Ibudilast for use in treating post-COVID symptoms

Abstract

A method for treating post-COVID symptoms in a patient in need of treatment thereof comprises administering to the patient a therapeutically effective amount of ibudilast or a pharmaceutical salt thereof.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 305,483, filed February 1, 2022, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Ibudilast is widely used in Japan to relieve symptoms associated with ischemic stroke or bronchial asthma. Recent clinical trials have examined its use in the treatment of multiple sclerosis (MS), an inflammatory disease of the central nervous system (News.Medical.Net; Pharmaceutical News, 2 Aug. 2005). As disclosed in the publication, the clinical trial was expected to treat "relapsing-remitting MS," but no mention was made of progressive multiple sclerosis. In U.S. Patent No. 6,395,747, ibudilast is disclosed as a treatment for multiple sclerosis, which is generally understood to mean relapsing and remitting multiple sclerosis, not progressive multiple sclerosis. U.S. Patent Application Publication No. 20060160843 discloses ibudilast for the treatment of intermittent and short-term pain, but not pain associated with progressive neurodegenerative diseases. However, U.S. Patent No. 9,314,452 discloses ibudilast as a treatment for amyotrophic lateral sclerosis, a progressive neurodegenerative disease. Similarly, U.S. Patent No. 8,138,201 discloses ibudilast as a treatment for primary progressive multiple sclerosis and / or secondary progressive multiple sclerosis.

[0003] Although the use of ibudilast for several different indications has been previously reported, to the best of our knowledge, its use in treating post-COVID symptoms (also known as "long COVID", "post-COVID syndrome" and "acute sequelae of SARS-CoV-2") in patients has remained largely unexplored until now. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] U.S. Patent No. 6,395,747 [Patent Document 2] US Patent Application Publication No. 20060160843 [Patent Document 3] U.S. Patent No. 9,314,452 [Patent Document 4] U.S. Patent No. 8,138,201 [Non-patent literature]

[0005] [Non-Patent Document 1] News.Medical.Net; Pharmaceutical News, 2 Aug. 2005 Summary of the Invention

[0006] In one aspect, provided is a method of treating post-COVID symptoms in a patient in need thereof, comprising, consisting essentially of, or consisting of administering to the patient a therapeutically effective amount of ibudilast, or a pharmaceutical salt thereof.

[0007] In some embodiments, post-COVID symptoms may include anxiety, generalized pain or discomfort, fatigue, insomnia, cognitive impairment, depression, shortness of breath, post-traumatic stress disorder, joint pain, muscle pain, chest pain or tension, palpitations, smell or taste dysfunction, sleep disorders, hair loss, or a rash.

[0008] In some embodiments, the post-COVID symptoms include cognitive impairment, which includes one or both of memory loss and impaired concentration.

[0009] In some embodiments, ibudilast or a pharmaceutically acceptable salt thereof is administered orally. In some embodiments, ibudilast or a pharmaceutically acceptable salt thereof is administered intravenously. In some embodiments, ibudilast or a pharmaceutically acceptable salt thereof is administered by subcutaneous injection. In some embodiments, ibudilast or a pharmaceutically acceptable salt thereof is administered by intramuscular injection. In some embodiments, ibudilast or a pharmaceutically acceptable salt thereof is administered by inhalation.

[0010] In some embodiments, ibudilast or a pharma- ceutically acceptable salt thereof is administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days or more. In some embodiments, ibudilast or a pharma- ceutically acceptable salt thereof is administered for at least 2 months.

[0011] In some embodiments, ibudilast or a pharma- ceutically acceptable salt thereof is administered at least once daily.In some embodiments, ibudilast or a pharma- ceutically acceptable salt thereof is administered twice daily.

[0012] In some embodiments, the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is 0.1 mg to 720 mg per day. In some embodiments, the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is 30 mg to 200 mg per day. In some embodiments, the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is 60 mg to 600 mg per day. In some embodiments, the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is 100 mg to 480 mg per day. In some embodiments, the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is selected from the group consisting of 30 mg / day, 40 mg / day, 50 mg / day, 60 mg / day, 90 mg / day, 100 mg / day, 110 mg / day, 120 mg / day, 150 mg / day, 180 mg / day, 190 mg / day, 200 mg / day, 210 mg / day, 240 mg / day, 270 mg / day, 300 mg / day, 360 mg / day, 400 mg / day, 440 mg / day, 480 mg / day, 520 mg / day, 580 mg / day, 600 mg / day, 620 mg / day, 640 mg / day, 680 mg / day, and 720 mg / day.

[0013] In some embodiments, the therapeutically effective amount is administered as a single dose or divided into 2, 3, or 4 doses. In some embodiments, ibudilast is administered continuously.

[0014] In some embodiments, ibudilast or its pharmaceutically acceptable salt is the only active agent administered to the patient.In some embodiments, ibudilast or its pharmaceutically acceptable salt is administered to the patient together with at least one other active agent.In some embodiments, at least one other active agent comprises or consists of corticosteroids, COX-2 (cyclooxygenase-2) inhibitors, NSAIDs (nonsteroidal anti-inflammatory drugs), SSRIs (selective serotonin reuptake inhibitors), SNRIs (serotonin and norepinephrine reuptake inhibitors), tricyclic antidepressants, antihistamines, beta-blockers, cannabidiol, ATP (adenosine triphosphate), ifenprodil tartrate, neurotropin, gabapentin, pregabalin, mirtazapine, or a combination of two or more thereof. [Brief description of the drawings]

[0015] [Figure 1] FIG. 1 shows the concentration of TNFα in the presence of medium, vehicle, ibudilast alone (at 1, 10 or 100 μM), LPS with vehicle, LPS with ibudilast, "Wuhan" spike protein with LPS and vehicle, "Wuhan" spike protein with LPS and ibudilast, "Delta" spike protein with LPS and vehicle, "Delta" spike protein with LPS and ibudilast, "Omicron" spike protein with LPS and vehicle, or "Omicron" spike protein with LPS and ibudilast, using cells from donor 1. [Diagram 2]FIG. 2 shows the concentration of TNFα in the presence of medium, vehicle, ibudilast alone (at 1, 10 or 100 μM), LPS with vehicle, LPS with ibudilast, "Wuhan" spike protein with LPS and vehicle, "Wuhan" spike protein with LPS and ibudilast, "Delta" spike protein with LPS and vehicle, "Delta" spike protein with LPS and ibudilast, "Omicron" spike protein with LPS and vehicle, or "Omicron" spike protein with LPS and ibudilast, using cells from donor 2. [Diagram 3] FIG. 3 shows the concentration of TNFα in the presence of medium, vehicle, ibudilast alone (at 1, 10 or 100 μM), LPS with vehicle, LPS with ibudilast, "Wuhan" spike protein with LPS and vehicle, "Wuhan" spike protein with LPS and ibudilast, "Delta" spike protein with LPS and vehicle, "Delta" spike protein with LPS and ibudilast, "Omicron" spike protein with LPS and vehicle, or "Omicron" spike protein with LPS and ibudilast, using cells from donor 3. [Figure 4] FIG. 4 shows the concentration of IL-6 in the presence of medium, vehicle, ibudilast alone (at 1, 10 or 100 μM), LPS with vehicle, LPS with ibudilast, "Wuhan" spike protein with LPS and vehicle, "Wuhan" spike protein with LPS and ibudilast, "Delta" spike protein with LPS and vehicle, "Delta" spike protein with LPS and ibudilast, "Omicron" spike protein with LPS and vehicle, or "Omicron" spike protein with LPS and ibudilast, using cells from donor 2. [Diagram 5]Figure 5 shows the concentration of IL-6 in the presence of medium, vehicle, ibudilast alone (at 1, 10 or 100 μM), LPS with vehicle, LPS with ibudilast, "Wuhan" spike protein with LPS and vehicle, "Wuhan" spike protein with LPS and ibudilast, "Delta" spike protein with LPS and vehicle, "Delta" spike protein with LPS and ibudilast, "Omicron" spike protein with LPS and vehicle, or "Omicron" spike protein with LPS and ibudilast, using cells from donor 3. [Figure 6] Using cells from donor 1, medium, vehicle, "Omicron" spike protein with vehicle, "Omicron" spike protein with ibudilast (at 1, 10 or 100 μM) (1.0 μg / ml), "Omicron" spike protein with crosslinker and ibudilast (at 1, 10 or 100 μM) (1.0 μg / ml), "Omicron" spike protein with ibudilast (at 1, 10 or 100 μM) (5.0 μg / ml), "Omicron" spike protein with crosslinker and ibudilast (at 1, 10 or 100 μM) (5.0 μg / ml), "Omicron" spike protein with LPS and BzATP (1.0 μg / ml), "Omicron" spike protein with LPS and BzATP (5.0 μg / ml), and concentrations of TNFα in the presence of LPS and BzATP are shown. [Figure 7]Using cells from donor 2, medium, vehicle, "Omicron" spike protein with vehicle, "Omicron" spike protein with ibudilast (at 1, 10 or 100 μM) (1.0 μg / ml), "Omicron" spike protein with crosslinker and ibudilast (at 1, 10 or 100 μM) (1.0 μg / ml), "Omicron" spike protein with ibudilast (at 1, 10 or 100 μM) (5.0 μg / ml), "Omicron" spike protein with crosslinker and ibudilast (at 1, 10 or 100 μM) (5.0 μg / ml), "Omicron" spike protein with LPS and BzATP (1.0 μg / ml), "Omicron" spike protein with LPS and BzATP (5.0 μg / ml), and concentrations of TNFα in the presence of LPS and BzATP are shown. [Figure 8] Using cells from donor 3, medium, vehicle, "Omicron" spike protein with vehicle, "Omicron" spike protein with ibudilast (at 1, 10 or 100 μM) (1.0 μg / ml), "Omicron" spike protein with crosslinker and ibudilast (at 1, 10 or 100 μM) (1.0 μg / ml), "Omicron" spike protein with ibudilast (at 1, 10 or 100 μM) (5.0 μg / ml), "Omicron" spike protein with crosslinker and ibudilast (at 1, 10 or 100 μM) (5.0 μg / ml), "Omicron" spike protein with LPS and BzATP (1.0 μg / ml), "Omicron" spike protein with LPS and BzATP (5.0 μg / ml), and concentrations of TNFα in the presence of LPS and BzATP are shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] The practice of the present disclosure employs conventional methods of chemistry, biochemistry, and pharmacology within the skill of those skilled in the art, unless otherwise indicated. Such techniques are fully explained in the literature. See, for example, A. L. Lehninger, Biochemistry (Worth Publishers, Inc., current addition); Morrison and Boyd, Organic Chemistry (Allyn and Bacon, Inc., current addition); J. March, Advanced Organic Chemistry (McGraw Hill, current addition); Remington: The Science and Practice of Pharmacy, A. Gennaro, Ed., 20th Ed.; FDA's Orange Book, Goodman & Gilman The Pharmacological Basis of Therapeutics, J. Griffith Hardman, L. L. Limbird, A. Gilman, 11th Ed., 2005; The Merck Manual, 18th edition, 2007; and The Merck Manual of Medical Information 2003.

[0017] All publications cited herein, including internet articles, the FDA Orange Book (available on the FDA website), books, handbooks, journal articles, patents, and patent applications, whether supra or infra, are hereby incorporated by reference in their entirety.

[0018] definition Before describing the present disclosure in detail, it is to be understood that this disclosure is not limited to particular modes of administration, patient populations, or the like, as such can vary, as will become apparent from the accompanying specification.

[0019] It should be noted that, as used herein and in the intended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a "drug" includes a single drug as well as two or more of the same or different drugs, reference to an "optional excipient" refers to a single optional excipient as well as two or more of the same or different optional excipients, etc.

[0020] In describing and claiming this disclosure, the following terminology will be used in accordance with the definitions set out below.

[0021] As used herein, the terms "comprising" or "comprises" are intended to mean that the compositions and methods include the recited elements but do not exclude other elements. "Consisting essentially of," when used to define compositions and methods, is intended to mean excluding other elements that are essential to the combination for the purposes described. Thus, a composition consisting essentially of the elements defined herein does not exclude other materials or steps that do not materially affect the basic and novel characteristics of the claimed invention. "Consisting of" is intended to mean that it does not contain other ingredients and substantial method steps beyond trace elements. Embodiments defined by each of these transitional terms are within the scope of the present invention. When an embodiment is defined by one of these terms (e.g., "comprising"), it is understood that the disclosure also includes alternative embodiments such as "consisting essentially of" and "consisting of" for said embodiment.

[0022] A "pharmaceutically acceptable excipient or carrier" refers to an excipient that may optionally be included in a composition of the present disclosure and that causes no significant adverse toxicological effects in a patient.

[0023] "Pharmaceutically acceptable salts" include, but are not limited to, amino acid salts, salts prepared with inorganic acids, such as chlorides, sulfates, phosphates, diphosphates, bromides and nitrates, or salts prepared from the corresponding inorganic acid forms of any of the above, such as hydrochlorides, or salts prepared with organic acids, such as malate, maleate, fumarate, tartrate, succinate, ethylsuccinate, citrate, acetate, lactate, methanesulfonate, benzoate, ascorbate, para-toluenesulfonate, palmoate, salicylate and stearate, as well as estolate, gluceptate and lactobionate.Similarly, salts containing pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium and ammonium (including substituted ammonium).

[0024] As used herein, "active molecule" or "active agent" includes any agent, drug, compound, composition, or mixture that provides some pharmacological, often beneficial, effect that can be demonstrated in vivo or in vitro. This includes foods, dietary supplements, nutrients, nutraceuticals, drugs, vaccines, antibodies, vitamins, and other beneficial agents. As used herein, these terms further include any physiologically or pharmacologically active substance that produces a local or systemic effect in a patient. In a specific embodiment, the active molecule or active agent may include ibudilast or a pharmaceutically acceptable salt thereof.

[0025] "Substantially" or "essentially" means nearly entirely or completely, e.g., 95% or more of a given amount.

[0026] "Optional" or "optionally" means that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not occur.

[0027] The terms "subject," "individual," or "patient" are used interchangeably herein and refer to a vertebrate, preferably a mammal, including, but not limited to, mice, rodents, rats, monkeys, humans, farm animals, dogs, cats, sport animals, and pets.

[0028] The term "pharmacologically effective amount" or "therapeutically effective amount" of a composition or agent provided herein refers to a non-toxic but sufficient amount of the composition or agent to provide a desired response, such as reduction or recovery from the acute sequelae of SARS-CoV-2. The exact amount required will vary from subject to subject, depending on the species, age and general condition of the subject, the severity of the condition being treated, the particular drug(s) used, the mode of administration, etc. The appropriate "effective" amount in any individual case can be determined by one of skill in the art using routine experimentation, based on the information provided herein.

[0029] The term "about" is understood by those skilled in the art and varies to some extent depending on the context in which it is used. When a term is used that is not clear to those skilled in the art given the context in which it is used, "about" means up to plus or minus 10% of the particular term. For example, in some embodiments, it means plus or minus 5% of the particular term. Certain ranges are indicated herein by numerical values ​​preceded by the term "about". The term "about" is used herein to provide literal support for the exact number it precedes, and a number that is close to or approximately the number it precedes. In determining whether a number is close to or approximately a specifically stated number, the unstated number that is close or approximately may be a number that provides a substantial equivalent to the specifically stated number in the context in which it is presented.

[0030] As used herein, the term "post-COVID symptoms" or "long COVID" or "post-COVID syndrome" or "acute sequelae of SARS-CoV-2" refers to one or more new, recurrent or ongoing symptoms that may last for weeks or months after an initial infection with the virus that causes COVID-19. Non-limiting examples of such symptoms include anxiety, generalized pain or discomfort, fatigue, insomnia, cognitive impairment (e.g., memory loss and difficulty concentrating), depression, shortness of breath, post-traumatic stress disorder, joint pain, muscle pain, chest pain or tension, palpitations, smell or taste dysfunction, sleep disorders, hair loss, and rash.

[0031] As used herein, the term "treatment" or "treating" refers to any treatment of a condition or associated disorder in a patient, including inhibition of the condition or associated disorder, i.e., arresting or suppressing the development of clinical symptoms such as anxiety, generalized pain or discomfort, fatigue, insomnia, cognitive impairment, depression, shortness of breath, post-traumatic stress disorder, joint pain, muscle pain, chest pain or tension, palpitations, smell or taste dysfunction, sleep disorders, hair loss, and rashes.

[0032] In some embodiments, the term treating refers to improved clinical outcomes with delayed administration of ibudilast after infection with SARS-CoV-2 and onset of symptoms. The term "clinical outcomes" refers to any clinical observation or measurement of a patient's response to treatment. Non-limiting examples of clinical outcomes include clinical observations or assessments using the Digit Sign Substitution Test, Trail Making Test, Rey's Auditory Verbal Learning Test, Fatigue Severity Scale, 7-item Generalized Anxiety Scale, or 5-item World Health Organization Well-Being Scale, or any combination thereof, in patients who respond to treatment.

[0033] Other objects, features and advantages of the present disclosure will become apparent from the following detailed description. It should be understood, however, that the detailed description and specific examples, while indicating specific embodiments of the present disclosure, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description.

[0034] The methods of the present disclosure are based on the administration of the molecule ibudilast, which is a small molecule drug (molecular weight 230.3) having the structure shown below. [ka]

[0035] Ibudilast is also found in ChemBank ID 3227, CAS number 50847-11-5, and Beilstein Handbook Reference No. 5-24-03-00396. Its molecular formula corresponds to C14H18N2O. Ibudilast is also known by various chemical names, including 2-methyl-1-(2-(1-methylethyl)pyrazolo(1,5-a)pyridin-3-yl)1-propanone, 3-isobutyryl-2-isopropylpyrazolo(1,5-a)pyridine; and 1-(2-isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-2-methyl-propan-1-one. Other synonyms of ibudilast include ibudilastam (Latin), BRN 0656579, KC-404, and MN-166. The trade name is Ketas®. As referred to herein, ibudilast is meant to include any and all pharma- ceutically acceptable salt forms, prodrug forms (e.g., the corresponding ketal, oxime, oxime derivative, hydrazone or semicarbazone), solvates, etc. thereof appropriate for use in the intended formulation for administration.

[0036] Ibudilast is also a selective inhibitor of cyclic nucleotide phosphodiesterases (PDE) 3A, 4, 10A1 and 11A1 (Gibson et al., Eur J Pharmacol 538:39-42, 2006), has toll-like receptor-4 (TLR4) antagonist activity (Yang et al., Cell Death and Disease (2016) 7, e2234; doi:10.1038 / cddis.2016.140), and has been reported to have leukotriene D4 and PAF antagonist activity. Its profile appears to be effectively anti-inflammatory and unique compared to other PDE inhibitors and anti-inflammatory agents. PDEs catalyze the hydrolysis of the phosphoester bond on the 3'-carbon to generate the corresponding 5'-nucleotide monophosphate. Thus, they regulate the cellular concentration of cyclic nucleotides. Because many extracellular receptors for hormones and neurotransmitters utilize cyclic nucleotides as second messengers, PDEs also regulate the cellular response to these extracellular signals. There are at least eight classes of PDEs: 2+ / Calmodulin-dependent PDE (PDE1); cGMP-stimulated PDE (PDE2); cGMP-inhibited PDE (PDE3); cAMP-specific PDE (PDE4); cGMP-binding PDE (PDE5); photoreceptor PDE (PDE6); high-affinity cAMP-specific PDE (PDE7); and high-affinity cGMP-specific PDE (PDE9). Ibudilast acts to suppress inflammation through its action on inflammatory cells (e.g., glial cells), resulting in the suppression of the release of both pro-inflammatory and neuroactive mediators. Ibudilast can also suppress the production of pro-inflammatory cytokines (IL-1β, TNF-α) and enhance the production of anti-inflammatory cytokines (IL-4, IL-10).References pertinent to the above include: Obernolte, R., et al. (1993) "The cDNA of a human lymphocyte cyclic-AMP phosphodiesterase (PDE IV) reveals a multigene family" Gene 129:239-247; Rile, G., et al. (2001) "Potentiation of ibudilast inhibition of platelet aggregation in the presence of endothelial cells" Thromb. Res. 102:239-246; Souness, JE, et al. (1994) "Possible role of cyclic AMP phosphodiesterases in the actions of ibudilast on eosinophil thromboxane generation and airways smooth muscle tone" Br. J. Pharmacol. 111:1081-1088; Suzumura, A., et al. (1999) "Ibudilast suppresses TNF.alpha.production by glial cells functioning mainly as type III phosphodiesterase inhibitor in CNS” Brain Res.837:203-212;Takuma,K.,et al.(2001)”Ibudilast attenuates astrocyte apoptosis via cyclic GMP signaling pathway in an in vitro reperfusion model” Br.J.Pharmacol.133:841-848. Regarding the treatment of CNS cancer, ibudilast shows good CNS penetration. (Sanftner et al Xenobiotica 2009 39:964-977).

[0037] Ibudilast is also an allosteric inhibitor of p-hydroxyphenylpyruvate (HPP) tautomerase activity of macrophage inhibitory factor (MIF) (Cho et al., PNAS-USA, 2010 June 107:11313-8), thereby inhibiting the catalytic and chemotactic functions of MIF. It was unexpectedly found by the present inventors that ibudilast also reduces the plasma level of MIF. Such reduction in MIF plasma level is unexpected, since there is no known relationship between the allosteric inhibition of MIF and the MIF concentration in plasma. However, since MIF is involved in intracellular signal transduction through the activation of CD44 or CD74 in complex with chemokine receptors CXCR2 and CXCR4, both MIF inhibition by ibudilast and reduction in MIF plasma level may minimize the proinflammatory effects of MIF.

[0038] As stated above, reference to any one or more of the drugs described herein, particularly ibudilast, is meant to encompass, where applicable, any and all enantiomers, racemic mixtures, prodrugs, pharma- ceutically acceptable salt forms, hydrates (e.g., monohydrates, dihydrates, etc.), solvates, mixtures of enantiomers including different physical forms (e.g., crystalline solids, amorphous solids), metabolites, and the like.

[0039] Treatment and Administration Methods As stated above, in one aspect, the disclosure is directed to a method of treating post-COVID symptoms in a subject in need of such treatment, comprising, consisting essentially of, or consisting of administering a therapeutically effective amount of ibudilast or a pharmaceutical salt thereof to the subject. Such administration is effective to attenuate or reverse the post-COVID symptoms in the subject. The post-COVID symptoms include one or more selected from anxiety, generalized pain or discomfort, fatigue, insomnia, cognitive impairment, depression, shortness of breath, post-traumatic stress disorder, joint pain, muscle pain, chest pain or tension, palpitations, olfactory or gustatory dysfunction, sleep disorders, hair loss, and rash. In some embodiments, the post-COVID symptoms include, consist essentially of, or consist of cognitive impairment.

[0040] In another aspect, a method is provided for treating cognitive impairment in a patient suffering from or diagnosed with post-COVID symptoms, comprising, consisting essentially of, or consisting of administering to a subject a therapeutically effective amount of ibudilast or a pharmaceutical salt thereof.

[0041] In some embodiments, ibudilast or a pharma- ceutically acceptable salt thereof is administered in a daily dosage range of about 0.1 mg to 720 mg daily, about 30 mg to 200 mg daily, about 60 mg to 600 mg daily, or about 100 mg to 480 mg daily. Further dosage amounts are discussed below.

[0042] Ibudilast administration can be achieved by various delivery modes of ibudilast, including formulation.Preferred delivery methods of ibudilast-based therapeutic formulation include systemic delivery and local delivery.Such administration routes include, but are not limited to, oral, intraarterial, intrathecal, intraspinal, intramuscular, intraperitoneal, intranasal and inhalation routes.

[0043] More specifically, the ibudilast-based formulation may be administered for treatment by any suitable route, including but not limited to oral, rectal, nasal (including inhalation), topical (including transdermal, aerosol, buccal and sublingual), vaginal, parenteral (including subcutaneous, intravenous, intramuscular and intradermal), intrathecal and pulmonary. In some embodiments, the ibudilast-based formulation is administered orally. In some embodiments, the ibudilast-based formulation is administered by injection. The preferred route will of course vary depending on the condition and age of the recipient, the particular syndrome being treated, and the particular combination of drugs being used.

[0044] In some embodiments, ibudilast or a pharma- ceutically acceptable salt thereof is administered orally.In some embodiments, ibudilast or a pharma- ceutically acceptable salt thereof is administered by injection.

[0045] When the ibudilast composition comprises two or more active agents, it can be administered as a single combination composition comprising the combination of ibudilast and at least one additional active agent.From the viewpoint of patient compliance and ease of administration, such an approach is preferred, since patients do not like to take multiple pills or dosage forms, often multiple times daily, over the course of treatment.Alternatively, the combination of the present disclosure is administered as a separate dosage form.When the drugs comprising the therapeutic composition of the present disclosure are administered as separate dosage forms and require simultaneous administration, ibudilast and each additional active agent can be administered simultaneously, sequentially in any order, or separately.

[0046] Dosage The therapeutic amount can be empirically determined and varies depending on the particular condition being treated, the subject, and the efficacy and toxicity of each active agent contained in the composition. The actual dose administered will vary depending on the age, weight, and general condition of the subject, as well as the severity of the condition being treated, the judgment of the medical professional, and the particular combination being administered.

[0047] The therapeutically effective amount can be adjusted to the requirements of each particular case. In general, the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof ranges from about 0.1 mg / day to 720 mg / day, about 40 to 600 mg / day, or about 100 to 480 mg / day, or more preferably from about 1 to 240 mg / day, about 30 to 240 mg / day, about 30 to 200 mg / day, about 30 to 120 mg / day, about 1 to 120 mg / day, about 50 to 150 mg / day, about 60 to 150 mg / day, about 60 to 120 mg / day, or about 60 to 100 mg / day in a total daily dose, administered either as a single dose or multiple doses. In some embodiments, the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof ranges from about 30 to 200 mg / day, administered either as a single dose or multiple doses. In some embodiments, multiple doses include two, three or four doses per day.

[0048] Preferred dosage amounts include doses of greater than about 20 mg BID or TID, i.e., preferred dosage amounts are greater than about 30 mg / day, 60 mg / day, 90 mg / day, 120 mg / day, 150 mg / day, 180 mg / day, 210 mg / day, 240 mg / day, 270 mg / day, 300 mg / day, 360 mg / day, 400 mg / day, 440 mg / day, 480 mg / day, 520 mg / day, 580 mg / day, 600 mg / day, 620 mg / day, 640 mg / day, 680 mg / day, and 720 mg / day or more.

[0049] In some embodiments, a therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is at least 30 mg / day, at least 40 mg / day, at least 50 mg / day, at least 60 mg / day, at least 70 mg / day, at least 80 mg / day, at least 90 mg / day, at least 100 mg / day, at least 110 mg / day, at least 120 mg / day, at least 130 mg / day, at least 140 mg / day, at least 150 mg / day, at least 160 mg / day, at least 170 mg / day, at least 180 mg / day, at least 190 mg / day, at least 200 mg / day, at least 250 mg / day, at least 300 mg / day, at least 350 mg / day, at least 360 mg / day, at least 370 mg / day, at least 380 mg / day, at least 390 mg / day, at least 400 mg / day, at least 410 mg / day, at least 420 mg / day, at least 430 mg / day, at least 440 mg / day, at least 450 mg / day, at least 460 mg / day, at least 470 mg / day, at least 480 mg / day, at least 490 mg / day, at least 500 mg / day, at least 510 mg / day, at least 520 mg / day, at least 530 mg / day, at least 540 mg / day, at least 550 mg / day, at least 560 mg / day, at least 570 mg / day, at least 580 mg / day, at least 590 mg / day, at least 600 mg / day, at least 610 mg / day, at least 620 mg / day, at least 630 mg / day, 25mg / day, at least 250mg / day, at least 275mg / day, at least 300mg / day, at least 325mg / day, at least 350mg / day, at least 375mg / day, at least 400mg / day, at least 425mg / day, at least 450mg / day, at least 475mg / day, at least 500mg / day, at least 525mg / day, at least 550mg / day, at least 575mg / day, at least 600mg / day, at least 625mg / day, at least 650mg / day, at least 675mg / day, at least 700mg / day, or at least 720mg / day. In some embodiments, the therapeutically effective amount of ibudilast or its pharma- ceutically acceptable salt is at least 60mg / day. In some embodiments, the therapeutically effective amount of ibudilast or its pharma-ceutically acceptable salt is at least 100mg / day.

[0050] Depending on the dosage and the exact condition being treated, administration may be once, twice, three times, or four times daily over a time course of one to several days, weeks, months, or even years, or even for the patient's lifetime. Exemplary dosing regimens last for at least about 1 week, about 1-4 weeks, 1-3 months, 1-6 months, 1-52 weeks, 1-24 months, or longer. In some embodiments, ibudilast or a pharma- ceutically acceptable salt thereof is administered for 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, or 30 days. In some embodiments, ibudilast or a pharmaceutically acceptable salt thereof is administered for 2 months or less. In some embodiments, ibudilast or a pharmaceutically acceptable salt thereof is administered for at least 2 months. In some embodiments, ibudilast or a pharmaceutically acceptable salt thereof is administered for at least 6 months. In some embodiments, ibudilast or a pharmaceutically acceptable salt thereof is administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months or more. In some embodiments, ibudilast or a pharmaceutically acceptable salt thereof is administered for about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years or more. In some embodiments, ibudilast or a pharmaceutically acceptable salt thereof is administered for at least 1 year. In some embodiments, ibudilast or a pharmaceutically acceptable salt thereof is administered for at least 2 years. In some embodiments, ibudilast or a pharmaceutically acceptable salt thereof is administered as one single dose.

[0051] In some embodiments, the therapeutically effective amount of ibudilast or its pharmaceutically acceptable salt is administered in a single dose per day. In some embodiments, the therapeutically effective amount of ibudilast or its pharmaceutically acceptable salt is administered in two doses per day. In some embodiments, the therapeutically effective amount of ibudilast or its pharmaceutically acceptable salt is administered in three doses per day. In some embodiments, the therapeutically effective amount of ibudilast or its pharmaceutically acceptable salt is administered in four doses per day. In some embodiments, the therapeutically effective amount of ibudilast or its pharmaceutically acceptable salt is administered continuously.

[0052] In some embodiments, ibudilast or a pharmaceutically acceptable salt thereof is administered at least once every day. In some embodiments, ibudilast or a pharmaceutically acceptable salt thereof is administered at least twice every day. In some embodiments, ibudilast or a pharmaceutically acceptable salt thereof is administered once every day. In some embodiments, ibudilast or a pharmaceutically acceptable salt thereof is administered twice every day.

[0053] In practical terms, any given composition or unit dose of active agent of the present disclosure can be administered in various dosing schedules, depending on the clinician's judgment, the patient's needs, etc. Specific dosing schedules are known to those skilled in the art or can be determined experimentally using routine methods. Exemplary dosing schedules include, but are not limited to, administration 5 times a day, 4 times a day, 3 times a day, 2 times a day, once a day, every other day, 3 times a week, twice a week, once a week, twice a month, once a month, etc.

[0054] formulation Ibudilast may be administered in a composition of a formulation that may optionally contain one or more additional components as described below.

[0055] Excipients / Carriers In addition to ibudilast or its pharmaceutically acceptable salt, the composition of the present disclosure may further comprise one or more pharmaceutically acceptable excipients or carriers.Exemplary excipients include, but are not limited to, polyethylene glycol (PEG), PEG 400, (2-hydroxypropyl)-β-cyclodextrin, hydrogenated castor oil (HCO), cremophor, carbohydrates, starch (e.g., corn starch), inorganic salts, antimicrobial agents, antioxidants, binders / fillers, surfactants, lubricants (e.g., calcium stearate or magnesium stearate), glidants such as talc, disintegrants, diluents, buffers, acids, bases, film coats, combinations thereof, etc.

[0056] The composition of the present disclosure may include one or more carbohydrates, such as sugars, derivatized sugars, such as alditols, aldonic acids, esterified sugars, and / or sugar polymers.Specific carbohydrate excipients include, for example, monosaccharides, such as fructose, maltose, galactose, glucose, D-mannose, sorbose, etc.; disaccharides, such as lactose, sucrose, trehalose, cellobiose, etc.; polysaccharides, such as raffinose, melezitose, maltodextrin, dextran, starch, etc.; and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitol, sorbitol (glucitol), pyranosylsorbitol, myoinositol, etc.

[0057] Also suitable for use in the compositions of the present disclosure are potato and corn based starches, such as sodium starch glycolate and directly compressible modified starches.

[0058] Further representative excipients include inorganic salts or buffers, such as citric acid, sodium chloride, potassium chloride, sodium sulfate, potassium nitrate, sodium phosphate monobasic, sodium phosphate dibasic, and combinations thereof.

[0059] The composition of the present disclosure may also contain one or more antioxidants.Antioxidants are used to prevent oxidation, thereby preventing the deterioration of drugs or other components of preparations.Suitable antioxidants for use in the present disclosure include, for example, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite, and combinations thereof.

[0060] Further exemplary excipients include surfactants such as polysorbates, e.g., "Tween 20" and "Tween 80", and pluronics, e.g., F68 and F88 (both available from BASF, Mount Olive, NJ), sorbitan esters, lipids (e.g., phospholipids, e.g., lecithin and other phosphatidylcholines, and phosphatidylethanolamines), fatty acids and fatty acid esters, steroids, e.g., cholesterol, and chelating agents, e.g., EDTA, zinc, and other such suitable cations. In some embodiments, the surfactant may include a polyethoxylated castor oil derivative (e.g., Cremophor EL, Kolliphor ELP, etc.). Other non-limiting excipients include alcohol (e.g., ethanol), propylene glycol, glycolys, or polyethylene glycol (PEG).

[0061] In addition, the composition of the present disclosure may optionally include one or more acids or bases.Non-limiting examples of acids that can be used include acids selected from the group consisting of hydrochloric acid, acetic acid, phosphoric acid, citric acid, malic acid, lactic acid, formic acid, trichloroacetic acid, nitric acid, perchloric acid, phosphoric acid, sulfuric acid, fumaric acid, and combinations thereof.Non-limiting examples of suitable bases include, but are not limited to, bases selected from the group consisting of sodium hydroxide, sodium acetate, ammonium hydroxide, potassium hydroxide, ammonium acetate, potassium acetate, sodium phosphate, potassium phosphate, sodium citrate, sodium formate, sodium sulfate, potassium sulfate, potassium fumarate, and combinations thereof.

[0062] The amount of any individual excipient in the composition varies depending on the role of the excipient, the dosage requirements of the active agent component, and the specific needs of the composition. Typically, the optimal amount of any individual excipient is determined by routine experimentation, i.e., by preparing compositions containing various amounts of excipient (ranging from low to high), examining stability and other parameters, and then determining the range in which optimal performance is achieved without significant adverse effects.

[0063] Generally, however, the excipient is present in the composition in an amount of about 1% to about 99% by weight of the excipient, preferably about 5% to about 98% by weight, and more preferably about 15% to about 95% by weight. Generally, the amount of excipient present in the ibudilast compositions of the present disclosure is selected from at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or even 95% by weight.

[0064] These aforementioned pharmaceutical excipients, along with other excipients, are described in "Remington: The Science & Practice of Pharmacy", 19th ed., Williams & Williams, (1995), the "Physician's Desk Reference", 52nd ed., Medical Economics, Montvale, NJ (1998), and Kibbe, AH, Handbook of Pharmaceutical Excipients, 3rd Edition, American Pharmaceutical Association, Washington, DC, 2000.

[0065] Other Active Substances A formulation (or kit) according to the present disclosure may contain, in addition to ibudilast or a pharma- ceutically acceptable salt thereof, one or more other therapeutically active agents.

[0066] Preferably, the one or more other therapeutic agents possess a different mechanism of action from ibudilast. Such active ingredients can be found listed in FDA's Orange Book, Goodman & Gilman The Pharmacological Basis of Therapeutics, J. Griffith Hardman, LL Limbird, A. Gilman, 11th Ed., 2005, The Merck Manual, 18th edition, 2007, and The Merck Manual of Medical Information 2003.

[0067] In some embodiments, the one or more other therapeutically active agents are corticosteroids, COX-2 (cyclooxygenase-2) inhibitors, NSAIDs (nonsteroidal anti-inflammatory drugs), SSRIs (selective serotonin reuptake inhibitors), SNRIs (serotonin and norepinephrine reuptake inhibitors), tricyclic antidepressants, antihistamines, beta-blockers, cannabidiol, ATP (adenosine triphosphate), ifenprodil tartrate, neurotropin, gabapentin, pregabalin, mirtazapine, or a combination of two or more thereof.

[0068] In some embodiments, the one or more other therapeutically active agents are one or more corticosteroids.Non-limiting examples of corticosteroids include cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, hydrocortisone, amcinonide, budesonide, desonide, fluocinolone acetonide, fluocinonide, halcinonide, triamcinolone acetonide, beclomethasone, fluocortolone, halometasone, mometasone, alclometasone dipropionate, betamethasone dipropionate, betamethasone valerate, clobetasol propionate, clobetasone butyrate, fluprednidene acetate, and mometasone furoate.

[0069] In some embodiments, the one or more other therapeutically active agents are one or more NSAIDs. Non-limiting examples of NSAIDs include ibuprofen, naproxen, diclofenac, mefenamic acid, etoricoxib, indomethacin, and aspirin (e.g., high-dose aspirin).

[0070] In some embodiments, the one or more other therapeutically active agents are one or more COX-2 inhibitors. Non-limiting examples of COX-2 inhibitors include celecoxib, rofecoxib, and valdecoxib.

[0071] In some embodiments, the one or more other therapeutically active agents are one or more SSRIs. Non-limiting examples of SSRIs include citalopram, escitalopram, fluoxetine, paroxetine, dapoxetine, vortioxetine, fluvoxamine, and sertraline.

[0072] In some embodiments, the one or more other therapeutically active agents are one or more SNRIs. Non-limiting examples of SNRIs include desvenlafaxine, duloxetine, venlafaxine, and levomilnacipran.

[0073] In some embodiments, the one or more other therapeutically active agents are one or more tricyclic antidepressants. Non-limiting examples of tricyclic antidepressants include amitriptyline, amoxapine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, and trimipramine.

[0074] In some embodiments, the one or more other therapeutically active agents are one or more antihistamines.Non-limiting examples of antihistamines include diphenhydramine, cetirizine, chlorpheniramine, cyclizine, dimenhydrinate, doxylamine, hydroxyzine, meclizine, carbinoxamine, cyproheptadine, desloratadine, emedastine, levocetirizine brompheniramine, clemastine, fexofenadine and loratadine.

[0075] In some embodiments, the one or more other therapeutically active agents are one or more beta-blockers. Non-limiting examples of beta-blockers include atenolol, betaxolol, bisoprolol, esmolol, acebutolol, metoprolol tartrate, metoprolol succinate, and nebivolol.

[0076] The dosages provided above are meant to be a guideline only; the exact amount of the secondary active agent administered during combination therapy with ibudilast or a pharma- ceutically acceptable salt thereof will, of course, be adjusted accordingly and will depend on factors such as the intended patient population, the particular symptom or condition being treated, potential synergistic effects between the active agents being administered, and the like, and would be readily determined by one of skill in the art based on the guidance provided herein.

[0077] Sustained delivery formulations Preferably, the composition is formulated to improve the stability and extend the half-life of ibudilast or its pharmaceutically acceptable salt.For example, ibudilast or its pharmaceutically acceptable salt can be delivered in a controlled release formulation or sustained release formulation.Controlled release formulation or sustained release formulation is prepared by incorporating ibudilast or its pharmaceutically acceptable salt into a carrier or vehicle, such as liposomes, non-resorbable impermeable polymers, such as ethylene vinyl acetate copolymers and Hytrel® copolymers, swellable polymers, such as hydrogels, or resorbable polymers, such as collagen and certain polyacids or polyesters, such as those used to make resorbable sutures.In addition, ibudilast or its pharmaceutically acceptable salt can be encapsulated, adsorbed, or associated with particulate carriers.Examples of particulate carriers include those derived from polymethylmethacrylate polymers, and microparticles derived from poly(lactide) and poly(lactide-co-glycolide), known as PLG. See, e.g., Jeffery et al., Pharm. Res. (1993) 10:362-368; and McGee et al., J. Microencap. (1996).

[0078] Suitable sustained release polymers for this purpose are known in the art and include hydrophobic polymers such as cellulose ethers.Non-limiting examples of suitable cellulose ethers include ethyl cellulose, cellulose acetate, etc.; polyvinyl esters such as polyvinyl acetate, polyacrylic esters, methacrylic and acrylate polymers (pH independent); high molecular weight polyvinyl alcohols and waxes such as fatty acids and glycerides, methacrylic acid ester neutral polymers, polyvinyl alcohol-maleic anhydride copolymers, etc.; ethyl acrylate-methyl methacrylate copolymers; aminoalkyl methacrylate copolymers; and mixtures thereof.

[0079] Mode of delivery The compositions of ibudilast or its pharma- ceutically acceptable salt described herein include all types of formulations, particularly suitable for systemic or intrathecal administration.Oral dosage forms include tablets, lozenges, capsules, syrups, oral suspensions, emulsions, granules and pellets.In some embodiments, the oral dosage form is a tablet.In some embodiments, the tablet is a sustained release tablet.In some embodiments, the oral dosage form is a capsule.In some embodiments, the capsule is a sustained release capsule.

[0080] Alternative formulations include aerosols, transdermal patches, gels, creams, ointments, suppositories, powders or lyophilized agents that can be reconstituted, and liquids.Examples of suitable diluents for reconstituting solid compositions before injection include bacteriostatic water for injection, 5% dextrose in water, phosphate buffered saline, Ringer's solution, saline, sterile water, deionized water, and combinations thereof.For liquid pharmaceutical compositions, solutions and suspensions are envisioned.Preferably, the compositions of ibudilast or its pharmaceutically acceptable salts of the present disclosure are suitable for oral administration.

[0081] Turning now to oral delivery formulations, tablets can be made by compression or molding, optionally with one or more auxiliary ingredients or additives.Compressed tablets are prepared by compressing the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropylmethylcellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethylcellulose) and / or surfactant or dispersant, using a suitable tablet press.

[0082] Molded tablets are made, for example, by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable tablet press. Tablets can be optionally coated or scored, and can be formulated to provide slow or controlled release of active ingredients, for example, using various percentages of hydroxypropylmethylcellulose to provide a desired release profile. Tablets can also be optionally provided with coatings, such as thin films, sugar coatings, or enteric coatings, to release in parts of the intestine other than the stomach. Processes, equipment, and contract manufacturers for making tablets and capsules are well known in the art.

[0083] Formulations for topical administration in the mouth include lozenges, which generally contain the active ingredient in a flavored base such as sucrose and acacia or tragacanth, and pastilles, which contain the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia.

[0084] Pharmaceutical compositions for topical administration may also be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

[0085] Alternatively, the formulation may be in the form of a patch (e.g., a transdermal patch) or dressing, such as a bandage or adhesive plaster, impregnated with the active ingredient and optionally one or more excipients or diluents. Topical formulations may further include compounds that enhance absorption or penetration of the ingredient through the skin or other affected areas, such as dimethylsulfoxidem bisabolol, oleic acid, isopropyl myristate, and D-limonene, to name a few.

[0086] In emulsions, the oily phase is composed of known ingredients in a known manner. This phase may simply comprise an emulsifier (also known as an emulgent), but desirably comprises a mixture of at least one emulsifier with fats and / or oils. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. Together, the emulsifiers, with or without stabilizers, constitute the so-called emulsifying wax, which, together with the oils and / or fats, constitute the so-called emulsifying ointment base that forms the oily dispersed phase of the cream formulation. Exemplary emulgents and emulsion stabilizers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate.

[0087] Formulations for rectal administration are typically in the form of a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

[0088] Formulations suitable for vaginal administration generally take the form of a suppository, tampon, cream, gel, paste, foam, or spray.

[0089] Formulations suitable for nasal administration in which the carrier is a solid include coarse powders having a particle size in the range of, for example, about 20 to about 500 microns. Such formulations are typically administered by rapid inhalation through the nasal passages, for example, from a container of the powder held close to the nose. Alternatively, formulations for nasal delivery may be in the form of a liquid, for example, a nasal spray or nasal drops.

[0090] The aerosolizable formulation for inhalation may be in dry powder form (e.g., suitable for administration by dry powder inhaler) or may be in liquid form, for example, for use in a nebulizer. Nebulizers for delivering aerosolized solutions include AERx® (Aradigm), Ultravent® (Mallinkrodt), and Acorn II® (Marquest Medical Products). The compositions of the present disclosure may also be delivered using a pressurized metered dose inhaler (MDI), such as the Ventolin® metered dose inhaler, that contains a solution or suspension of the drug combination described herein in a pharma- ceutical inert liquid propellant, such as a chlorofluorocarbon or fluorocarbon.

[0091] Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile solutions suitable for injection, as well as aqueous and non-aqueous sterile suspensions.

[0092] The parenteral formulations of the disclosure may optionally be contained in unit-dose or multi-dose sealed containers, for example ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the type previously described.

[0093] The formulations of the present disclosure may also be sustained release formulations, such that each drug component is slowly released or absorbed over time, as compared to non-sustained release formulations.Sustained release formulations may use prodrug forms of the active agent, delayed release drug delivery systems, such as liposomes or polymer matrices, hydrogels, or covalent attachment of polymers, such as polyethylene glycol, to the active agent.

[0094] In addition to the ingredients particularly mentioned above, the formulations of the present disclosure may optionally include other agents conventional in the pharmaceutical art, and for example, the particular type of formulation used for oral dosage forms; compositions for oral administration may include additional agents as sweeteners, thickeners, or flavoring agents.

[0095] kit Also provided herein are kits containing at least one composition of the disclosure, along with instructions for use.

[0096] In some embodiments, the kit contains at least one combination composition described herein with instructions.For example, in the case where each drug is administered as an individual or separate dosage form, the kit includes each drug that constitutes the composition of the present disclosure, plus ibudilast, with instructions.The drug components can be packaged in any manner suitable for administration, as long as the package clearly indicates the manner in which each drug component should be administered when considered together with instructions for administration.

[0097] For example, in an exemplary kit containing ibudilast and one other active agent, the kit may be organized for any suitable period, such as by day. As an example, on day 1, a representative kit may include a unit dosage of each of ibudilast and one other active agent. If each drug is administered twice daily, two rows of unit dosage forms of each of ibudilast and one other active agent may be included in the kit, corresponding to day 1, along with instructions on the timing of administration. Alternatively, if one or more drugs differ in the timing or amount of unit dosage forms administered compared to other drug members of the combination, such will be reflected in the packaging and instructions. Various embodiments according to the above can be easily envisioned, and these will of course depend on the particular combination of drugs, their corresponding dosage forms, recommended dosages, intended patient population, etc., in addition to the ibudilast used for treatment. The packaging may be in any form commonly used for packaging pharmaceutical products, and may utilize any of several features, such as different colors, wrapping, tamper-evident packaging, blister packs, desiccants, etc.

[0098] While the present disclosure has been described in conjunction with preferred specific embodiments, it should be understood that the foregoing description and the following examples are intended to illustrate, but not to limit, the scope of the present disclosure. Other aspects, advantages and modifications within the scope of the present disclosure will be apparent to those skilled in the art to which this disclosure pertains.

[0099] All references mentioned in this application, including any patents, published patent applications, books, handbooks, journal publications, or the FDA Orange Book, are hereby incorporated by reference in their entirety.

[0100] The following examples are provided for the purpose of illustrating various embodiments of the present disclosure, and are not meant to limit the present disclosure in any way. Those skilled in the art will easily understand that the present disclosure is well adapted to carry out the objects and obtain the stated goals and advantages, as well as the objects, goals and advantages inherent therein. The examples, together with the methods described herein, are representative of the current embodiments, are exemplary, and are not intended as limitations on the scope of the present disclosure. Modifications therein and other uses encompassed within the spirit of the present disclosure, as defined by the scope of the claims, will occur to those skilled in the art. EXAMPLES

[0101] Example 1: Pilot study of post-COVID syndrome

[0102] The pilot study will be conducted with an enrollment goal of 20-40 patients (female or male; 18 years of age or older; with a confirmed history of COVID-19 with secondary symptoms for >6 weeks). Patients will receive ibudilast capsules, 20 mg-30 mg bid or matching placebo capsules bid orally for 8 weeks. Efficacy endpoints will be assessed by one or more of the following: Post-COVID-19 Functional Status (PCFS) Scale Fatigue Severity Scale (FSS) ·Digit Sign Substitution Test (DSST) Health-Related Quality of Life Questionnaire (SF-36 Questionnaire) ·Cognitive impairment questionnaire, 20 items (PDQ-20) Trail Making Examination Parts A and B Serum biomarkers (e.g., inflammatory cytokine levels)

[0103] Example 2: Multicenter Clinical Trial

[0104] We will conduct a multi-arm, open-label, programmatic, adaptive randomized controlled trial of 800-1000 patients over 16 years of age who have had confirmed COVID-19 and symptoms lasting >3 months. A lead-in period of 4-8 weeks should be used when standard treatment is initiated. Adaptive randomization allows real-time testing of various interventions. More participants should be randomized to more effective interventions, while frequent interim analyses will facilitate discontinuation of interventions if futility criteria are met and allow new interventions to be introduced and tested. The interventions will last 4 weeks and all participants will be followed for 8 weeks after completing treatment. The trial is to have three intervention arms and a standard care arm. An interdisciplinary scientific committee will determine and prioritize the interventions to be tested based on evolving evidence. Symptoms such as anxiety, generalized pain or discomfort, fatigue, insomnia, cognitive impairment, depression, shortness of breath, post-traumatic stress disorder, joint pain, muscle pain, chest pain or tension, palpitations, dysfunction of smell or taste, sleep disturbance, hair loss, and rash will be assessed. Primary outcomes should be assessed using the validated Post-COVID-19 Functional Status Scale (PCFS) (for symptoms such as anxiety and generalized pain or discomfort). Secondary outcomes should be assessed by the Bargained Scale Symptom Checklist, De Paul Symptom Questionnaire 2, Health-Related Quality of Life (SF36) (for symptoms such as fatigue, insomnia, cognitive impairment, shortness of breath, joint pain, muscle pain, chest pain or tension, palpitations, dysfunction of smell or taste, and sleep disturbance), 6-minute walk test, and reintegration into normal life. Rash and hair loss should be assessed by regular physical assessment. Post-traumatic disorders should be assessed by in-trial and interval medical histories.

[0105] Example 3: Effect of ibudilast on spike protein-mediated cytokine release from human monocyte-derived microglia

[0106] Peripheral blood mononuclear cells (PBMCs) were isolated from three healthy donors. Monocytes were purified from the PBMC population, seeded in 96-well plates and differentiated into microglia (iMDMs) by adding cytokines; M-CSF, GM-CSF, NGF-β, CCL2 and IL-34 at 37 °C for 5 days.

[0107] iMDMs were preincubated with vehicle control (DMSO, 0.1%) or ibudilast (1.0, 10, 100 μM) for 30 min, followed by the addition of recombinant SARS-CoV-2 spike protein ("original [Wuhan]" (Acro Biosystems SPN C52H9), "Delta" [B.1.617.2] (Acro Biosystems SPN-C52He), "Omicron" [B.1.1.529] (Acro Biosystems SPD-C522e) (1.0 or 5.0 μg / mL) in the absence or presence of a crosslinker (anti-6X His tag antibody, Abcam; ab18184) and cultured for an additional 6 or 20 h. Positive control stimulation was also performed by addition of LPS (10, 100 ng / mL) for 6 or 20 h, and where indicated, BzATP (100 μM) stimulation was performed for the last 2 h of the culture period.

[0108] After 6 and 20 hours, cell culture supernatants were collected and then stored at -20°C to quantify the levels of IL-6 and TNFα, both of which are inflammatory cytokines. Since inflammatory cytokines, especially IL-6 and TNFα, are known to be associated with long-term COVID (Schultheiβ et al. Cell Rep. Med., 2022 June 21, 3(6):100663), a reduction in the levels of these cytokines by ibudilast would suggest an improvement in clinical symptoms caused by elevated IL-6 and TNF-α. The results are shown in Figures 1 to 8.

[0109] Stimulation with SARS spike protein alone did not induce cytokine release. Addition of LPS elicited cytokine release. Ibudilast was observed to reduce IL-6 and TNFα levels when a "low" concentration (10 ng / mL) of LPS was added together with spike protein (all variants).

[0110] The combination of spike protein and LPS increased TNFα levels in all donors. Ibudilast reduced the levels of TNFα induced by (LPS + spike protein) in all donors. See Figures 1-3.

[0111] The combination of spike protein and LPS increased IL-6 levels in donors 2 and 3. Ibudilast reduced the (LPS + spike protein)-induced levels of IL-6 in donors 2 and 3. In donor 1, LPS alone significantly enhanced IL-6 release, and additional spike protein did not further enhance IL-6 release. See Figures 4-5.

[0112] Using the "Omicron" spike protein, an increase in TNFα levels and their reduction by ibudilast were evident under certain test conditions. See Figures 6-8. Dose-dependent curves are observed under conditions of "Omicron" spike protein (1.0 μg / ml) containing crosslinker and ibudilast (at 1, 10 or 100 μM) for all three donors, and under conditions of "Omicron" spike protein (5.0 μg / ml) containing crosslinker and ibudilast (at 1, 10 or 100 μM) for donor 3.

[0113] Certain embodiments Embodiment 1. A method of treating post-COVID symptoms in a patient in need of treatment thereof, comprising administering to the patient a therapeutically effective amount of ibudilast or a pharmaceutical salt thereof.

[0114] Embodiment 2. The method of embodiment 1, wherein the post-COVID symptoms include one or more selected from anxiety, generalized pain or discomfort, fatigue, insomnia, cognitive impairment, depression, shortness of breath, post-traumatic stress disorder, joint pain, muscle pain, chest pain or tension, palpitations, smell or taste dysfunction, sleep disorders, hair loss, or rash.

[0115] Embodiment 3. The method of embodiment 2, wherein the post-COVID symptoms include cognitive impairment, and the cognitive impairment includes one or both of memory loss and decreased concentration.

[0116] Embodiment 4. The method of any one of embodiments 1-3, wherein ibudilast or a pharma- ceutically acceptable salt thereof is administered orally.

[0117] Embodiment 5. The method of any one of embodiments 1-3, wherein ibudilast or a pharma- ceutically acceptable salt thereof is administered intravenously.

[0118] Embodiment 6. The method of any one of embodiments 1-3, wherein ibudilast or a pharma- ceutically acceptable salt thereof is administered by subcutaneous injection.

[0119] Embodiment 7. The method of any one of embodiments 1-3, wherein ibudilast or a pharma- ceutically acceptable salt thereof is administered by intramuscular injection.

[0120] Embodiment 8. The method of any one of embodiments 1-3, wherein ibudilast or a pharma- ceutically acceptable salt thereof is administered by inhalation.

[0121] Embodiment 9. The method of any one of embodiments 1-8, wherein ibudilast or a pharma- ceutically acceptable salt thereof is administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days or more.

[0122] Embodiment 10. The method of any one of embodiments 1-8, wherein ibudilast or a pharma- ceutically acceptable salt thereof is administered for at least two months.

[0123] Embodiment 11. The method of any one of embodiments 1-10, wherein ibudilast or a pharma- ceutically acceptable salt thereof is administered at least once daily.

[0124] Embodiment 12. The method of any one of embodiments 1-10, wherein ibudilast or a pharma- ceutically acceptable salt thereof is administered twice daily.

[0125] Embodiment 13. The method of any one of embodiments 1-12, wherein the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is 0.1 mg to 720 mg per day.

[0126] Embodiment 14. The method of any one of embodiments 1-12, wherein the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is at least 30 mg / day.

[0127] Embodiment 15. The method of any one of embodiments 1-12, wherein the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is 30 mg to 200 mg per day.

[0128] Embodiment 16. The method of any one of embodiments 1-12, wherein the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is between 60 mg and 600 mg daily.

[0129] Embodiment 17. The method of any one of embodiments 1-12, wherein the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is 100 mg to 480 mg daily.

[0130] Embodiment 18. The method of any one of embodiments 1-12, wherein the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is selected from the group consisting of 30 mg / day, 40 mg / day, 50 mg / day, 60 mg / day, 90 mg / day, 100 mg / day, 110 mg / day, 120 mg / day, 150 mg / day, 180 mg / day, 190 mg / day, 200 mg / day, 210 mg / day, 240 mg / day, 270 mg / day, 300 mg / day, 360 mg / day, 400 mg / day, 440 mg / day, 480 mg / day, 520 mg / day, 580 mg / day, 600 mg / day, 620 mg / day, 640 mg / day, 680 mg / day, and 720 mg / day.

[0131] Embodiment 19. The method of any one of embodiments 1 to 18, wherein the therapeutically effective amount is administered as a single dose or divided into 2, 3, or 4 doses.

[0132] Embodiment 20. The method of any one of embodiments 1-19, wherein ibudilast is administered continuously.

[0133] Embodiment 21 The method of any one of embodiments 1-20, wherein ibudilast, or a pharma- ceutically acceptable salt thereof, is the only active agent administered to the patient.

[0134] Embodiment 22. The method of any one of embodiments 1-20, wherein ibudilast or a pharma- ceutically acceptable salt thereof is administered to the patient with at least one other active agent.

[0135] Embodiment 23. The method of embodiment 22, wherein the at least one other active agent comprises a corticosteroid, a COX-2 (cyclooxygenase-2) inhibitor, an NSAID (nonsteroidal anti-inflammatory drug), an SSRI (selective serotonin reuptake inhibitor), an SNRI (serotonin and norepinephrine reuptake inhibitor), a tricyclic antidepressant, an antihistamine, a beta-blocker, cannabidiol, ATP (adenosine triphosphate), ifenprodil tartrate, a neurotropin, gabapentin, pregabalin, mirtazapine, or a combination of two or more thereof.

[0136] Equivalent Although the present disclosure has been specifically disclosed by certain embodiments and optional features, it is to be understood that modifications, improvements, and variations of the present disclosure embodied herein may be made by those skilled in the art, and such modifications, improvements, and variations are considered to be within the scope of the present disclosure. The materials, methods, and examples provided herein are representative of certain embodiments, are illustrative, and are not intended as limitations on the scope of the present disclosure.

[0137] The present disclosure is described broadly and generically herein. Each of the narrower species and subgeneric groupings falling within the generic disclosure also forms part of the present disclosure. This includes the generic description of the present disclosure with a condition or negative limitation that removes any subject matter from the genus, regardless of whether the excised material is specifically described herein.

[0138] Furthermore, where features or aspects of the disclosure are described in terms of a Markush group, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual members or subgroups of members of the Markush group.

[0139] Use of the term "or" in the claims is used to mean "and / or," unless expressly indicated to refer to alternatives only or the alternatives are not mutually exclusive, however, the present disclosure supports a definition that refers to alternatives only and "and / or."

Claims

1. 1. A composition for treating post-COVID symptoms in a patient in need thereof, comprising ibudilast or a pharmaceutical salt thereof.

2. 10. The composition of claim 1, wherein the post-COVID symptoms include one or more selected from anxiety, generalized pain or discomfort, fatigue, insomnia, cognitive impairment, depression, shortness of breath, post-traumatic stress disorder, joint pain, muscle pain, chest pain or tension, palpitations, olfactory or taste dysfunction, sleep disturbance, hair loss, and rash.

3. 3. The composition of claim 2, wherein the post-COVID symptoms include cognitive impairment, and the cognitive impairment includes one or both of memory loss and decreased concentration.

4. 4. The composition of claim 1, wherein ibudilast or a pharmaceutically acceptable salt thereof is administered orally, intravenously, by subcutaneous injection, intramuscular injection, or by inhalation.

5. 4. The composition of any one of claims 1 to 3, wherein ibudilast or a pharmaceutically acceptable salt thereof is administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days or more.

6. 4. The composition of claim 1, wherein ibudilast or a pharmaceutically acceptable salt thereof is administered for at least two months.

7. 4. The composition of any one of claims 1 to 3, wherein ibudilast or a pharmaceutically acceptable salt thereof is administered at least once daily.

8. 4. The composition of any one of claims 1 to 3, wherein ibudilast or a pharmaceutically acceptable salt thereof is administered twice daily.

9. 4. The composition of any one of claims 1 to 3, wherein ibudilast or a pharmaceutically acceptable salt thereof is administered in an amount of at least 30 mg / day.

10. 4. The composition of any one of claims 1 to 3, wherein ibudilast or a pharmaceutically acceptable salt thereof is administered in an amount of 0.1 mg to 720 mg, 30 mg to 200 mg, 60 mg to 600 mg, or 100 mg to 480 mg per day.

11. 4. The composition of any one of claims 1 to 3, wherein ibudilast or a pharmaceutically acceptable salt thereof is administered in an amount selected from the group consisting of 30 mg / day, 40 mg / day, 50 mg / day, 60 mg / day, 90 mg / day, 100 mg / day, 110 mg / day, 120 mg / day, 150 mg / day, 180 mg / day, 190 mg / day, 200 mg / day, 210 mg / day, 240 mg / day, 270 mg / day, 300 mg / day, 360 mg / day, 400 mg / day, 440 mg / day, 480 mg / day, 520 mg / day, 580 mg / day, 600 mg / day, 620 mg / day, 640 mg / day, 680 mg / day, and 720 mg / day.

12. A composition described in any one of claims 1 to 3, wherein ibudilast or a pharmaceutically acceptable salt thereof is administered as a single dose or divided into two, three, or four doses.

13. 4. The composition of claim 1, wherein ibudilast or a pharmaceutically acceptable salt thereof is administered continuously.

14. 4. The composition of any one of claims 1 to 3, wherein ibudilast or a pharmaceutically acceptable salt thereof is the only active agent administered to the patient.

15. 4. The composition of any one of claims 1 to 3, wherein ibudilast or a pharmaceutically acceptable salt thereof is administered to the patient together with at least one other active agent.

16. 16. The composition of claim 15, wherein the at least one other active agent comprises a corticosteroid, a COX-2 (cyclooxygenase-2) inhibitor, an NSAID (nonsteroidal anti-inflammatory drug), an SSRI (selective serotonin reuptake inhibitor), an SNRI (serotonin and norepinephrine reuptake inhibitor), a tricyclic antidepressant, an antihistamine, a beta-blocker, cannabidiol, ATP (adenosine triphosphate), ifenprodil tartrate, a neurotropin, gabapentin, pregabalin, mirtazapine, or a combination of two or more thereof.

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