Ibudilast for preventing ocular cancer metastasis

Abstract

A method for preventing cancer metastasis in a patient in need thereof comprises administering to the patient a therapeutically effective amount of ibudilast, or a pharmaceutical salt thereof.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 225820, filed July 26, 2021, which is incorporated by reference in its entirety. [Background technology]

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

[0003] While the use of ibudilast has been previously reported for a number of different indications, to the inventors' knowledge, its use in preventing cancer metastasis in patients has not previously been studied extensively. Summary of the Invention

[0004] In one embodiment, the method disclosed herein is a method of preventing metastasis of cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of ibudilast or a pharmaceutical salt thereof.

[0005] In another aspect, a method disclosed herein is a method of ameliorating cancer metastasis in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of ibudilast or a pharmaceutical salt thereof.

[0006] In another aspect, a method disclosed herein is a method of minimizing metastasis of cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of ibudilast or a pharmaceutical salt thereof.

[0007] In some embodiments, ibudilast is administered in combination with one or more additional active agents, hi some embodiments, the one or more additional active agents are selected from the group consisting of chemotherapy, immunotherapy, epigenetic therapy, or liver-directed therapy. In some embodiments, the one or more additional active agents are selected from the group consisting of ICON-1, AU-011, dacarbazine, interferon-alpha, temozolomide, cisplatin, tamoxifen, treosulfan, fotemustine, crizotinib, ipilimumab, tremelimumab, nivolumab, pembrolizumab, atezolizumab, IMCgp100, glembatumumab, selumetinib, trametinib, sotrastaurin, LXS196, AEB071, BYL719, binimetinib, sunitinib, cabozantinib, sorafenib, carboplatin, paclitaxel, valproic acid, vorinostat, PLX51107, tumor infiltrating lymphocytes, glembatumumab vedontin, and entinostat. In some embodiments, ibudilast is administered in combination with one or more of the following: surgery, brachytherapy, charged particle radiation therapy, laser therapy, photodynamic therapy, radiofrequency ablation, stereotactic radiotherapy, hepatic arterial infusion, isolated hepatic perfusion, percutaneous hepatic perfusion, and prophylactic hepatic radiotherapy. In some embodiments, ibudilast is administered to a patient as an adjuvant therapy. In some embodiments, the cancer is selected from angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma, and teratoma, cancer of the mediastinum and pleura, or cancer of the circulatory system selected from 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, ribosome-binding protein 1 (RIPC) 1 (RIPC), ribosome-binding protein ... cancer of the respiratory tract selected from: malignant lymphoma, chondroitin hamartoma, or mesothelioma; cancer of the gastrointestinal system selected from: squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma, carcinoma, leiomyosarcoma, ductal carcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma, adenocarcinoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma, adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, or leiomyoma; adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia;Cancer of the genitourinary tract selected from squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, sarcoma of the prostate, seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, or lipoma; cancer of the liver selected from hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, pheochromocytoma, insulinoma, vasoactive intestinal peptide tumor, islet cell tumor, or glucagonoma; osteogenic sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma , carcinoma of the bone selected from chondrotic exostoses (osteochondral exostoses), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, or giant cell tumor; central nervous system malignant lymphoma, osteoma, hemangioma, granuloma, xanthomas, osteitis deformans, meningioma, meningeal sarcoma, gliomatosis, astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pineal tumor), oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, cancer of the nervous system selected from spinal neurofibroma, meningioma, glioma, or sarcoma; endometrial cancer, cervical cancer, preneoplastic cervical dysplasia, ovarian cancer, serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiable Cancer of the reproductive system selected from among carcinoma, granulosa theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma, vulvar squamous cell carcinoma, vulvar intraepithelial carcinoma, vulvar adenocarcinoma, vulvar fibrosarcoma, vulvar melanoma, 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 among myeloid, acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome, Hodgkin's disease, or non-Hodgkin's lymphoma; cancer of the lips, tongue, gums, floor of the mouth, palate, parotid gland, salivary gland, tongue cancer of the oral cavity selected from peach, oropharynx, nasopharyngeal, pyriform sinus, or hypopharyngeal cancer; cancer of the skin selected from malignant melanoma, cutaneous melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dendritic nevus, lipoma, hemangioma, dermatofibroma, or keloid carcinoma; cancer of the adrenal gland, neuroblastoma, cancer of connective and soft tissue, cancer of the retroperitoneum and peritoneum, cancer of the eye, intraocular melanoma, cancer of the adnexa, breast cancer, cancer of the head and neck, anal cancer, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, cancer of the endocrine glands and related structures, secondary and unspecified malignant neoplasms of the lymph nodes, secondary malignant neoplasms of the respiratory and digestive systems;or a secondary malignant neoplasm at another site. In some embodiments, the cancer is an eye cancer. In some embodiments, the eye cancer is an uveal melanoma. In some embodiments, ibudilast or a pharmacologic acceptable salt thereof is administered for at least 3 months. In some embodiments, ibudilast or a pharmacologic acceptable salt thereof is administered for at least 6 months. In some embodiments, ibudilast or a pharmacologic acceptable salt thereof is administered for at least 1 year. In some embodiments, ibudilast or a pharmacologic acceptable salt thereof is administered for at least 2 years. In some embodiments, ibudilast or a pharmacologic acceptable salt thereof is administered at least once a day. In some embodiments, ibudilast or a pharmacologic acceptable salt thereof is administered orally. In some embodiments, the therapeutically effective amount of ibudilast or a pharmacologic acceptable salt thereof is 0.1 mg to 720 mg per day. In some embodiments, the therapeutically effective amount of ibudilast or a pharmacologic acceptable salt thereof is at least 30 mg / day. In some embodiments, the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is 30 mg to 200 mg per day. In some embodiments, the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is 60 mg to 600 mg per day. In some embodiments, the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is 100 mg to 480 mg per day. In some embodiments, the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is selected from the group consisting of 30 mg / day, 60 mg / day, 90 mg / day, 100 mg / day, 120 mg / day, 150 mg / day, 180 mg / day, 210 mg / day, 240 mg / day, 270 mg / day, 300 mg / day, 360 mg / day, 400 mg / day, 440 mg / day, 480 mg / day, 520 mg / day, 580 mg / day, 600 mg / day, 620 mg / day, 640 mg / day, 680 mg / day, and 720 mg / day. In some embodiments, the therapeutically effective amount is administered as a single dose or divided into two, three, or four doses. In some embodiments, ibudilast is administered continuously. [Brief description of the drawings]

[0008] [Figure 1A] FIG. 1A illustrates the results of a transwell migration assay in which Omm1.3 cells were stimulated with hepatocyte-conditioned medium and uveal melanoma exosomes (HCM+UM-Exo) in the presence of vehicle (DMSO), 10 μM diacerein, 1.0 μM reparixin, 0.25 μM crizotinib, or 25 μM ibudilast. [Figure 1B] Figure 1B illustrates the number of migrated cells under a microscope from the transwell migration assay, three fields for each condition. Experiments were repeated three times ±sd, p<0.001. [Figure 1C] Figure 1C illustrates Omm1.3 cells in a scratch assay, where after scratching, cells were incubated in control HCM or in HCM of hepatocytes exposed to UM exosomes with or without 25 μM ibudilast. Images were taken at zero time point or after 48 hours under a microscope at 10x magnification. [Figure 2A] Figure 2A illustrates the quantification of bioluminescence intensity (excluding eye bioluminescence) for each mouse in the abdominal region in the evaluation of ibudilast in the metastatic UM mouse model. Means were calculated for each cohort, ± SEM, p<0.05, comparing ibudilast treatment with vehicle. [Figure 2B] FIG. 2B illustrates representative images of H&E stained mouse liver sections derived from a metastatic UM mouse model. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] The practice of the present disclosure will employ, unless otherwise indicated, conventional methods of chemistry, biochemistry, and pharmacology within the skill of the art. Such techniques are fully explained in the literature. See, for example, AL Lehninger, Biochemistry (Worth Publishers, Inc., current addition); Morrison and Boyd, Organic Chemistry (Allyn and Bacon, Inc., current addition); J. March, Advanced Organic Chemistry (McGraw Hill, current addition); Remington: The Science and Practice of Pharmacy, A. Gennaro, Ed., 20th Ed.; FDA's Orange Book, Goodman & Gilman The Pharmacological Basis of Therapeutics, J. Griffith Hardman, LL Limbird, A. Gilman, 11th Ed., 2005, The Merck Manual, 18th edition, 2007, and The Merck Manual of Medical Information 2003.

[0010] All publications cited herein, including internet articles, the FDA Orange Book (available at the FDA website), books, handbooks, journal articles, patents, and patent applications, whether supra or infra, are hereby incorporated by reference in their entirety.

[0011] 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, etc., which may vary, as will become apparent from the accompanying description.

[0012] It should be noted that, as used in this specification and the intended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly indicates otherwise. Thus, for example, a reference to "a drug" includes not only a single drug but two or more drugs, either the same or different, a reference to "an optional excipient" includes not only a single optional excipient but two or more optional excipients, either the same or different, etc.

[0013] In describing and claiming this disclosure, the following terminology will be used in accordance with the definitions set out below.

[0014] The term "comprising" as used herein is intended to mean that the compositions and methods include the recited elements but do not exclude other elements. "Consisting essentially of" as used to define compositions and methods shall mean excluding other elements that are critical to the combination for the described purpose. Thus, a composition consisting essentially of the elements defined herein will not exclude other materials or steps that do not substantially affect the basic and novel feature(s) of the claimed invention. "Consisting of" shall mean excluding other components beyond trace elements, and substantial method steps. Embodiments defined by each of these transition terms are within the scope of the invention. When an embodiment is defined by one of these terms (e.g., "comprising"), it should be understood that the disclosure also includes alternative embodiments, such as "consisting essentially of" and "consisting of" in the preceding embodiment.

[0015] "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 toxicological effects in a patient.

[0016] "Pharmaceutically acceptable salts" include, but are not limited to, amino acid salts, salts prepared with inorganic acids (e.g., chlorides, sulfates, phosphates, diphosphates, bromides, nitrates, etc.), or salts prepared from the inorganic acid forms corresponding to any of the above (e.g., hydrochlorides, etc.), or salts prepared with organic acids (e.g., malate, maleate, fumarate, tartrate, succinate, ethylsuccinate, citrate, acetate, lactate, methanesulfonate, benzoate, ascorbate, para-toluenesulfonate, palmitate, salicylate, stearate, etc.), as well as estolate, gluceptate, and lactobionate salts. Similarly, salts containing pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium (including substituted ammonium).

[0017] As used herein, "active molecule" or "active agent" includes any agent, drug, compound, composition of matter, or mixture that provides some pharmacological (often beneficial) effect that can be demonstrated in vivo or in vitro. This includes foods, dietary supplements, nutrients, nutraceuticals, drugs, vaccines, antibodies, vitamins, and other beneficial agents. As used herein, these terms further include any physiologically or pharmacologically active substance that produces a local or systemic effect in a patient. In certain embodiments, the active molecule or active agent may include ibudilast or a pharmaceutically acceptable salt thereof.

[0018] "Substantially" or "essentially" means nearly completely or completely, e.g., 95% or more of a given amount.

[0019] "Optional" or "optionally" means that the subsequently described circumstance may or may not occur, so that the description includes cases where the circumstance occurs and cases where the circumstance does not occur.

[0020] The terms "subject," "individual," or "patient" are used interchangeably herein and refer to a vertebrate, preferably a mammal, including, but not limited to, mice, rodents, rats, monkeys, humans, farm animals, dogs, cats, sport animals, and pets.

[0021] The term "pharmacologically effective amount" or "therapeutically effective amount" of a composition or agent provided herein refers to a non-toxic but sufficient amount of the composition or agent to provide a desired response, such as prevention of cancer metastasis. The exact amount required will vary from subject to subject, depending on the subject's species, age, general condition, severity of the condition being treated, the particular drug(s) used, method of administration, etc. The appropriate "effective" amount in any individual case can be determined by one of ordinary skill in the art using routine experimentation based on the information provided herein.

[0022] As used herein, the term "preventing cancer metastasis" includes one or more of treating, ameliorating, minimizing cancer metastasis in a patient. In some embodiments, preventing leads to the absence of cancer metastasis in a patient. In some embodiments, preventing leads to the minimization of cancer metastasis in a patient. In some embodiments, preventing leads to the absence or minimization of cancer metastasis in a patient.

[0023] The term "about" is understood by those skilled in the art and varies somewhat depending on the context in which it is used. If there are uses of the term that are not clear to those skilled in the art given the context in which it is used, "about" means up to ±10% of the particular term. For example, in some embodiments, it means plus or minus 5% of the particular term. A particular range is provided herein, and the numerical value is preceded by the term "about". The term "about" is used herein to literally support not only the exact number that it precedes, but also numbers that are close to or approximately the same as the number that it precedes. In determining whether a number is close to or approximately the same as a specifically recited number, the near or approximate unrecited number may be a number that provides a substantial equivalent to the specifically recited number in the context in which it is provided.

[0024] 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 illustration 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.

[0025] 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 in the following formula: [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 18It 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 of ibudilast include Ibudilastum (Latin), BRN 0656579, KC-404, MN-166. Its brand name is Ketas®. As referred to herein, ibudilast is meant to include any of its pharma- ceutically acceptable salt forms, prodrug forms (e.g., the corresponding ketals, oximes, oxime derivatives, hydrazones, or hemicarbazones), solvates, etc., as appropriate for use in its formulations intended for administration.

[0027] Ibudilast is also reported to be a selective inhibitor of cyclic nucleotide phosphodiesterases (PDEs) 3A, 4, 10A1, and 11A1 (Gibson et al., Eur J Pharmacol 538: 39-42, 2006), has toll-like receptor-4 (TLR4) antagonist activity (Yang et al., Cell Death and Disease (2016) 7, e2234; doi:10.1038 / cddis.2016.140), and has leukotriene D4 and PAF antagonist activity. Its profile appears to be effectively anti-inflammatory and unique compared to other PDE inhibitors and anti-inflammatory agents. PDEs catalyze the hydrolysis of the phosphoester bond on the 3'-carbon to produce the corresponding 5'-nucleotide monophosphate. Hence, they regulate the cellular concentration of cyclic nucleotides. Because the extracellular receptors for many hormones and neurotransmitters utilize cyclic nucleotides as second messengers, PDEs also regulate the cellular response to these extracellular signals. There are at least eight classes of PDEs: Ca 2+ / Calmodulin-dependent PDE (PDE1), cGMP-stimulated PDE (PDE2), cGMP-inhibited PDE (PDE3), cAMP-specific PDE (PDE4), cGMP-binding PDE (PDE5), photoreceptor PDE (PDE6), high-affinity cAMP-specific PDE (PDE7), high-affinity cGMP-specific PDE (PDE9). Ibudilast acts to suppress inflammation through its action on inflammatory cells (e.g., glial cells), resulting in the suppression of the release of both pro-inflammatory and neuroactive mediators. Ibudilast may also suppress the production of pro-inflammatory cytokines (IL-1s, TNF-α) and enhance the production of anti-inflammatory cytokines (IL-4, IL-10). References related to the foregoing include:Obernolte, R., et al. (1993) “The cDNA of a human lymphocyte cyclic-AMP phosphodiesterase (PDE IV) reveals a multigene family” Gene 129: 239-247; Rile, G., et al. (2001) “Potentiation of ibudilast inhibition of platelet aggregation in the presence of endothelial cells” Thromb. Res. 102: 239-246; Souness, JE, et al. (1994) “Possible role of cyclic AMP phosphodiesterases in the actions of ibudilast on eosinophil thromboxane generation and airways smooth muscle tone” Br. J. Pharmacol. 111: 1081-1088; Suzumura, A., et al. (1999) “Ibudilast suppresses TNF.alpha. production by glial cells functioning mainly as type III phosphodiesterase inhibitor in CNS” Brain Res. 837: 203-212; Takuma, K., et al. (2001) “Ibudilast attenuates astrocyte apoptosis via cyclic GMP signaling pathway in an in vitro reperfusion model” Br. J. Pharmacol. 133: 841-848. Regarding the treatment of CNS cancers, ibudilast shows good CNS penetration. (Sanftner et al Xenobiotica 2009 39: 964-977).

[0028] Ibudilast is also an allosteric inhibitor of p-hydroxyphenylpyruvate (HPP) tautomerase activity of macrophage inhibitory factor (MIF) (Cho et al., PNAS-USA, 2010 June 107: 11313-8), thereby inhibiting the catalytic and chemotactic functions of MIF. Unexpectedly, the inventors have found that ibudilast also reduces the plasma levels of MIF. This reduction in MIF plasma levels is unexpected, since there is no known association between the allosteric inhibition of MIF and the concentration of MIF in plasma. However, since MIF is involved in intracellular signaling via the activation of CD44 or CD74 in complex with chemokine receptors CXCR2 and CXCR4, both MIF inhibition by ibudilast and reduction in MIF plasma levels can minimize the proinflammatory effects of MIF.

[0029] As noted above, reference to any one or more of the drugs described herein (particularly ibudilast) is meant to encompass, where applicable, 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., crystalline solids, amorphous solids), metabolites, and the like.

[0030] Treatment and Administration Methods As noted above, in one embodiment, the present disclosure is directed to a method of preventing cancer metastasis in a patient in need thereof, the method comprising, consisting essentially of, or consisting of administering to the patient a therapeutically effective amount of ibudilast or a pharmaceutical salt thereof.

[0031] In another aspect, provided herein is a method of ameliorating cancer metastasis in a patient in need thereof, the method comprising, consisting essentially of, or consisting of administering to the patient a therapeutically effective amount of ibudilast or a pharmaceutical salt thereof.

[0032] In another aspect, provided herein is a method of minimizing cancer metastasis in a patient in need thereof, the method comprising, consisting essentially of, or consisting of administering to the patient a therapeutically effective amount of ibudilast or a pharmaceutical salt thereof.

[0033] In some embodiments, ibudilast is administered in combination with one or more additional active agents. The one or more additional active agents may be selected from the group consisting of chemotherapy, immunotherapy, epigenetic therapy, or liver-directed therapy. Non-limiting examples of chemotherapy include dacarbazine in combination with interferon-α, cisplatin in combination with tamoxifen and sunitinib, and fotemustine. Non-limiting examples of immunotherapy include immune checkpoint inhibitors such as anti-CTLA-4 therapy, anti-PD-L1 therapy, or anti-PD-1 therapy, tumor infiltrating lymphocytes (TIL), antibody-drug conjugates such as glembatumumab vedotin, and T cell redirection therapy such as IMCgp100. Immunotherapies include, but are not limited to, ipilimumab, tremelimumab, nivolumab, pembrolizumab, a combination of ipilimumab and nivolumab, and dendritic cell vaccines. Non-limiting examples of epigenetic therapies include histone deacetylase (HDAC) inhibitors such as vorinostat or PEMDAC (pembrolizumab and entinostat), bromodomain and extraterminal (BET) inhibitors (such as PLX51107). Non-limiting examples of liver-directed therapies include isolated liver perfusion (IHP) and percutaneous liver perfusion (PHP).

[0034] In some embodiments, the one or more additional active agents are selected from the group consisting of ICON-1, AU-011, dacarbazine, interferon-alpha, temozolomide, cisplatin, tamoxifen, treosulfan, fotemustine, crizotinib, ipilimumab, tremelimumab, nivolumab, pembrolizumab, atezolizumab, IMCgp100, glembatumumab, selumetinib, trametinib, sotrastaurin, LXS196, AEB071, BYL719, binimetinib, sunitinib, cabozantinib, sorafenib, carboplatin, paclitaxel, valproic acid, vorinostat, PLX51107, tumor infiltrating lymphocytes, glembatumumab vedontin, and entinostat.

[0035] In some embodiments, ibudilast is administered in combination with one or more selected from the group consisting of surgery, brachytherapy, charged particle radiation therapy, laser therapy, photodynamic therapy, radiofrequency ablation, stereotactic radiotherapy, hepatic intra-arterial infusion, isolated liver perfusion, percutaneous liver perfusion, and prophylactic hepatic radiotherapy.

[0036] In some embodiments, ibudilast is administered to the patient as an adjuvant therapy.

[0037] 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; b. Cancer of the respiratory tract selected from 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 mesothelioma; c. A cancer of the gastrointestinal system selected from squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma, carcinoma, leiomyosarcoma, ductal carcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma, adenocarcinoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma, adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, or leiomyoma; d. Cancer of the genitourinary tract selected from adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia, squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, adenocarcinoma, sarcoma of the prostate, seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, or lipoma; e. Cancer of the liver selected from hepatocellular carcinoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, pheochromocytoma, insulinoma, vasoactive intestinal peptide tumor, pancreatic islet cell tumor, or glucagonoma; f. Cancer of the bone selected from osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, chondrocartilaginous exostosis (osteochondral exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, or giant cell tumor; g. Nervous system cancer selected from central nervous system malignant lymphoma, osteoma, hemangioma, granuloma, xanthomas, osteitis deformans, meningioma, meningeal sarcoma, gliomatosis, astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pineal tumor), oligodendroglioma, schwannoma, retinoblastoma, congenital tumor, spinal neurofibroma, meningioma, glioma, or sarcoma; h. a 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, vulvar squamous cell carcinoma, vulvar intraepithelial carcinoma, vulvar adenocarcinoma, vulvar fibrosarcoma, vulvar melanoma, 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; i. a cancer of the blood system selected from myeloid, acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome, Hodgkin's disease, or non-Hodgkin's lymphoma; j. Cancer of the oral cavity selected from lip cancer, tongue cancer, gum cancer, floor of the mouth cancer, palate cancer, parotid gland cancer, salivary gland cancer, tonsil cancer, oropharynx cancer, nasopharyngeal cancer, pyriform sinus cancer, or hypopharyngeal cancer; k. a cancer of the skin selected from malignant melanoma, cutaneous melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, lenticular nevus, lipoma, hemangioma, dermatofibroma, or keloid carcinoma; or l. Cancer selected from adrenal gland cancer, neuroblastoma, cancer of connective and soft tissue, cancer of the retroperitoneum and peritoneum, eye cancer, intraocular melanoma, adnexal cancer, breast cancer, head and neck cancer, anal cancer, thyroid cancer, parathyroid cancer, adrenal gland cancer, cancer of the endocrine glands and associated structures, secondary and unspecified malignant neoplasms of lymph nodes, secondary malignant neoplasms of the respiratory and digestive systems, or secondary malignant neoplasms of other sites.

[0038] In some embodiments, the cancer is breast cancer, prostate cancer, liver cancer, colon cancer, cervical cancer, uterine cancer, ovarian cancer, lung cancer, head and neck cancer, pancreatic cancer, gastric cancer, or renal cancer. In some embodiments, the cancer is one or more solid tumors.

[0039] In some embodiments, the cancer is an eye cancer, hi some embodiments, the eye cancer is uveal melanoma.

[0040] In some embodiments, ibudilast or a pharma- ceutically acceptable salt thereof is administered in a daily dosage ranging from about 0.1 mg to 720 mg per day, about 30 mg to 200 mg per day, about 40 mg to 600 mg per day, or about 100 mg to 480 mg per day.

[0041] Administration of ibudilast can be achieved through various delivery methods of ibudilast, including formulation.Preferred delivery methods of ibudilast-based therapeutic formulation include systemic delivery and local delivery.These administration routes include but are not limited to oral, intraarterial, intrathecal, intraspinal, intramuscular, intraperitoneal, intranasal, and inhalation routes.

[0042] More specifically, the ibudilast-based formulation of the present disclosure may be administered for therapy by any suitable route, including but not limited to oral, rectal, nasal, topical (including transdermal, aerosol, buccal, sublingual), vaginal, parenteral (including subcutaneous, intravenous, intramuscular, intradermal), intrathecal, and pulmonary.In some embodiments, the ibudilast-based formulation is administered orally.In some embodiments, the ibudilast-based formulation is administered via injection.The preferred route will of course vary according to the condition and age of the recipient, the particular syndrome being treated, and the particular combination of drugs being used.

[0043] In some embodiments, ibudilast or a pharma- ceutically acceptable salt thereof is administered orally.In some embodiments, ibudilast or a pharma- ceutically acceptable salt thereof is administered via injection.

[0044] When the ibudilast composition of the present disclosure comprises two or more active agents, it may be administered as a single combination composition comprising a combination of ibudilast and at least one additional active agent. Because patients are often reluctant to take multiple pills or dosage forms (often multiple times a day) over the course of treatment, such an approach is preferred in terms of patient compliance and ease of administration. Alternatively, the combination of the present disclosure is administered as a separate dosage form. When the drugs comprising the therapeutic composition of the present disclosure are administered as separate dosage forms and simultaneous administration is required, ibudilast and each of the additional active agents may be administered simultaneously, sequentially in any order, or separately.

[0045] dose Therapeutic amounts can be empirically determined and vary depending on the particular condition being treated, the subject, and the efficacy and toxicity of each of the active agents contained in the composition. The actual dose administered will vary depending on the age, weight, general condition of the subject, and the severity of the condition being treated, the judgment of the health care professional, and the particular combination being administered.

[0046] The therapeutically effective amount can be determined by those skilled in the art and is adjusted to the requirements of each particular case. In general, the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is in the range of about 0.1 mg / day to about 720 mg / day, about 40 to about 600 mg / day, or about 100 to about 480 mg / day, more preferably about 1 to about 240 mg / day, about 30 to about 240 mg / day, about 30 to about 200 mg / day, about 30 to about 120 mg / day, about 1 to about 120 mg / day, about 50 to about 150 mg / day, about 60 to about 150 mg / day, about 60 to about 120 mg / day, or about 60 to about 100 mg / day, administered either as a single dose or multiple doses. In some embodiments, the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is about 30 to about 200 mg / day, administered either as a single dose or multiple doses. In some embodiments, the therapeutically effective amount of ibudilast or a pharmaceutically acceptable salt thereof is about 60-600 mg / day, administered either as a single dose or multiple doses. In some embodiments, the therapeutically effective amount of ibudilast or a pharmaceutically acceptable salt thereof is about 100-480 mg / day, administered either as a single dose or multiple doses. In some embodiments, multiple doses include 2, 3, or 4 doses per day.

[0047] Preferred dosage amounts include dosage amounts of greater than about 20 mg BID or TID, i.e., greater than about 30 mg / day, greater than 60 mg / day, greater than 90 mg / day, greater than 100 mg / day, greater than 120 mg / day, greater than 150 mg / day, greater than 180 mg / day, greater than 210 mg / day, greater than 240 mg / day, greater than 270 mg / day, greater than 300 mg / day, greater than 360 mg / day, greater than 400 mg / day, greater than 440 mg / day, greater than 480 mg / day, greater than 520 mg / day, greater than 580 mg / day, greater than 600 mg / day, greater than 620 mg / day, greater than 640 mg / day, greater than 680 mg / day, greater than 720 mg / day, or more.

[0048] In some embodiments, the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is at least 30 mg / day, at least 40 mg / day, at least 50 mg / day, at least 60 mg / day, at least 70 mg / day, at least 80 mg / day, at least 90 mg / day, at least 100 mg / day, at least 110 mg / day, at least 120 mg / day, at least 130 mg / day, at least 140 mg / day, at least 150 mg / day, at least 160 mg / day, at least 170 mg / day, at least 180 mg / day, at least 190 mg / day, at least 200 mg / day, at least 210 mg / day, at least 220 mg / day, at least 230 mg / day, at least 240 mg / day, at least 250 mg / day, at least 260 mg / day, at least 270 mg / day, at least 280 mg / day, at least 290 mg / day, at least 300 mg / day, at least 310 mg / day, at least 320 mg / day, at least 330 mg / day, at least 340 mg / day, at least 350 mg / day, at least 360 mg / day, at least 370 mg / day, at least 380 mg / day, at least 390 mg / day, at least 400 mg / day, at least 410 mg / day, at least 420 mg / day, at least 430 mg / day, at least 440 mg / day, at least 450 mg / day, at least 460 mg / day, at least 470 mg / day, at least 480 mg / day, at least 490 mg / day, at least 500 mg / day, at least 510 mg / day, 225mg / day, at least 250mg / day, at least 275mg / day, at least 300mg / day, at least 325mg / day, at least 350mg / day, at least 375mg / day, at least 400mg / day, at least 425mg / day, at least 450mg / day, at least 475mg / day, at least 500mg / day, at least 525mg / day, at least 550mg / day, at least 575mg / day, at least 600mg / day, at least 625mg / day, at least 650mg / day, at least 675mg / day, at least 700mg / day, or at least 720mg / day. In some embodiments, the therapeutically effective amount of ibudilast or its pharma- ceutically acceptable salt is at least 60mg / day. In some embodiments, the therapeutically effective amount of ibudilast or its pharma-ceutically acceptable salt is at least 100mg / day.

[0049] Depending on the dosage and the exact condition being treated, administration can be once, twice, three or four times a day for a time course of one day to several days, weeks, months or even years, or even for the patient's lifetime. Exemplary dosing regimens last for at least about 1 week, about 1-4 weeks, 1-3 months, 1-6 months, 1-52 weeks, 1-24 months, or longer. In some embodiments, ibudilast or a pharmaceutically acceptable salt thereof is administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days. In some embodiments, ibudilast or a pharmaceutically acceptable salt thereof is administered for less than 3 months. In some embodiments, ibudilast or a pharmaceutically acceptable salt thereof is administered for at least 3 months. In some embodiments, ibudilast or a pharmaceutically acceptable salt thereof is administered for at least 6 months. In some embodiments, ibudilast or a pharmaceutically acceptable salt thereof is administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months or more. In some embodiments, ibudilast or a pharmaceutically acceptable salt thereof is administered for about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years or more. In some embodiments, ibudilast or a pharmaceutically acceptable salt thereof is administered for at least 1 year. In some embodiments, ibudilast or a pharmaceutically acceptable salt thereof is administered for at least 2 years. In some embodiments, ibudilast or a pharmaceutically acceptable salt thereof is administered as one single dose.

[0050] In some embodiments, the therapeutically effective amount of ibudilast or its pharmaceutically acceptable salt is administered in a single dose per day.In some embodiments, the therapeutically effective amount of ibudilast or its pharmaceutically acceptable salt is administered in two doses per day.In some embodiments, the therapeutically effective amount of ibudilast or its pharmaceutically acceptable salt is administered in three doses per day.In some embodiments, the therapeutically effective amount of ibudilast or its pharmaceutically acceptable salt is administered in four doses per day.In some embodiments, the therapeutically effective amount of ibudilast or its pharmaceutically acceptable salt is administered continuously.

[0051] In some embodiments, ibudilast or a pharmaceutically acceptable salt thereof is administered at least once a day.In some embodiments, ibudilast or a pharmaceutically acceptable salt thereof is administered at least twice a day.In some embodiments, ibudilast or a pharmaceutically acceptable salt thereof is administered once a day.In some embodiments, ibudilast or a pharmaceutically acceptable salt thereof is administered twice a day.

[0052] Virtually any given composition or unit dose of active agent of the present disclosure can be administered in a variety of administration schedules, depending on the clinician's judgment, the patient's needs, etc. Specific administration schedules are known to those skilled in the art or can be determined empirically using routine methods. Exemplary administration schedules include, but are not limited to, administration 5 times a day, 4 times a day, 3 times a day, 2 times a day, once a day, every other day, 3 times a week, twice a week, once a week, twice a month, once a month, etc.

[0053] formulation Ibudilast may be administered in a composition of a formulation that may optionally contain one or more additional ingredients, as described below.

[0054] Excipients / Carriers In addition to ibudilast or a pharma- ceutically acceptable salt thereof, the compositions of the present disclosure may further comprise one or more pharma- ceutically acceptable excipients or carriers.Exemplary excipients include, but are not limited to, polyethylene glycol (PEG), PEG 400, (2-hydroxypropyl)-β-cyclodextrin, hydrogenated castor oil (HCO), cremophor, carbohydrates, starches (e.g., corn starch), inorganic salts, antibacterial agents, antioxidants, binders / fillers, surfactants, lubricants (e.g., calcium or magnesium stearate), lubricants such as talc, disintegrants, diluents, buffers, acids, bases, film coats, combinations thereof, and the like.

[0055] The compositions of the present disclosure may include one or more carbohydrates, such as sugars, derivatized sugars (such as alditols), aldonic acids, esterified sugars, and / or sugar polymers. Specific carbohydrate excipients include 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.; alditols, such as mannitol, xylitol, maltitol, lactitol, xylitol, sorbitol (glucitol), pyranosyl sorbitol, myo-inositol, etc.

[0056] Also suitable for use in the compositions of the present disclosure are starches derived from potato and corn, such as sodium starch glycolate and directly compressible modified starches.

[0057] 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.

[0058] The compositions of the present disclosure may also contain one or more antioxidants.Antioxidants are used to prevent oxidation, thereby preventing the deterioration of drug(s) or other components of the preparation.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.

[0059] Additional exemplary excipients include surfactants such as polysorbates, e.g., "Tween 20" and "Tween 80", and pluronics such as F68 and F88 (both available from BASF, Mount Olive, NJ), sorbitan esters, lipids (e.g., phospholipids such as lecithin and other phosphatidylcholines, and phosphatidylethanolamines), fatty acids and fatty acid esters, steroids such as cholesterol, chelating agents (EDTA, zinc, other suitable cations). In some embodiments, the surfactant may include a polyethoxylated castor oil derivative (e.g., Cremophor EL, Kolliphor ELP, etc.). Other non-limiting excipients include alcohols (e.g., ethanol), propylene glycol, glycolysers, or polyethylene glycols (PEG).

[0060] In addition, the composition of the present disclosure may optionally include one or more acids or bases.Non-limiting examples of acids that can be used include acids selected from the group consisting of hydrochloric acid, acetic acid, phosphoric acid, citric acid, malic acid, lactic acid, formic acid, trichloroacetic acid, nitric acid, perchloric acid, phosphoric acid, sulfuric acid, fumaric acid, and combinations thereof.Non-limiting examples of suitable bases include, but are not limited to, bases selected from the group consisting of sodium hydroxide, sodium acetate, ammonium hydroxide, potassium hydroxide, ammonium acetate, potassium acetate, sodium phosphate, potassium phosphate, sodium citrate, sodium formate, sodium sulfate, potassium sulfate, potassium fumarate, and combinations thereof.

[0061] The amount of any individual excipient in the composition varies depending on the role of the excipient, the dosage requirements of the active ingredient, and the specific needs of the composition.Typically, the optimal amount of any individual excipient is determined through routine experimentation, i.e., by preparing compositions containing various amounts of excipient (ranging from low to high), examining stability and other parameters, and then determining the range in which optimal performance is achieved without significant adverse effects.

[0062] However, the excipients are generally present in the compositions in an amount of about 1% to about 99% by weight of the excipient, preferably about 5% to about 98% by weight, and more preferably about 15% to about 95% by weight. Generally, the amount of excipients present in the ibudilast compositions of the present disclosure is selected from at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or even 95% by weight.

[0063] These aforementioned pharmaceutical excipients, along with other excipients, are described in “Remington: The Science & Practice of Pharmacy,” 19th ed., Williams & Williams, (1995), the “Physician's Desk Reference”, 52.sup.nd ed., Medical Economics, Montvale, NJ (1998), and Kibbe, AH, Handbook of Pharmaceutical Excipients, 3.sup.rd Edition, American Pharmaceutical Association, Washington, DC, 2000.

[0064] Sustained Delivery Formulations The composition is preferably formulated to improve the stability and extend the half-life of ibudilast or its pharma- ceutically acceptable salt.For example, ibudilast or its pharma- ceutically acceptable salt may be delivered in a controlled or sustained release formulation.Controlled or sustained release formulations are prepared by incorporating ibudilast or its pharma- ceutically acceptable salt into carriers or solvents such as liposomes, non-absorbable impermeable polymers such as ethylene vinyl acetate copolymers and Hytrel® copolymers, swellable polymers such as hydrogels, or resorbable polymers such as collagen, and certain polyacids or polyesters used to make resorbable sutures.In addition, ibudilast or its pharma- ceutically acceptable salt can be encapsulated, adsorbed, or associated with particulate carriers.Examples of particulate carriers include carriers derived from polymethylmethacrylate polymers, and microparticles derived from poly(lactide) and poly(lactide-co-glycolide), known as PLG. See, e.g., Jeffery et al., Pharm. Res. (1993) 10:362-368, and McGee et al., J. Microencap. (1996).

[0065] Suitable sustained release polymers for this purpose are known in the art and include hydrophobic polymers such as cellulose ethers. Non-limiting examples of suitable cellulose ethers include ethyl cellulose, cellulose acetate, etc., polyvinyl esters (such as polyvinyl acetates, polyacrylic esters, methacrylic and acrylate polymers (pH independent types)), high molecular weight polyvinyl alcohols and waxes (such as fatty acids and glycerides, methacrylic ester neutral polymers, polyvinyl alcohol-maleic anhydride copolymers), ethyl acrylate-methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, and mixtures thereof.

[0066] Mode of Delivery The ibudilast or its pharma- ceutically acceptable salt composition described herein includes any type of formulation, particularly suitable for systemic or intrathecal administration.Oral dosage forms include tablets, lozenges, capsules, syrups, oral suspensions, emulsions, granules, and pellets.In some embodiments, the oral dosage form is a tablet.In some embodiments, the tablet is a sustained release tablet.In some embodiments, the oral dosage form is a capsule.In some embodiments, the capsule is a sustained release capsule.

[0067] Alternative formulations include aerosols, transdermal patches, gels, creams, ointments, suppositories, powders, or lyophilisates that can be reconstituted, as well as liquids.Examples of suitable diluents for reconstituting solid compositions (e.g., before injection) include bacteriostatic water for injection, 5% dextrose in water, phosphate buffered saline, Ringer's solution, saline, sterile water, deionized water, and combinations thereof.For liquid pharmaceutical compositions, solutions and suspensions are envisaged.Preferably, the ibudilast or its pharmaceutically acceptable salt composition of the present disclosure is suitable for oral administration.

[0068] Turning now to oral delivery formulations, tablets can be made by compression or molding, optionally with one or more accessory ingredients or additives. Compressed tablets are prepared by compressing, for example in a suitable tablet press, the active ingredient in a free-flowing form, such as a 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 surface-active or dispersing agent.

[0069] Molded tablets are prepared, for example, by molding a mixture of powdered compounds moistened with an inert liquid diluent, for example, in a suitable tablet press. Tablets can be optionally coated or scored, and can be formulated to provide slow or controlled release of active ingredients, for example, using hydroxypropylmethylcellulose in various proportions to provide a desired release profile. Tablets can be optionally provided with coatings, such as thin films, sugar coatings, or enteric coatings, to provide release in parts of the intestine other than the stomach. The processes, equipment, and contract manufacturers for tablet and capsule manufacturing are well known in the art.

[0070] Formulations for topical administration in the mouth include lozenges, which generally contain the active ingredient in a flavored base such as sucrose and acacia or tragacanth, and pastilles, which contain the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia.

[0071] Pharmaceutical compositions for topical administration may also be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils.

[0072] Alternatively, the formulation may be in the form of a patch (e.g., a transdermal patch) or a dressing, such as a bandage or adhesive plaster, impregnated with the active ingredient and, optionally, one or more excipients or diluents. Topical formulations may additionally contain compounds which enhance absorption or penetration of the ingredient through the skin or other affected areas, such as dimethylsulfoxidem, bisabolol, oleic acid, isopropyl myristate, D-limonene, to name a few.

[0073] For emulsions, the oily phase is composed of known ingredients in a known manner. While this phase may simply comprise an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with fats and / or oils. A hydrophilic emulsifier is preferably included together with a lipophilic emulsifier that acts as a stabilizer. The emulsifier(s) with or without stabilizer(s) constitute the so-called emulsifying wax, which together with the oils and / or fats constitute the so-called emulsifying ointment base that forms the oil-dispersed phase of the cream formulation. Exemplary emulgents and emulsion stabilizers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate.

[0074] Formulations for rectal administration are typically in the form of a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

[0075] Formulations suitable for vaginal administration generally take the form of a suppository, tampon, cream, gel, paste, foam, or spray.

[0076] Formulations suitable for nasal administration, where the carrier is a solid, include coarse powders, for example having a particle size ranging from about 20 to about 500 microns. Such formulations are typically administered by rapid inhalation through the nasal cavity, for example from a container of the powder held close to the nose. Alternatively, formulations for nasal delivery may be in the form of a liquid, for example a nasal spray or nasal drops.

[0077] The aerosolizable formulation for inhalation may be in dry powder form (e.g., suitable for administration by a dry powder inhaler), or alternatively, may be in liquid form, e.g., for use in a nebulizer. Nebulizers for delivering aerosolized solutions include AERx® (Aradigm), Ultravent® (Mallinkrodt), Acorn II® (Marquest Medical Products). The compositions of the present disclosure may also be delivered using a pressurized metered dose inhaler (MDI) (e.g., Ventolin® metered dose inhaler) that contains a solution or suspension of the drug combination as described herein in a medicamentously inert liquid propellant (e.g., chlorofluorocarbon or fluorocarbon).

[0078] Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile solutions suitable for injection, as well as aqueous and non-aqueous sterile suspensions.

[0079] The parenteral formulations of the disclosure may optionally be contained in unit-dose or multi-dose sealed containers, such as ampoules and vials, and stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, such as water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the type previously described.

[0080] The formulations of the present disclosure may also be sustained release formulations, such that each of the drug components is slowly released or absorbed over time, as compared to non-sustained release formulations. A sustained release formulation may employ a prodrug form of the active agent, a delayed release drug delivery system such as a liposome or polymer matrix, a hydrogel, or a covalent bond of a polymer such as polyethylene glycol to the active agent.

[0081] In addition to the ingredients specifically mentioned above, the formulations of the present disclosure may optionally include other agents conventional in the pharmaceutical art, and for example, the particular type of formulation used in oral dosage forms; compositions for oral administration may also include additional agents as sweeteners, thickeners, or flavoring agents.

[0082] kit Also provided herein are kits that contain at least one composition of the present disclosure and are accompanied by instructions for use.

[0083] In some embodiments, the kit contains at least one combination composition described herein and is accompanied by instructions for use.For example, when each of the drugs themselves is administered as an individual or separate dosage form, the kit contains ibudilast in addition to each of the drugs that make up the composition of the present disclosure and is accompanied by instructions for use.The drug components may be packaged in any manner suitable for administration, as long as the packaging clearly indicates how each of the drug components is administered when considered along with the instructions for administration.

[0084] For example, in the case of an exemplary kit including ibudilast and one other active agent, the kit may be organized by any suitable time period (such as by day). As an example, on day 1, a representative kit may include a unit dosage of each of ibudilast and one other active agent. If each of the drugs is administered twice a day, the kit may contain two rows of unit dosage forms of each of ibudilast and one other active agent, corresponding to day 1, along with instructions regarding the timing of administration. Alternatively, if one or more drugs have different timing or amounts of unit dosage forms administered compared to other constituent drugs of the combination, this will be reflected in the packaging and instructions. Various embodiments according to the above may be readily envisioned and will of course depend on the particular combination of drugs used in the treatment in addition to ibudilast, their corresponding dosage forms, recommended doses, intended patient population, etc. The packaging may be in any form commonly used in pharmaceutical packaging and may utilize any of a number of features, such as different colors, wrapping packaging, tamper-evident packaging, blister packaging, desiccants, etc.

[0085] While the present disclosure has been described in terms of preferred specific embodiments, it should be understood that the foregoing description as well as the following examples are intended to illustrate, and not to limit, the scope of the present disclosure. Other aspects, advantages, and modifications within the scope of the present disclosure will be apparent to those skilled in the art to which this disclosure pertains.

[0086] All references mentioned in this application, including patents, published patent applications, books, handbooks, journal publications, or the FDA Orange Book, are hereby incorporated by reference in their entirety.

[0087] The following examples are provided 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 appreciate that the present disclosure is well adapted to carry out the objects and obtain the goals and advantages mentioned, as well as those objects, goals, and advantages inherent therein. The examples, together with the methods described herein, are currently representative and exemplary of the embodiments and are not intended to limit the scope of the present disclosure. Those skilled in the art will recognize modifications in the examples and other uses that are encompassed within the spirit of the present disclosure as defined by the scope of the claims. EXAMPLES

[0088] Example 1: Ibudilast in an in vitro uveal melanoma (UM) assay

[0089] Exosome isolation. Exosomes were isolated from UM cell lines kept in serum-free medium for 24 hours. The medium was collected and subjected to successive centrifugation steps, starting with a spin at 3,000×g, to remove dead cells and cell debris. The supernatant from this step is spun at 20,000×g to pellet microvesicles and large EVs. Finally, the supernatant from this step is centrifuged at 100,000×g to pellet the exosome fraction.

[0090] Transwell migration assay. In vitro migration assays were performed in BioCoat Matrigel Invasion chambers (BD Biosciences) with 5x104 Omm1.3 cells seeded in 500μL serum-free medium. Conditioned medium from hepatocytes treated or not with UM-exosomes was used as a chemoattractant in the lower chamber. Cells were treated with vehicle (DMSO), 0.25μM crizotinib, or 25μM ibudilast for 24 hours. Migrated cells were fixed in 100% methanol and stained with 1% toluidine blue. Images of stained cells were taken through a microscope and quantified by counting cells in triplicate samples.

[0091] Wound healing assay. Omm1.3 and MP41 cells were scraped with a sterile 200 μL pipette tip. Cells were washed in PBS and replaced with fresh RPMI 1640 complete medium pretreated with UM-Exo, or hepatocyte-conditioned medium (HCM). Images of the wound area were recorded using an inverted phase contrast microscope at the indicated time points.

[0092] Diacerein, reparixin, crizotinib, and ibudilast were evaluated in migration assays. As shown in Figure 1A, most inhibitors had little or only partial effect on blocking UM cell migration into UM-exosome-stimulated hepatocyte-conditioned medium (HCM). In contrast, ibudilast dramatically inhibited cell migration. Quantification of migrating cells is summarized in Figure 1B. Furthermore, ibudilast suppressed the wound healing ability of UM cell lines Omm1.3 (Figure 1C) and MP41 (data not shown) when exposed to HCM and UM-exosomes (HCM + UM-exo).

[0093] Example 2: Ibudilast in a metastatic uveal melanoma (UM) mouse model

[0094] Mice were intravenously injected with vehicle (PBS) or 10 μg of UM exosomes isolated from 92.1 9 cells in 100 μL of PBS for 7 days. GFP-Luc-Omm1.3 cells were then injected retroorbitally into mice as described by Surriga et al. (Mol. Cancer Ther., 2013, 12:2817-26). Ibudilast was dissolved at a concentration of 1 mg / ml in saline containing 10% v / v polyoxyethylene hydrogenated castor oil 60 (HCO60). After 1 week, mice were treated daily with vehicle or 7.5 mg / kg ibudilast intraperitoneally and monitored for the development of metastases. All mice showed strong signals in the eye as the injection site. Mice were monitored weekly for luminescence using luciferin (Gold Biotechnology). After 7 weeks, livers and lungs were collected and analyzed for luminescence. Experiments were performed under Institutional Animal Care and Use Committee (IACUC)-approved protocols and followed animal guidelines for proper and humane use of animals. Statistical significance was determined by two-sample Student's t-test.

[0095] By measuring bioluminescence signal intensity only in the abdominal region, it was found that UM-exosome-treated mice developed metastases within 5 weeks after cell injection, while the metastatic signal was still not very large in the vehicle control mice. Furthermore, the exosome-educated group treated with ibudilast showed inhibition of metastatic spread. Quantification of bioluminescence over time for each group is shown in Figure 2A. Autopsy images from a representative mouse show that mice pretreated with UM-exosomes had higher bioluminescence in the lungs and liver compared to controls, and there was no bioluminescence signal in the organs of UM-exosome and ibudilast-treated animals. H&E staining of liver sections from all three cohorts verified the presence of cancer cell clusters in the vehicle-treated UM-exosome-induced mice, but not in the livers of the UM-exosome-induced mice treated with ibudilast (Figure 2B).

[0096] Specific Embodiments Embodiment 1. A method of preventing metastasis of cancer in a patient in need thereof, the method comprising: Administering to the patient a therapeutically effective amount of ibudilast or a pharmaceutical salt thereof.

[0097] Embodiment 2. A method of ameliorating cancer metastasis in a patient in need thereof, the method comprising: Administering to the patient a therapeutically effective amount of ibudilast or a pharmaceutical salt thereof.

[0098] Embodiment 3. A method of minimizing cancer metastasis in a patient in need thereof, the method comprising: Administering to the patient a therapeutically effective amount of ibudilast or a pharmaceutical salt thereof.

[0099] Embodiment 4 The method of any one of embodiments 1-3, wherein ibudilast is administered in combination with one or more additional active agents.

[0100] Embodiment 5. The method of embodiment 4, wherein the one or more additional active agents are selected from the group consisting of chemotherapy, immunotherapy, epigenetic therapy, and liver-directed therapy.

[0101] Embodiment 6. The method of embodiment 4, wherein the one or more additional active agents are selected from the group consisting of ICON-1, AU-011, dacarbazine, interferon-alpha, temozolomide, cisplatin, tamoxifen, treosulfan, fotemustine, crizotinib, ipilimumab, tremelimumab, nivolumab, pembrolizumab, atezolizumab, IMCgp100, glembatumumab, selumetinib, trametinib, sotrastaurin, LXS196, AEB071, BYL719, binimetinib, sunitinib, cabozantinib, sorafenib, carboplatin, paclitaxel, valproic acid, vorinostat, PLX51107, tumor infiltrating lymphocytes, glembatumumab vedontin, and entinostat.

[0102] Embodiment 7. The method of any one of embodiments 1-3, wherein ibudilast is administered in combination with one or more selected from the group consisting of surgery, brachytherapy, charged particle radiation therapy, laser therapy, photodynamic therapy, radiofrequency ablation, stereotactic radiotherapy, hepatic intra-arterial infusion, isolated hepatic perfusion, percutaneous hepatic perfusion, and prophylactic hepatic radiotherapy.

[0103] Embodiment 8 The method of any one of embodiments 1-7, wherein ibudilast is administered to the patient as an adjuvant therapy.

[0104] Embodiment 9. 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; b. Cancer of the respiratory tract selected from 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 mesothelioma; c. A cancer of the gastrointestinal system selected from squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma, carcinoma, leiomyosarcoma, ductal carcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma, adenocarcinoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma, adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, or leiomyoma; d. Cancer of the genitourinary tract selected from adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia, squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, adenocarcinoma, sarcoma of the prostate, seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, or lipoma; e. Cancer of the liver selected from hepatocellular carcinoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, pheochromocytoma, insulinoma, vasoactive intestinal peptide tumor, pancreatic islet cell tumor, or glucagonoma; f. Cancer of the bone selected from osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, chondrocartilaginous exostosis (osteochondral exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, or giant cell tumor; g. Nervous system cancer selected from central nervous system malignant lymphoma, osteoma, hemangioma, granuloma, xanthomas, osteitis deformans, meningioma, meningeal sarcoma, gliomatosis, astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pineal tumor), oligodendroglioma, schwannoma, retinoblastoma, congenital tumor, spinal neurofibroma, meningioma, glioma, or sarcoma; h. a 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, vulvar squamous cell carcinoma, vulvar intraepithelial carcinoma, vulvar adenocarcinoma, vulvar fibrosarcoma, vulvar melanoma, 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; i. a cancer of the blood system selected from myeloid, acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome, Hodgkin's disease, or non-Hodgkin's lymphoma; j. Cancer of the oral cavity selected from lip cancer, tongue cancer, gum cancer, floor of the mouth cancer, palate cancer, parotid gland cancer, salivary gland cancer, tonsil cancer, oropharynx cancer, nasopharyngeal cancer, pyriform sinus cancer, or hypopharyngeal cancer; k. a cancer of the skin selected from malignant melanoma, cutaneous melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, lenticular nevus, lipoma, hemangioma, dermatofibroma, or keloid carcinoma; or l. The method according to any one of embodiments 1 to 8, wherein the cancer is selected from adrenal gland cancer, neuroblastoma, cancer of connective and soft tissue, cancer of the retroperitoneum and peritoneum, eye cancer, intraocular melanoma, adnexal cancer, breast cancer, head and neck cancer, anal cancer, thyroid cancer, parathyroid cancer, adrenal gland cancer, cancer of the endocrine glands and related structures, secondary and unspecified malignant neoplasms of lymph nodes, secondary malignant neoplasms of the respiratory and digestive systems, or secondary malignant neoplasms of other sites.

[0105] Embodiment 10. The method of any one of embodiments 1-9, wherein the cancer is an eye cancer.

[0106] Embodiment 11 The method of embodiment 10, wherein the eye cancer is uveal melanoma.

[0107] Embodiment 12 The method of any one of embodiments 1-11, wherein ibudilast or a pharma- ceutically acceptable salt thereof is administered for at least 3 months.

[0108] Embodiment 13 The method of any one of embodiments 1-11, wherein ibudilast or a pharma- ceutically acceptable salt thereof is administered for at least 6 months.

[0109] Embodiment 14 The method of any one of embodiments 1-11, wherein ibudilast or a pharma- ceutically acceptable salt thereof is administered for at least one year.

[0110] Embodiment 15 The method of any one of embodiments 1-11, wherein ibudilast or a pharma- ceutically acceptable salt thereof is administered for at least two years.

[0111] Embodiment 16 The method of any one of embodiments 1-15, wherein ibudilast or a pharma- ceutically acceptable salt thereof is administered at least once daily.

[0112] Embodiment 17 The method of any one of embodiments 1-16, wherein ibudilast or a pharma- ceutically acceptable salt thereof is administered orally.

[0113] Embodiment 18. The method of any one of embodiments 1-17, wherein the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is 0.1 mg to 720 mg per day.

[0114] Embodiment 19. The method of any one of embodiments 1-17, wherein the therapeutically effective amount of ibudilast, or a pharma- ceutically acceptable salt thereof, is at least 30 mg / day.

[0115] Embodiment 20. The method of any one of embodiments 1-17, wherein the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is 30 mg to 200 mg per day.

[0116] Embodiment 21. The method of any one of embodiments 1-17, wherein the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is 60 mg to 600 mg per day.

[0117] Embodiment 22. The method of any one of embodiments 1-17, wherein the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is 100 mg to 480 mg per day.

[0118] Embodiment 23. The method of any one of embodiments 1-17, wherein the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is selected from the group consisting of 30 mg / day, 60 mg / day, 90 mg / day, 100 mg / day, 120 mg / day, 150 mg / day, 180 mg / day, 210 mg / day, 240 mg / day, 270 mg / day, 300 mg / day, 360 mg / day, 400 mg / day, 440 mg / day, 480 mg / day, 520 mg / day, 580 mg / day, 600 mg / day, 620 mg / day, 640 mg / day, 680 mg / day, and 720 mg / day.

[0119] Embodiment 24. The method of any one of embodiments 1-23, wherein the therapeutically effective amount is administered as a single dose or divided into two, three, or four doses.

[0120] Embodiment 25 The method of any one of embodiments 1-24, wherein ibudilast is administered continuously.

[0121] Equivalent Although the present disclosure has been specifically disclosed by certain embodiments and optional features, it should be understood that modifications, improvements, and variations of the present disclosure embodied herein may be utilized 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 as limitations on the scope of the present disclosure.

[0122] The present disclosure is described broadly and generically herein. Each of the narrower species and subgeneric groupings included in the general disclosure also form part of the present disclosure. This includes the general description of the present disclosure with a condition or negative limitation that removes any subject matter from the genus, regardless of whether the excised material is specifically recited herein.

[0123] Furthermore, where features or aspects of the present disclosure are described in terms of a Markush group, those skilled in the art will recognize that the present disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0124] Use of the term "or" in the claims is used to mean "and / or" unless expressly indicated to refer only to alternatives, or the alternatives are mutually exclusive, but the present disclosure supports a definition that refers only to alternatives and "and / or."

[0125] As will be understood by those skilled in the art, for all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass all possible subranges. and combinations of those subranges. Any recited range can be easily recognized as fully descriptive and allowing that same range to be broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be easily broken down into a lower third, middle third, upper third, etc. Also, as will be understood by those skilled in the art, all terms such as "up to," "at least," "greater than," "less than," etc. refer to ranges that include the recited numbers and can then be broken down into subranges as described above. Finally, as will be understood by those skilled in the art, a range includes each individual member.

[0126] Other embodiments are within the scope of the following claims.

Claims

**Claim 1** A composition for preventing, ameliorating, or minimizing the metastasis of ocular cancer in a patient in need thereof, comprising a therapeutically effective amount of ibudilast or a pharmaceutically acceptable salt thereof. **Claim 2** The composition according to claim 1, wherein the ocular cancer is uveal melanoma. **Claim 3** The composition according to claim 1 or 2, wherein ibudilast or the pharmaceutically acceptable salt thereof is administered for at least 3 months. **Claim 4** The composition according to claim 1 or 2, wherein ibudilast or the pharmaceutically acceptable salt thereof is administered for at least 6 months. **Claim 5** The composition according to claim 1 or 2, wherein ibudilast or the pharmaceutically acceptable salt thereof is administered for at least 1 year. **Claim 6** The composition according to claim 1 or 2, wherein ibudilast or the pharmaceutically acceptable salt thereof is administered for at least 2 years. **Claim 7** The composition according to claim 1 or 2, wherein ibudilast or the pharmaceutically acceptable salt thereof is administered at least once a day. **Claim 8** The composition according to claim 1 or 2, wherein ibudilast or the pharmaceutically acceptable salt thereof is administered orally. **Claim 9** The composition according to claim 1 or 2, wherein ibudilast or the pharmaceutically acceptable salt thereof is administered in an amount of 0.1 mg to 720 mg per day. **Claim 10** The composition according to claim 1 or 2, wherein ibudilast or the pharmaceutically acceptable salt thereof is administered in an amount of at least 30 mg / day. **Claim 11** The composition according to claim 1 or 2, wherein ibudilast or the pharmaceutically acceptable salt thereof is administered in an amount of 30 mg to 200 mg per day. **Claim 12** The composition according to claim 1 or 2, wherein ibudilast or the pharmaceutically acceptable salt thereof is administered in an amount of 60 mg to 600 mg per day. **Claim 13** The composition according to claim 1 or 2, wherein ibudilast or the pharmaceutically acceptable salt thereof is administered in an amount of 100 mg to 480 mg per day.

14. The composition according to claim 1 or 2, wherein ibudilast or a pharmaceutically acceptable salt thereof is administered in an amount selected from the group consisting of 30 mg / day, 60 mg / day, 90 mg / day, 100 mg / day, 120 mg / day, 150 mg / day, 180 mg / day, 210 mg / day, 240 mg / day, 270 mg / day, 300 mg / day, 360 mg / day, 400 mg / day, 440 mg / day, 480 mg / day, 520 mg / day, 580 mg / day, 600 mg / day, 620 mg / day, 640 mg / day, 680 mg / day, 720 mg / day.

15. The composition according to claim 1 or 2, wherein ibudilast or a pharmaceutically acceptable salt thereof is administered as a single dose or divided into two, three, or four doses.

16. The composition according to claim 1 or 2, wherein ibudilast or a pharmaceutically acceptable salt thereof is administered continuously.

Images