Methods for Treating Chemical Gas Exposure

Abstract

Disclosed is a method of treating chemical-induced lung injury in a subject in need thereof, comprising administering to the subject 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 U.S. Provisional Patent Application No. 63 / 143,750, filed January 29, 2021, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Ibudilast has been widely used in Japan to relieve symptoms associated with ischemic stroke or bronchial asthma. Recent clinical trials have explored its use in the treatment of multiple sclerosis (MS), an inflammatory disease of the central nervous system (News.Medical.Net; Pharmaceutical News, August 2, 2005). As disclosed in this publication, the clinical trials were expected to treat "relapsing-remitting MS," but there is no mention 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] While the use of ibudilast has been reported to date for many diverse indications, to the best of the inventors' knowledge, its use in the treatment of chemical-induced acute lung injury in patients has remained largely unexplored until now. Summary of the Invention

[0004] In one aspect, disclosed herein is a method of treating chemical-induced lung injury in a subject in need thereof, comprising, consisting essentially of, or consisting of administering to the subject a therapeutically effective amount of ibudilast, or a pharmaceutical salt thereof.

[0005] In some embodiments, the lung injury is induced by a chemical selected from chlorine, sulfur mustard gas, phosgene, lewisite, hydrogen chloride, sulfur dioxide, hydrogen sulfide, nitrogen dioxide, ammonia, hydrofluoric acid, ozone, methyl isocyanate, and combinations of two or more thereof.

[0006] In some embodiments, the lung injury comprises chemical burns, pulmonary edema, laryngeal edema, lung tissue apoptosis, pneumonia, interstitial pneumonia, bronchitis, bronchiolitis, fibrosis, acute respiratory distress syndrome, respiratory spasm, or a combination of two or more thereof.

[0007] 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 intravenously. In some embodiments, ibudilast, or a pharma- ceutically acceptable salt thereof, is administered by subcutaneous injection. In some embodiments, ibudilast, or a pharma- ceutically acceptable salt thereof, is administered by intramuscular injection. In some embodiments, ibudilast, or a pharma- ceutically acceptable salt thereof, is administered by inhalation.

[0008] 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 3 months.

[0009] In some embodiments, ibudilast, or a pharma- ceutically acceptable salt thereof, is administered at least once a day. In some embodiments, ibudilast, or a pharma- ceutically acceptable salt thereof, is administered twice a day.

[0010] 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 40 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, 60 mg / day, 90 mg / day, 100 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.

[0011] 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 sequentially.

[0012] In some embodiments, ibudilast or a pharmaceutically acceptable salt thereof is the only active agent administered to the patient.In some embodiments, ibudilast or a pharmaceutically acceptable salt thereof 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 a corticosteroid. [Brief description of the drawings]

[0013] [Figure 1] 1 shows the PaO2 / FiO2 results for four animals tested in the acute lung injury sheep model: negative control (Control-N), positive control (Control-P), high MN-166 dose, low MN-166 dose. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] The practice of the present disclosure utilizes conventional methods of chemistry, biochemistry, and pharmacology 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 Edition; FDA's Orange Book, Goodman & Gilman The Pharmacological Basis of Therapeutics, J. Griffith Hardman, L. L. Limbird, A. Gilman, 11th Edition, 2005; The Merck Manual, 18th Edition, 2007; and The Merck Manual of Medical Information 2003.

[0015] All publications cited herein, whether supra or infra, including internet articles, the FDA Orange Book (available at the FDA website), books, handbooks, journal articles, patents, and patent applications, are hereby incorporated by reference in their entirety.

[0016] 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 may vary, as will be apparent from the accompanying description.

[0017] 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 two or more of the same or different drugs as well as a singular drug, reference to "an optional excipient" refers to two or more of the same or different optional excipients as well as a single optional excipient, and so forth.

[0018] In describing and claiming the present disclosure, the following terminology will be used in accordance with the definitions set out below.

[0019] 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 others. "Consisting essentially of," when used to define compositions and methods, means excluding any other elements that are of essential importance to the combination for the stated purpose. 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 feature(s) of the claimed invention. "Consisting of" means excluding more than trace amounts of other ingredients and substantial method steps. 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 to be understood that the disclosure also includes alternative embodiments of said embodiment, such as "consisting essentially of" and "consisting of."

[0020] 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 to a patient.

[0021] "Pharmaceutically acceptable salts" include, but are not limited to, salts prepared with inorganic acids such as amino acid salts, for example chlorides, sulfates, phosphates, diphosphates, bromides, and nitrates, or salts prepared from any preceding corresponding inorganic acid form, for example 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).

[0022] As described herein, "active molecule" or "active agent" includes any agent, drug, compound, composition of matter or mixture that produces a pharmacological, often beneficial, effect that can be demonstrated in-vivo or in vitro. This includes foods, nutritional supplements, nutrients, dietary supplements, drugs, vaccines, antibodies, vitamins, and other beneficial agents. As used herein, the term further includes any physiologically or pharmacologically active substance that produces a localized or systemic effect in a patient. In certain embodiments, the active molecule or active agent can include ibudilast or a pharmaceutically acceptable salt thereof.

[0023] "Substantially" or "essentially" means nearly all or completely, e.g., 95% or more of a given amount.

[0024] "Optional" or "optionally" means that the situation described thereafter may or may not occur, so that the statement includes cases where the situation occurs and cases where it does not occur.

[0025] The terms "subject," "individual," or "patient" are used interchangeably herein to refer to a vertebrate, preferably a mammal, including, but not limited to, murines, rodents, rats, monkeys, humans, farm animals, dogs, cats, sport animals, and pets.

[0026] As provided herein, the term "pharmacologically effective amount" or "therapeutically effective amount" of a composition or agent refers to a non-toxic but sufficient amount of the composition or agent to produce a desired response, such as reduction or recovery of chemical-induced lung injury. The exact amount required will vary from subject to subject, depending on the subject's race, age, and general condition, the severity of the condition being treated, the particular drug or drugs utilized, 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 testing, based on the information provided herein.

[0027] 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. If there is a use of the term 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 provided herein with numbers preceded by the term "about". The term "about" is used herein to literally support the exact number it precedes, as well as numbers that are close to or near the number it precedes. In determining whether a number is close to or near a number recited in detail, the unrecited close or near number may be a number that defines a substantial equivalent of the recited number in the context in which it is provided.

[0028] As used herein, the term "treatment" or "treating" means any treatment of a condition or associated disorder in a patient, including arresting the condition or associated disorder, i.e., arresting or inhibiting the development of clinical symptoms such as chemical burns, pulmonary edema, laryngeal edema, lung tissue apoptosis, pneumonia, interstitial pneumonia, bronchitis, bronchiolitis, fibrosis, acute respiratory distress syndrome, respiratory spasm, or a combination of two or more thereof, and / or relieving the condition or associated disorder, i.e., causing a reduction in clinical symptoms.

[0029] In some embodiments, the term treating refers to the improvement in clinical outcome by delayed administration of ibudilast after the development of lung injury and symptoms.The term "clinical outcome" refers to any clinical observation or measurement of the patient's response to treatment.Non-limiting examples of clinical outcome include the clinical observation or measurement of alveolar inflammation, pulmonary edema, lung tissue apoptosis, lung tissue necrosis, airway destruction, or any combination thereof in patients who respond to treatment.

[0030] 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 particular embodiments of the present disclosure, are given by way of example only, since various changes and modifications within the spirit and scope of the present disclosure will become apparent to those skilled in the art from this detailed description.

[0031] 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.

[0032] [ka]

[0033] Ibudilast is also found in ChemBank ID 3227, CAS # 50847-11-5, and Beilstein Handbook Reference No. 5-24-03-00396. Its molecular formula is C 14 H 18 It corresponds to NO. 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 for ibudilast include ibudilastum (Latin), BRN 0656579, KC-404, and MN-166. Its trade name is Ketas®. Ibudilast, as referred to herein, is intended to include any and all pharma- ceutically acceptable salt forms thereof, prodrug forms (e.g., the corresponding ketal, oxime, oxime derivative, hydrazone, or semicarbazone), solvates, etc., as appropriate for use in its intended formulation for administration.

[0034] Ibudilast is also a selective inhibitor of cyclic nucleotide phosphodiesterases (PDEs) 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 phosphate ester bond on the 3' carbon to yield the corresponding 5'-nucleotide monophosphate. Thus, PDEs regulate the cellular concentrations of cyclic nucleotides. Because extracellular receptors for many hormones and neurotransmitters utilize cyclic nucleotides as second messengers, PDEs also regulate the cellular response to these extracellular signals. There are at least eight types of PDEs: 2+ / Calmodulin-dependent PDE (PDE1); cGMP-stimulating PDE (PDE2); cGMP-inhibiting 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 both the release of proinflammatory and neuroactive mediators. Ibudilast can also suppress the production of proinflammatory cytokines (IL-1β, TNF-α) and enhance the production of anti-inflammatory cytokines (IL-4, IL-10).References for 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. With regard to the treatment of cancers of the CNS, ibudilast exhibits good CNS penetration. (Sanftner et al., Xenobiotica 2009, 39:964-977).

[0035] Ibudilast is also an allosteric inhibitor of p-hydroxyphenylpyruvate (HPP) tautomerase activity of macrophage inhibitory factor (MIF) (Cho et al., PNAS-USA, June 2010, 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 levels of MIF. Such a reduction in MIF plasma levels is unexpected, since there is no known association between allosteric inhibition of MIF and MIF concentrations in plasma. However, since MIF is involved in intracellular signaling via activation of CD44 or CD74 in complex with the chemokine receptors CXCR2 and CXCR4, both MIF inhibition and reduction of MIF plasma levels by ibudilast can minimize the proinflammatory effects of MIF.

[0036] As noted above, reference to any one or more of the drugs described herein, particularly ibudilast, is intended to encompass, where applicable, any and all enantiomers, mixtures of enantiomers including racemic mixtures, prodrugs, pharma- ceutically acceptable salt forms, hydrates (e.g., monohydrates, dihydrates, etc.), solvates, different physical forms (e.g., crystallized solids, amorphous solids), metabolites, and the like.

[0037] Treatment and Administration Methods As stated above, in one aspect, the present disclosure relates to a method for treating chemical-induced lung injury in a subject in need thereof, comprising, consisting essentially of, or consisting of administering to the subject a therapeutically effective amount of ibudilast, or a pharmaceutical salt thereof. Such administration is effective to attenuate or reverse the chemical-induced lung injury in the subject. The lung injury comprises or consists of chemical burns, pulmonary edema, laryngeal edema, lung tissue apoptosis, pneumonia, interstitial pneumonia, bronchitis, bronchiolitis, fibrosis, acute respiratory distress syndrome, respiratory spasm, or a combination of two or more thereof.

[0038] In some embodiments, ibudilast or a pharma- ceutically acceptable salt thereof is administered in a daily dosage ranging from about 0.1 mg to 720 mg per day, about 30 mg to 200 mg per day, about 40 mg to 600 mg per day, or about 100 mg to 480 mg per day. In some embodiments, a decrease in the plasma level of macrophage migration inhibitory factor in the subject is observed within 12 hours after the first dose of ibudilast is administered. In some embodiments, a decrease in the plasma level of macrophage migration inhibitory factor in the subject is observed within 12 hours after administration of ibudilast for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days.

[0039] Ibudilast administration may be achieved through various delivery modes of ibudilast, including formulation.Preferred delivery methods of ibudilast-based therapeutic formulation include systemic and local delivery.Such administration routes include but are not limited to oral, intraarterial, intrathecal, intraspinal, intramuscular, intraperitoneal, intranasal and inhalation routes.

[0040] More specifically, the ibudilast-based formulations of the present disclosure may be administered for treatment by any suitable route, including, but not limited to, oral, rectal, nasal, topical (including transdermal, aerosol, buccal and sublingual), vaginal, parenteral (including subcutaneous, intravenous, intramuscular and intradermal), intrathecal and pulmonary. In some embodiments, the ibudilast-based formulations are administered orally. In some embodiments, the ibudilast-based formulations are administered via 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 utilized.

[0041] 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 via injection.

[0042] When the ibudilast composition of the present disclosure comprises two or more active agents, it may be administered as a single combination composition comprising the combination of ibudilast and at least one additional active agent.In terms of patient compliance and ease of administration, such an approach is preferred, since patients often do not like to take multiple pills or dosage forms, often multiple times a day, for the duration 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 of the additional active agents may be administered simultaneously, sequentially in any order, or separately.

[0043] Dosage Therapeutic amounts can be empirically determined and will vary 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.

[0044] The therapeutically effective amount can be determined by those skilled in the art and adjusted to the requirements of each particular case. In general, the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is administered in a total daily dosage range of 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 in an amount between 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, either as a single dose or as multiple doses. In some embodiments, the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is administered at about 30-200 mg / day, either as a single dose or as multiple doses, in some embodiments, multiple doses include two, three, or four doses per day.

[0045] Preferred dosages include dosages of greater than about 20 mg BID or TID, i.e., 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.

[0046] In some embodiments, the 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 210 mg / day, at least 220 mg / day, at least 230 mg / day, at least 240 mg / day, at least 250 mg / day, at least 260 mg / day, at least 270 mg / day, at least 280 mg / day, at least 290 mg / day, at least 300 mg / day, at least 310 mg / day, at least 320 mg / day, at least 330 mg / day, at least 340 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, 225mg / 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 a pharma- ceutically acceptable salt thereof is at least 60mg / day. In some embodiments, the therapeutically effective amount of ibudilast or a pharma-ceutically acceptable salt thereof is at least 100mg / day.

[0047] Depending on the dosage and the exact condition being treated, administration may be once, twice, three times, or four times a day, for a course ranging from one day to several days, weeks, months, and even years, and even the lifespan of the patient. 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 pharmaceutically 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 3 months or less. In some embodiments, ibudilast or a pharma- ceutically acceptable salt thereof is administered for at least 3 months. In some embodiments, ibudilast or a pharma- ceutically acceptable salt thereof is administered for at least 6 months. 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, or 12 months or longer. In some embodiments, ibudilast or a pharma- ceutically acceptable salt thereof is administered for about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years or longer. In some embodiments, ibudilast or a pharma- ceutically acceptable salt thereof is administered for at least 1 year. In some embodiments, ibudilast or a pharma- ceutically acceptable salt thereof is administered for at least 2 years. In some embodiments, ibudilast or a pharma- ceutically acceptable salt thereof is administered as a one-time single dose.

[0048] In some embodiments, the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is administered in a single dosage per day. In some embodiments, the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is administered in two dosages per day. In some embodiments, the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is administered in three dosages per day. In some embodiments, the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is administered in four dosages per day. In some embodiments, the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is administered continuously.

[0049] In some embodiments, ibudilast or a pharmaceutically acceptable salt thereof is administered at least once a day. In some embodiments, ibudilast or a pharmaceutically acceptable salt thereof is administered at least twice a day. In some embodiments, ibudilast or a pharmaceutically acceptable salt thereof is administered once a day. In some embodiments, ibudilast or a pharmaceutically acceptable salt thereof is administered twice a day.

[0050] In practical terms, a unit dose of any given composition or active agent of the present disclosure can be administered in a variety of dosing schedules, depending on the clinician's judgment, the patient's needs, and the like. Particular 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, and the like.

[0051] formulation Ibudilast may be administered in a composition in a formulation that may optionally contain one or more of the additional ingredients described below.

[0052] Excipients / Carriers In addition to ibudilast or a pharma- ceutically acceptable salt thereof, the composition of the present disclosure may further comprise one or more pharma- ceutically 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, starches (e.g., corn starch), inorganic salts, antibacterial 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, and the like.

[0053] The compositions of the present disclosure may include one or more carbohydrates, such as sugars, e.g., sugar derivatives, 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), pyranosyl sorbitol, myo-inositol, etc.

[0054] 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.

[0055] 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.

[0056] The composition of the present disclosure may also contain one or more antioxidants.Antioxidants are used to prevent oxidation, thereby preventing the deterioration of drug(s) or other preparation components.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.

[0057] Additional 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 esters, steroids, e.g., cholesterol, and chelating agents, e.g., EDTA, zinc, and other such suitable cations. In some embodiments, surfactants may include polyethoxylated castor oil derivatives (e.g., Cremophor EL, Kolliphor ELP, etc.). Other non-limiting excipients include alcohols (e.g., ethanol), propylene glycol, glyderol, or polyethylene glycol (PEG).

[0058] 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 those 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, those 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.

[0059] The amount of any individual excipient in the composition varies depending on the role of the excipient, the required dosage of the active ingredient, and the specific needs of the composition.Typically, the optimal amount of any individual excipient is determined through routine testing, i.e., by preparing compositions containing various amounts of excipient (ranging from low to high amounts), examining stability and other parameters, and then determining the range in which optimal performance is achieved without significant adverse effects.

[0060] Generally, however, the excipients are present in the composition in an amount of about 1% to about 99% by weight, preferably about 5% to about 98% by weight, and more preferably about 15% to about 95% by weight of the excipient. Generally, the amount of excipients present in the ibudilast compositions of the present disclosure is selected from the following: 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.

[0061] These aforementioned pharmaceutical excipients, along with other excipients, are described in Remington: The Science & Practice of Pharmacy, 19th ed., Williams & Williams, (1995), Physician's Desk Reference, 52.sup.nd ed., Medical Economics, Montvale, NJ (1998), and Kibbe, AH, Handbook of Pharmaceutical Excipients, 3.sup.rd ed., American Pharmaceutical Association, Washington, DC, 2000.

[0062] 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.

[0063] Preferably, the one or more other therapeutic agents are therapeutic agents having a mechanism of action different from that of ibudilast. Such active ingredients can be found listed in FDA's Orange Book, Goodman & Gilman The Pharmacological Basis of Therapeutics, J. Griffith Hardman, LLLimbird, A. Gilman, 11th Edition, 2005, The Merck Manual, 18th Edition, 2007, and The Merck Manual of Medical Information 2003.

[0064] 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 propionate, betamethasone dipropionate, betamethasone valerate, clobetasol propionate, clobetasone butyrate, fluprednidene acetate, and mometasone furoate.

[0065] The dosage amounts provided above are intended as a guideline only; the exact amount of a second active agent administered in 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 synergy between the active agents being administered, and the like, and can be readily determined by one of skill in the art based on the guidance provided herein.

[0066] 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 may be delivered in a controlled or extended release formulation.Controlled or extended release formulations are prepared by incorporating ibudilast or its pharmaceutically acceptable salt into a carrier or vehicle, for example, liposomes, non-absorbable impermeable polymers such as ethylene vinyl acetate copolymers and Hytrel® copolymers, swellable polymers such as hydrogels, or absorbable polymers such as collagen, and certain polyacids or polyesters such as those used to make absorbable 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, as well as 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).

[0067] Suitable extended 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 acid esters, methacrylic acid and acrylate polymers (pH-dependent); fatty acids and glycerides, methacrylic acid ester neutral polymers, high molecular weight polyvinyl alcohols such as polyvinyl alcohol-maleic anhydride copolymers and waxes; ethyl acrylate-methyl methacrylate copolymers; aminoalkyl methacrylate copolymers; and mixtures thereof.

[0068] Mode of delivery The compositions of ibudilast or its pharma- ceutically acceptable salts described herein include all kinds of formulations, particularly formulations suitable for systemic or intrathecal administration.Oral dosage forms include tablets, lozenges, capsules, syrups, oral suspensions, emulsions, granules, and pellets.Release tablets.In some embodiments, the oral dosage form is a capsule.In some embodiments, the capsule is an extended release capsule.

[0069] Alternative formulations include aerosols, transdermal patches, gels, creams, ointments, suppositories, powders, or lyophilized formulations that can be reconstituted, as well as liquids.Examples of suitable diluents for reconstituting solid compositions, for example before injection, include bacteriostatic water for injection, 5% dextrose in water, phosphate buffered saline, Ringer's solution, normal saline, sterile water, deionized water, and combinations thereof.For liquid pharmaceutical compositions, solutions and suspensions are envisioned.Preferably, the compositions of ibudilast or its pharma-ceutically acceptable salts of the present disclosure are suitable for oral administration.

[0070] Now, turning to oral delivery formulations, tablets can be made by compression or molding, optionally with one or more auxiliary materials or additives.Compressed tablets are prepared by compressing the active ingredient in a free-flowing form, such as powder or granules, optionally mixed with binders (e.g., povidone, gelatin, hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethylcellulose) and / or surfactants or dispersants, in a suitable tablet press.

[0071] 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 may be optionally coated or scored, and may be formulated to provide slow or controlled release of the active ingredient, for example, using hydroxypropyl methylcellulose in various proportions to provide the desired release characteristics. Tablets may be optionally provided with a coating, such as a thin film, sugar coating, or enteric coating, to provide release in parts of the intestine other than the stomach. Processes, equipment, and toll manufacturers for making tablets and capsules are well known in the art.

[0072] 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.

[0073] Pharmaceutical compositions for topical administration may also be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

[0074] Alternatively, the formulation may be in the form of a patch (e.g., a transdermal patch) or a dressing such as a bandage or adhesive plaster impregnated with the active ingredient and optionally one or more excipients or diluents. Topical formulations may additionally contain compounds that enhance absorption or penetration of the ingredient through the skin or other affected areas, such as dimethylsulfoxide, bisabolol, oleic acid, isopropyl myristate, and D-limonene, to name a few.

[0075] For emulsions, the oily phase is composed in a known manner from known ingredients. While this phase may simply comprise one emulsifier (alternatively known as a diuretic), it is preferred to comprise at least one emulsifier and a mixture of fats and / or oils. A hydrophilic emulsifier is preferably included together with a lipophilic emulsifier that acts as a stabilizer. Together, the emulsifier(s), with or without stabilizer(s), constitute the so-called emulsifying wax, which, together with the oils and / or fats, constitutes the so-called emulsifying ointment base that forms the oily dispersed phase of the cream formulation. Exemplary diuretics and emulsion stabilizers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate.

[0076] Formulations for rectal administration are typically in the form of a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

[0077] Formulations suitable for vaginal administration generally take the form of a suppository, tampon, cream, gel, paste, foam, or spray.

[0078] Suitable formulations for nasal administration include those in which the carrier is solid, for example a coarse powder having a particle size in the range of about 20 to about 500 microns. Such formulations are typically administered by rapid inhalation through the nasal passage, for example from a container of the powder placed near the nose. Alternatively, formulations for nasal delivery may be in the form of a liquid, for example a nasal spray or nasal drops.

[0079] Aerosolized formulations for inhalation may be in dry powder form (e.g., suitable for administration by dry powder inhaler), or alternatively, may be in liquid form, for example, for use in nebulizers. Nebulizers for delivery of 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, for example, a Ventolin® metered dose inhaler, that contains a solution or suspension of the drug combination described herein in a pharma- ceutically inert liquid propellant, such as, for example, a chlorofluorocarbon or a fluorocarbon.

[0080] 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.

[0081] The parenteral formulations of the disclosure may optionally be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example, water, for injection immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

[0082] The formulation of the present disclosure may also be an extended release formulation, in which each component of the drug is slowly released or absorbed over time, as compared to a non-extended release formulation.Extended release formulations may utilize a prodrug form of the active agent, a delayed release drug delivery system such as a liposome or polymer matrix, a hydrogel, or a covalent bond between the active agent and a polymer such as polyethylene glycol.

[0083] In addition to the ingredients specifically mentioned above, the formulations of the present disclosure may optionally contain other agents conventional in the pharmaceutical art and, for example, the particular types of formulations utilized for oral dosage forms; compositions for oral administration may also contain additional agents as sweeteners, thickeners, or flavoring agents.

[0084] kit Also provided herein are kits containing at least one composition of the disclosure, along with instructions for use.

[0085] In some embodiments, the kit contains at least one combination composition described herein with instructions.For example, when each drug is administered as an individual or separate dosage form, the kit contains ibudilast in addition to each drug that constitutes the composition of the present disclosure, and with instructions.The drug components may be packaged in any manner suitable for administration, as long as the package clearly indicates the manner in which each drug component is administered, considering that the package is accompanied by instructions for administration.

[0086] For example, with respect to an exemplary kit that includes ibudilast and one other active agent, the kit may be configured for any suitable period, such as by day. As an example, for 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 a day, the kit may include two unit dosage forms of each of ibudilast and one other active agent corresponding to day 1, along with instructions regarding the timing of administration. Alternatively, if one or more drugs differ in timing or amount of unit dosage forms compared to other constituent drugs of the combination, this will be reflected in the packaging and instructions. Various embodiments based on the above can be easily envisioned, and will of course depend on the specific combination of drugs utilized in the treatment in addition to ibudilast, their corresponding dosage forms, recommended dosages, intended patient population, etc. The packaging may be in any form commonly utilized for packaging pharmaceutical products, and may utilize any number of features, such as different colors, packaging materials, tamper-evident packaging, blister packaging, moisture barriers, etc.

[0087] While the present disclosure has been described in connection with certain preferred embodiments, it should be understood that, as with the foregoing, the following examples are intended to be illustrative and not limiting of the scope of the present disclosure. Other aspects, advantages and modifications within the scope of the present disclosure will be apparent to those of skill in the art to which the present disclosure pertains.

[0088] 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.

[0089] The following examples are presented for the purpose of illustrating various embodiments of the present disclosure, and are not intended to limit the present disclosure in any manner. Those skilled in the art will readily recognize that the present disclosure is well adapted to carry out the objects and obtain the objectives and advantages set forth herein, as well as those inherent therein. The examples, together with the methods described herein, are presently representative and exemplary of the embodiments, and are not intended to limit the scope of the present disclosure. Modifications 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

[0090] Chlorine Efficacy Study in Mice The purpose of this study was to evaluate the efficacy of ibudilast against whole-body oxygen inhalation exposure in C57BL / 6 mice. Animals were exposed to chlorine gas at 575 ppm (LD 50 / 7d) for 11 minutes. Groups receive ibudilast by tail vein injection once daily starting 1 hour after chlorine exposure (low dose: approximately 4-6 mg / kg, medium dose: approximately 6-7.5 mg / kg, high dose: approximately 7.5-10 mg / kg) according to the table below and continuing daily for 7 days. One group is exposed to a PDE4 inhibitor (rolipram) to serve as a positive control. At 24 hours after chlorine exposure, animals undergo pulmonary function testing using an EMKA total body pulmonary function system followed by collection of lavage fluid for cell count and differential white blood cell analysis and collection of the left lung lobe for histopathology analysis. Prior to performing efficacy evaluations, one group of 10 animals (group 0 in the table below) is exposed to chlorine to verify lethality of an 11 minute exposure at 575 ppm. At the end of this part of the study, animals are euthanized without performing a terminal procedure.

[0091] research design

[0092] [Table 1]

[0093] Purchase a total of 139 C57BL / 6 mice (including spares). Animals will be approximately 8-10 weeks old upon arrival and will undergo a minimum of 7 days of quarantine.

[0094] After administration of chlorine, animals are monitored continuously for the first 4 hours. During this period, animals remain in the exposure facility with minimal external noise (i.e., door slamming). Animals are monitored a minimum of three additional times (approximately 5-7 hours post-chlorine, approximately 11-13 hours post-chlorine, and approximately 17-19 hours post-chlorine). After 24 hours, animals are monitored once daily for the duration of the study. Animals are monitored for lethargy, hunched posture, rapid breathing, and excessive urination and diarrhea. Body weights are collected prior to chlorine exposure and at necropsy.

[0095] On the day of scheduled euthanasia (day 8), animals following chlorine exposure undergo pulmonary function testing. Only animals that survive until scheduled euthanasia undergo pulmonary function analysis. Animals determined to be moribund do not undergo pulmonary function testing.

[0096] At the end of the study, 8 days after chlorine exposure, animals are euthanized. Moribund animals are euthanized as needed throughout the duration of the study. Necropsy is performed 8 days after chlorine exposure. The left lobe is fixed for histopathology. The right lobe is washed and snap frozen. Collected lavage samples are analyzed for cell counts and differential white blood cell counts. EXAMPLES

[0097] Chlorine-induced acute lung injury (ALI) sheep model: Protocol 1 The sheep model allows the measurement of a wide variety of cardiopulmonary variables to a very high degree, which can be used as endpoints for treatment or fluid resuscitation. Sheep, unlike rodents, can be intubated or tracheotomized with minimal damage to the airway and can be mechanically ventilated using standard clinical equipment. In addition, the sheep model mimics the clinical situation very well with regard to the basic standard of care for acute lung injury, i.e., fluid resuscitation, pulmonary function monitoring, and mechanical ventilation. The blood volume of sheep is large enough to provide samples for frequent intermittent blood gas analysis and circulating cell counting without hypovolemic shock. Sheep can be easily studied in the unanesthetized state. Importantly, the ovine response to inflammation (both physiological and genomic) is actually similar to that of humans, unlike porcine and rodent models.

[0098] Surgical preparation: After a quarantine period of at least 7-14 days, sheep are surgically prepared for measurements of heart rate, systemic arterial pressure, pulmonary arterial pressure (including cardiac output), pulmonary artery wedge pressure, left atrial pressure, core body temperature, and central venous pressure. Procedures with these instruments are performed under isoflurane anesthesia via an endotracheal tube.

[0099] Briefly, 36 adult female sheep are pre-anesthetized with 15-20 mg / kg intramuscular ketamine followed by 10-15 mg / kg IV ketamine. After endotracheal intubation, anesthesia is maintained using inhaled isoflurane. The sheep are mechanically ventilated and surgery is performed utilizing strict aseptic technique. Analgesia is provided by long-acting (72 h) buprenorphine.

[0100] 16-gauge, 24-inch arterial and venous catheters are placed into the descending aorta and vena cava using incisions over the femoral artery and vein. The catheters are sutured in place using 1 / 0 Ethibond sutures and exposed through a small incision into the flank skin, and the wound is closed in a simple continuous pattern with 2 / 0 Vicryl. A Swan-Ganz thermodilution pulmonary artery catheter is placed into the pulmonary artery via the right external jugular vein using a commercially available percutaneous catheter introducer system. A catheter (inner diameter 0.062 inches, outer diameter 0.125 inches) is also placed into the left atrium through the fifth intercostal space. Lidocaine, 1 to 3 mg / kg, is applied topically to the cardiac surface to prevent possible arrhythmias during cannulation of the left atrium of the heart. A small incision by puncture into the chest wall exposes the tubes. The ribs are held together using two 1 / 0 or 2 / 0 simple interrupted stainless steel wire sutures. The muscle and subcutaneous tissue are sutured in two layers using a simple continuous pattern with 2 / 0 Vicryl. The skin is closed in a simple continuous pattern with 2 / 0 Vicryl. A double IV dose of cefazolin (2 g) is administered during surgery to reduce the risk of infection. The sheep are then allowed 5-7 days with free access to food and water to recover from anesthesia and heal from surgery before undergoing the ALI protocol. Analgesia during and after surgery is provided with long-acting (72 hours) buprenorphine. SR (0.1-0.27 mg / kg) using a subcutaneous injection.

[0101] During the recovery period, sheep are connected to hemodynamic monitors, given IV fluid resuscitation with lactated Ringer's solution, and provided with food and water. Vascular catheters and lines are continuously flushed with heparinized saline.

[0102] Baseline Variables: Following a 5-7 day surgical recovery period, baseline measurements of respiratory and hemodynamic variables are performed in awake, unanesthetized sheep.

[0103] Baseline variables included the following: Cardiopulmonary hemodynamics: Heart rate, Mean arterial pressure, Cardiac output, Left atrial pressure, Central venous pressure, Pulmonary artery pressure, Pulmonary artery occlusion pressure, and Calculated variables: cardiac index, systemic and pulmonary artery resistance index, pulmonary capillary pressure, and left and right ventricular stroke volume index; ·Central body temperature Arterial and venous blood gas analysis, complete blood count: PO2, CO2, SO2, hematocrit, hemoglobin, pH, electrolytes (Na, K, Ca, Cl), lactate, and glucose, Calculated variables - arterial oxygen pressure (PaO2) / inspiratory oxygen pressure (FiO2) ratio and pulmonary shunt fraction, Complete blood count.

[0104] Exclusion Criteria: Sheep will be excluded from the study if any of the following symptoms are present: PaO2<90mmHg on room air Hematocrit <20%, Hemoglobin < 7g / dL Core body temperature >40°C (normal sheep body temperature is approximately 39.6°C), ·Leukocytes>10k / μL.

[0105] Induction of ALI: Immediately prior to the start of the study, sheep will receive ketamine anesthetic at 5 mg / kg via IV injection followed by long-acting (72 hour) buprenorphine analgesia at 0.1 mg / kg via SC injection. A tracheotomy will be performed and anesthesia will be maintained using IV propofol with an initial bolus of 50 mg, then adjusted to effect. Sheep will be ventilated with a tidal volume (TV) of 12 mL / kg at a positive end-expiratory pressure (PEEP) of 5 cm H2O. The bladder will be catheterized via a Foley catheter threaded through the urethra to allow continuous urine collection for measurement of urine output. Animals will undergo chest x-rays prior to chlorine exposure and prior to euthanasia (if applicable).

[0106] Injury is induced by intratracheal delivery of chlorine at concentrations of 150 ppm or 200 ppm in air for 30 min via a closed ventilator circuit connected to a chlorine bath. The ventilator is set to a tidal volume of 12 mL / kg, a PEEP of 5 cm H2O, and a respiratory rate of 20 b / min. This setting allows for comparable exposure between animals.

[0107] The chlorine level of the inhaled gas is certified as a premixed blend of chlorine and medical air delivered undiluted by the ventilator. The total flow rate of the chlorine / air mixture is determined by a mass flow meter with a stainless steel component placed immediately after the regulator. The chlorine bath is preheated (24 hours) to 40°C with an electric warmer to ensure proper mixing of the gases. During the 30 minutes of injury, blood gas analysis is performed every 10 minutes and cardiopulmonary variables are recorded. Possible chlorine leakage during exposure is monitored by at least two monitors. The exposure is performed in a special room equipped with negative pressure and a toxic gas evacuation hood. At least three TICU personnel wearing designated PPE, including protective masks, induce the exposure and provide care. After the 30 minutes of chlorine exposure, the sheep is ventilated with air (without chlorine) for 10 minutes to flush residual chlorine from both the sheep's airway and the ventilator circuit. The sheep is then removed from the ventilator and transferred to the ICU station.

[0108] Post-injury monitoring: After the sheep are transferred to the ICU station, they are placed on a ventilator (Avea APVcmv mode: RR 20b / m, TV 12mL / kg, PEEP 5cm H2O) connected to a hemodynamic monitor and monitored for 48 hours in an awake state. The sheep are humanely euthanized under deep anesthesia and analgesia at 48 hours after injury. The sheep are humanely euthanized if one of the following occurs during the study and does not recover within 1 hour despite resuscitation attempts: ·PaO2 / FiO2 ratio<50mmHg PaCO2>90mmHg MAP < 50mmHg.

[0109] Grouping and Treatment: Following injury, sheep are randomly assigned to one of four groups: 1. Control: group exposed to chlorine and treated with an equivalent volume of vehicle; 2. Positive control: group exposed to chlorine and treated with a PDE4 inhibitor (rolipram); 3. MN-166 (high dose): a group exposed to chlorine and treated with high doses of MN-166 (up to 100 mg / kg); and 4. MN-166 (low dose): group exposed to chlorine and treated with low doses of MN-166 (up to 50 mg / kg).

[0110] Each group contains 8 sheep. The total number of sheep in the entire study is 36 with 1 sheep per group for possible technical errors (36 = 8 sheep per group x 4 groups + 4 sheep for experimental failures / errors (1 sheep per group)). During the study, sheep will be fluid resuscitated with lactated Ringer's solution 2 mL / kg / h.

[0111] Endpoints: Following treatment, study assessments will be performed in the same manner as the baseline variables. A description of each assessment is provided below. 1. Pulmonary function is assessed by: 1) intermittent (every 6 hours) arterial and venous blood gas analysis, including arterial and venous PaO2, CO2, SO2, base excess, pH, and SO2. In addition, arterial hematocrit, hemoglobin, electrolytes, glucose, and lactate are measured every 6 hours. The PaO2 / FiO2 ratio is calculated to determine the severity of ARDS. Bilateral pulmonary infiltrates are confirmed by chest x-rays taken at the end of the study. Chest x-rays are also taken prior to injury. Pulmonary shunt fraction is calculated by standard formulas; and 2) pulmonary mechanics, i.e., lung compliance, airway peak and pause pressures, and dead space, are obtained every 6 hours from ventilator readings. 2. Lung injury and edema formation are assessed postmortem by chest x-ray, as well as histology (alveolar and interstitial edema), and lung water content (ratio of wet to dry weight). Histology of lung tissue also includes parenchymal congestion, hemorrhage, accumulation of inflammatory cells, atelectasis, and airway epithelial denudation. 3. Cardiopulmonary hemodynamics will be monitored continuously and baseline variables will be recorded every 6 hours. 4. Systemic vascular permeability is assessed by determining net cumulative fluid balance (fluid intake and urine volume measured every 6 hours), plasma protein, and fluid accumulation in body cavities (thorax and abdomen) over a 48 hour period. 5. Total peripheral blood cell counts are determined every 6 hours.

[0112] Sampling: 1) Arterial blood is collected every 6 hours for the first 24 hours and every 12 hours for the next 24 hours, and aliquots of plasma and serum are stored at 20° C. for future evaluation, 2) aliquots of urine are collected at the indicated time points and stored at 20° C., 3) Bronchoalveolar lavage is performed at the end of the study and aliquots are frozen and stored at 20° C., 4) Animals are humanely euthanized 48 hours after injury and aliquots of trachea, bronchi, lung parenchyma, heart, liver, and kidneys are frozen and stored at −80° C. and fixed in formalin. Thoracic and abdominal fluid volumes are measured, if present, and total protein is measured.

[0113] Statistical Analysis: Statistical analysis is performed using GraphPad Prism 8 software with two-way or one-way ANOVA and T-tests where applicable.

[0114] Pulmonary function. Respiratory parameters will be assessed intermittently and quantifiable comparisons will be made between treatment groups. The relative severity of ARDS in the various treatment groups will be assessed from calculated PaO2 / FiO2 ratios. Other variables to be assessed include pulmonary infiltrates, pulmonary shunt fraction and pulmonary mechanics.

[0115] Lung injury and edema formation. Postmortem comparison of histological samples is evaluated and comparisons are made between treatment groups to assess the effectiveness of ibudilast drug treatment. The extent of hemorrhage, inflammatory cell accumulation, atelectasis, and airway epithelial denudation is quantified. Differences in lung water content are determined by chest x-ray and compared.

[0116] Systemic Vascular Permeability. Net cumulative fluid balance is measured over a 48 hour period and compared between drug treated, untreated and positive control groups to assess efficacy. EXAMPLES

[0117] Chlorine-induced acute lung injury (ALI) sheep model: Protocol 2 Surgical preparation: After at least 7-14 days of quarantine, sheep were surgically prepared for measurements of heart rate, systemic arterial pressure, pulmonary arterial pressure (including cardiac output), pulmonary artery occlusion pressure, left atrial pressure, core temperature, and central venous pressure. These instrumented procedures were performed under isoflurane anesthesia via an endotracheal tube.

[0118] Briefly, 36 adult ewes were pre-anesthetized with 15-20 mg / kg intramuscular ketamine followed by 10-15 mg / kg IV ketamine. After endotracheal intubation, anesthesia was maintained using inhaled isoflurane. The sheep were mechanically ventilated and surgery was performed utilizing strict aseptic technique. Analgesia was provided by long-acting (72 h) buprenorphine.

[0119] 16-gauge, 24-inch arterial and venous catheters were placed in the descending aorta and vena cava using incisions over the femoral artery and vein. The catheters were sutured in place using 1 / 0 Ethibond sutures and exposed through a small incision in the flank skin, and the wound was closed in a simple continuous pattern with 2 / 0 Vicryl. A Swan-Ganz thermodilution pulmonary artery catheter was placed in the pulmonary artery via the right external jugular vein using a commercially available percutaneous catheter introducer system. A catheter (inner diameter 0.062 inches, outer diameter 0.125 inches) was also placed in the left atrium through the fifth intercostal space. Lidocaine, 1-3 mg / kg, was applied topically to the cardiac surface to prevent possible arrhythmias during cannulation of the left atrium of the heart. A small incision by puncture in the chest wall exposed the tubes. The ribs were held together using two 1 / 0 or 2 / 0 simple interrupted stainless steel wire sutures. The muscle and subcutaneous tissue were sutured in two layers using a simple running pattern with 2 / 0 Vicryl. The skin was closed in a simple running pattern with 2 / 0 Vicryl. A double IV dose of cefazolin (2 g) was administered during surgery to reduce the risk of infection. The sheep were then allowed 5-7 days with free access to food and water to recover from anesthesia and heal from surgery before undergoing the ALI protocol. Analgesia during and after surgery was provided with long-acting (72 hours) buprenorphine. SR (0.1-0.27 mg / kg) subcutaneously.

[0120] During the recovery period, sheep were connected to hemodynamic monitors, given IV fluid resuscitation with lactated Ringer's solution, and given food and water. Vascular catheters and lines were continuously flushed with heparinized saline.

[0121] Baseline Variables: Following a 5-7 day surgical recovery period, baseline measurements of respiratory and hemodynamic variables were performed in awake, unanesthetized sheep.

[0122] Baseline variables included the following: Cardiopulmonary hemodynamics: Heart rate, Mean arterial pressure, Cardiac output, Left atrial pressure, Central venous pressure, Pulmonary artery pressure, Pulmonary artery occlusion pressure, and Calculated variables: cardiac index, systemic and pulmonary artery resistance index, pulmonary capillary pressure, and left and right ventricular stroke volume index; ·Central body temperature Arterial and venous blood gas analysis, complete blood count: PO2, CO2, SO2, hematocrit, hemoglobin, pH, electrolytes (Na, K, Ca, Cl), lactate, and glucose, Calculated variables - arterial oxygen pressure (PaO2) / inspiratory oxygen pressure (FiO2) ratio and pulmonary shunt fraction, Complete blood count.

[0123] Exclusion criteria: Sheep were excluded from the study if any of the following symptoms were present: PaO2<90mmHg on room air Hematocrit <20%, Hemoglobin < 7g / dL Core body temperature >40°C (normal sheep body temperature is approximately 39.6°C), ·Leukocytes>10k / μL.

[0124] Induction of ALI: Immediately prior to the start of the study, sheep received ketamine anesthesia at 5 mg / kg IV injection followed by long-acting (72 hour) buprenorphine analgesia at 0.1 mg / kg SC injection. A tracheotomy was performed and anesthesia was maintained using IV propofol with an initial bolus of 50 mg, then titrated to effect. Sheep were ventilated with a tidal volume (TV) of 12 mL / kg at a positive end-expiratory pressure (PEEP) of 5 cm H2O. For measurement of urine output, the bladder was catheterized via a Foley catheter threaded through the urethra to allow continuous urine collection. Animals were to undergo chest x-rays prior to chlorine exposure and prior to euthanasia (when applicable).

[0125] Injury was induced by intratracheal delivery of chlorine at a concentration of 210 ppm in air for 30 min via a closed ventilator circuit connected to a chlorine bath. The ventilator was set to a tidal volume of 12 mL / kg, a PEEP of 5 cm H2O, and a respiratory rate of 20 b / min. This setting allowed for comparable exposures between animals.

[0126] The chlorine level of the inhaled gas was certified as a premixed blend of chlorine and medical air delivered undiluted by the ventilator. The total flow rate of the chlorine / air mixture was determined by a mass flow meter with a stainless steel component placed immediately after the regulator. The chlorine bath was preheated (24 h) to 40°C with an electric warmer to ensure proper mixing of the gases. During the 30 min of injury, blood gas analysis was performed every 10 min and cardiopulmonary variables were recorded. Possible chlorine leakage during exposure was monitored by at least two monitors. The exposure was performed in a special room equipped with negative pressure and a toxic gas evacuation hood. At least three TICU personnel wearing designated PPE, including protective masks, induced the exposure and provided care. After the 30 min of chlorine exposure, the sheep were ventilated with air (no chlorine) for 10 min to flush residual chlorine from both the sheep's airway and the ventilator circuit. The sheep were then removed from the ventilator and transferred to the ICU station.

[0127] Post-injury monitoring: After the sheep were transferred to the ICU station, they were placed on a ventilator (Avea APVcmv mode: RR 20b / m, TV 12mL / kg, PEEP 5cm H2O) connected to a hemodynamic monitor and monitored for 48 hours in an awake state. The sheep were humanely euthanized under deep anesthesia and analgesia 48 hours after injury. The sheep were humanely euthanized if one of the following occurred during the study and did not recover within 1 hour despite resuscitation attempts: ·PaO2 / FiO2 ratio<50mmHg PaCO2>90mmHg MAP < 50mmHg.

[0128] Grouping and Treatment: Following injury, sheep were randomly assigned to one of four groups: 1. Negative control: group exposed to chlorine and treated with an equal volume of vehicle (5% Kolliphor EL and 50% propylene glycol and saline); 2. Positive control: group exposed to chlorine and treated with a PDE4 inhibitor (rolipram, 3 mg); 3. MN-166 (high dose): a group exposed to chlorine and treated with high dose MN-166 (20 mg); and 4. MN-166 (low dose): A group exposed to chlorine and treated with low dose MN-166 (10 mg).

[0129] Each sheep received a final volume of 20 mL over a 30 minute infusion.

[0130] Each group contained 8 sheep. The total number of sheep in the entire study was 36 with 1 sheep per group for possible technical errors (36 = 8 sheep per group x 4 groups + 4 sheep for experimental failures / errors (1 sheep per group)). During the study, sheep were fluid resuscitated with lactated Ringer's solution 2 mL / kg / h.

[0131] Endpoints: After treatment, study assessments were performed in the same manner as the baseline variables. A description of each assessment is provided below. 1. Pulmonary function was assessed by: 1) intermittent (every 6 hours) arterial and venous blood gas analysis, including arterial and venous PaO2, CO2, SO2, base excess, pH, and SO2. In addition, arterial hematocrit, hemoglobin, electrolytes, glucose, and lactate were measured every 6 hours. The PaO2 / FiO2 ratio was calculated to determine the severity of ARDS. Bilateral pulmonary infiltrates were confirmed by chest x-rays taken at the end of the study. Chest x-rays were also taken before injury. Pulmonary shunt fraction was calculated by standard formulas; and 2) pulmonary mechanics, i.e., lung compliance, airway peak and pause pressures, and dead space, were obtained every 6 hours from ventilator readings. 2. Lung injury and edema formation were assessed postmortem by chest X-ray, as well as histological examination (alveolar and interstitial edema) and lung water content (ratio of wet to dry weight). Histological examination of lung tissue also included parenchymal congestion, hemorrhage, accumulation of inflammatory cells, atelectasis, and airway epithelial denudation. 3. Cardiopulmonary hemodynamics was monitored continuously and baseline variables were recorded every 6 hours. 4. Systemic vascular permeability was assessed by determination of net cumulative fluid balance (ingested fluids and urine volume measured every 6 hours), plasma protein, and fluid accumulation in body cavities (thorax and abdomen) over a 48 hour period. 5. Total peripheral blood cell counts were determined every 6 hours.

[0132] Sampling: 1) arterial blood was collected every 6 hours for the first 24 hours and every 12 hours for the next 24 hours, and aliquots of plasma and serum were stored at -20°C for future evaluation; 2) aliquots of urine were collected at the indicated time points and stored at -20°C; 3) bronchoalveolar lavage was performed at the end of the study and aliquots were frozen and stored at -20°C.

[0133] Necropsy: 48 hours after Cl2 exposure (or when euthanasia criteria were met [see above]), sheep were exsanguinated under anesthesia with an IV infusion of 100 mg xylazine, 1500 mg ketamine, and 0.3 mg fast-acting buprenorphine, consistent with recommendations from the Panel on Euthanasia of the American Veterinary Medical Association. Immediately prior to necropsy, chest x-rays were performed using a portable digital x-ray machine, when applicable.

[0134] Postmortem Sampling: After euthanasia, the heart and entire lungs and upper airways were excised. Organ weights and images of the heart and lungs were obtained. Aliquots of trachea, bronchi, lung parenchyma, heart, liver, and kidneys were stored frozen at -80°C and fixed in formalin. Thoracic and abdominal fluid volumes were measured, if present, and total protein was measured. An aliquot of lung tissue was also taken for measurement of lung wet to dry weight ratios.

[0135] Statistical Analysis: Statistical analysis was performed using GraphPad Prism 8 software with two-way or one-way ANOVA and T-tests where applicable.

[0136] Interim Study Results: PaO2 / FiO2 ratios were calculated at each time point after chlorine exposure. The PaO2 / FiO2 results (mmHg) for four animals at various time points [negative control (Control-N), positive control (Control-P), high dose MN-166, low dose MN-166] are shown in the following table and Figure 1.

[0137] [Table 2]

[0138] After chlorine exposure, a worsening of the PaO2 / FiO2 ratio was observed in all groups by 3 hours after chlorine exposure. In negative control animals treated with vehicle alone, PaO2 / FiO2 remained below 200mmHg (moderate ARDS) or below 100mmHg (severe ARDS) at all time points. In positive control animals (treated with rolipram, 3mg), PaO2 / FiO2 was below 300mmHg (mild ARDS) at 18 hours after chlorine gas exposure and remained below 200mmHg or below 100mmHg at 24 hours. Animals treated with low dose MN-166 (10mg) improved PaO2 / FiO2 to above 300mmHg at 6 hours after chlorine gas exposure and remained above 300mmHg. PaO2 / FiO2 values ​​in animals treated with high dose MN-166 (20 mg) never fell below 300 mmHg at any time point and rose to over 400 mmHg by the 30 hour time point. EXAMPLES

[0139] Administration of ibudilast to human patients with chemical-induced lung injury Up to 100 mg of ibudilast is administered to a human patient suffering from symptoms from chemical-induced lung injury due to chlorine, sulfur mustard gas, phosgene, lewisite, hydrogen chloride, sulfur dioxide, hydrogen sulfide, nitrogen dioxide, ammonia, hydrofluoric acid, ozone, methyl isocyanate, or a combination of two or more thereof (e.g., one or more of chemical burns, pulmonary edema, laryngeal edema, lung tissue apoptosis, pneumonia, interstitial pneumonia, bronchitis, bronchiolitis, fibrosis, acute respiratory distress syndrome, or respiratory spasm).

[0140] Response to ibudilast is assessed by respiratory rate measurements, blood oxygen level measurements (i.e., by pulse oximetry), dyspnea scales (e.g., modified medical research council dyspnea score), pulmonary function tests (i.e., by spirometer), chest imaging studies (i.e., chest x-ray, chest CT), or any combination of two or more of these.

[0141] Specific Embodiments Embodiment 1. A method of treating chemical-induced lung injury in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of ibudilast, or a pharmaceutical salt thereof.

[0142] Embodiment 2. The method of embodiment 1, wherein the lung injury is induced by a chemical selected from chlorine, sulfur mustard gas, phosgene, lewisite, hydrogen chloride, sulfur dioxide, hydrogen sulfide, nitrogen dioxide, ammonia, hydrofluoric acid, ozone, methyl isocyanate, and combinations of two or more thereof.

[0143] Embodiment 3. The method of embodiment 1 or embodiment 2, wherein the lung injury comprises chemical burns, pulmonary edema, laryngeal edema, lung tissue apoptosis, pneumonia, interstitial pneumonia, bronchitis, bronchiolitis, fibrosis, acute respiratory distress syndrome, respiratory spasm, or a combination of two or more thereof.

[0144] Embodiment 4 The method of any one of embodiments 1-3, wherein ibudilast, or a pharma- ceutically acceptable salt thereof, is administered orally.

[0145] Embodiment 5. The method of any one of embodiments 1-3, wherein the ibudilast, or a pharma- ceutically acceptable salt thereof, is administered intravenously.

[0146] Embodiment 6 The method of any one of embodiments 1-3, wherein the ibudilast, or a pharma- ceutically acceptable salt thereof, is administered by subcutaneous injection.

[0147] Embodiment 7. The method of any one of embodiments 1-3, wherein the ibudilast, or a pharma- ceutically acceptable salt thereof, is administered by intramuscular injection.

[0148] Embodiment 8 The method of any one of embodiments 1-3, wherein ibudilast, or a pharma- ceutically acceptable salt thereof, is administered by inhalation.

[0149] 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.

[0150] Embodiment 10. The method of any one of embodiments 1-8, wherein the ibudilast, or a pharma- ceutically acceptable salt thereof, is administered for at least 3 months.

[0151] Embodiment 11. The method of any one of embodiments 1-10, wherein the ibudilast, or a pharma- ceutically acceptable salt thereof, is administered at least once a day.

[0152] Embodiment 12. The method of any one of embodiments 1-10, wherein ibudilast, or a pharma- ceutically acceptable salt thereof, is administered twice daily.

[0153] 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.

[0154] 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 30 mg to 200 mg per day.

[0155] 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 between 40 mg and 600 mg per day.

[0156] 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 100 mg to 480 mg per day.

[0157] 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 selected from the group consisting of 30 mg / day, 60 mg / day, 90 mg / day, 100 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.

[0158] Embodiment 18. The method of any one of embodiments 1-17, wherein the therapeutically effective amount is administered as a single dose or divided into two, three or four doses.

[0159] Embodiment 19. The method of any one of embodiments 1-17, wherein ibudilast is administered sequentially.

[0160] Embodiment 20 The method of any one of embodiments 1-19, wherein ibudilast, or a pharma- ceutically acceptable salt thereof, is the only active agent administered to the patient.

[0161] Embodiment 21 The method of any one of embodiments 1-19, wherein ibudilast, or a pharma- ceutically acceptable salt thereof, is administered to the patient with at least one other active agent.

[0162] Embodiment 22 The method of embodiment 21, wherein the at least one other active agent comprises a corticosteroid.

[0163] Equivalent Although the present disclosure is disclosed in detail by certain embodiments and optional features, it is to be understood that modifications, improvements and variations of the present disclosure implemented as disclosed herein may be employed 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 and illustrative of specific embodiments, and are not intended to limit the scope of the present disclosure.

[0164] The disclosure is described broadly and generically herein. Each of the narrower types and subgeneric classifications falling within the generic disclosure also form part of the disclosure. This includes the generic description of the disclosure with a conditional or negative limitation that removes any subject matter from that class, regardless of whether the excised material is specifically described herein.

[0165] Additionally, when features or aspects of the disclosure are described in terms of Markush word groups, those skilled in the art will understand that the disclosure is also described in terms of any individual members or subgroup members of the Markush word group.

[0166] Use of the term "or" in the claims is used to mean "and / or" unless expressly indicated to represent only alternatives or unless the alternatives are mutually exclusive, even if the present disclosure supports a definition that represents only alternatives as well as "and / or."

Claims

1. 1. A composition for the treatment of chemical-induced lung injury in a subject in need thereof, comprising ibudilast, or a pharma- ceutically acceptable salt thereof.

2. 2. The composition of claim 1, wherein the lung injury is induced by a chemical selected from chlorine, sulfur mustard gas, phosgene, lewisite, hydrogen chloride, sulfur dioxide, hydrogen sulfide, nitrogen dioxide, ammonia, hydrofluoric acid, ozone, methyl isocyanate, and combinations of two or more thereof.

3. 3. The composition of claim 1 or claim 2, wherein the lung injury comprises chemical burns, pulmonary edema, laryngeal edema, lung tissue apoptosis, pneumonia, interstitial pneumonia, bronchitis, bronchiolitis, fibrosis, acute respiratory distress syndrome, respiratory spasm, or a combination of two or more thereof.

4. The composition of any one of claims 1 to 3, wherein ibudilast, or the pharma- ceutically acceptable salt thereof, is administered orally, intravenously, by subcutaneous injection, by intramuscular injection, or by inhalation.

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

6. The composition of any one of claims 1 to 4, wherein ibudilast, or the pharma- ceutically acceptable salt thereof, is administered for at least three months.

7. The composition of any one of claims 1 to 6, wherein ibudilast, or the pharma- ceutically acceptable salt thereof, is administered at least once a day.

8. The composition of any one of claims 1 to 6, wherein ibudilast, or the pharma- ceutically acceptable salt thereof, is administered twice daily.

9. 9. The composition of any one of claims 1 to 8, wherein the therapeutically effective amount of ibudilast, or the pharma- ceutically acceptable salt thereof, is 0.1 mg to 720 mg, 30 mg to 200 mg, 40 mg to 600 mg, or 100 mg to 480 mg per day.

10. 9. The composition of any one of claims 1 to 8, wherein the therapeutically effective amount of ibudilast, or the pharma- ceutically acceptable salt thereof, is selected from the group consisting of 30 mg / day, 60 mg / day, 90 mg / day, 100 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.

11. The composition of any one of claims 1 to 10, wherein the therapeutically effective amount is administered as a single dose or divided into two, three or four doses.

12. The composition of any one of claims 1 to 10, wherein ibudilast is administered continuously.

13. The composition of any one of claims 1 to 12, wherein ibudilast, or the pharma- ceutically acceptable salt thereof, is the only active agent administered to the patient.

14. The composition of any one of claims 1 to 12, wherein ibudilast, or the pharma- ceutically acceptable salt thereof, is administered to a patient together with at least one other active agent.

15. 15. The composition of claim 14, wherein the at least one other active agent comprises a corticosteroid.

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