Ibudilast oral formulations and methods of use thereof

Abstract

The present disclosure relates to higher dosage oral formulations of ibudilast, such as tablet or capsule formulations, and corresponding methods of treatment.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 904,519, filed Sep. 23, 2019, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] The small molecule ibudilast (3-isobutyryl-2-isopropylpyrazolo[1,5-a]pyridine) is an inhibitor of macrophage inhibitory factor (MIF) (Cho et al., PNAS-USA, June 2010 107:11313-8), a selective inhibitor of cyclic nucleotide phosphodiesterases (PDEs) 3A, 4, 10A1, and 11A1 (Gibson et al., Eur. J. Pharmacol., 538:39-42, 2006), and has Toll-like receptor 4 (TLR4) antagonist activity (Yang et al., Cell Death and Disease (2016) 7, e2234; doi:10.1038 / cddis.2016.140). Ibudilast distributes well in the CNS (Sanftner et al., Xenobiotica 2009 39:964-977), and at clinically relevant plasma or CNS concentrations, it selectively inhibits macrophage migration inhibitory factor (MIF) and secondarily inhibits PDE3, 4, 10 and 11. Ibudilast also acts as a leukotriene D4 antagonist, an anti-inflammatory PAF antagonist, and a vasodilator (Thompson Current Drug Reports). Ibudilast is believed to exert a neuroprotective role in the mammalian central nervous system, possibly through the suppression of glial cell activation (Mizuno et al., Neuropharmacology 46:404-411, 2004).

[0003] 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. Summary of the Invention

[0004] In one aspect, provided herein is a pharmaceutical composition comprising ibudilast and at least one pharmaceutically acceptable excipient, the pharmaceutical composition being in the form of a tablet or capsule, the tablet or the capsule having a dissolution profile in which at least about 12% of the ibudilast is released from the tablet or the capsule in about 2 hours when tested in a USP Apparatus Type II at 50 rpm in 900 mL of simulated gastric fluid medium at 37°C. In some embodiments, the tablet has a coating comprising polyvinyl alcohol, a plasticizer, and a pigment. In some embodiments, the at least one pharmaceutically acceptable excipient comprises microcrystalline cellulose, lactose, or hypromellose, or any combination of two or more thereof. In some embodiments, the tablet or capsule has a dissolution profile in which at least about 25% of the ibudilast is released from the tablet or capsule in about 4 hours when tested in a USP Apparatus Type II at (a) 50 rpm in 900 mL of simulated gastric fluid medium at 37° C. for 2 hours, followed by (b) 50 rpm in 900 mL of phosphate buffer containing 0.3% w / w sodium lauryl sulfate, pH 6.8, for an additional 2 hours at 37° C. In some embodiments, the tablet or capsule has a dissolution profile in which at least about 60% of the ibudilast is released from the tablet or capsule in about 12 hours when tested in a USP Apparatus Type II at (a) 50 rpm in 900 mL of simulated gastric fluid medium at 37° C. for 2 hours, followed by (b) 50 rpm in 900 mL of phosphate buffer containing 0.3% w / w sodium lauryl sulfate, pH 6.8, for an additional 10 hours at 50 rpm at 37° C. In some embodiments, the tablet or capsule has a dissolution profile in which at least about 90% of the ibudilast is released from the tablet or capsule in about 24 hours when tested in a USP Apparatus Type II: (a) 2 hours at 50 rpm in 900 mL of simulated gastric fluid medium at 37° C., followed by an additional 22 hours at 50 rpm in 900 mL of phosphate buffer, pH 6.8, containing 0.3% w / w sodium lauryl sulfate at 37° C.In some embodiments, the tablet or capsule contains from about 10 mg to about 100 mg of ibudilast.

[0005] In another aspect, provided herein is a pharmaceutical composition comprising ibudilast and at least one pharmaceutically acceptable excipient, the pharmaceutical composition being in the form of a tablet or capsule, the tablet or the capsule having a dissolution profile in which ibudilast is not released from the tablet or the capsule in about 2 hours when tested in a USP Apparatus Type II at 50 rpm in 900 mL of simulated gastric fluid medium at 37°C. In some embodiments, the tablet has a coating comprising a copolymer dispersant of methacrylic acid and ethyl acrylate; triethyl citrate; and talc. In some embodiments, the at least one pharmaceutically acceptable excipient comprises microcrystalline cellulose, lactose, or hypromellose, or any combination of two or more thereof. In some embodiments, the tablet or capsule has a dissolution profile in which about 10% to about 20% of the ibudilast is released from the tablet or capsule in about 4 hours when tested in a USP Apparatus Type II: (a) 2 hours at 50 rpm in 900 mL of simulated gastric fluid medium at 37° C., followed by an additional 2 hours at 50 rpm in 900 mL of phosphate buffer, pH 6.8, containing 0.3% w / w sodium lauryl sulfate at 37° C. In some embodiments, the tablet or capsule has a dissolution profile in which about 55% to about 65% of the ibudilast is released from the tablet or capsule in about 12 hours when tested in a USP Apparatus Type II: (a) 2 hours at 50 rpm in 900 mL of simulated gastric fluid medium at 37° C., followed by an additional 10 hours at 50 rpm in 900 mL of phosphate buffer containing 0.3% w / w sodium lauryl sulfate, pH 6.8, at 37° C.In some embodiments, the tablet or capsule has a dissolution profile in which about 85% to about 95% of the ibudilast is released from the tablet or capsule in about 24 hours when tested in a USP Apparatus Type II: (a) 2 hours at 50 rpm in 900 mL of simulated gastric fluid medium at 37° C., followed by an additional 22 hours at 50 rpm in 900 mL of phosphate buffer containing 0.3% w / w sodium lauryl sulfate, pH 6.8, at 37° C. In some embodiments, the tablet or capsule contains about 10 mg to about 100 mg of the ibudilast.

[0006] In another aspect, provided herein is a pharmaceutical composition comprising about 3% w / w to about 15% w / w ibudilast, about 30% w / w to about 40% w / w lactose, about 30% w / w to about 40% w / w microcrystalline cellulose, about 15% w / w to about 25% w / w hypromellose, about 0.2% w / w to about 0.8% w / w magnesium stearate, and about 0.5% w / w to about 5% w / w colloidal silicon dioxide. In some embodiments, the lactose is lactose monohydrate. In some embodiments, the pharmaceutical composition comprises about 10% w / w ibudilast, about 35% w / w lactose monohydrate, about 33.5% w / w microcrystalline cellulose, about 20% w / w hypromellose, about 0.5% w / w magnesium stearate, and about 1% w / w colloidal silicon dioxide. In some embodiments, the composition is in the form of a tablet. In some embodiments, the tablet has a coating. In some embodiments, the coating comprises polyvinyl alcohol, a plasticizer, and a pigment. In some embodiments, the coating comprises a copolymer dispersant of methacrylic acid and ethyl acrylate; triethyl citrate; and talc. In some embodiments, the composition is in the form of a capsule. In some embodiments, the composition does not comprise hydroxypropylmethylcellulose-phthalate. In some embodiments, the composition does not comprise hydrogenated castor oil. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0007] 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.

[0008] 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.

[0009] 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 and figures.

[0010] 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.

[0011] In describing and claiming the present disclosure, the following terminology will be used in accordance with the definitions set out below.

[0012] 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 substantially affect the basic and novel feature(s) of the claimed invention. "Consisting of" means excluding more than trace elements 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."

[0013] "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.

[0014] 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.

[0015] "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).

[0016] 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.

[0017] "Substantially" or "essentially" means nearly all or completely, for example, 90% or 95% or more of a given amount.

[0018] The terms "subject", "individual" or "patient" are used interchangeably herein to refer to a vertebrate, preferably a mammal. Mammals include, but are not limited to, mice, rodents, rats, monkeys, humans, farm animals, dogs, cats, sport animals and pets. In some embodiments, the subject, individual or patient relates to a human.

[0019] As used 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 bring about a desired response, such as reduction or reversal of any disease or disorder described herein. 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, and the like. 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.

[0020] 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.

[0021] As used herein, the term "treatment" or "treating" refers to any treatment of a disease or condition or related disorder in a patient, including preventing the disease or condition, i.e., arresting or suppressing the development of clinical symptoms. "Treatment" or "treating" also includes arresting the development of a disease or reversing a symptom or symptoms. In various aspects and embodiments of the present disclosure, beneficial or desired clinical results include, but are not limited to, reduction, alleviation, or amelioration of one or more symptoms or negative effects of any disease or disorder described herein, improvement in one or more clinical outcomes, reduction in the extent of any disease or disorder described herein, delay or slowing the progression of any disease or disorder described herein, remission, alleviation, or stabilization of the condition of any disease or disorder described herein, and other beneficial results described herein.

[0022] In some embodiments, the term "treating" refers to an improvement in a clinical outcome. The term "clinical outcome" refers to any clinical observation or measurement related to a patient's response to a treatment.

[0023] 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.

[0024] Described herein is a high-dosage form of ibudilast, which includes tablet form and capsule form.High-dosage form facilitates ease of administration and improves patient compliance.In some embodiments, high-dosage form is a tablet form or capsule form with a specific dissolution profile as described herein.In some embodiments, high-dosage form is a tablet form or capsule form with a specific ingredient profile as described herein.

[0025] Ibudilast 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]

[0026] 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, prodrug forms (e.g., corresponding ketals), solvates, and the like, as appropriate for use in its intended formulation for administration.

[0027] Ibudilast is an inhibitor of macrophage inhibitory factor (MIF). 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) 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 concentration of cyclic nucleotides. Because extracellular receptors for many hormones and neurotransmitters utilize cyclic nucleotides as second messengers, PDEs also regulate cellular responses to these extracellular signals. There are at least eight types of PDEs: Ca2+ / 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 both proinflammatory and neuroactive mediator release. 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. Ibudilast exhibits good CNS penetration; Sanftner et al., Xenobiotica, (2009) 39:964-977.

[0028] 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.

[0029] Ingredient Profile In one embodiment, a pharmaceutical composition comprises, consists essentially of, or consists of about 3% w / w to about 15% w / w ibudilast, about 30% w / w to about 40% w / w lactose, about 30% w / w to about 40% w / w microcrystalline cellulose, about 15% w / w to about 25% w / w hypromellose, about 0.2% w / w to about 0.8% w / w magnesium stearate, and about 0.5% w / w to about 5% w / w colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises, consists essentially of, or consists of about 5% w / w to about 15% w / w ibudilast, about 30% w / w to about 40% w / w lactose, about 30% w / w to about 35% w / w microcrystalline cellulose, about 15% w / w to about 25% w / w hypromellose, about 0.2% w / w to about 0.8% w / w magnesium stearate, and about 0.5% w / w to about 5% w / w colloidal silicon dioxide.

[0030] In some embodiments, the pharmaceutical composition comprises, consists essentially of, or consists of about 10% w / w ibudilast, about 35% w / w lactose monohydrate, about 33.5% w / w microcrystalline cellulose, about 20% w / w hypromellose, about 0.5% w / w magnesium stearate, and about 1% w / w colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises, consists essentially of, or consists of about 5% w / w ibudilast, about 37% w / w lactose, about 38.5% w / w microcrystalline cellulose, about 18% w / w hypromellose, about 0.5% w / w magnesium stearate, and about 1% w / w colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises, consists essentially of, or consists of about 10% w / w ibudilast, about 35% w / w lactose, about 33.5% w / w microcrystalline cellulose, about 20% w / w hypromellose, about 0.5% w / w magnesium stearate, and about 1% w / w colloidal silicon dioxide. In some embodiments, the lactose is lactose monohydrate.

[0031] In some embodiments, the pharmaceutical composition comprises from about 1% w / w to about 20% w / w of ibudilast, from about 1% w / w to about 25% w / w of ibudilast, from about 1% w / w to about 30% w / w of ibudilast, from about 1% w / w to about 35% w / w of ibudilast, from about 1% w / w to about 40% w / w of ibudilast, from about 1% w / w to about 45% w / w of ibudilast, from about 1% w / w to about 50% w / w of ibudilast, from about 3% w / w to about 20% w / w of ibudilast, from about 3% w / w to about 25% w / w of ibudilast, from about 3% w / w to about 30% w / w of ibudilast, from about 3% w / w to about 35% w / w of ibudilast, from about 3% w / w to about 40% w / w ibudilast, about 3% w / w to about 45% w / w ibudilast, about 3% w / w to about 50% w / w ibudilast, about 5% w / w to about 10% w / w ibudilast, about 5% w / w to about 15% w / w ibudilast, about 5% w / w to about 20% w / w ibudilast, about 5% w / w to about 25% w / w ibudilast, about 5% w / w to about 30% w / w ibudilast, about 5% w / w to about 35% w / w ibudilast, about 5% w / w to about 40% w / w ibudilast, about 5% w / w to about 45% w / w ibudilast, about 5% w / w to about 50% w / w ibudilast, about 10% w / w to about 15% w / w ibudilast, about 10% w / w to about 20% w / w ibudilast, about 10% w / w to about 25% w / w ibudilast, about 10% w / w to about 30% w / w ibudilast, about 10% w / w to about 35% w / w ibudilast, about 10% w / w to about 40% w / w ibudilast, about 10% w / w to about 45% w / w ibudilast, or about 10% w / w to about 50% w / w ibudilast. In some embodiments, the pharmaceutical composition comprises about 5% w / w to about 15% w / w ibudilast.

[0032] In some embodiments, the pharmaceutical composition comprises about 1% w / w, about 2% w / w, about 3% w / w, about 4% w / w, about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, about 10% w / w, about 11% w / w, about 12% w / w, about 13% w / w, about 14% w / w, about 15% w / w, about 16% w / w, about 17% w / w, about 18% w / w, about 19% w / w, about 20% w / w, about 21% w / w, about 22% w / w, about 23% w / w, about 24% w / w, about 25% w / w, about 26% w / w, about 27% w / w, about 28% w / w, about 29% w / w, about 30% w / w, about 31% In some embodiments, the pharmaceutical composition comprises about 10% w / w ibudilast. In some embodiments, the pharmaceutical composition comprises about 5% w / w ibudilast.

[0033] In one embodiment, the lactose content is about 15% w / w to about 20% w / w, about 15% w / w to about 25% w / w, about 15% w / w to about 30% w / w, about 15% w / w to about 35% w / w, about 15% w / w to about 40% w / w, about 15% w / w to about 45% w / w, about 15% w / w to about 50% w / w, about 15% w / w to about 55% w / w, about 15% w / w to about 60% w / w, about 20% w / w to about 25% w / w, about 20% w / w to about 30% w / w, about 20% w / w to about 35% w / w, about 20% w / w to about 40% lactose, about 20% w / w to about 45% w / w lactose, about 20% w / w to about 50% w / w lactose, about 20% w / w to about 55% w / w lactose, about 20% w / w to about 60% w / w lactose, about 25% w / w to about 30% w / w lactose, about 25% w / w to about 35% w / w lactose, about 25% w / w to about 40% w / w lactose, about 25% w / w to about 45% w / w lactose, about 25% w / w to about 50% w / w lactose, about 25% w / w to about 55% w / w lactose, about 25% w / w to about 60% w / w lactose, about 30% w / w to about 35% w / w lactose, about 30% The pharmaceutical composition comprises from about 30% w / w to about 40% w / w lactose, from about 30% w / w to about 45% w / w lactose, from about 30% w / w to about 50% w / w lactose, from about 30% w / w to about 55% w / w lactose, from about 30% w / w to about 60% w / w lactose, from about 35% w / w to about 40% w / w lactose, from about 35% w / w to about 45% w / w lactose, from about 35% w / w to about 50% w / w lactose, from about 35% w / w to about 55% w / w lactose, or from about 35% w / w to about 60% w / w lactose. In some embodiments, the pharmaceutical composition comprises from about 30% w / w to about 40% w / w lactose.

[0034] In some embodiments, the pharmaceutical composition comprises about 15% w / w, about 16% w / w, about 17% w / w, about 18% w / w, about 19% w / w, about 20% w / w, about 21% w / w, about 22% w / w, about 23% w / w, about 24% w / w, about 25% w / w, about 26% w / w, about 27% w / w, about 28% w / w, about 29% w / w, about 30% w / w, about 31% w / w, about 32% w / w, about 33% w / w, about 34% w / w, about 35% w / w, about 36% w / w, about 37% w / w, about 38% w / w, about 39% w / w, about 40% w / w, about 41% w / w, about 42% w / w, about 43% w / w, about 44% In some embodiments, the pharmaceutical composition comprises about 35% w / w lactose. In some embodiments, the pharmaceutical composition comprises about 37% w / w lactose.

[0035] In one embodiment, about 15% w / w to about 20% w / w lactose monohydrate, about 15% w / w to about 25% w / w lactose monohydrate, about 15% w / w to about 30% w / w lactose monohydrate, about 15% w / w to about 35% w / w lactose monohydrate, about 15% w / w to about 40% w / w lactose monohydrate, about 15% w / w to about 45% w / w lactose monohydrate, about 15% w / w to about 50% w / w lactose monohydrate, about 15% w / w to about 55% w / w lactose monohydrate, about 15% w / w to about 60% w / w lactose monohydrate, about 20% w / w to about 25% w / w lactose monohydrate, about 20% w / w to about 30% lactose monohydrate, about 20% w / w to about 35% w / w lactose monohydrate, about 20% w / w to about 40% w / w lactose monohydrate, about 20% w / w to about 45% w / w lactose monohydrate, about 20% w / w to about 50% w / w lactose monohydrate, about 20% w / w to about 55% w / w lactose monohydrate, about 20% w / w to about 60% w / w lactose monohydrate, about 25% w / w to about 30% w / w lactose monohydrate, about 25% w / w to about 35% w / w lactose monohydrate, about 25% w / w to about 40% w / w lactose monohydrate, about 25% w / w to about 45% w / w lactose monohydrate, about 25% lactose monohydrate from about 25% w / w to about 55% w / w, lactose monohydrate from about 25% w / w to about 60% w / w, lactose monohydrate from about 30% w / w to about 35% w / w, lactose monohydrate from about 30% w / w to about 40% w / w, lactose monohydrate from about 30% w / w to about 45% w / w, lactose monohydrate from about 30% w / w to about 50% w / w, lactose monohydrate from about 30% w / w to about 55% w / w, lactose monohydrate from about 30% w / w to about 60% w / w, lactose monohydrate from about 35% w / w to about 40% w / w, lactose monohydrate from about 35% w / w to about 45% w / w lactose monohydrate, about 35% w / w to about 50% w / w lactose monohydrate, about 35% w / w to about 55% w / w lactose monohydrate, or about 35% w / w to about 60% w / w lactose monohydrate.In some embodiments, the pharmaceutical composition comprises about 30% w / w to about 40% w / w lactose monohydrate.

[0036] In some embodiments, the pharmaceutical composition comprises about 15% w / w, about 16% w / w, about 17% w / w, about 18% w / w, about 19% w / w, about 20% w / w, about 21% w / w, about 22% w / w, about 23% w / w, about 24% w / w, about 25% w / w, about 26% w / w, about 27% w / w, about 28% w / w, about 29% w / w, about 30% w / w, about 31% w / w, about 32% w / w, about 33% w / w, about 34% w / w, about 35% w / w, about 36% w / w, about 37% w / w, about 38% w / w, about 39% w / w, about 40% w / w, about 41% w / w, about 42% w / w, about 43% w / w, about 44% In some embodiments, the pharmaceutical composition comprises about 35% w / w lactose monohydrate. In some embodiments, the pharmaceutical composition comprises about 37% w / w lactose monohydrate.

[0037] In one embodiment, the cellulose is from about 15% w / w to about 20% w / w microcrystalline cellulose, from about 15% w / w to about 25% w / w microcrystalline cellulose, from about 15% w / w to about 30% w / w microcrystalline cellulose, from about 15% w / w to about 35% w / w microcrystalline cellulose, from about 15% w / w to about 40% w / w microcrystalline cellulose, from about 15% w / w to about 45% w / w microcrystalline cellulose, from about 15% w / w to about 50% w / w microcrystalline cellulose, from about 15% w / w to about 55% w / w microcrystalline cellulose, from about 15% w / w to about 60% w / w microcrystalline cellulose, from about 20% w / w to about 25% w / w microcrystalline cellulose, from about 20% w / w to about 30% w / w microcrystalline cellulose, from about 20% w / w to about 35% microcrystalline cellulose, about 20% w / w to about 40% w / w microcrystalline cellulose, about 20% w / w to about 45% w / w microcrystalline cellulose, about 20% w / w to about 50% w / w microcrystalline cellulose, about 20% w / w to about 55% w / w microcrystalline cellulose, about 20% w / w to about 60% w / w microcrystalline cellulose, about 25% w / w to about 30% w / w microcrystalline cellulose, about 25% w / w to about 35% w / w microcrystalline cellulose, about 25% w / w to about 40% w / w microcrystalline cellulose, about 25% w / w to about 45% w / w microcrystalline cellulose, about 25% w / w to about 50% w / w microcrystalline cellulose, about 25% w / w to about 55% w / w microcrystalline cellulose, about 25% w / w to about 60% The pharmaceutical composition comprises about 30% w / w to about 35% w / w microcrystalline cellulose, about 30% w / w to about 40% w / w microcrystalline cellulose, about 30% w / w to about 45% w / w microcrystalline cellulose, about 30% w / w to about 50% w / w microcrystalline cellulose, about 30% w / w to about 55% w / w microcrystalline cellulose, about 30% w / w to about 60% w / w microcrystalline cellulose, about 35% w / w to about 40% w / w microcrystalline cellulose, about 35% w / w to about 45% w / w microcrystalline cellulose, about 35% w / w to about 50% w / w microcrystalline cellulose, about 35% w / w to about 55% w / w microcrystalline cellulose, or about 35% w / w to about 60% w / w microcrystalline cellulose.In some embodiments, the pharmaceutical composition comprises about 30% w / w to about 35% w / w microcrystalline cellulose.In some embodiments, the pharmaceutical composition comprises about 30% w / w to about 38.5% w / w microcrystalline cellulose.

[0038] In some embodiments, the pharmaceutical composition comprises about 15% w / w, about 16% w / w, about 17% w / w, about 18% w / w, about 19% w / w, about 20% w / w, about 21% w / w, about 22% w / w, about 23% w / w, about 24% w / w, about 25% w / w, about 26% w / w, about 27% w / w, about 28% w / w, about 29% w / w, about 30% w / w, about 30.5% w / w, about 31% w / w, about 31.5% w / w, about 32% w / w, about 32.5% w / w, about 33% w / w, about 33.5% w / w, about 34% w / w, about 34.5% w / w, about 35% w / w, about 35.5% w / w, about 36% In some embodiments, the microcrystalline cellulose comprises about 36.5% w / w, about 37% w / w, about 37.5% w / w, about 38% w / w, about 38.5% w / w, about 39% w / w, about 39.5% w / w, about 40% w / w, about 41% w / w, about 42% w / w, about 43% w / w, about 44% w / w, about 45% w / w, about 46% w / w, about 47% w / w, about 48% w / w, about 49% w / w, about 50% w / w, about 51% w / w, about 52% w / w, about 53% w / w, about 54% w / w, about 55% w / w, about 56% w / w, about 57% w / w, about 58% w / w, about 59% w / w, or about 60% w / w. In some embodiments, the pharmaceutical composition comprises about 33.5% w / w microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 38.5% w / w microcrystalline cellulose.

[0039] In one embodiment, about 15% w / w to about 20% w / w hypromellose, about 15% w / w to about 25% w / w hypromellose, about 15% w / w to about 30% w / w hypromellose, about 15% w / w to about 35% w / w hypromellose, about 15% w / w to about 40% w / w hypromellose, about 15% w / w to about 45% w / w hypromellose, about 15% w / w to about 50% w / w hypromellose, about 15% w / w to about 55% w / w hypromellose, about 15% w / w to about 60% w / w hypromellose, about 20% w / w to about 25% w / w hypromellose, about 20% w / w to about 30% Hypromellose from about 20% w / w to about 35% w / w, Hypromellose from about 20% w / w to about 40% w / w, Hypromellose from about 20% w / w to about 45% w / w, Hypromellose from about 20% w / w to about 50% w / w, Hypromellose from about 20% w / w to about 55% w / w, Hypromellose from about 20% w / w to about 60% w / w, Hypromellose from about 25% w / w to about 30% w / w, Hypromellose from about 25% w / w to about 35% w / w, Hypromellose from about 25% w / w to about 40% w / w, Hypromellose from about 25% w / w to about 45% w / w, Hypromellose from about 25% w / w to about 50% Hypromellose from about 25% w / w to about 55% w / w, Hypromellose from about 25% w / w to about 60% w / w, Hypromellose from about 30% w / w to about 35% w / w, Hypromellose from about 30% w / w to about 40% w / w, Hypromellose from about 30% w / w to about 45% w / w, Hypromellose from about 30% w / w to about 50% w / w, Hypromellose from about 30% w / w to about 55% w / w, Hypromellose from about 30% w / w to about 60% w / w, Hypromellose from about 35% w / w to about 40% w / w, Hypromellose from about 35% w / w to about 45% w / w, Hypromellose from about 35% w / w to about 50% In some embodiments, the pharmaceutical composition comprises about 15% w / w to about 25% w / w hypromellose.

[0040] In some embodiments, the pharmaceutical composition comprises about 15% w / w, about 16% w / w, about 17% w / w, about 18% w / w, about 19% w / w, about 20% w / w, about 21% w / w, about 22% w / w, about 23% w / w, about 24% w / w, about 25% w / w, about 26% w / w, about 27% w / w, about 28% w / w, about 29% w / w, about 30% w / w, about 30.5% w / w, about 31% w / w, about 31.5% w / w, about 32% w / w, about 32.5% w / w, about 33% w / w, about 34% w / w, about 35% w / w, about 36% w / w, about 37% w / w, about 38% w / w, about 39% w / w, about 40% w / w, about 41% w / w, about 42% w / w, about 43% w / w, about 44% w / w, about 45% w / w, about 46% w / w, about 47% w / w, about 48% w / w, about 49% w / w, about 50% w / w, about 51% w / w, about 52% w / w, about 53% w / w, about 54% w / w, about 55% w / w, about 56% w / w, about 57% w / w, about 58% w / w, about 59% w / w, about 60% w / w, about 61% w / w, about 62% w / w, about 63% w / w, about 64% w / w, about 65% w / w, about 66% w / w, about In some embodiments, the pharmaceutical composition comprises about 20% w / w of hypromellose. In some embodiments, the pharmaceutical composition comprises about 18% w / w of hypromellose.

[0041] In one embodiment, the magnesium stearate is from about 0.1% w / w to about 0.3% w / w, from about 0.1% w / w to about 0.4% w / w, from about 0.1% w / w to about 0.5% w / w, from about 0.1% w / w to about 0.6% w / w, from about 0.1% w / w to about 0.7% w / w, from about 0.1% w / w to about 0.8% w / w, from about 0.1% w / w to about 0.9% w / w, from about 0.1% w / w to about 1.0% w / w, from about 0.1% w / w to about 1.5% w / w, from about 0.1% w / w to about 2.0% w / w, from about 0.1% Magnesium stearate from about 0.1% w / w to about 3.0% w / w, magnesium stearate from about 0.1% w / w to about 3.5% w / w, magnesium stearate from about 0.1% w / w to about 4.0% w / w, magnesium stearate from about 0.1% w / w to about 4.5% w / w, magnesium stearate from about 0.1% w / w to about 5.0% w / w, magnesium stearate from about 0.2% w / w to about 0.3% w / w, magnesium stearate from about 0.2% w / w to about 0.4% w / w, magnesium stearate from about 0.2% w / w to about 0.5% w / w, magnesium stearate from about 0.2% w / w to about 0.6% w / w, magnesium stearate from about 0.2% w / w to about 0.7% Magnesium stearate w / w, from about 0.2% w / w to about 0.8% w / w magnesium stearate, from about 0.2% w / w to about 0.9% w / w magnesium stearate, from about 0.2% w / w to about 1.0% w / w magnesium stearate, from about 0.2% w / w to about 1.5% w / w magnesium stearate, from about 0.2% w / w to about 2.0% w / w magnesium stearate, from about 0.2% w / w to about 2.5% w / w magnesium stearate, from about 0.2% w / w to about 3.0% w / w magnesium stearate, from about 0.2% w / w to about 3.5% w / w magnesium stearate, from about 0.2% w / w to about 4.0% w / w magnesium stearate, from about 0.The pharmaceutical composition comprises 2% w / w to about 4.5% w / w magnesium stearate, or about 0.2% w / w to about 5.0% w / w magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.2% w / w to about 0.8% w / w magnesium stearate.

[0042] In some embodiments, the pharmaceutical composition comprises about 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% w / w, about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1.0% w / w, about 1.1% w / w, about 1.2% w / w, about 1.3% w / w, about 1.4% w / w, about 1.5% w / w, about 1.6% w / w, about 1.7% w / w, about 1.8% w / w, about 1.9% w / w, about 2.0% w / w, about 2.1% w / w, about 2.2% w / w, about 2.3% w / w, about 2.4% w / w, about 2.5% w / w, about 2.6% w / w, about 2.7% In some embodiments, the pharmaceutical composition comprises about 0.5% w / w magnesium stearate.

[0043] In another embodiment, the colloidal silicon dioxide is from about 0.1% w / w to about 0.3% w / w, from about 0.1% w / w to about 0.2% w / w, from about 0.1% w / w to about 0.4% w / w, from about 0.1% w / w to about 0.5% w / w, from about 0.1% w / w to about 0.6% w / w, from about 0.1% w / w to about 0.7% w / w, from about 0.1% w / w to about 0.8% w / w, from about 0.1% w / w to about 0.9% w / w, from about 0.1% w / w to about 1.0% w / w, from about 0.1% Colloidal silicon dioxide from about 0.1% w / w to about 1.5% w / w, colloidal silicon dioxide from about 0.1% w / w to about 2.0% w / w, colloidal silicon dioxide from about 0.1% w / w to about 2.5% w / w, colloidal silicon dioxide from about 0.1% w / w to about 3.0% w / w, colloidal silicon dioxide from about 0.1% w / w to about 3.5% w / w, colloidal silicon dioxide from about 0.1% w / w to about 4.0% w / w, colloidal silicon dioxide from about 0.1% w / w to about 4.5% w / w, colloidal silicon dioxide from about 0.1% w / w to about 5.0% w / w, colloidal silicon dioxide from about 0.1% w / w to about 10.0% w / w, colloidal silicon dioxide from about 0.1% w / w to about 15.0% colloidal silicon dioxide from about 0.1% w / w to about 20.0% w / w, colloidal silicon dioxide from about 0.2% w / w to about 0.3% w / w, colloidal silicon dioxide from about 0.2% w / w to about 0.4% w / w, colloidal silicon dioxide from about 0.2% w / w to about 0.5% w / w, colloidal silicon dioxide from about 0.2% w / w to about 0.6% w / w, colloidal silicon dioxide from about 0.2% w / w to about 0.7% w / w, colloidal silicon dioxide from about 0.2% w / w to about 0.8% w / w, colloidal silicon dioxide from about 0.2% w / w to about 0.9% w / w, colloidal silicon dioxide from about 0.2% w / w to about 1.0% w / w colloidal silicon dioxide, from about 0.2% w / w to about 1.5% w / w colloidal silicon dioxide, from about 0.2% w / w to about 2.0% w / w colloidal silicon dioxide, from about 0.2% w / w to about 2.5% w / w colloidal silicon dioxide, about 0.2% w / w to about 3.0% w / w colloidal silicon dioxide, about 0.2% w / w to about 3.5% w / w colloidal silicon dioxide, about 0.2% w / w to about 4.0% w / w colloidal silicon dioxide, about 0.2% w / w to about 4.5% w / w colloidal silicon dioxide, or about 0.2% w / w to about 5.0% w / w colloidal silicon dioxide, about 0.2% w / w to about 10.0% w / w colloidal silicon dioxide, about 0.2% w / w to about 15.0% w / w colloidal silicon dioxide, about 0.2% w / w to about 20.0% w / w colloidal silicon dioxide, about 0.3% w / w to about 0.4% colloidal silicon dioxide from about 0.3% w / w to about 0.5% w / w, colloidal silicon dioxide from about 0.3% w / w to about 0.6% w / w, colloidal silicon dioxide from about 0.3% w / w to about 0.7% w / w, colloidal silicon dioxide from about 0.3% w / w to about 0.8% w / w, colloidal silicon dioxide from about 0.3% w / w to about 0.9% w / w, colloidal silicon dioxide from about 0.3% w / w to about 1.0% w / w, colloidal silicon dioxide from about 0.3% w / w to about 1.5% w / w, colloidal silicon dioxide from about 0.3% w / w to about 2.0% w / w, colloidal silicon dioxide from about 0.3% w / w to about 2.5% colloidal silicon dioxide from about 0.3% w / w to about 3.0% w / w, colloidal silicon dioxide from about 0.3% w / w to about 3.5% w / w, colloidal silicon dioxide from about 0.3% w / w to about 4.0% w / w, colloidal silicon dioxide from about 0.3% w / w to about 4.5% w / w, or colloidal silicon dioxide from about 0.3% w / w to about 5.0% w / w, colloidal silicon dioxide from about 0.3% w / w to about 10.0% w / w, colloidal silicon dioxide from about 0.3% w / w to about 15.0% w / w, colloidal silicon dioxide from about 0.3% w / w to about 20.0% w / w, colloidal silicon dioxide from about 0.4% w / w to about 0.5% w / w colloidal silicon dioxide, from about 0.4% w / w to about 0.6% w / w colloidal silicon dioxide, from about 0.4% w / w to about 0.7% w / w colloidal silicon dioxide, from about 0.4% w / w to about 0.3% w / w colloidal silicon dioxide, from about 0.4% w / w to about 0.9% w / w colloidal silicon dioxide, about 0.4% w / w to about 1.0% w / w colloidal silicon dioxide, about 0.4% w / w to about 1.5% w / w colloidal silicon dioxide, about 0.4% w / w to about 2.0% w / w colloidal silicon dioxide, about 0.4% w / w to about 2.5% w / w colloidal silicon dioxide, about 0.4% w / w to about 3.0% w / w colloidal silicon dioxide, about 0.4% w / w to about 3.5% w / w colloidal silicon dioxide, about 0.4% w / w to about 4.0% w / w colloidal silicon dioxide, about 0.4% w / w to about 4.5% w / w colloidal silicon dioxide, about 0.4% w / w to about 5.0% colloidal silicon dioxide from about 0.4% w / w to about 10.0% w / w, colloidal silicon dioxide from about 0.4% w / w to about 15.0% w / w, colloidal silicon dioxide from about 0.4% w / w to about 20.0% w / w, colloidal silicon dioxide from about 0.5% w / w to about 0.6% w / w, colloidal silicon dioxide from about 0.5% w / w to about 0.7% w / w, colloidal silicon dioxide from about 0.5% w / w to about 0.3% w / w, colloidal silicon dioxide from about 0.5% w / w to about 0.9% w / w, colloidal silicon dioxide from about 0.5% w / w to about 1.0% w / w, colloidal silicon dioxide from about 0.5% w / w to about 1.5% colloidal silicon dioxide from about 0.5% w / w to about 2.0% w / w, colloidal silicon dioxide from about 0.5% w / w to about 2.5% w / w, colloidal silicon dioxide from about 0.5% w / w to about 3.0% w / w, colloidal silicon dioxide from about 0.5% w / w to about 3.5% w / w, colloidal silicon dioxide from about 0.5% w / w to about 4.0% w / w, colloidal silicon dioxide from about 0.5% w / w to about 4.5% w / w, colloidal silicon dioxide from about 0.5% w / w to about 5.0% w / w, colloidal silicon dioxide from about 0.5% w / w to about 10.0% w / w, colloidal silicon dioxide from about 0.5% w / w to about 15.0% w / w colloidal silicon dioxide, or from about 0.5% w / w to about 20.0% w / w colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises from about 0.5% w / w to about 5% w / w colloidal silicon dioxide.

[0044] In some embodiments, the pharmaceutical composition comprises about 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% w / w, about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1.0% w / w, about 1.1% w / w, about 1.2% w / w, about 1.3% w / w, about 1.4% w / w, about 1.5% w / w, about 1.6% w / w, about 1.7% w / w, about 1.8% w / w, about 1.9% w / w, about 2.0% w / w, about 2.1% w / w, about 2.2% w / w, about 2.3% w / w, about 2.4% w / w, about 2.5% w / w, about 2.6% w / w, about 2.7% w / w, about 2.8% w / w, about 2.9% w / w, about 3.0% w / w, about 3.1% w / w, about 3.2% w / w, about 3.3% w / w, about 3.4% w / w, about 3.5% w / w, about 3.6% w / w, about 3.7% w / w, about 3.8% w / w, about 3.9% w / w, about 4.0% w / w, about 4.1% w / w, about 4.2% w / w, about 4.3% w / w, about 4.4% w / w, about 4.5% w / w, about 4.6% w / w, about 4.7% w / w, about 4.8% w / w, about 4.9% w / w, about 5.0% w / w, about 5 colloidal silicon dioxide at about 10% w / w, about 2.7% w / w, about 2.8% w / w, about 2.9% w / w, about 3.0% w / w, about 3.1% w / w, about 3.2% w / w, about 3.3% w / w, about 3.4% w / w, about 3.5% w / w, about 3.6% w / w, about 3.7% w / w, about 3.8% w / w, about 3.9% w / w, about 4.0% w / w, about 4.1% w / w, about 4.2% w / w, about 4.3% w / w, about 4.4% w / w, about 4.5% w / w, about 4.6% w / w, about 4.7% w / w, about 4.8% w / w, about 4.9% w / w, about 5.0% w / w In some embodiments, the pharmaceutical composition comprises about 1.0% w / w colloidal silicon dioxide.

[0045] In some embodiments, the composition is in the form of a capsule. In some embodiments, the composition is in the form of a tablet. In some embodiments, the tablet has a coating. In some embodiments, the coating comprises polyvinyl alcohol, a plasticizer, a pigment, or any combination thereof. In some embodiments, the coating comprises polyvinyl alcohol, a plasticizer, and a pigment. In some embodiments, the coating comprises polyvinyl alcohol. In some embodiments, the coating comprises a plasticizer. In some embodiments, the coating comprises a pigment. In some embodiments, the coating comprises a copolymer dispersant of methacrylic acid and ethyl acrylate; triethyl citrate; talc; or any combination thereof. In some embodiments, the coating comprises a copolymer dispersant of methacrylic acid and ethyl acrylate; triethyl citrate; and talc. In some embodiments, the coating comprises a copolymer dispersant of methacrylic acid and ethyl acrylate. In some embodiments, the coating comprises triethyl citrate. In some embodiments, the coating comprises talc.

[0046] In some embodiments, the composition does not include hydroxypropyl methylcellulose-phthalate and hydrogenated castor oil. In some embodiments, the composition does not include hydroxypropyl methylcellulose-phthalate. In some embodiments, the composition does not include hydrogenated castor oil.

[0047] Dissolution Profile In one aspect, a pharmaceutical composition comprising, consisting essentially of, or consisting of ibudilast and at least one pharma- ceutically acceptable excipient, having a dissolution profile in which at least about 12% of said ibudilast is released from said composition in about 2 hours when tested in a USP Apparatus Type II at 50 rpm in 900 mL of simulated gastric fluid medium at 37° C. In some embodiments, provided herein is a pharmaceutical composition comprising, consisting essentially of, or consisting of ibudilast and at least one pharma- ceutically acceptable excipient, in the form of a tablet or capsule, said tablet or said capsule having a dissolution profile in which at least about 12% of said ibudilast is released from said tablet or said capsule in about 2 hours when tested in a USP Apparatus Type II at 50 rpm in 900 mL of simulated gastric fluid medium at 37° C. In some embodiments, the simulated gastric fluid medium is prepared by adding 20 g sodium chloride and 70 mL hydrochloric acid (37% w / w) to 10 L of water and adjusting to pH 1.2 using additional hydrochloric acid as needed.

[0048] In some embodiments, at least about 8%, at least about 9%, at least about 10%, at least about 11%, at least about 12%, at least about 13%, at least about 14%, at least about 15%, at least about 16%, at least about 17%, at least about 18%, or at least about 19%, but not more than 20%, of the ibudilast was released from the composition or from the tablet or capsule in about 2 hours when tested in a USP Apparatus Type II at 50 rpm in 900 mL simulated gastric fluid medium at 37° C.

[0049] In some embodiments, about 8% to about 10%, about 8% to about 12%, about 8% to about 15%, about 8% to about 18%, about 8% to about 20%, about 10% to about 13%, about 10% to about 15%, or about 10% to about 20% of the ibudilast is released from the composition or from the tablet or capsule in about 2 hours when tested in a USP Apparatus Type II at 50 rpm in 900 mL simulated gastric fluid medium at 37° C.

[0050] In some embodiments, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20% of the ibudilast was released from the composition or from the tablet or capsule in about 2 hours when tested in a USP Apparatus Type II at 50 rpm in 900 mL simulated gastric fluid medium at 37° C.

[0051] In some embodiments, the tablet has a coating comprising, consisting essentially of, or consisting of polyvinyl alcohol, a plasticizer, a pigment, or any combination thereof. In some embodiments, the tablet has a coating comprising, consisting essentially of, or consisting of polyvinyl alcohol, a plasticizer, and a pigment. In some embodiments, the tablet has a coating comprising polyvinyl alcohol. In some embodiments, the tablet has a coating comprising a plasticizer. In some embodiments, the tablet has a coating comprising a pigment.

[0052] In some embodiments, the at least one pharma- ceutically acceptable excipient comprises, consists essentially of, or consists of lactose monohydrate, microcrystalline cellulose, or hypromellose, or any combination of two or more thereof.

[0053] In some embodiments, the composition or tablet or capsule has a dissolution profile in which at least about 25% of said ibudilast is released from the composition or from the tablet or capsule in about 4 hours when tested in a USP Apparatus Type II: (a) 2 hours at 50 rpm in 900 mL of simulated gastric fluid medium at 37° C., followed by an additional 2 hours at 50 rpm in 900 mL of phosphate buffer containing 0.3% w / w sodium lauryl sulfate, pH 6.8, at 37° C.

[0054] In some embodiments, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29%, at least about 30%, at least about 31%, at least about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, or at least about 39%, but not more than 40%, of ibudilast is released from the composition or from the tablet or capsule in about 4 hours when tested in a USP Apparatus Type II at 50 rpm for (a) 2 hours in 900 mL of simulated gastric fluid medium at 37° C. at 50 rpm, followed by (b) an additional 2 hours in 900 mL of phosphate buffer containing 0.3% w / w sodium lauryl sulfate, pH 6.8, at 37° C. at 50 rpm.

[0055] In some embodiments, about 25% to about 30%, about 25% to about 35%, about 25% to about 40%, about 28% to about 30%, about 28% to about 35%, about 28% to about 40%, about 30% to about 35%, or about 30% to about 40% of the ibudilast is released from the composition or from the tablet or capsule in about 4 hours when tested in a USP Apparatus Type II: (a) 2 hours at 50 rpm in 900 mL of simulated gastric fluid medium at 37° C., followed by an additional 2 hours at 50 rpm in 900 mL of phosphate buffer containing 0.3% w / w sodium lauryl sulfate, pH 6.8, at 37° C.

[0056] In some embodiments, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, or about 40% of the ibudilast was released from the composition or from the tablet or capsule in about 4 hours when tested in a USP Apparatus Type II: (a) 2 hours at 50 rpm in 900 mL of simulated gastric fluid medium at 37° C., followed by an additional 2 hours at 50 rpm in 900 mL of phosphate buffer containing 0.3% w / w sodium lauryl sulfate, pH 6.8, at 37° C.

[0057] In some embodiments, the composition or tablet or capsule has a dissolution profile in which at least about 60% of said ibudilast is released from the composition or from the tablet or capsule in about 12 hours when tested in a USP Apparatus Type II: (a) 2 hours at 50 rpm in 900 mL of simulated gastric fluid medium at 37° C., followed by an additional 10 hours at 50 rpm in 900 mL of phosphate buffer containing 0.3% w / w sodium lauryl sulfate, pH 6.8, at 37° C.

[0058] In some embodiments, at least about 60%, at least about 61%, at least about 62%, at least about 63%, at least about 64%, at least about 65%, at least about 66%, at least about 67%, at least about 68%, at least about 69%, at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, or at least about 79%, but not more than 80%, of the ibudilast is released from the composition or from the tablet or capsule in about 12 hours when tested in a USP Apparatus Type II at 50 rpm for (a) 2 hours in 900 mL of simulated gastric fluid medium at 37° C. at 50 rpm, followed by an additional 10 hours in 900 mL of phosphate buffer containing 0.3% w / w sodium lauryl sulfate, pH 6.8, at 37° C.

[0059] In some embodiments, about 60% to about 65%, about 60% to about 70%, about 60% to about 75%, about 60% to about 80%, about 65% to about 70%, about 65% to about 80%, about 70% to about 75%, or about 70% to about 80% of the ibudilast is released from the composition or from the tablet or capsule in about 12 hours when tested in a USP Apparatus Type II after (a) 2 hours at 50 rpm in 900 mL of simulated gastric fluid medium at 37° C., followed by an additional 10 hours at 50 rpm in 900 mL of phosphate buffer containing 0.3% w / w sodium lauryl sulfate, pH 6.8, at 37° C.

[0060] In some embodiments, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 88% of the ibudilast was released from the composition or from the tablet or capsule in about 12 hours when tested in a USP Apparatus Type II after (a) 2 hours at 50 rpm in 900 mL of simulated gastric fluid medium at 37° C., followed by an additional 10 hours at 50 rpm in 900 mL of phosphate buffer containing 0.3% w / w sodium lauryl sulfate, pH 6.8, at 37° C.

[0061] In some embodiments, the composition or tablet or capsule has a dissolution profile in which at least about 90% of said ibudilast is released from the composition or from the tablet or capsule in about 24 hours when tested in a USP Apparatus Type II: (a) 2 hours at 50 rpm in 900 mL of simulated gastric fluid medium at 37° C., followed by an additional 22 hours at 50 rpm in 900 mL of phosphate buffer containing 0.3% w / w sodium lauryl sulfate, pH 6.8, at 37° C.

[0062] In some embodiments, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the ibudilast is released from the composition or from the tablet or capsule in about 24 hours when tested in a USP Apparatus Type II at 50 rpm for (a) 2 hours in 900 mL of simulated gastric fluid medium at 37° C. at 50 rpm, followed by an additional 22 hours in 900 mL of phosphate buffer containing 0.3% w / w sodium lauryl sulfate, pH 6.8, at 37° C.

[0063] In some embodiments, about 90% to about 95%, or about 90% to about 99% of the ibudilast is released from the composition or from the tablet or capsule in about 24 hours when tested in a USP Apparatus Type II after (a) 2 hours at 50 rpm in 900 mL of simulated gastric fluid medium at 37° C., followed by an additional 22 hours at 50 rpm in 900 mL of phosphate buffer containing 0.3% w / w sodium lauryl sulfate, pH 6.8, at 37° C.

[0064] In some embodiments, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% of the ibudilast is released from the composition or from the tablet or capsule in about 24 hours when tested in a USP Apparatus Type II: (a) 2 hours at 50 rpm in 900 mL of simulated gastric fluid medium at 37° C., followed by an additional 22 hours at 50 rpm in 900 mL of phosphate buffer containing 0.3% w / w sodium lauryl sulfate, pH 6.8, at 37° C.

[0065] In another aspect, a pharmaceutical composition comprising, consisting essentially of, or consisting of ibudilast and at least one pharma- ceutically acceptable excipient, having a dissolution profile in which ibudilast is not released from said composition in about 2 hours when tested in a USP Apparatus Type II at 50 rpm in 900 mL of simulated gastric fluid medium at 37° C. In some embodiments, provided herein is a pharmaceutical composition comprising, consisting essentially of, or consisting of ibudilast and at least one pharma- ceutically acceptable excipient, in the form of a tablet or capsule, said tablet or said capsule having a dissolution profile in which ibudilast is not released from said tablet or said capsule in about 2 hours when tested in a USP Apparatus Type II at 50 rpm in 900 mL of simulated gastric fluid medium at 37° C.

[0066] In some embodiments, the composition or tablet or capsule has an improved Cmax compared to an intermediate release formulation when administered to a human subject according to a dosing protocol consisting of a 3-day titration phase followed by an 11-day multiple dosing phase. max wherein the tablet or capsule is administered once daily as a 50 mg dose during a 3-day titration phase, and the tablet or capsule is administered once daily as a 100 mg dose during an 11-day multiple dose phase. In some embodiments, the composition or tablet or capsule exhibits improved C compared to an intermediate release formulation when administered to a human subject according to a dosing protocol consisting of a 3-day titration phase followed by an 11-day multiple dose phase. max and similar AUC, wherein the tablet or capsule is administered once daily as a 50 mg dose during a 3-day titration phase and the tablet or capsule is administered once daily as a 100 mg dose during an 11-day multiple-dose phase.

[0067] In some embodiments, the tablet has a coating comprising, consisting essentially of, or consisting of: a copolymer dispersant of methacrylic acid and ethyl acrylate; triethyl citrate; talc; or any combination thereof. In some embodiments, the coating comprises, consisting essentially of, or consisting of: a copolymer dispersant of methacrylic acid and ethyl acrylate; triethyl citrate; and talc. In some embodiments, the coating comprises a copolymer dispersant of methacrylic acid and ethyl acrylate. In some embodiments, the coating comprises triethyl citrate. In some embodiments, the coating comprises talc.

[0068] In some embodiments, at least one pharma- ceutically acceptable excipient comprises, consists essentially of, or consists of lactose monohydrate, microcrystalline cellulose, or hypromellose, or any combination of two or more thereof. In some embodiments, at least one pharma-ceutically acceptable excipient comprises, consists essentially of, or consists of lactose monohydrate, microcrystalline cellulose, hypromellose, magnesium stearate, and colloidal silicon dioxide, or any combination of two or more thereof.

[0069] In some embodiments, the composition or tablet or capsule has a dissolution profile in which about 10% to about 20% of the ibudilast is released from the tablet in about 4 hours when tested in a USP Apparatus Type II: (a) 2 hours at 50 rpm in 900 mL of simulated gastric fluid medium at 37° C., followed by an additional 2 hours at 50 rpm in 900 mL of phosphate buffer, pH 6.8, containing 0.3% w / w sodium lauryl sulfate at 37° C. In some embodiments, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20% of the ibudilast was released from the composition or from the tablet or capsule in about 4 hours when tested in a USP Apparatus Type II: (a) 2 hours at 50 rpm in 900 mL of simulated gastric fluid medium at 37° C., followed by an additional 2 hours at 50 rpm in 900 mL of phosphate buffer containing 0.3% w / w sodium lauryl sulfate, pH 6.8, at 37° C.

[0070] In some embodiments, the composition or tablet or capsule has a dissolution profile in which about 55% to about 65% of the ibudilast is released from the composition or from the tablet or capsule in about 12 hours when tested in a USP Apparatus Type II: (a) 2 hours at 50 rpm in 900 mL of simulated gastric fluid medium at 37° C., followed by an additional 10 hours at 50 rpm in 900 mL of phosphate buffer containing 0.3% w / w sodium lauryl sulfate, pH 6.8, at 37° C. In some embodiments, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, or about 65% of the ibudilast is released from the composition or from the tablet or capsule in about 12 hours when tested in a USP Apparatus Type II: (a) 2 hours at 50 rpm in 900 mL of simulated gastric fluid medium at 37° C., followed by an additional 10 hours at 50 rpm in 900 mL of phosphate buffer containing 0.3% w / w sodium lauryl sulfate, pH 6.8, at 37° C.

[0071] In some embodiments, the composition or tablet or capsule has a dissolution profile in which about 85% to about 95% of the ibudilast is released from the composition or from the tablet or capsule in about 24 hours when tested in a USP Apparatus Type II: (a) 2 hours at 50 rpm in 900 mL of simulated gastric fluid medium at 37° C., followed by an additional 22 hours at 50 rpm in 900 mL of phosphate buffer containing 0.3% w / w sodium lauryl sulfate, pH 6.8, at 37° C. In some embodiments, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, or about 95% of the ibudilast is released from the composition or from the tablet or capsule in about 24 hours when tested in a USP Apparatus Type II: (a) 2 hours at 50 rpm in 900 mL of simulated gastric fluid medium at 37° C., followed by an additional 22 hours at 50 rpm in 900 mL of phosphate buffer containing 0.3% w / w sodium lauryl sulfate, pH 6.8, at 37° C.

[0072] In another aspect, provided herein is a method for extended release of ibudilast over 24 hours in a subject. In some embodiments, the method comprises administering to the subject a pharmaceutical composition comprising, consisting essentially of, or consisting of about 3% w / w to about 15% w / w ibudilast, about 30% w / w to about 40% w / w lactose, about 30% w / w to about 40% w / w microcrystalline cellulose, about 15% w / w to about 25% w / w hypromellose, about 0.2% w / w to about 0.8% w / w magnesium stearate, and about 0.5% w / w to about 5% w / w colloidal silicon dioxide. In some embodiments, the method comprises administering to the subject a pharmaceutical composition comprising, consisting essentially of, or consisting of about 10% w / w ibudilast, about 35% w / w lactose monohydrate, about 33.5% w / w microcrystalline cellulose, about 20% w / w hypromellose, about 0.5% w / w magnesium stearate, and about 1% w / w colloidal silicon dioxide. In some embodiments, the method comprises administering to the subject a pharmaceutical composition comprising, consisting essentially of, or consisting of about 5% w / w ibudilast, about 37% w / w lactose, about 38.5% w / w microcrystalline cellulose, about 18% w / w hypromellose, about 0.5% w / w magnesium stearate, and about 1% w / w colloidal silicon dioxide. In some embodiments, the method comprises administering to the subject a pharmaceutical composition comprising, consisting essentially of, or consisting of 10% w / w ibudilast, about 35% w / w lactose, about 33.5% w / w microcrystalline cellulose, about 20% w / w hypromellose, about 0.5% w / w magnesium stearate, and about 1% w / w colloidal silicon dioxide. In some embodiments, the lactose is lactose monohydrate.

[0073] Treatment In another embodiment, any one of the compositions described herein is used to treat any one or more of the diseases or disorders described herein.Therefore, the method for treating one or more of the diseases or disorders described herein using a therapeutically effective amount of the compositions described herein is another embodiment of this disclosure.

[0074] In some embodiments, the disease or disorder is a neurodegenerative disease, a genetic biochemical disorder, a progressive neurodegenerative disease, or a symptom thereof. Exemplary neurodegenerative diseases / disorders include, but are not limited to, Alzheimer's disease, senile dementia of the Alzheimer type, or Pick's disease (lobar atrophy), multiple sclerosis, neurodegenerative diseases including syndromes with progressive dementia and other prominent neurological abnormalities, progressive neurodegenerative diseases that mainly affect adults and include progressive neurodegenerative forms of Huntington's disease, multiple system atrophy with dementia and ataxia and / or Parkinson's disease symptoms, progressive supranuclear palsy (Steel-Richardson-Olszewski), diffuse Lewy body disease, or corticodentatinigral degeneration. Additional subjects may be suffering from progressive neurodegenerative diseases which primarily affect young adults and children and include Hallervorden-Spatz disease and progressive familial myoclonic epilepsy, syndromes which gradually develop abnormalities in posture and movement, or diseases including palsy agitans (Parkinson's disease), striatonigral degeneration, progressive supranuclear palsy, torsion dystonia (torsion spasms; deformation muscular dystonia), spasmodic torticollis and other focal dyskinesias, familial tremor, or diseases including Gilles de la Tourette syndrome, progressive ataxia, syndromes of cerebellar degeneration or spinocerebellar degeneration, cerebellar cortical degeneration or spinocerebellar degeneration including olivopontocerebellar atrophy (OPCA), spinocerebellar degeneration (Friedreich's ataxia and related disorders).Neurodegenerative diseases / disorders include, but are not limited to, progressive neurodegenerative diseases including central autonomic nervous system failure (Shy-Drager syndrome), syndromes of muscle weakness and wasting without sensory changes (motor neuron diseases), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, infantile spinal muscular atrophy (Werdnig-Hoffmann), juvenile spinal muscular atrophy (Wohlfahrt-Kugelberg-Welander), or other forms of familial spinal muscular atrophy, primary lateral sclerosis or hereditary spastic paraplegia, syndromes of muscle weakness and wasting combined with sensory changes (progressive neuromuscular atrophy; chronic familial polyneuropathy), peroneal muscular atrophy (Charcot-Marie-Tooth), hypertrophic interstitial polyneuropathy (Defferin-Sottas), or various forms of chronic progressive neuropathy, syndromes of progressive vision loss. Neurodegenerative diseases / disorders include, but are not limited to, pigmentary degeneration of the retina (retinitis pigmentosa), or hereditary optic atrophy (Leber's disease), motor neuron disease and progressive ataxia; glaucoma; retinal detachment; sporadic progressive neurodegenerative diseases, multifocal motor neuropathy with conduction block, motor neuropathy with paraproeinemia, motor-predominant peripheral neuropathy, olivopontocerebellar atrophy, Machado-Joseph disease, familial progressive neurodegenerative diseases such as familial amyotrophic lateral sclerosis, spinal muscular atrophy, familial spastic paraplegia, inherited biochemical disorders, arthrogryposis multiplex congenita, or progressive juvenile bulbar palsy (Fatio-Londe). Examples of inherited biochemical disorders are superoxide dismutase deficiency, hexosaminidase A and B deficiency, or androgen receptor mutations (Kennedy syndrome). Progressive neurodegenerative diseases can include viral and prion diseases, such as HTLV-1 associated myelopathy, progressive multifocal leukoencephalopathy, Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker disease, kuru, fatal familial insomnia, or Alpers disease.

[0075] "Progressive neurodegenerative disease" refers to any neurodegenerative disease that is in a progressive state (i.e., is getting worse compared to baseline level) or has such progressive characteristics. Thus, a progressive state is a worsening of symptoms over time and can be sudden or gradual. Examples of progressive neurodegenerative diseases include Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, and progressive forms of multiple sclerosis, except relapsing / remitting multiple sclerosis.

[0076] In some embodiments, the disease or disorder is an ophthalmic disease / disorder or injury associated with a neurodegenerative disease / disorder or a neuro-ophthalmological disorder. In some embodiments, the ophthalmic disease / disorder or injury is retinal injury. In some embodiments, the ophthalmic disease / disorder or injury is macular injury. In some embodiments, the ophthalmic disease / disorder or injury is macular thinning. In some embodiments, the neurodegenerative disease / disorder is progressive multiple sclerosis. Exemplary neuro-ophthalmological disorders include, but are not limited to, papilledema and idiopathic intracranial hypertension (IIH); anterior ischemic optic neuropathy (AION); optic neuritis; oculomotor cranial neuropathy; and Horner's syndrome.

[0077] In some embodiments, the disease or disorder is alcoholism and depression and / or dysphoria. Examples include alcohol use disorder (AUD), which may be accompanied by depression or dysphoria. In some embodiments, the depression is mild depression, moderate depression, or severe depression. In some embodiments, the dysphoria is high dysphoria, moderate dysphoria, or low dysphoria.

[0078] In some embodiments, the disease or disorder is glioblastoma, recurrent glioblastoma or its associated symptoms. In some embodiments, the disease or disorder is glioblastoma. In some embodiments, the disease or disorder is recurrent glioblastoma.

[0079] With regard to treating glioblastoma or recurrent glioblastoma, in some embodiments, the patient is a human patient. In some embodiments, the patient has an extra copy of the epidermal growth factor receptor (EGFR) gene or expresses abnormally high levels of EGFR. In some embodiments, abnormally high levels of EGRF represent higher levels of EGRF in cancer patients compared to lower levels of EGFR in individuals without cancer. In some embodiments, the patient has loss of heterozygosity for chromosome 10. In some embodiments, the patient shows amplification of chromosome 7. In some embodiments, the patient has a mutated gene selected from the group consisting of TP53, PDGFRA, IDH1, PTEN and NF1. In some embodiments, the patient expresses NEFL, GABRA1, SYT1 or SLC12A5.

[0080] In some embodiments, the disease or disorder is multiple sclerosis or progressive multiple sclerosis. There are four recognized types of multiple sclerosis: (1) relapsing / remitting multiple sclerosis (RR multiple sclerosis), (2) secondary progressive multiple sclerosis (SP multiple sclerosis), (3) progressive relapsing multiple sclerosis (PR multiple sclerosis), and (4) primary progressive multiple sclerosis (PP multiple sclerosis). RR multiple sclerosis is not considered to fall within the scope of the claims, but other forms of multiple sclerosis, namely SP multiple sclerosis, PR multiple sclerosis and PP multiple sclerosis, are considered as an aspect of the present invention. In all types of progressive MS, there is loss of function over time, regardless of relapses.

[0081] "Relapsing / Remitting Multiple Sclerosis (RR Multiple Sclerosis)" is characterized by relapses (also known as exacerbations) during which new symptoms appear and old symptoms may return or worsen. Relapses are followed by periods of remission during which the person fully or partially recovers from the deficits acquired during the relapse. Relapses may last for days, weeks or months, and recovery may be slow and gradual or almost immediate. The majority of people who present with multiple sclerosis are first diagnosed with relapsing / remitting multiple sclerosis. This is typically when the person is in their 20s or 30s, although diagnosis may be known much earlier or later. Approximately twice as many women as men present with this variant.

[0082] In "secondary progressive multiple sclerosis (SP multiple sclerosis)," people who initially had relapsing-remitting multiple sclerosis begin to experience a gradual deterioration of neurological function, with or without relapses. After a few years, many people who have had relapsing / remitting multiple sclerosis progress to the secondary progressive phase of the disease. This is characterized by a gradual worsening of the disease between relapses. In the early phase of secondary progressive MS, people may still experience a few relapses, but after a while these change into a generalized progression. People often do not return to their previous level of functioning after a relapse. People with secondary progressive MS may experience good and bad days or weeks, but do not truly recover, apart from some remission after a relapsing episode. After 10 years, 50% of people with relapsing / remitting multiple sclerosis will have secondary progressive. By 25-30 years, that figure will rise to 90%.

[0083] "Progressive relapsing multiple sclerosis (PR multiple sclerosis)" shows a clear progression in disability level from the time symptoms first begin, but with distinct episodes of relapse that may or may not be associated with some recovery after the acute episode. From onset, this form of multiple sclerosis follows a progressive course punctuated by relapses. There is significant recovery shortly after a relapse, but between relapses there is a gradual worsening of symptoms.

[0084] "Primary progressive multiple sclerosis (PP multiple sclerosis)" is characterized by a gradual progression of the disease from its onset without any remissions or relapses. There may be periods of stable disease activity, and, like secondary progressive, there may be good and bad days or weeks. PP multiple sclerosis differs from relapsing / remitting MS and secondary progressive MS in that onset is typically in the late 30s or early 40s, men are as likely to develop it as women, and the initial disease activity is in the spinal cord, not in the brain. Primary progressive multiple sclerosis often migrates into the brain, but is less likely to damage brain areas than relapsing / remitting or secondary progressive, for example, people with primary progressive MS are less likely to develop cognitive problems.

[0085] In some embodiments, the progressive multiple sclerosis has progressed beyond relapsing-remitting multiple sclerosis. In some embodiments, the progressive multiple sclerosis is primary progressive multiple sclerosis. In some embodiments, primary progressive multiple sclerosis is characterized by disease progression from onset, with occasional plateaus and temporary minor improvements allowed, but without distinct relapses. In some embodiments, the progressive multiple sclerosis is secondary progressive multiple sclerosis. In some embodiments, secondary progressive multiple sclerosis is characterized as an initial relapsing-remitting course, followed by progression with or without occasional relapses, minor remissions, and plateaus.

[0086] In some embodiments, the disease or disorder is uveal melanoma.

[0087] In some embodiments, the disease or disorder is chemotherapy-induced myotoxicity and / or chemotherapy-induced cardiotoxicity. In some embodiments, the disease or disorder is chemotherapy-induced neuropathy.

[0088] In another embodiment, any one of the compositions described herein is used in a method of suppressing myeloid-derived suppressor cells (MDSCs) in a patient diagnosed with or suffering from cancer, comprising administering to the patient a therapeutically effective amount of a composition described herein.

[0089] In another embodiment, any one of the compositions described herein is used in a method of reducing immunosuppression in a patient diagnosed with or suffering from cancer, comprising administering to the patient a therapeutically effective amount of a composition described herein.

[0090] In another embodiment, any one of the compositions described herein is used in a method of reducing the number of regulatory T cells in a patient diagnosed with or suffering from cancer, comprising administering to the patient a therapeutically effective amount of a composition described herein.

[0091] In another embodiment, any one of the compositions described herein is used in a method of increasing CD4+ T cell count in a patient diagnosed with or suffering from cancer, comprising administering to the patient a therapeutically effective amount of a composition described herein.

[0092] In some embodiments, the cancer is a cancer of the circulatory system selected from angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma, and teratoma, cancer of the mediastinum and pleura, or vascular tumors; cancer of the nasal cavity and middle ear, cancer of the paranasal sinuses, cancer of the larynx, cancer of the trachea, cancer of the bronchi and lungs, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), bronchogenic carcinoma, squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma, alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroitin hamartoma, or cancer of the respiratory tract selected from squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma, carcinoma, leiomyosarcoma, ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma, adenocarcinoma, carcinoid tumor, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma, adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, or leiomyoma; cancer of the gastrointestinal system selected from adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia, squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, adenocarcinoma, prostate Cancer of the genitourinary tract selected from: hepatoma, seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, or lipoma; cancer of the liver selected from: hepatoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, pheochromocytoma, insulinoma, vasoactive intestinal peptide tumor, islet cell tumor, or glucagonoma; cancer of the spinal cord selected from: osteogenic sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma, multiple myeloma, malignant giant cell tumor, spinal cord tumor, Cancer of the bone selected from chordoma, osteochronfroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, or giant cell tumor; cancer of the nervous system selected from primary CNS lymphoma, osteoma, hemangioma, granuloma, xanthomatosis, osteitis deformans, meningioma, meningeal sarcoma, gliomatosis, astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, spinal neurofibroma, meningioma, glioma, or sarcoma;Cancer of the reproductive system selected from endometrial cancer, cervical cancer, preneoplastic cervical dysplasia, ovarian cancer, serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, granulosa-theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma, squamous cell carcinoma of the vulva, carcinoma in situ of the vulva, adenocarcinoma of the vulva, fibrosarcoma of the vulva, melanoma of the vulva, vaginal clear cell carcinoma, vaginal squamous cell carcinoma, vaginal botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube cancer, placental cancer, penile cancer, prostate cancer, or testicular cancer; cancer of the blood system selected from myeloid, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes, Hodgkin's disease, or non-Hodgkin's lymphoma; cancer of the lip, tongue, gums, floor of the mouth, palate, parotid gland, salivary gland, a cancer of the oral cavity selected from carcinoma, tonsillar cancer, oropharynx cancer, nasopharyngeal cancer, pyriform sinus cancer, or hypopharyngeal cancer; a cancer of the skin selected from malignant melanoma, cutaneous melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, dysplastic nevi, lipoma, hemangioma, dermatofibroma, or keloid cancer; or a cancer selected from adrenal gland cancer, neuroblastoma, connective and soft tissue cancer, retroperitoneal and peritoneal cancer, eye cancer, intraocular melanoma, uveal melanoma, adnexal cancer, breast cancer, head and / or neck cancer, anal cancer, thyroid cancer, parathyroid cancer, adrenal gland cancer, endocrine glands and associated structures cancer, secondary and unspecified malignant neoplasm of lymph nodes, secondary malignant neoplasm of the respiratory and digestive system, or secondary malignant neoplasm of other sites. In some embodiments, the cancer is glioblastoma multiforme (GBM). In some embodiments, the cancer is not glioblastoma multiforme (GBM);

[0093] In another aspect, any one of the compositions described herein is used in a method of suppressing myeloid-derived suppressor cells (MDSCs) in a patient diagnosed with or suffering from a microbial infection, comprising administering to the patient a therapeutically effective amount of a composition described herein.

[0094] In another aspect, any one of the compositions described herein is used in a method of reducing immunosuppression in a patient diagnosed with or suffering from a microbial infection, comprising administering to the patient a therapeutically effective amount of a composition described herein.

[0095] In another embodiment, any one of the compositions described herein is used in a method of reducing the number of regulatory T cells in a patient diagnosed with or suffering from a microbial infection, comprising administering to the patient a therapeutically effective amount of a composition described herein.

[0096] In another embodiment, any one of the compositions described herein is used in a method of increasing CD4+ T cell count in a patient diagnosed with or suffering from a microbial infection, comprising administering to the patient a therapeutically effective amount of a composition described herein.

[0097] In another aspect, any one of the compositions described herein is used in a method of suppressing myeloid-derived suppressor cells (MDSCs) in a patient diagnosed with or suffering from sepsis, comprising administering to the patient a therapeutically effective amount of a composition described herein.

[0098] In another aspect, any one of the compositions described herein is used in a method of reducing immunosuppression in a patient diagnosed with or suffering from sepsis, comprising administering to the patient a therapeutically effective amount of a composition described herein.

[0099] In another embodiment, any one of the compositions described herein is used in a method of reducing the number of regulatory T cells in a patient diagnosed with or suffering from sepsis, comprising administering to the patient a therapeutically effective amount of a composition described herein.

[0100] In another embodiment, any one of the compositions described herein is used in a method of increasing CD4+ T cell count in a patient diagnosed with or suffering from sepsis, comprising administering to the patient a therapeutically effective amount of a composition described herein.

[0101] Method of administration In another aspect, the present disclosure relates to the oral administration of ibudilast or its pharma- ceutically acceptable salt.In terms of patient compliance and ease of administration, such an approach may be preferred, since patients often do not like to take multiple pills or dosage forms, often multiple times a day, for the duration of treatment.In some embodiments, ibudilast is administered in a single daily dosage form.In some embodiments, the single daily dosage form is a tablet.In some embodiments, the single daily dosage form is a capsule.

[0102] 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.

[0103] The therapeutically effective amount can be determined by one skilled in the art and will be adjusted to the requirements of each particular case. In general, the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof will be in the range of about a total daily dosage.

[0104] In some embodiments, the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is at least about 5 mg, at least about 10 mg, at least about 20 mg, at least about 25 mg, at least about 30 mg, at least about 35 mg, at least about 40 mg, at least about 45 mg, at least about 50 mg, at least about 55 mg, at least about 60 mg, at least about 65 mg, at least about 70 mg, at least about 75 mg, at least about 80 mg, at least about 85 mg, at least about 90 mg, at least about 95 mg, at least about 100 mg, at least about 110 mg, at least about 120 mg, at least about 130 mg, at least about 140 mg, at least about 150 mg, at least about 160 mg, at least about 170 mg, at least about 180 mg, at least about 190 mg, or at least about 200 mg. In some embodiments, the therapeutically effective amount of ibudilast or a pharma-ceutically acceptable salt thereof is at least about 50 mg.

[0105] In some embodiments, a therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is about 5 mg to about 10 mg, 5 mg to about 20 mg, 5 mg to about 30 mg, 5 mg to about 40 mg, 5 mg to about 50 mg, 5 mg to about 60 mg, 5 mg to about 70 mg, 5 mg to about 80 mg, 5 mg to about 90 mg, 5 mg to about 100 mg, 5 mg to about 150 mg, 5 mg to about 200 mg, 10 mg to about Approximately 20mg, 10mg to approximately 30mg, 10mg to approximately 40mg, 10mg to approximately 50mg, 10mg to approximately 60mg, 10mg to approximately 70mg, 10mg to approximately 80mg, 10mg to approximately 90mg, 10 mg~about 100mg, 10mg~about 150mg, 10mg~about 200mg, 20mg~about 30mg, 20mg~about 40mg, 20mg~about 50mg, 20mg~about 60mg, 20mg~about 7 0mg, 20mg~about 80mg, 20mg~about 90mg, 20mg~about 100mg, 20mg~about 250mg, 20mg~about 200mg, 30mg~about 40mg, 30mg~about 50mg, 3 0mg~about 60mg, 30mg~about 70mg, 30mg~about 80mg, 30mg~about 90mg, 30mg~about 100mg, 30mg~about 250mg, 30mg~about 200mg, 40mg~about 50 mg, 40 mg to about 60 mg, 40 mg to about 70 mg, 40 mg to about 80 mg, 40 mg to about 90 mg, 40 mg to about 100 mg, 40 mg to about 250 mg, 40 mg to about 200 mg, 50 mg to about 60 mg, 50 mg to about 70 mg, 50 mg to about 80 mg, 50 mg to about 90 mg, 50 mg to about 100 mg, 50 mg to about 250 mg, or 50 mg to about 200 mg. In some embodiments, the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is about 10 mg to about 100 mg.

[0106] In some embodiments, the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is about 5 mg, about 10 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg. In some embodiments, the therapeutically effective amount of ibudilast or a pharma-ceutically acceptable salt thereof is about 50 mg.

[0107] In some embodiments, the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is at least about 5 mg / day, at least about 10 mg / day, at least about 20 mg / day, at least about 25 mg / day, at least about 30 mg / day, at least about 35 mg / day, at least about 40 mg / day, at least about 45 mg / day, at least about 50 mg / day, at least about 55 mg / day, at least about 60 mg / day, at least about 65 mg / day, at least about 70 mg / day, at least about 75 mg / day, at least about 80 mg / day, at least about 85 mg / day, at least about 90 mg / day, at least about 95 mg / day, at least about 100 mg / day, at least about 100 mg / day, at least about 15 ... mg / day, at least about 80 mg / day, at least about 85 mg / day, at least about 90 mg / day, at least about 95 mg / day, at least about 100 mg / day, at least about 110 mg / day, at least about 120 mg / day, at least about 130 mg / day, at least about 140 mg / day, at least about 150 mg / day, at least about 160 mg / day, at least about 170 mg / day, at least about 180 mg / day, at least about 190 mg / day, or at least about 200 mg / day. In some embodiments, the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is at least about 50 mg / day.

[0108] In some embodiments, the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is from about 5 mg / day to about 10 mg / day, 5 mg / day to about 20 mg / day, 5 mg / day to about 30 mg / day, 5 mg / day to about 40 mg / day, 5 mg / day to about 50 mg / day, 5 mg / day to about 60 mg / day, 5 mg / day to about 70 mg / day, 5 mg / day to about 80 mg / day, 5 mg / day to about 90 mg / day, 5 mg / day to about 100 mg / day, 5 mg / day to about 150 mg / day, 5 mg / day to about 200 mg / day, 10 mg / day to about 20 mg / day , 10mg / day ~ about 30mg / day, 10mg / day ~ about 40mg / day, 10mg / day ~ about 50mg / day, 10mg / day ~ about 60mg / day, 10mg / day ~ about 70mg / day, 10mg / day ~ about 80mg / day, 10mg / day ~ about 90mg / day, 10mg / day ~ About 100mg / day, 10mg / day to about 150mg / day, 10mg / day to about 200mg / day, 20mg / day to about 30mg / day, 20mg / day to about 40mg / day, 20mg / day to about 50mg / day, 20mg / day to about 60mg / day, 20mg / day to about 70mg / day day, 20 mg / day ~ approx. 80 mg / day, 20 mg / day ~ approx. 90 mg / day, 20 mg / day ~ approx. 100 mg / day, 20 mg / day ~ approx. 250 mg / day, 20 mg / day ~ approx. 200 mg / day, 30 mg / day ~ approx. g / day ~ approx. 60 mg / day, 30 mg / day ~ approx. 70 mg / day, 30 mg / day ~ approx. 80 mg / day, 30 mg / day ~ approx. 90 mg / day, 30 mg / day ~ approx. 100 mg / day, 30 mg / day ~ approx. 0 mg / day, 40 mg / day to about 60 mg / day, 40 mg / day to about 70 mg / day, 40 mg / day to about 80 mg / day, 40 mg / day to about 90 mg / day, 40 mg / day to about 100 mg / day, 40 mg / day to about 250 mg / day, 40 mg / day to about 200 mg / day, 50 mg / day to about 60 mg / day, 50 mg / day to about 70 mg / day, 50 mg / day to about 80 mg / day, 50 mg / day to about 90 mg / day, 50 mg / day to about 100 mg / day, 50 mg / day to about 250 mg / day, or 50 mg / day to about 200 mg / day. In some embodiments, the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is about 10 mg / day to about 100 mg / day.

[0109] In some embodiments, the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is about 5 mg / day, about 10 mg / day, about 20 mg / day, about 25 mg / day, about 30 mg / day, about 35 mg / day, about 40 mg / day, about 45 mg / day, about 50 mg / day, about 55 mg / day, about 60 mg / day, about 65 mg / day, about 70 mg / day, about 75 mg / day, about 80 mg / day, about 85 mg / day, about 90 mg / day, about 95 mg / day, about 100 mg / day, about 110 mg / day, about 120 mg / day, about 130 mg / day, about 140 mg / day, about 150 mg / day, about 160 mg / day, about 170 mg / day, about 180 mg / day, about 190 mg / day, or about 200 mg / day. In some embodiments, the therapeutically effective amount of ibudilast, or a pharma- ceutically acceptable salt thereof, is about 50 mg / day.

[0110] Depending on the dosage and the exact condition being treated, administration may be once, twice, three times, or four times daily, for a course ranging from one day to several days, weeks, months, and even years, as well as the lifespan of the patient. Exemplary dosing regimens last for at least about 1 week, about 1-4 weeks, about 1-8 weeks, 1-12 weeks, 1-16 weeks, 1-20 weeks, 1-24 weeks, 1-36 weeks, 1-48 weeks, 1-52 weeks, 1-60 weeks, 1-72 weeks, 1-84 weeks, 1-96 weeks, 1 week to 1 year, 1 week to 2 years, 1 week to 3 years, 1 week to 4 years, 1 week to 5 years, or longer. In some embodiments, the dosing regimen is at least about 12, 24, 36, 48, 60, 72, 84, or 96 weeks. In some embodiments, the dosing regimen is about 12, 24, 36, 48, 60, 72, 84, or 96 weeks. In some embodiments, the dosing regimen is at least about 1 year, 2 years, 3 years, 4 years, or 5 years. In some embodiments, the dosing regimen is about 1 year, 2 years, 3 years, 4 years, or 5 years.

[0111] 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.

[0112] Excipients / Carriers The compositions of the present disclosure may further comprise one or more additional 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, antimicrobial agents, antioxidants, binders / fillers, surfactants, lubricants (e.g., calcium stearate), glidants such as talc, disintegrants, diluents, buffers, acids, bases, film coats, combinations thereof, and the like. In some embodiments, the compositions do not comprise hydrogenated castor oil. In some embodiments, the compositions do not comprise hydroxypropylmethylcellulose-phthalate. In some embodiments, the compositions do not comprise hydrogenated castor oil and hydroxypropylmethylcellulose-phthalate.

[0113] The compositions of the present disclosure may further comprise 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.

[0114] 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.

[0115] 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.

[0116] The composition of the present disclosure may also optionally 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.

[0117] Additional exemplary excipients include surfactants such as polysorbates, e.g., "Tween 20" and "Tween 80," and pluronics, such as F68 and F88 (both of which are available from BASF, Mount Olive, NJ), sorbitan esters, lipids (e.g., phospholipids such as lecithin and other phosphatidylcholines, and phosphatidylethanolamines), fatty acids and fatty esters, steroids such as cholesterol, and chelating agents such as EDTA, zinc and other such suitable cations.

[0118] 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.

[0119] 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.

[0120] Generally, however, the additional excipients are present in the composition in an amount of about 0.1% to about 25% by weight of the composition. Generally, the amount of excipient present in the ibudilast compositions of the present disclosure is selected from the following: at least about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25% by weight (% w / w) of the composition, including increments therein.

[0121] 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.

[0122] Other Active Substances The formulation (or kit) according to the present disclosure may contain one or more additional active agents in addition to ibudilast or its pharma- ceutically acceptable salt. In some embodiments, the one or more other therapeutic agents are therapeutic agents that have 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.

[0123] Mode of delivery The compositions described herein encompass all kinds of oral formulations. Oral dosage forms include tablets, lozenges, capsules, syrups, oral suspensions, emulsions, granules, microbeads, and pellets. In some embodiments, the oral dosage form is a tablet, capsule, granule, or microbead dosage form. In some embodiments, the oral dosage form is a tablet. In some embodiments, the tablet is an extended release tablet. In some embodiments, the oral dosage form is a capsule. In some embodiments, the capsule is an extended release capsule. In some embodiments, the oral dosage form is a liquid dosage form. In some embodiments, the oral dosage form is an extended release formulation.

[0124] Alternative formulations include powders or lyophilized forms that can be reconstituted, as well as liquids. With respect to liquid pharmaceutical compositions, solutions and suspensions are contemplated.

[0125] Tablets can be made by compression or molding, optionally with one or more accessory ingredients or additives. Compressed tablets are prepared, for example, by compressing in a suitable tablet press the active ingredient in a free-flowing form, such as powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropylmethylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethylcellulose) and / or a surfactant or dispersant.

[0126] 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.

[0127] The formulation of the present disclosure may also be an extended release formulation, such that each component of the drug is slowly released or absorbed over time, compared to a non-sustained release formulation.In some embodiments, the composition is formulated to improve the stability and extend the half-life of ibudilast or a pharmaceutically acceptable salt thereof.For example, ibudilast or a pharmaceutically acceptable salt thereof is delivered in a controlled or extended release formulation.Controlled or extended release formulations are prepared by incorporating ibudilast or a pharmaceutically acceptable salt thereof into a carrier or vehicle, for example, into 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 a pharmaceutically acceptable salt thereof can be encapsulated, adsorbed to, 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).

[0128] 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.

[0129] Sustained release formulations may utilize prodrug forms of the active agent, slow release drug delivery systems such as liposomes or polymer matrices, hydrogels, or covalent attachment of the active agent to a polymer such as polyethylene glycol.

[0130] 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.

[0131] kit Also provided herein are kits comprising any one of the compositions of the present disclosure, along with instructions for use.

[0132] For example, the kit includes ibudilast, or a pharma- ceutically acceptable salt thereof, accompanied by instructions for use. The ibudilast, or a pharma- ceutically acceptable salt thereof, may be packaged in any manner suitable for administration, so long as the packaging clearly indicates the manner in which the drug component is to be administered, given that the packaging is accompanied by instructions for administration.

[0133] For example, in an exemplary kit containing ibudilast or a pharma- ceutically acceptable salt thereof, 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 ibudilast or a pharma- ceutically acceptable salt thereof. If each drug is administered twice a day, the kit may include two unit dosage forms of ibudilast or a pharma- ceutically acceptable salt thereof corresponding to day 1, together with instructions on the timing of administration. Alternatively, if ibudilast or a pharma- ceutically acceptable salt thereof has different administration timing or amount, 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 ibudilast or a pharma- ceutically acceptable salt thereof and the drugs utilized in the treatment, 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 of a number of features, such as different colors, packaging materials, tamper-evident packaging, blister packaging, moisture barriers, etc.

[0134] 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.

[0135] 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.

[0136] 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

[0137] Ibudilast Composition I [Table 1] EXAMPLES

[0138] Ibudilast Tablets IA A 20 mg dose tablet was prepared using the formulation according to Example 1:

[0139] [Table 2] EXAMPLES

[0140] Ibudilast Composition II [Table 3] EXAMPLES

[0141] Ibudilast Tablet II-A A 30 mg dose tablet was prepared using the formulation according to Example 3:

[0142] [Table 4] EXAMPLES

[0143] Ibudilast Tablet II-B A 60 mg dose tablet was prepared using the formulation according to Example 3:

[0144] [Table 5] EXAMPLES

[0145] Ibudilast Composition III [Table 6]

[0146] Using this formulation, it is possible to prepare forms of ibudilast in various dosage amounts. EXAMPLES

[0147] Ibudilast Tablet III-A A 50 mg dose tablet was prepared using the formulation according to Example 6:

[0148] [Table 7]

[0149] Using the formulation of Example 6, lower dose tablets (eg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, or 45 mg) can be similarly prepared. EXAMPLES

[0150] Ibudilast Tablets III-B A 50 mg dose tablet was prepared using the formulation according to Example 6:

[0151] [Table 8]

[0152] Using the formulation of Example 6, lower dose tablets (eg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, or 45 mg) can be similarly prepared. EXAMPLES

[0153] Ibudilast Capsules III-C Various ibudilast dosages in capsule form (e.g., 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, or 50 mg) are prepared by filling empty capsules with the formulation according to Example 6, adjusting the fill weight according to the desired dosage. EXAMPLES

[0154] Dissolution Test Ibudilast Tablet II-B (Example 4), Tablet III-A (Example 7), and Tablet III-B (Example 8) were evaluated for their respective dissolution profiles at 4, 7, 12, 15, 18, and 24 hours when tested in a USP Apparatus Type II at (a) 2 hours at 50 rpm in 900 mL of simulated gastric fluid medium at 37° C., followed by (b) 2 to 22 hours at 50 rpm in 900 mL of phosphate buffer containing 0.3% w / w sodium lauryl sulfate, pH 6.8, at 37° C. The data for the percentage drug release at each time point are shown in Table 9. [Table 9] EXAMPLES

[0155] A Phase I Pharmacokinetic Study of Extended-Release, High-Dose Ibudilast Tablets in Healthy Volunteers (Part 1) Due to the high daily dose levels (60-100 mg / day) required to achieve neuroprotective effects in target indications (e.g., progressive MS, drug addiction, amyotrophic lateral sclerosis), patients take many capsules (6-10 capsules / day). This study investigated the pharmacokinetics, safety, and tolerability of two extended-release (ER) formulations (tablets III-A and III-B) compared to a commercially available 10 mg ibudilast immediate-release (IR) capsule (PINATOS®).

[0156] Ibudilast plasma concentration-time data were received from 12 subjects who participated in this randomized, three-way crossover study. Each subject received one of three treatments: Two doses of 50 mg ibudilast (IR capsules) given 12 hours apart A single dose of 100 mg of tablet III-A (administered as 2 × 50 mg tablets) A single dose of 100 mg of tablet III-B (administered as 2 × 50 mg tablets)

[0157] Each treatment was separated by a 14 day washout period. During each study period, samples were collected up to 168 hours after dosing.

[0158] Plasma concentrations were subjected to non-compartmental analysis. Nominal sampling times were used in this analysis. Plasma samples below the limit of quantification (BLQ) before the first quantifiable concentration were replaced with "0" for pharmacokinetic parameter calculations, while other BLQ samples were reported as missing. The following parameters were calculated: [Table 10]

[0159] Predose plasma concentrations during periods 2 and 3 were measurable in several subjects, suggesting some carryover from the previous dose. These predose concentrations were max, and were therefore replaced by 0 in the analysis. However, these concentrations were also included as originally reported for the 168 hour samples during periods 1 and 2. Steady-state MN-166 concentrations were estimated by nonparametric overlay of both the individual and mean single-dose concentration-time data, and these estimated steady-state concentrations were also subjected to noncompartmental analysis.

[0160] The mean plasma concentration time profiles were comparable among the three formulations. Plasma concentrations were highly variable both within and between subjects.

[0161] average t max were 4.17 and 9.67 hours for tablet III-A and tablet III-B formulations, respectively, suggesting a faster absorption rate from tablet III-A formulation. Thus, the mean C max was approximately 20% higher in tablet III-A (57.1 ng / mL) compared to tablet III-B (45.1 ng / mL). Notably, the absorption lag time observed for tablet III-B formulation was t max The extent of absorption, as measured by AUC, after single-dose administration was also slightly higher for tablet III-A (1840 ng*h / mL) compared with tablet III-B formulation (1640 ng*h / mL).

[0162] C of tablet III-A and tablet III-B formulations compared to the IR formulation max were approximately 30% and 10% higher, respectively, despite a two-fold increase in morning dosing, suggesting that both tablets III-A and III-B exhibited extended-release properties. The mean AUC (1790 ng*h / mL) of the IR formulation was comparable to that of the tablet III-A formulation and was slightly higher on average (9%) compared to the tablet III-B formulation.

[0163] The relative bioavailability, calculated as the individual AUC ratios of the ER formulation to the IR formulation, averaged 104% and 94% for tablet III-A and tablet III-B formulations, respectively, suggesting comparable relative bioavailability for all three formulations. Notably, the relative bioavailability ranged from 62 to 148% for tablet III-A and 47 to 156% for tablet III-B, demonstrating a large variability.

[0164] Terminal half-lives were similar for all three formulations, averaging between 52 and 58 hours.

[0165] Given the large variability, both the mean and individual plasma concentration time profiles were extrapolated to steady state. Overall, 24-hour steady-state levels were comparable among the three formulations. Mean steady-state estimated PK parameters were also comparable for the three formulations. Finally, exposure was generally consistent within each subject between formulations. EXAMPLES

[0166] A Phase I Pharmacokinetic Study of Extended-Release, High-Dose Ibudilast Tablets in Healthy Volunteers (Part 2) Twelve additional subjects from Example 11 were enrolled in the subsequent study. Subjects were randomized to receive either (1) the ER formulation (tablet III-A), or (2) the IR formulation (commercially available 10 mg ibudilast immediate release (IR) capsules (PINATOS®) administered in the following manner: · Titration phase (Days 1-3): 50 mg tablet III-A (one tablet) or 50 mg IR (five 10 mg capsules) administered once daily for 3 days. Multiple-dose phase (days 4-14): 100 mg tablets III-A (2 tablets) once daily or 50 mg IR (5 capsules every 12 hours) twice daily for 11 days. On day 14, for the IR capsules, only the morning dose was administered.

[0167] Preliminary plasma concentration data was received and subjected to non-compartmental analysis. Parameters were calculated as described in Example 11.

[0168] Overall preliminary conclusions: For both formulations, mean T max By 12 hours, mean plasma concentrations were only slightly higher in the ER formulation. Greater fluctuations were observed following administration of the ER formulation for the two subjects experiencing relatively high concentrations. Steady-state C max were comparable on average for the IR and ER formulations. Steady-state C min and AUC 0-24 was lower in the ER formulation compared to the IR formulation. Single-dose data predicted steady-state parameters well for the IR formulation and less well for the ER formulation. The final results are shown in Table 10. [Table 11] EXAMPLES

[0169] Phase I Pharmacokinetic Study of Extended-Release, High-Dose Ibudilast Tablets in Healthy Volunteers - Effect of Food The objectives of this study were (a) to determine the single-dose pharmacokinetics (PK) and relative bioavailability of an extended-release (ER) ibudilast tablet formulation (50 mg) compared with an immediate-release (IR) capsule formulation of ibudilast (five 10 mg capsules) in healthy volunteers in the fasted state; and (b) to determine the effect of food on the single-dose PK of the ER ibudilast 50 mg tablet formulation.

[0170] Tablet III-A and the commercially available 10 mg ibudilast immediate release (IR) capsule from PINATOS® were investigated in this study.

[0171] Subjects received three treatments in a crossover fashion, administered one week apart: · ER: A single dose (50 mg) of ER tablet administered without food (fasted state). · ER: A single dose (50 mg) of ER tablet administered after a high-calorie breakfast (fed state). · IR: A single dose (50 mg) of IR formulation (five 10 mg IR capsules; PINATOS®) administered without food (fasted state).

[0172] Blood samples (approximately 2 mL per sample) were collected pre-dose and 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 32, 48, 72, 96, and 168 hours post-dose (last treatment of each series only) for each treatment.

[0173] Subjects followed a standardized meal schedule except for the mornings of dosing days (Days 1, 8, and 15). After a snack on the night of admission, subjects fasted overnight (10 hours). On the morning of dosing days, fasting continued until 4 hours after each study drug treatment in fasting procedures. In fed procedures, a high-fat (approximately 50 percent of the total caloric content of the meal) and high-calorie (approximately 800-1000 calories) test meal was administered 30 minutes prior to dosing. This test meal provided approximately 150, 250, and 500-600 calories from protein, carbohydrate, and fat, respectively. Subjects consumed this meal in 30 minutes or less. The standardized meal resumed 4 hours post-dose in all subjects and continued until subjects left the clinic 32 hours post-dose.

[0174] Preliminary plasma concentration data was received and subjected to non-compartmental analysis. Parameters were calculated as described in Example 11. Results are shown in Table 10.

[0175] Section A. A pharmaceutical composition comprising ibudilast and at least one pharma- ceutical acceptable excipient, in the form of a tablet or capsule, said tablet or said capsule having a dissolution profile in which at least about 12% of said ibudilast is released from said tablet or said capsule in about 2 hours when tested in a USP Apparatus Type II at 50 rpm in 900 mL of simulated gastric fluid medium at 37° C.

[0176] Section B. The pharmaceutical composition of section A, wherein the tablet has a coating comprising polyvinyl alcohol, a plasticizer, and a pigment.

[0177] Section C. The pharmaceutical composition of section A or B, wherein the at least one pharma- ceutically acceptable excipient comprises microcrystalline cellulose, lactose, or hypromellose, or any combination of two or more thereof.

[0178] Section D. The pharmaceutical composition of any one of sections A-C, wherein the tablet or capsule has a dissolution profile in which at least about 25% of the ibudilast is released from the tablet or capsule in about 4 hours when tested in a USP Apparatus Type II for (a) 2 hours at 50 rpm in 900 mL of simulated gastric fluid medium at 37° C., followed by (b) an additional 2 hours at 50 rpm in 900 mL of phosphate buffer containing 0.3% w / w sodium lauryl sulfate, pH 6.8, at 37° C.

[0179] Section E. The pharmaceutical composition of any one of sections A-D, wherein the tablet or capsule has a dissolution profile in which at least about 60% of the ibudilast is released from the tablet or capsule in about 12 hours when tested in a USP Apparatus Type II for (a) 2 hours at 50 rpm in 900 mL of simulated gastric fluid medium at 37° C., followed by (b) an additional 10 hours at 50 rpm in 900 mL of phosphate buffer containing 0.3% w / w sodium lauryl sulfate, pH 6.8, at 37° C.

[0180] Section F. The pharmaceutical composition of any one of sections A-E, wherein the tablet or capsule has a dissolution profile in which at least about 90% of the ibudilast is released from the tablet or capsule in about 24 hours when tested in a USP Apparatus Type II for (a) 2 hours at 50 rpm in 900 mL of simulated gastric fluid medium at 37° C., followed by (b) an additional 22 hours at 50 rpm in 900 mL of phosphate buffer containing 0.3% w / w sodium lauryl sulfate, pH 6.8, at 37° C.

[0181] Item G. The pharmaceutical composition according to any one of items A to F, wherein the tablet or capsule contains about 10 mg to about 100 mg of ibudilast.

[0182] Section H. A pharmaceutical composition comprising ibudilast and at least one pharma- ceutical acceptable excipient, in the form of a tablet or capsule, said tablet or said capsule having a dissolution profile such that ibudilast is not released from said tablet or said capsule in about 2 hours when tested in a USP Apparatus Type II at 50 rpm in 900 mL of simulated gastric fluid medium at 37°C.

[0183] Section I. The pharmaceutical composition of section H, wherein the tablet has a coating comprising a copolymer dispersing agent of methacrylic acid and ethyl acrylate; triethyl citrate; and talc.

[0184] Section J. The pharmaceutical composition of section H or I, wherein at least one pharma- ceutically acceptable excipient comprises microcrystalline cellulose, lactose, or hypromellose, or any combination of two or more thereof.

[0185] Section K. The pharmaceutical composition of any one of sections H-J, wherein the tablet or capsule has a dissolution profile in which about 10% to about 20% of the ibudilast is released from the tablet or capsule in about 4 hours when tested in a USP Apparatus Type II at (a) 900 mL of simulated gastric fluid medium at 37° C. at 50 rpm for 2 hours, followed by (b) 900 mL of phosphate buffer containing 0.3% w / w sodium lauryl sulfate, pH 6.8, at 37° C. for an additional 2 hours at 50 rpm.

[0186] Section L. The pharmaceutical composition of any one of sections H-K, wherein the tablet or capsule has a dissolution profile in which about 55% to about 65% of the ibudilast is released from the tablet or capsule in about 12 hours when tested in a USP Apparatus Type II for (a) 2 hours at 50 rpm in 900 mL of simulated gastric fluid medium at 37° C., followed by an additional 10 hours at 50 rpm in 900 mL of phosphate buffer containing 0.3% w / w sodium lauryl sulfate, pH 6.8, at 37° C.

[0187] Section M. The pharmaceutical composition of any one of sections H to L, wherein the tablet or capsule has a dissolution profile in which about 85% to about 95% of the ibudilast is released from the tablet or capsule in about 24 hours when tested in a USP Apparatus Type II for (a) 2 hours at 50 rpm in 900 mL of simulated gastric fluid medium at 37° C., followed by (b) an additional 22 hours at 50 rpm in 900 mL of phosphate buffer containing 0.3% w / w sodium lauryl sulfate, pH 6.8, at 37° C.

[0188] Item N. The pharmaceutical composition of any one of items H to M, wherein the tablet or capsule contains about 10 mg to about 100 mg of ibudilast.

[0189] Section O. When the tablet or capsule is administered to a human subject according to a dosing protocol consisting of a 3-day titration phase followed by an 11-day multiple dosing phase, the tablet or capsule exhibits improved C activity compared to an intermediate release formulation.max wherein the tablet or capsule is administered once daily as a 50 mg dose during a 3 day titration phase, and the tablet or capsule is administered once daily as a 100 mg dose during an 11 day multiple dose phase.

[0190] Item P. A pharmaceutical composition comprising about 3% w / w to about 15% w / w ibudilast, about 30% w / w to about 40% w / w lactose, about 30% w / w to about 40% w / w microcrystalline cellulose, about 15% w / w to about 25% w / w hypromellose, about 0.2% w / w to about 0.8% w / w magnesium stearate, and about 0.5% w / w to about 5% w / w colloidal silicon dioxide.

[0191] Item Q. The pharmaceutical composition of item P, wherein the lactose is lactose monohydrate.

[0192] Paragraph R. The pharmaceutical composition of paragraph P or Q comprising about 10% w / w ibudilast, about 35% w / w lactose monohydrate, about 33.5% w / w microcrystalline cellulose, about 20% w / w hypromellose, about 0.5% w / w magnesium stearate, and about 1% w / w colloidal silicon dioxide.

[0193] Item S. The pharmaceutical composition of any one of items P to R, which is in the form of a tablet.

[0194] Section T. The pharmaceutical composition of Section S, wherein the tablet has a coating.

[0195] Paragraph U. The pharmaceutical composition of Paragraph T, wherein the coating comprises polyvinyl alcohol, a plasticizer, and a pigment.

[0196] Paragraph V. The pharmaceutical composition of Paragraph T, wherein the coating comprises a copolymer dispersant of methacrylic acid and ethyl acrylate; triethyl citrate; and talc.

[0197] Section W. The pharmaceutical composition of any one of Sections P-V, which is in the form of a capsule.

[0198] Item X. The pharmaceutical composition of any one of items PW, which does not contain hydroxypropylmethylcellulose phthalate.

[0199] Item Y. A pharmaceutical composition according to any one of items P to X, which does not contain hydrogenated castor oil.

[0200] 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.

[0201] 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.

[0202] 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.

[0203] 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. A pharmaceutical composition consisting of about 3% w / w to about 15% w / w ibudilast, about 30% w / w to about 40% w / w lactose, about 30% w / w to about 40% w / w microcrystalline cellulose, about 15% w / w to about 25% w / w hypromellose, about 0.2% w / w to about 0.8% w / w magnesium stearate, and about 0.5% w / w to about 5% w / w colloidal silicon dioxide.

2. 2. The pharmaceutical composition of claim 1, wherein the lactose is lactose monohydrate.

3. 3. The pharmaceutical composition of claim 1 or claim 2, comprising about 10% w / w ibudilast, about 35% w / w lactose monohydrate, about 33.5% w / w microcrystalline cellulose, about 20% w / w hypromellose, about 0.5% w / w magnesium stearate, and about 1% w / w colloidal silicon dioxide.

4. The pharmaceutical composition according to any one of claims 1 to 3, which is in the form of a tablet.

5. The pharmaceutical composition of claim 4 , wherein the tablet has a coating.

6. 6. The pharmaceutical composition of claim 5, wherein the coating comprises polyvinyl alcohol, a plasticizer, and a pigment.

7. 6. The pharmaceutical composition of claim 5, wherein the coating comprises a copolymer dispersant of methacrylic acid and ethyl acrylate; triethyl citrate; and talc.

8. The pharmaceutical composition according to any one of claims 1 to 3, which is in the form of a capsule.

9. The pharmaceutical composition according to any one of claims 1 to 8, which does not contain hydroxypropylmethylcellulose-phthalate.

10. The pharmaceutical composition according to any one of claims 1 to 9, which does not contain hydrogenated castor oil.

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