. In some embodiments, the PDE inhibitor or a pharmaceutically acceptable salt thereof may be formulated as a liquid formulation, and administration may include the application of the liquid formulation as an aerosol. In some embodiments, a PDE inhibitor or a pharmaceutically acceptable salt thereof may be formulated as a solid dosage form, and administration may include the application of the solid dosage form as a powder aerosol. In some embodiments, a PDE inhibitor or a pharmaceutically acceptable salt thereof may be formulated as a gel dosage form, and administration may include the application of the gel dosage form by contacting at least a portion of the nasal cavity with the gel dosage form. In some embodiments, administration may include intranasal application of the liquid, solid, or gel dosage form to one or both nostrils. In some embodiments, administration may be performed during or after a coronavirus infection. In some embodiments, the method may further include a second administration.In some embodiments, the second administration may include remdesivir, chloroquine, lopinavir, ritonavir, favilavir, interferon-beta, antiviral agents, oxygen, or any combination thereof. In some embodiments, the administration may be at least once, twice, or three times within a 24-hour period. In some embodiments, chemosmia may include anosmia, hyposmia, ageusia, dysosmia, parosmia, phantosmia, or any combination thereof. In some embodiments, the PDE inhibitor or a pharmaceutically acceptable salt thereof may be theophylline or a pharmaceutically acceptable salt thereof, roflumilast or a pharmaceutically acceptable salt thereof, cilostazol or a pharmaceutically acceptable salt thereof, any derivative thereof or a pharmaceutically acceptable salt thereof, or any combination thereof. In some embodiments, the therapeutically effective dose may include a practical amount of a PDE inhibitor or a pharmaceutically acceptable salt thereof in amounts of less than about 100 mg, less than about 10 mg, less than about 1 mg, less than about 500 μg, or less than about 100 μg. In some embodiments, administration of a PDE inhibitor or a pharmaceutically acceptable salt thereof may result in blood concentrations of the PDE inhibitor or a pharmaceutically acceptable salt thereof of less than about 10 mg / dl, less than about 1 mg / dl, or less than about 100 μg / dl during the course of treatment. In some embodiments, the PDE inhibitor or a salt thereof may include theophylline or a pharmaceutically acceptable salt thereof. In some embodiments, after administration and during the course of treatment, theophylline, theophylline metabolites, N-demethylated theophylline, or any combination thereof may be present in the blood in amounts of less than about 10 mg / dl, less than about 1 mg / dl, or less than about 100 μg / dl.In some embodiments, human salivary or nasal mucus cAMP or cGMP levels can increase by at least about 10% after approximately 30 days of continuous treatment with a therapeutically effective dose of a PDE inhibitor or a pharmaceutically acceptable salt thereof, compared to these levels in humans before administration. In some embodiments, human smell acuity can increase by at least about 5% after approximately 30 days of continuous treatment with a therapeutically effective dose of a PDE inhibitor or a pharmaceutically acceptable salt thereof, compared to these levels in humans before administration, as measured by the detection threshold (DT). In some embodiments, human smell acuity can increase by at least about 5% after approximately 30 days of continuous treatment with a therapeutically effective dose of a PDE inhibitor or a pharmaceutically acceptable salt thereof, compared to these levels in humans before administration, as measured by the recognition threshold (RT). In some embodiments, olfactory acuity in humans can be increased by at least about 5% after approximately 30 days of continuous treatment with a therapeutically effective dose of a PDE inhibitor or a pharmaceutically acceptable salt thereof, compared to these levels in humans before administration, as measured by magnitude estimation (ME). In some embodiments, olfactory acuity in humans can be increased by at least about 5% after approximately 30 days of continuous treatment with a therapeutically effective dose of a PDE inhibitor or a pharmaceutically acceptable salt thereof, compared to these levels in humans before administration, as measured by hedonic method (H). In some embodiments, chemosensory impairment can be diagnosed by detecting subthreshold levels of sonic hedgehog in a human-derived biological sample, by detecting subthreshold levels of cyclic nucleotides in a human-derived biological sample, or by any combination thereof. In some embodiments, chemosensory impairment can be diagnosed by determining a detection threshold, determining a recognition threshold, and by magnitude estimation for at least one of pyridine, nitrobenzene, thiophene, and amyl acetate. In some embodiments, the formulation may include excipients. In some embodiments, the excipient may include water.In some embodiments, a PDE inhibitor or a pharmaceutically acceptable salt thereof may be administered in a unit dose form. In some embodiments, the unit dose formulation may be contained within a multi-dose nasal spray device that delivers the unit dose in a plume when activated. In some embodiments, the plume may have a droplet size distribution. In some embodiments, the droplet size distribution may include (a) less than about 5% of the droplets in the plume having a size of less than about 10 μm, (b) about 10% of the droplets in about 1 plume having a size of less than D10, with a D10 greater than 12.5 μm, (c) about 50% of the droplets in the plume having a size of less than D50, with a D50 of about 30 μm, (d) about 90% of the droplets in the plume having a size of less than D90, with a D90 of about 75 μm to about 100 μm, and (e) a span of about 1 to about 6, which can be calculated according to (D90-D10) / D50. In some embodiments, the PDE inhibitor or a pharmaceutically acceptable salt thereof may be theophylline or a pharmaceutically acceptable salt thereof. In some embodiments, the human may be assigned to be male or female at birth. In some embodiments, the human may be about 1 month to about 12 months of age, about 1 year to about 20 years of age, about 15 years to about 50 years of age, about 40 years to about 80 years of age, or about 60 years to about 110 years of age. In some embodiments, the human may have comorbidities. In some embodiments, comorbidities may be selected from the group consisting of schematic heart disease, hypertension, atrial fibrillation, stroke, renal failure, liver disease, cancer, diabetes, respiratory disease, and any combination thereof. In some embodiments, the comorbidity may be a respiratory disease. In some embodiments, the respiratory disease may be selected from asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, lung cancer, cystic fibrosis, pneumonia, pleural effusion, or any combination thereof. In some embodiments, coronavirus infection may originate from SARS-CoV-2 virus, SARS-CoV virus, MERS-CoV virus, HKU1 virus, OC43 virus, NL63 virus, 229E virus, or any combination thereof. [Modes for carrying out the invention]

[0004] Unless otherwise specified, open terms such as "contain," "containing," "include," and "including" mean "comprising."

[0005] This specification discloses methods of treatment involving the administration of phosphodiesterase (PDE) inhibitors, salts thereof, or combinations of PDE inhibitors or salts thereof. Where otherwise disclosed, the term "PDE inhibitor" may refer to compounds that can at least partially inhibit the function of PDE polypeptides, such as PDE1, PDE2, PDE3, PDE4, PDE5 polypeptides, or any combination thereof.

[0006] The PDE2 polypeptide can reduce aldosterone secretion. Such a reduction can play a crucial role in regulating elevated intracellular concentrations of cAMP and cGMP in platelets. Several regions of the brain can express PDE2, and rat experiments have shown that inhibition of PDE2 can enhance memory. Because PDE2 can localize to microvessels, particularly venous capillaries and endothelial cells, it may play a role in regulating fluid and cell overflow during inflammatory states. PDE2 may also be a good pharmacological target for pathological conditions such as sepsis, or for more localized inflammatory responses such as thrombin-induced edema formation in the lungs.

[0007] The PDE3 family hydrolyzes cAMP and cGMP, but in a sense, this suggests that in vivo, the hydrolysis of cAMP may be inhibited by cGMP. These can also be distinguished by their ability to be activated by several phosphorylation pathways, including the PKA and PI3K / PKB pathways. PDE3A can be expressed relatively highly in platelets, as well as cardiomyocytes and oocytes. PDE3B may be the major PDE in adipose tissue, liver, and pancreas, as well as in some cardiovascular tissues. Both PDE3A and PDE3B can be highly expressed in vascular smooth muscle cells and are likely to modulate contraction. PDE5 may be the best known regulator of vascular smooth muscle contraction, being the molecular target of several well-promoted drugs used to treat erectile dysfunction and pulmonary hypertension. In the lung, inhibition of PDE5 can counteract smooth muscle vasoconstriction, and PDE5 inhibitors are in clinical trials for the treatment of pulmonary hypertension.

[0008] Examples of PDE inhibitors include, for example, Filaminast, Picramilast, Rolipram, Org20241, MCI-154, Loflumilast, Tovorinone, Posical, Lixazinone, Zaprinast, Sildenafil, Pyrazolopyrimidinone, Motapizone, Pimobendan, Zardaverine, Siguazodane, CI-930, EMD53998, Imazodane, Saterinone, Lopurinone hydrochloride, 3-Pyridinecarbonitride derivatives, Dembuphylline, Albiphylline, Tolvaphylline, Doxophiline, Theophylline. Examples include pentophylline, nantherinone, cilostazol, cilostamide, MS857, pyroximon, milrinone, aminone, trafentrin, dipyridamole, papaverine, E4021, thienopyrimidine derivatives, triflusal, ICOS-351, tetrahydropiperazino[1,2-b]beta-carbolin-1,4-dione derivatives, carbolin derivatives, 2-pyrazolin-5-one derivatives, condensed pyridazine derivatives, quinazoline derivatives, anthranilic acid derivatives, and imidazoquinazoline derivatives. In some embodiments, one or more PDE inhibitors, or salts thereof, can be formulated into an intranasal administration composition. In some embodiments, the composition may contain a nonspecific PDE inhibitor or a salt thereof. In some embodiments, the composition may contain a PDE inhibitor or a salt thereof that is selective for a PDE subtype, e.g., PDE:1, 2, 3, 4, or 5. In some embodiments, the intranasal composition does not contain a PDE5 selective inhibitor. In some embodiments, the composition may be in liquid, power, solid, or gel form. In some embodiments, the PDE inhibitor or a salt thereof may be administered 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 embodiments, the formulation may be in unit dose form. In some embodiments, the formulation may contain a second active ingredient such as a corticosteroid, or an antihistamine, or a vasoconstrictor, or any combination thereof. In some embodiments, the formulation may not contain a second active ingredient. In some cases, the formulation may be a pharmaceutical composition. In some cases, the composition may be a pharmaceutical composition.

[0009] PDE inhibitors may be selective PDE inhibitors or nonspecific PDE inhibitors. Selective PDE inhibitors may include PDE1 selective inhibitors, PDE2 selective inhibitors, PDE3 selective inhibitors, PDE4 selective inhibitors, or PDE5 selective inhibitors. In some cases, selective PDE inhibitors may be specific to one or more of PDE1, PDE2, PDE3, PDE4, and PDE5. Nonspecific PDE inhibitors may include PDE inhibitors that inhibit at least two, three, four, or five of PDE1, PDE2, PDE3, PDE4, and PDE5.

[0010] PDE inhibitors can inhibit cell apoptosis by inhibiting TNF-alpha, TRAIL, and their metabolites. PDE inhibitors can activate the production and secretion of nitric oxide in all tissues, thereby inducing vasodilation or vasodilation in all blood vessels, including peripheral blood vessels (inhibiting intermittent claudication), distal limbs, and penile vessels contributing to penile erection.

[0011] Nonspecific PDE inhibitors may include theophylline, papaverine caffeine, IBMX (3-isobutyl-1-methylxanthine, aminophylline, doxophiline, cipamphylline, theobromine, pentoxifylline (oxpentifylline), and diprophylline. Theophylline is a methylxanthine derivative that, when administered as described herein, may have anti-inflammatory effects on the airways and may be useful in addressing the abnormal inflammation seen in asthma. In some cases, the anti-inflammatory effect may be achieved when theophylline is prescribed or administered at levels that produce systemic levels of theophylline in the blood that are far lower than those that cause side effects. Patients with emphysema and chronic bronchitis may also benefit from theophylline if their symptoms are partially related to reversible airway narrowing.

[0012] PDE1 selective inhibitors, formerly known as calcium and calmodulin-dependent phosphodiesterases, can include ebrunamenin-14-carboxylate ethyl ester (vinpocetine). In some cases, vinpocetine can be used to induce vasodilation in brain smooth muscle tissue.

[0013] PDE2 selective inhibitors include EHNA (erythro-9-(2-hydroxy-3-nonyl)adenine), 9-(6-phenyl-2-oxohexa-3-yl)-2-(3,4-dimethoxybenzyl)-purine-6-one (PDP), and BAY60-7750.

[0014] Selective PDE3 inhibitors may include enoximon, milrinone (Primacor), amrinone, cilostamide, cilostazol (Pletal), and trekincin. When administered as described herein, PDE3 inhibitors can induce sympathetic nerve stimulation to increase cardiac inotropy, chronotropy, and dromotropy. When administered as described herein, PDE3 inhibitors can also antagonize platelet aggregation, increase myocardial contractility, and enhance vascular and airway smooth muscle relaxation. PDE3A may be a regulator of this process. When administered as described herein, PDE3 inhibitors can effectively prevent aggregation. Cilastazol (Pletal) is approved for the treatment of intermittent claudication. Its mechanism of action may involve inhibition of platelet aggregation, along with inhibition of smooth muscle proliferation and vasodilation.

[0015] Examples of PDE4 selective inhibitors include mesembrine, rolipram, ibudilast (i.e., a neuroprotective agent and bronchodilator that can be used for the treatment of asthma and stroke), and roflumilast (Daxas) and cilomilast (Airflo) (i.e., PDE4 selective inhibitors that can be administered for the treatment of chronic obstructive pulmonary disease). PDE4 selective inhibitors can at least partially inhibit the release of inflammatory mediators, such as cytokines, or can at least partially inhibit the production of reactive oxygen species and immune cell infiltration. PDE4 inhibitors can also be used for the treatment of asthma, arthritis, and psoriasis.

[0016] Examples of PDE5 selective inhibitors include sildenafil, tadalafil, vardenafil, udenafil, and avanafil.

[0017] Definitions The singular forms “a,” “an,” and “the” are used herein to include plural referents unless the context clearly indicates otherwise. Thus, unless indicated to the contrary, the numerical parameters set forth in this application are approximations that may vary depending upon the desired properties to be obtained.

[0018] When used herein, the terms “about” or “approximately” may mean within an acceptable margin of error for a particular value as determined by those skilled in the art, and this depends in part on how the value is measured or determined, for example, on the limits of the measuring system. For example, “about” may mean plus or minus 10%, according to convention in the art. Alternatively, “about” may mean a range of plus or minus 20%, plus or minus 10%, plus or minus 5%, or plus or minus 1% of a given value. Or, particularly with respect to biological systems or biological processes, the term may mean within one order of magnitude, within five times, or within two times the value. Where a particular value is described in this application and claims, unless otherwise stated, the term “about” should be assumed to mean within an acceptable margin of error for that particular value. Also, where a range and / or sub-range of a value is provided, the range and / or sub-range may include the endpoints of the range and / or sub-range. When used herein, the term “substantially” may mean a value that approaches 100% of a given value. In some cases, this term can refer to an amount that may be at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, or 99.99% of the total amount. In some cases, this term can refer to an amount that may be about 100% of the total amount.

[0019] Terms such as “administer,” “administering,” and “administration,” as used herein, may refer to methods that may be used to enable the delivery of a compound or its salts or compositions to a desired site of action. Delivery may include direct application that affects tissues or areas of the body. The compositions provided herein may be administered by any method. Methods of administration may include inhalation, intra-arterial injection, intraventricular injection, intracisional injection, intramuscular injection, intraorbital injection, intraparenchymal injection, intraperitoneal injection, intraspinal injection, intrathecal injection, intravenous injection, intracardiac injection, stereotactic infusion, subcutaneous injection, or any combination thereof. Delivery may include parenteral administration (including intravenous, subcutaneous, intrathecal, intraperitoneal, intramuscular, intravascular, or infusion), oral administration, nasal administration, inhalation administration, duodenal administration, and rectal administration. Delivery may include topical administration to the external surface of a surface such as the skin (e.g., lotions, creams, gels, liquids, solids, powders, ointments). In some cases, a subject may be administered a compound, its salt, or composition in the absence of supervision. In some cases, a subject may be administered a composition under the supervision of a medical professional (e.g., a physician, nurse, medical assistant, ward staff, hospice staff, etc.). In some cases, a medical professional may administer the composition. In some cases, a cosmetic professional may administer the composition.

[0020] As used herein, “treating” a chemical impairment may include reducing the frequency or severity of one or more symptoms, eliminating one or more symptoms or their underlying causes, or improving or repairing damage. For example, treatment of a chemical impairment may include increasing the sensitivity of smell and taste in patients with coronavirus infections, such as COVID-19 patients, and / or causing regression or disappearance of the chemical impairment.

[0021] "Therapeutic dose" can refer to the amount of a compound or a salt thereof, with or without additional agents, that is effective in achieving its intended purpose. Individual patient needs may vary. Generally, the dose required to provide an effective amount of a compound, a salt thereof, or a composition containing one or both of these, and which can be adjusted by those skilled in the art, will vary depending on age, health, physical condition, sex, weight, the degree of the recipient's impairment, the frequency of treatment, and the nature and extent of the impairment.

[0022] The terms “subject,” “host,” “individual,” and “patient” are used interchangeably herein to refer to animals, typically mammals. Any suitable mammal may be administered with or treated with any of the compounds, salts, or compositions described herein. Non-limiting examples of mammals include humans, non-human primates (e.g., apes, gibbons, chimpanzees, orangutans, monkeys, macaques, etc.), domesticated animals (e.g., dogs and cats), livestock (e.g., horses, cattle, goats, sheep, pigs), and laboratory animals (e.g., mice, rats, rabbits, guinea pigs). Mammals may be of any age or any developmental stage; for example, a mammal may be a neonatal, infant, adolescent, adult, or in utero. In some embodiments, the mammal is a human. Humans may be approximately 1, 2, 5, 10, 20, 30, 40, 50, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, or over approximately 120 years of age. Humans may be approximately 1, 2, 5, 10, 20, 30, 40, 50, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, or under approximately 120 years of age. In some cases, humans may be under approximately 18 years of age. In some cases, humans may be over approximately 18 years of age. Mammals, such as humans, may be male or female.

[0023] As used herein, a reference to a PDE inhibitor, or to a particular PDE inhibitor, generally includes a reference to any salt, solvate, ester, or polymorph of the PDE inhibitor. “Salt” may include pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts include salts prepared by the reaction of compounds disclosed herein with minerals, organic acids, or inorganic bases, such as acetates, acrylates, adipicates, alginates, aspartates, benzoates, benzenesulfons, bisulfates, bisulfites, tartrates, bromides, butyrates, butyn-1,4-dioate, camphorates, camphor sulfons, capronates, caprylates, chlorobenzoates, chlorides, citrates, cyclopentanepropionates, decanoates, diglucons, dihydrogen phosphates, dinitrobenzoates, dodecyl sulfates, ethanesulfons, formates, fumarates, glucohepanoates, glycerophosphates, glycolates, hemisulfates, heptanoates, hexanoates, hexyn-1,6-dioate, hydroxybenzoates, γ-hydroxybutyrates, hydrochlorides, and hydrogen bromide. Examples include salts, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberinate, sebacinate, sulfonate, tartrate, thiocyanate, tosylate, undeconate, and xylenesulfonate.Furthermore, the compounds disclosed herein include, in their free base form, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and 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-hydroxyethanesulfonic acid, and benzoic acid. Examples of pharmaceutically acceptable organic acids include, but are not limited to, oxalen sulfonic acid, 2-naphthalene sulfonic acid, 4-methylbicyclo[2.2.2]octa-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-salt-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid, and can be prepared as pharmaceutically acceptable salts formed by reacting them with pharmaceutically acceptable inorganic or organic acids. Other acids, such as oxalic acid, are not pharmaceutically acceptable in themselves, but can be used to prepare salts that are useful as intermediates in obtaining compounds and / or pharmaceutically acceptable acid addition salts. In some embodiments, compounds disclosed herein that may contain free acid groups react with suitable bases, such as pharmaceutically acceptable metal cation hydroxides, carbonates, bicarbonates, sulfates, ammonia, or pharmaceutically acceptable organic primary, secondary, or tertiary amines. Typical alkali or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts. Exemplary examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, and N. + (C 1~4Examples include alkyl)4. Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, and piperazine. It should be understood that the compounds disclosed herein may also include quaternization of any basic nitrogen-containing group they contain. In some embodiments, water-soluble, oil-soluble, or dispersible products can be obtained by such quaternization. The compounds disclosed herein may be prepared as pharmaceutically acceptable salts formed when an acidic proton present in the parent compound can be substituted with a metal ion, such as an alkali metal ion, an alkaline earth ion, or an aluminum ion, or can be coordinated with an organic base. In some embodiments, the base addition salts may also be prepared by reacting the free acid form of the compounds disclosed herein with a pharmaceutically acceptable inorganic or organic base, including but not limited to organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, and N-methylglucamine, and inorganic bases such as aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydroxide. Furthermore, the salt forms of the disclosed compounds can be prepared using salts of the starting materials or intermediates.

[0024] Treatment method Disclosed herein are methods for treating chemosensory impairment in humans. In some cases, chemosensory impairment may result at least partially from or during or after a coronavirus infection, such as SARS-CoV-2. In some cases, the method may include administering a therapeutically effective dose of a phosphodiesterase (PDE) inhibitor or a pharmaceutically acceptable salt thereof to a human being to treat chemosensory impairment. In some cases, the coronavirus may include SARS-CoV-2 or a variant thereof that can cause the disease COVID-19. In some cases, the PDE inhibitor or a pharmaceutically acceptable salt thereof may be administered in formulation in unit dose form.

[0025] Disclosed herein are methods for treating a condition by administering a PDE inhibitor or a salt thereof as described herein. In some cases, administration may include administering a PDE inhibitor or a salt thereof in unit dose form. In some embodiments, typical daily intranasal, lingual, or pulmonary dosages are of an active ingredient containing a compound (i.e., a PDE inhibitor) in an amount of approximately 1.0 μg to 2000 mg per day, approximately 1.0 μg to 500.0 mg per day, approximately 10 μg to 100.0 mg per day, approximately 10 μg to 10 mg per day, approximately 10 μg to 1.0 mg per day, approximately 10 μg to 500 μg per day, or approximately 1 μg to 50 μg per day. These dosage ranges represent the total daily dosage of the active ingredient for a given patient. In some embodiments, the daily dose may be approximately: 2000 mg per day, 1000 mg per day, 500 mg per day, 100 mg per day, 10 mg per day, 1.0 mg per day, 500 μg per day, 300 μg per day, 200 μg per day, 100 μg per day, or less than 50 μg per day. In some embodiments, the daily dose may be at least approximately: 2000 mg per day, 1000 mg per day, 500 mg per day, 100 mg per day, 10 mg per day, 1.0 mg per day, 500 μg per day, 300 μg per day, 200 μg per day, 100 μg per day, or 50 μg per day. In some embodiments, preferred dosage levels of the compound per kilogram may be about 0.001 μg / kg to about 10.0 mg / kg of body weight per day, about 0.5 μg / kg to about 0.5 mg / kg of body weight per day, about 1.0 μg / kg to about 100 μg / kg of body weight per day, and about 2.0 μg / kg to about 50 μg / kg of body weight per day. In some embodiments, preferred dosage levels per kilogram may be about 10.0 mg / kg of body weight per day, 1 mg / kg of body weight per day, 500 μg / kg of body weight per day, 100 μg / kg of body weight per day, 10 μg / kg of body weight per day, or less than 1.0 μg / kg of body weight per day.In some embodiments, preferred dosage levels per kilogram 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 of the active ingredient, or 1.0 μg / kg body weight per day of the compound.

[0026] In some cases, the dose administered may be the same as, or less than, the dose administered to treat a particular disease. Dosage may be once daily, or several times or more times daily. For example, a PDE inhibitor or a salt thereof may be administered two, three, four, five, six, seven, eight, nine, ten times, or more times daily. In some cases, the composition may be administered once, two, or three times within a 24-hour period. In some cases, a PDE inhibitor or a salt thereof may be administered over a period of about one day, two days, three days, four days, five days, six days, seven days, one week, two weeks, three weeks, four weeks, five weeks, one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, twelve months, one year, two years, or for a lifetime. The amount of drug administered in the method of carrying out the present invention depends, of course, on the subject being treated, the severity of pain, the method of administration, and the judgment of the prescribing physician. The dose used in carrying out the present invention can produce the desired therapeutic or preventive effect without causing serious side effects.

[0027] In some embodiments, administration of an effective dose of a PDE inhibitor by intranasal, lingual, or pulmonary administration does not produce a detectable blood level of the PDE inhibitor. In some embodiments, administration of an effective dose of a PDE inhibitor by intranasal, lingual, or pulmonary administration produces blood concentrations of the PDE inhibitor of approximately 5 mg / dl, 2 mg / dl, 1 mg / dl, 500 μg / dl, 250 μg / dl, 100 μg / dl, 50 μg / dl, 25 μg / dl, 10 μg / dl, 5 μg / dl, or less than 1 μg / dl. In some embodiments, administration of an effective amount of PDE inhibitor by intranasal, lingual, or pulmonary administration results in blood concentrations of the PDE inhibitor of approximately 2 mg / dl, 1 mg / dl, 500 μg / dl, 250 μg / dl, 100 μg / dl, 50 μg / dl, 25 μg / dl, 10 μg / dl, 5 μg / dl, or greater than 1 μg / dl.

[0028] In some embodiments, administration of an effective dose of a PDE inhibitor or a salt thereof can increase salivary and / or nasal mucus cAMP or cGMP levels in humans by at least about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, or about 50% compared to these levels in humans before administration of a therapeutically effective dose of a PDE inhibitor or a pharmaceutically acceptable salt thereof. In some cases, an increase in salivary and / or nasal mucus cAMP or cGMP levels is observed approximately 1 to 10 days, 15 to 45 days, or 30 days after sequential treatment with a therapeutically effective dose of a PDE inhibitor or a pharmaceutically acceptable salt thereof.

[0029] Treatment methods include, but are not limited to, oral administration, transmucosal administration, oral administration, nasal administration such as inhalation, parenteral administration, intravenous, subcutaneous, intramuscular, sublingual, transdermal administration, and rectal administration. In some embodiments, the composition may be administered as a liquid nasal lavage solution, aerosol, powder aerosol, or a combination thereof. In some cases, administration may include intranasal application in one or both nostrils. In some embodiments, a gel composition may be administered into the nostrils. In some embodiments, a liquid composition may be administered as a nasal lavage. In some cases, administration of the composition may be performed during, after, or both during and after a coronavirus infection.

[0030] In some cases, the compositions described herein may be administered together with one or more additional therapeutic agents. For example, a PDE inhibitor or a salt thereof may be administered together with the second therapy. In some cases, the second therapy may be administered simultaneously or sequentially. In some cases, the additional therapeutic agents may include remdesivir, chloroquine, lopinavir, ritonavir, faviravir, interferon-beta, antiviral agents, oxygen, or any combination thereof. In some cases, the additional therapeutic agents may include nitric oxide, steroids, nonsteroidal anti-inflammatory drugs (NSAIDs), or any combination thereof.

[0031] In some cases, the subject may be diagnosed (e.g., diagnosed with chemosensory impairment) before treatment with a PDE inhibitor or a salt thereof. In some cases, the treatment method may include diagnosing chemosensory impairment in the subject. In some cases, the diagnosis may include an in vitro assay. In some cases, chemosensory impairment can be diagnosed by detecting subthreshold levels of sonic hedgehog in a human-derived biological sample. In some cases, the sample may be a nasal or saliva sample. In some cases, chemosensory impairment can be diagnosed by detecting subthreshold levels of cyclic nucleotides in a human-derived biological sample. In some cases, chemosensory impairment can be diagnosed by determining a detection threshold, determining a recognition threshold, and by magnitude estimation for at least one of pyridine, nitrobenzene, thiophene, and amyl acetate.

[0032] In some embodiments, the treatment method is by nasal administration or inhalation. Compositions for inhalation or inhalation include liquid and suspension formulations in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Compositions may be administered orally or via nasal respiratory routes for topical or systemic effects. Preferably, compositions in pharmaceutically acceptable solvents may be sprayed using an inert gas. The sprayed solution may be inhaled directly from a spraying device, or the spraying device may be attached to a face mask tent or an intermittent positive airway pressure (CPAP) device. Solutions, suspensions, or powder compositions may be administered preferably orally or nasally from a device that delivers the formulation in an appropriate manner. In some cases, the device may be a nasal spray device.

[0033] In some embodiments, the subject may be a human. In some embodiments, the subject may have or be suspected of having a disease or condition. The subject may be a patient, such as a patient being treated for a condition or disease such as heart disease, hypertension, atrial fibrillation, stroke, renal failure, liver disease, cancer, diabetes, respiratory disease, asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, lung cancer, cystic fibrosis, coronavirus infection, pneumonia, pleural effusion, or any combination thereof. The subject may be at risk of developing a condition or disease such as a respiratory disease. The subject may be in remission from a condition or disease such as cancer. The subject may be healthy.

[0034] In some embodiments, intranasal or lingual administration of an effective dose of a PDE inhibitor increases taste or smell sensitivity. In some embodiments, the increase in taste or smell sensitivity may be at least about 5%, 10%, 20%, 30%, 40%, 50%, 75%, or 100% compared to the untreated state. In some embodiments, taste or smell sensitivity is increased to at least about 5%, 10%, 20%, 30%, 40%, 50%, 75%, or 100% of the sensitivity of a normal individual. In some cases, the increase in taste or smell sensitivity can be measured at about 10–20 days, about 15–30 days, 25–50 days, 1 month–6 months, or about 6 months–3 years. In some embodiments, the increase in taste or smell sensitivity can be measured at about 30 days. In some embodiments, taste or smell sensitivity can be measured objectively. In some embodiments, taste or smell can be measured subjectively. In some cases, smell can be measured by detection thresholds, recognition thresholds, hedonic methods, magnitude estimation, or any combination thereof.

[0035] When administered in vivo, the compounds, their salts, and compositions may be administered in combination with one or more pharmaceutically acceptable carriers or excipients and in the dosages specified herein. The compounds, their salts, and compositions may be formulated in pharmaceutically acceptable neutral (free base) or salt forms.

[0036] In some embodiments, pharmaceutically acceptable carriers may include, but are not limited to, amino acids, peptides, proteins, non-biological polymers, biological polymers, monosaccharides, carbohydrates, gums, inorganic salts, and metal compounds that may exist alone or in combination. In some embodiments, pharmaceutically acceptable carriers may include native forms, derivatized forms, modified forms, or combinations thereof.

[0037] In some embodiments, the composition or formulation may include excipients. Excipients may include, but are not limited to, one or more of the following: water, fluidizers, lubricants, adhesives, surfactants, acidifiers, alkalizers, pH adjusters, antimicrobial and antiseptic agents, antioxidants, antistatic agents, buffers, chelating agents, wetting agents, gel-forming agents, or wetting agents. Excipients may also include colorants, coating agents, sweeteners, flavoring and fragrance agents, or masking agents. Compositions and formulations may include therapeutic agents having individual excipients, with or without a carrier, or having any preferred combination of multiple excipients. In some cases, the excipients may include glycerol.

[0038] The therapeutically effective dose may refer to the amount of a PDE inhibitor or its salt, with or without additional agents, that is effective in achieving its intended purpose. Individual patient needs may vary. Generally, the dose required to provide an effective amount of a compound, its salt, or a composition containing one or both of these, and which can be adjusted by those skilled in the art, will vary depending on age, health, physical condition, sex, weight, the degree of the recipient's impairment, the frequency of treatment, and the nature and extent of the impairment. Dosage may be in unit dose form.

[0039] The PDE inhibitors or salts thereof described herein can be formulated as aerosols. “Aerosol” can be any composition of a PDE inhibitor administered in an aerosolized formulation, including, for example, an inhalation spray, an inhalation solution, an inhalation suspension, a spray solution, or a nasal spray. The aerosolized formulation delivers a high concentration of the PDE inhibitor to the airways or one or more nasal cavities (nasal cavity). It can be delivered directly to the respiratory tract (e.g., one or both nostrils) and, in some cases, with a low systemic absorption rate. The solution for aerosolization typically contains at least one therapeutically effective PDE inhibitor or a salt thereof dissolved or suspended in an aqueous solution which may further contain one or more excipients (e.g., preservatives, viscosity modifiers, emulsifiers, or buffers). The solution can act as a carrier for the PDE inhibitor or a salt thereof. In some embodiments, the preservative may contain methylparaben or propylparaben. These formulations can deliver the PDE inhibitor to the respiratory tract, for example, by inhalation, to one or both nostrils.

[0040] In some embodiments, PDE inhibitors can be applied directly to the nasal or lingual epithelium as a liquid, cream, lotion, ointment, or gel. These may contain at least one therapeutically effective PDE inhibitor or a salt thereof. In some cases, the formulation may further contain at least one excipient (e.g., a preservative, viscosity modifier, emulsifier, or buffer) which can be formulated for administration such as a nasal spray or application with an applicator to at least a portion of one or more nasal cavities. In some embodiments, the preservative may be methylparaben or propylparaben. The pH of the formulation can be maintained at about 4.5 to about 7.0, or about 5.0 to about 7.0, or about 5.5 to about 6.5. The molar osmotic concentration of the formulation can also be adjusted to a molar osmotic concentration of about 250 to about 350 mosm / L.

[0041] In some embodiments, the phosphodiesterase inhibitor or pharmaceutically acceptable salt may be administered using a multiple-dose nasal spray device that delivers the dosage unit as a plume upon activation. The dosage unit contains an effective amount of a phosphodiesterase inhibitor, a pharmaceutically acceptable salt, an excipient, or any combination thereof. Taste or smell disorders can be chemosensory dysfunction, anosmia, hyposmia, ageusia, hypogeusia, dysosmia, phantosmia, or a combination thereof. The dosage unit may contain a PDE inhibitor or a pharmaceutically acceptable salt thereof, such as theophylline or a pharmaceutically acceptable salt thereof, roflumilast or a pharmaceutically acceptable salt thereof, cilostazol or a pharmaceutically acceptable salt thereof, a derivative of any of these (e.g., solvate, isomer, ester, amide, etc.) or a pharmaceutically acceptable salt thereof, or any combination thereof. The plume can have a droplet size distribution where (a) less than about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, or 9% of the droplets in the plume can have a size less than about 10 μm, (b) the droplets can have a D 10 and about 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15% of the droplets in the plume can have a size less than D 10 , (c) the droplets can have a D 50 of about 30 μm and about 40%, 45%, 50%, 55%, or 60% of the droplets in the plume can have a size less than D 50 , (d) the droplets can have a D 90 of about 75 to about 100 μm and about 80%, 85%, 90%, 95%, or 99% of the droplets in the plume can have a size less than D 90 , (e) the span of the droplet size distribution can be about 1 to about 6, and the span is calculated according to (D 90 -D 10 ) / D 50 . "D 10 ", "D 50 ", "D 90" and "span" are measured values ​​of the droplet or particle size distribution of the plume.

[0042] As used herein, “magnitude estimation” or “ME” may refer to the measurement of an object’s ability to determine the intensity of an irritant, such as an odorant or taste agent.

[0043] As used herein, “recognition threshold” or “RT” may refer to the measurement of an object’s ability to recognize the identity of an irritant such as an odorant or taste agent.

[0044] As used herein, “detection threshold” or “DT” may refer to a measurement of an object’s ability to perceive exposure to an irritant, such as a deodorant or taste agent, as pleasant or unpleasant.

[0045] As used herein, the “hedonic” value or “H” value may refer to the measurement of a subject’s response to an irritant such as a deodorant or flavoring agent, which is deemed undesirable or unpleasant.

[0046] In some cases, the administration of PDE inhibitors described herein can be used to prevent or treat diseases associated with or caused by coronaviruses. Such diseases may include, for example, anosmia, loss of taste, loss of smell, anosmia, loss of taste, osmoticism, paresmia, heterosmia, chemosensory dysfunction, cough, fever, malaise, shortness of breath, runny nose, sore throat, nasal congestion, or any combination thereof. Coronavirus infections may be caused by alpha-coronavirus, beta-coronavirus, gamma-coronavirus, delta-coronavirus, 229E-coronavirus, NL63-coronavirus, OC43-coronavirus, HKU1-coronavirus, MERS-CoV, SARS-CoV, SARS-CoV-2, their variant forms, or any combination thereof. In some cases, viruses such as coronaviruses may mutate. For example, when comparing the coronavirus to a reference sequence, the sequence is approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, Contains 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, and 100 or more nucleotide mutations. In some cases, coronaviruses contain genomes that have approximately 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or more than 99% sequence homology to a reference sequence.In some cases, coronaviruses contain genomes with approximately 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or less than 99% sequence homology to a reference sequence. In some cases, the reference sequence may be a reference sequence from the National Center for Biotechnology Information.

[0047] In some cases, the PDE inhibitors described herein may be used in patients with comorbidities. Such comorbidities include, for example, hypertension, pulmonary hypertension, congestive heart failure, renal failure, myocardial infarction, stable angina, unstable angina, variant (prinzmetallic) angina, atherosclerosis, cardiac edema, heart 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), subvesical urethral obstruction, incontinence, and decreased vascular patency (e.g., Examples include post-percutaneous transluminal coronary angioplasty (PTCA), peripheral vascular disease, respiratory disease, bronchitis, emphysema, lung cancer, cystic fibrosis, pneumonia, pleural effusion, allergic rhinitis, glaucoma, malignant diseases characterized by impaired bowel motility, such as irritable bowel syndrome (IBS), rheumatoid arthritis, bacterial infections, fungal infections, parasitic infections, viral infections, HIV, systemic lupus erythematosus, psoriasis, other autoimmune diseases, Huntington's disease, and amyotrophic lateral sclerosis (ALS), or any combination thereof. Treatment of comorbidities can be achieved by administering a therapeutically effective amount of the compounds and / or compositions described herein to the patient in need of treatment.

[0048] This specification also discloses methods for preparing the compositions described herein. Methods for preparing the compositions may include contacting the compounds or salts thereof described herein with other components described herein (e.g., carriers, diluents, excipients, etc.).

[0049] Example 1 Patients diagnosed with or previously diagnosed with COVID-19 who have at least partial loss of smell or taste related to COVID-19 are treated with intranasal administration of a theophylline-containing preparation, which is administered once daily into each nostril for approximately 30, 60, or 90 days.

[0050] Administration of the formulation results in an increase in the patient's sonic hedgehog level or cyclic nucleotide level over approximately 30, 60, or 90 days. Furthermore, this increase leads to a significant improvement in the patient's sense of taste and smell, and therefore at least partially improves loss of smell and taste.

[0051] Example 2 To treat anosmia in subjects who have recovered from COVID-19, a multi-dose nasal spray device is used that delivers medication units in a plume when activated, where anosmia is caused by COVID-19 and persists despite recovery from COVID-19. The multi-dose spray device is configured to deliver medication units of theophylline, roflumilast, cilostazol, or a combination thereof when administered intranasally by the device. The medication units contain an effective amount of theophylline, roflumilast, cilostazol, or a combination thereof in a pharmaceutically acceptable carrier containing one or more excipients. The plume has a droplet size distribution, where (a) less than approximately 5% of the droplets in the plume have a size of less than approximately 10 μm, and (b) larger than approximately 12.5 μm. 10 (Here, about 10% of the droplets in the plume are D 10 (c) D with a size less than 30 μm 50 (Here, approximately 50% of the droplets in the plume are D 50(d) D having a size less than (d) approximately 75 to approximately 100 μm 90 (Here, approximately 90% of the droplets in the plume are D 90 (e) having a size less than (D) and a span of about 1 to about 6 (where the span is (D) 90 -D 10 ) / D 50 (Calculated according to the following).

[0052] After administering the medication unit using a multi-dose device, the patient is examined and retreated over 30, 60, or 90 days, and the treatment of anosmia is monitored using the increase in the recognition threshold compared to before the initial dose.

[0053] Example 3 Patients first reported sensory dysfunction as either dysgeusia (i.e., loss of flavor) and / or olfactory dysfunction. This subjective response was recorded using a fixed, controlled, and forcibly selected tristimulus, stepwise technique, by objective psychophysical measurements of olfactory function administered to each patient (1, 2). The effectiveness and test results of this technique have been previously documented in a double-blind clinical trial (2). Four odors were used: pyridine (dead fish odor), nitrobenzene (bitter almond odor), thiophene (petroleum-like odor), and amyl acetate (banana oil odor). Detection threshold (DT) and recognition threshold (RT) values ​​for each odor were determined as previously described (1, 2). The thresholds were converted to bottle units (BU) as previously described (2), and the results were reported as M for the correct response to each odor in each treatment group. References: (1) Henkin, RIEvaluation and treatment of human olfactory dysfunction, in Otolaryngology (English, GMEd.), Lip pincott, Philadelphia, 1993, Vol. 2, pp. 1-86. (2) Henkin, RI, Schecter, PJ, Friedewald, WT, DeMets, DL, Raff, MSA double blind study of the effects of zinc sulfate on taste and smell dysfunction. Amer. J. Med. Sci. 1976;272:285-299.

[0054] Theophylline was administered to patients with loss of taste and smell due to COVID-19. A formulation containing 80 μg of theophylline was administered once daily via a nasal spray device in two swift actions. A baseline olfactory test was performed before the first dose of theophylline. A follow-up olfactory test was performed 3 months after the first dose. No adverse events were reported. The results are shown in Table 1. The patient's detection threshold (DT) and recognition threshold (RT) for pyridine (Pyr), nitrobenzene (NO2B), thiophene (Thio), and amyl acetate (AA) were determined pre-treatment (pre) and post-treatment (3M). In all four odor tests, the patient's detection and recognition thresholds improved. An improvement of one bottle unit means that the patient could detect and / or recognize an odor at a concentration 10 times lower than baseline. For example, the recognition threshold (RT) for AA improved by 8 bottle units, which is equivalent to an improvement of 8 orders of magnitude. In this case, the patient could detect and / or recognize an odor at a concentration 10 times lower. 8 Low concentrations of AA were detected. A bottle unit count of 5 or less is considered within the normal range. [Table 1]

[0055] While exemplary embodiments are shown and described herein, such embodiments are merely examples. Many modifications, changes, and substitutions are possible in the exemplary embodiments. It should be understood that various alternative forms to those described herein may be used. The present invention provides, for example, the following items: (Item 1) A method for treating chemical impairment in a human, wherein the chemical impairment arises at least partially from or during or after a coronavirus infection, and the method comprises administering to the human a therapeutically effective amount of a phosphodiesterase (PDE) inhibitor or a pharmaceutically acceptable salt thereof for the treatment of the chemical impairment. (i) The coronavirus includes SARS-CoV-2 or a variant thereof, (ii) The PDE inhibitor or a pharmaceutically acceptable salt thereof is administered in a formulation in a unit dose form, or (iii) any combination thereof, a method. (Item 2) The method according to item 1, wherein the therapeutically effective amount of the PDE inhibitor or a pharmaceutically acceptable salt thereof is formulated as a liquid, solid, or gel formulation. (Item 3) The method according to item 2, wherein the PDE inhibitor or a pharmaceutically acceptable salt thereof is formulated as the liquid formulation, and the administration includes the application of the liquid formulation as nasal irrigation. (Item 4) The method according to item 2, wherein the PDE inhibitor or a pharmaceutically acceptable salt thereof is formulated as the liquid formulation, and the administration includes the application of the liquid formulation as an aerosol. (Item 5) The method according to item 2, wherein the PDE inhibitor or a pharmaceutically acceptable salt thereof is formulated as a solid dosage form, and the administration includes the application of the solid dosage form as a powder aerosol. (Item 6) The method of item 2, wherein the PDE inhibitor or a pharmaceutically acceptable salt thereof is formulated as the gel formulation, and the administration includes the application of the gel formulation by bringing at least a portion of the nasal cavity (naris) into contact with the gel formulation. (Item 7) The method according to item 2, comprising intranasal application of the liquid formulation, the solid formulation, or the gel formulation in one nostril or both nostrils. (Item 8) The method according to item 1, wherein the administration is performed during or after the coronavirus infection. (Item 9) The method according to item 8, further comprising a second administration, wherein the second administration includes remdesivir, chloroquine, lopinavir, ritonavir, favilavir, interferon-beta, an antiviral agent, oxygen, or any combination thereof. (Item 10) The method according to item 1, wherein the administration is performed at least once, twice, or three times within a 24-hour period. (Item 11) The method according to item 1, wherein the chemical sensory impairment includes anosmia, hyposmia, ageusia, dysosmia, parosmia, phantosmia, or any combination thereof. (Item 12) The method according to item 1, wherein the PDE inhibitor or a pharmaceutically acceptable salt thereof is theophylline or a pharmaceutically acceptable salt thereof, roflumilast or a pharmaceutically acceptable salt thereof, cilostazol or a pharmaceutically acceptable salt thereof, any derivative thereof or a pharmaceutically acceptable salt thereof, or any combination thereof. (Item 13) The method according to item 1, wherein the therapeutically effective dose comprises a correct amount of the PDE inhibitor or a pharmaceutically acceptable salt thereof in a dose of less than approximately 100 mg, less than approximately 10 mg, less than approximately 1 mg, less than approximately 500 μg, or less than approximately 100 μg. (Item 14) The method according to item 1, wherein the administration of the PDE inhibitor or a pharmaceutically acceptable salt thereof produces a blood concentration of the PDE inhibitor or a pharmaceutically acceptable salt thereof of less than about 10 mg / dl, less than about 1 mg / dl, or less than about 100 μg / dl during the course of the treatment. (Item 15) The method according to item 1, wherein the PDE inhibitor or salt thereof comprises theophylline or a pharmaceutically acceptable salt thereof, and during the course of treatment following the administration, theophylline, a theophylline metabolite, N-demethylated theophylline, or any combination thereof is present in the blood in amounts less than about 10 mg / dl, less than about 1 mg / dl, or less than about 100 μg / dl. (Item 16) The method according to item 1, wherein salivary or nasal mucus cAMP or cGMP levels in the person increase by at least about 10% compared to the levels in the person before administration after about 30 days of continuous treatment with the therapeutically effective dose of the PDE inhibitor or a pharmaceutically acceptable salt thereof. (Item 17) The method according to item 1, wherein smell acuity increases by at least about 5% in the person, as measured by the detection threshold (DT), after about 30 days of continuous treatment with the therapeutically effective dose of the PDE inhibitor or a pharmaceutically acceptable salt thereof, compared to the levels in the person before the administration. (Item 18) The method according to item 1, wherein olfactory ability increases by at least about 5% in the person, as measured by the recognition threshold (RT), after about 30 days of continuous treatment with the therapeutically effective dose of the PDE inhibitor or a pharmaceutically acceptable salt thereof, compared to the levels in the person before the administration. (Item 19) The method according to item 1, wherein olfactory function increases by at least about 5% in the person, as measured by magnitude estimation (ME), after about 30 days of continuous treatment with the therapeutically effective dose of the PDE inhibitor or a pharmaceutically acceptable salt thereof, compared to the levels in the person before the administration. (Item 20) The method according to item 1, wherein olfactory function increases by at least about 5% in the person, as measured by hedonic method (H), after about 30 days of continuous treatment with the therapeutically effective dose of the PDE inhibitor or a pharmaceutically acceptable salt thereof, compared to the levels in the person before the administration. (Item 21) The method according to item 1, wherein the chemosensory dysfunction is diagnosed by detecting sonic hedgehogs below a threshold level in a human-derived biological sample, by detecting cyclic nucleotide levels below a threshold level in the human-derived biological sample, or by any combination thereof. (Item 22) The method according to item 1, wherein the chemical sensory impairment is diagnosed by determining a detection threshold, determining a recognition threshold, and by magnitude estimation for at least one of pyridine, nitrobenzene, thiophene, and amyl acetate. (Item 23) The method according to item 1, wherein the preparation comprises an excipient. (Item 24) The method according to item 23, wherein the excipient includes water. (Item 25) The PDE inhibitor or a pharmaceutically acceptable salt thereof is administered in a unit dose form by the formulation, and the unit dose formulation is contained in a multi-dose nasal spray device that delivers the unit dose by plume when activated, the plume having a droplet size distribution, the droplet size distribution consisting of (a) less than 5% of the droplets in the plume having a size of less than 10 μm, and (b) larger than 12.5 μm. 10 And, about 10% of the droplets in the plume are D 10 D 10 (c) D approximately 30 μm 50 And, about 50% of the droplets in the plume are D 50 D 50 (d) D approximately 75 μm to approximately 100 μm 90 And, about 90% of the droplets in the plume are D 90 (e) having a size less than (D 90 -D 10 ) / D 50 The method described in item 1, including the span, calculated according to the method described in item 1. (Item 26) The method according to item 25, wherein the PDE inhibitor or a pharmaceutically acceptable salt thereof is theophylline or a pharmaceutically acceptable salt thereof. (Item 27) The method described in item 1, wherein the aforementioned human is assigned to be male or female at birth. (Item 28) The method described in item 27, wherein the person is approximately 1 to 12 months old, approximately 1 to 20 years old, approximately 15 to 50 years old, approximately 40 to 80 years old, or approximately 60 to 110 years old. (Item 29) The method described in item 27, wherein the aforementioned human has comorbidities. (Item 30) The method according to item 29, wherein the comorbidity is selected from the group consisting of schematic heart disease, hypertension, atrial fibrillation, stroke, renal failure, liver disease, cancer, diabetes, respiratory disease, and any combination thereof. (Item 31) The method according to item 30, wherein the comorbidity is the respiratory disease, and the respiratory disease is selected from asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, lung cancer, cystic fibrosis, pneumonia, pleural effusion, or any combination thereof. (Item 32) The method according to item 1, wherein the coronavirus infection is derived from SARS-CoV-2 virus, SARS-CoV virus, MERS-CoV virus, HKU1 virus, OC43 virus, NL63 virus, 229E virus, or any combination thereof.

Claims

1. A formulation for the treatment of loss of smell in humans, comprising theophylline or a pharmaceutically acceptable salt thereof, wherein the loss of smell is caused by or occurs during or after coronavirus SARS-CoV-2 infection. A therapeutically effective amount of theophylline or a pharmaceutically acceptable salt thereof is administered intranasally in unit dose form contained within a multi-dose nasal spray device. formulation.

2. The formulation according to claim 1, wherein the formulation is formulated as a liquid formulation.

3. The formulation according to claim 2, wherein the liquid formulation is administered as an aerosol.

4. The formulation according to claim 2, wherein the liquid formulation is administered transnasally through one nostril or both nostrils.

5. The formulation according to claim 1, wherein the formulation is administered during or after the coronavirus SARS-CoV-2 infection.

6. The formulation according to claim 5, wherein the formulation is administered in combination with remdesivir, chloroquine, lopinavir, ritonavir, favivir, interferon-beta, an antiviral agent, oxygen, or any combination thereof.

7. The formulation according to claim 1, wherein the formulation is administered at least once, at least twice, or at least three times within a 24-hour period.

8. The preparation according to claim 1, wherein the therapeutically effective amount comprises a correct amount of theophylline or a pharmaceutically acceptable salt thereof in an amount of less than 100 mg, less than 10 mg, less than 1 mg, less than 500 μg, or less than 100 μg.

9. The formulation according to claim 1, wherein the salivary or nasal mucus cAMP or cGMP levels in the human increase by at least 10% after 30 days of continuous treatment with the formulation compared to the levels in the human prior to administration of the formulation.

10. The formulation according to claim 1, wherein smell acuity increases by at least 5% in the person after 30 days of continuous treatment with the formulation, compared to the levels in the person before administration of the formulation, as measured by the detection threshold (DT).

11. The formulation according to claim 1, wherein olfactory ability, after 30 days of continuous treatment with the formulation, increases by at least 5% in the person, as measured by the recognition threshold (RT), compared to the levels in the person before administration of the formulation.

12. The formulation according to claim 1, wherein the loss of smell is diagnosed by detecting sonic hedgehogs below a threshold level in a human-derived biological sample, by detecting cyclic nucleotide levels below a threshold level in the human-derived biological sample, or by any combination thereof.

13. The formulation according to claim 1, wherein the loss of smell is diagnosed by determining a detection threshold, by determining a recognition threshold, and by magnitude estimation for at least one of pyridine, nitrobenzene, thiophene, and amyl acetate.

14. The formulation according to claim 1, wherein the formulation further comprises an excipient.

15. The formulation according to claim 14, wherein the excipient includes water.

16. The plurality of metered nasal spray devices deliver the unit dose as a plume upon activation, the plume having a droplet size distribution, the droplet size distribution having (a) less than 5% of the droplets in the plume having a size less than 10 μm, (b) D １０ wherein 10% of the droplets in the plume have a size less than the D １０ less than, D １０ , (c) D of 30 μm ５０ wherein 50% of the droplets in the plume have a size less than the D ５０ less than, D ５０ , (d) D of 75 μm to 100 μm ９０ wherein 90% of the droplets in the plume have a size less than the D ９０ less than, D90, and (e) a span of 1 to 6, the span being calculated according to (D ９０ - D １０ ) / D ５０ The formulation according to claim 1, comprising a span.

17. The formulation according to claim 1, wherein the human is assigned to be male or female at birth.

18. The formulation according to claim 17, wherein the human is 1 to 12 months old, 1 to 20 years old, 15 to 50 years old, 40 to 80 years old, or 60 to 110 years old.

19. The formulation according to claim 17, wherein the human has a comorbidity.

20. The formulation according to claim 19, wherein the comorbidity is selected from the group consisting of schematic (schemic) heart disease, hypertension, atrial fibrillation, stroke, renal failure, liver disease, cancer, diabetes, respiratory disease, and any combination thereof.

21. The preparation according to claim 20, wherein the comorbidity is the respiratory disease, and the respiratory disease is selected from asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, lung cancer, cystic fibrosis, pneumonia, pleural effusion, or any combination thereof.

22. The preparation according to any one of claims 1 to 21, wherein the daily dose of theophylline or a pharmaceutically acceptable salt thereof is about 10 μg to about 10 mg per day.

23. The formulation according to claim 22, wherein the daily dose of theophylline or a pharmaceutically acceptable salt thereof is about 10 μg to about 2 mg per day.

24. The formulation according to any one of claims 1 to 23, wherein the formulation is administered over a period of at least three months.

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