Injectable preparation of Ib illustration

Abstract

The pharmaceutical composition for injection consists of a buffered aqueous solution containing (a) about 5% w / v to about 15% w / v of sulfobutylether-β-cyclodextrin (SBE-β-CD) and about 0.05% w / v to about 0.5% w / v of ibudilast, or (b) about 5% w / v to about 25% w / v of polyoxyl castor oil and about 1% w / v to about 5% w / v of ibudilast.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of priority of U.S. Provisional Application No. 63 / 388,834, filed on July 13, 2022, the content of which is incorporated herein by reference in its entirety.

Background Art

[0002] Low - molecular - weight ibudilast (3 - isobutyryl - 2 - isopropylpyrazolo[1,5 - a]pyridine) is an inhibitor of macrophage migration inhibitory factor (MIF) (Cho et al., PNAS - USA, 2010 June 107:11313 - 8), 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 toll - like receptor - 4 (TLR4) antagonist activity (Yang et al., Cell Death and Disease (2016) 7, e2234; doi:10.1038 / cddis.2016.140). Ibudilast is well - distributed in the CNS (Sanftner et al., Xenobiotica, 2009 39:964 - 977) at clinically relevant plasma or CNS concentrations. Ibudilast selectively inhibits macrophage migration inhibitory factor (MIF) and then selectively inhibits PDE 3, 4, 10 and 11. Ibudilast also acts as a leukotriene D4 antagonist, an anti - inflammatory agent, a PAF antagonist and a vasodilator (Thompson Current Drug Reports). Ibudilast is thought to play a neuroprotective role in the mammalian central nervous system, perhaps by suppressing the activation of glial cells (Mizuno et al., Neuropharmacology 46:404 - 411, 2004).

[0003] Ibuprofen is widely used in Japan to relieve symptoms associated with ischemic stroke or bronchial asthma. In recent clinical trials, its use in the treatment of multiple sclerosis (MS), an inflammatory disease of the central nervous system, has been investigated (News.Medical.Net; Pharmaceutical News, 2 Aug. 2005). As disclosed in this publication, this clinical trial was expected to treat "relapsing-remitting MS", but progressive multiple sclerosis was not mentioned. In U.S. Patent No. 6,395,747, ibuprofen is disclosed as a treatment for multiple sclerosis, which is generally understood to mean relapsing and remitting multiple sclerosis rather than progressive multiple sclerosis. U.S. Patent Application Publication No. 20060160843 discloses ibuprofen for the treatment of intermittent and short-term pain, but this is not pain associated with progressive neurodegenerative diseases. However, U.S. Patent No. 9,314,452 discloses ibuprofen as a treatment for amyotrophic lateral sclerosis, a progressive neurodegenerative disease. Similarly, U.S. Patent No. 8,138,201 discloses ibuprofen as a treatment for primary progressive multiple sclerosis and / or secondary progressive multiple sclerosis.

[0004] In the advanced stages of the disease, patients may not be able to swallow pills, thus potentially limiting the options for drug therapy. An injectable formulation of ibuprofen would be highly desirable and would improve administration until patients can receive an oral dose of ibuprofen. The technology disclosed herein meets this need.

Prior Art Documents

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Non-Patent Literature

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Summary of the Invention

[0007] In one aspect, a pharmaceutical composition is provided herein that consists of a buffered aqueous solution containing from about 5% w / v to about 15% w / v of sulfobutyl ether-β-cyclodextrin (SBE-β-CD) and from about 0.05% w / v to about 0.5% w / v of ibudilast. In some embodiments, the buffered aqueous solution contains disodium phosphate (Na2HPO4) and sodium dihydrogen phosphate (NaH2PO4). In some embodiments, Na2HPO4 is present in the buffered aqueous solution in an amount of about 0.2% w / v, and NaH2PO4 is present in the buffered aqueous solution in an amount of about 0.06% w / v. In some embodiments, SBE-β-CD is present in the buffered aqueous solution in an amount of about 10% w / v. In some embodiments, ibudilast is present in the buffered aqueous solution in an amount of about 0.1% w / v.

[0008] In another aspect, a pharmaceutical composition is provided herein that consists of about 10% w / v of SBE-β-CD; about 0.2% w / v of disodium phosphate; about 0.06% w / v of sodium dihydrogen phosphate; about 0.1% w / v of ibudilast; and a suitable amount of water.

[0009] In another aspect, a pharmaceutical composition comprising a buffered aqueous solution containing from about 5% w / v to about 25% w / v of polyoxyl castor oil and from about 1% w / v to about 5% w / v of ibudilast is provided herein. In some embodiments, the buffered aqueous solution contains from about 10% w / v to about 20% w / v of polyoxyl castor oil. In some embodiments, the buffered aqueous solution further contains from about 20% w / v to about 60% w / v of propylene glycol. In some embodiments, propylene glycol is present in the buffered aqueous solution in an amount of about 40% w / v. In some embodiments, the polyoxyl castor oil is polyoxyl-35 castor oil. In some embodiments, the buffered aqueous solution contains disodium phosphate (Na2HPO4) and sodium dihydrogen phosphate (NaH2PO4). In some embodiments, Na2HPO4 is present in the buffered aqueous solution in an amount of about 0.2% w / v and NaH2PO4 is present in the buffered aqueous solution in an amount of about 0.06% w / v. In some embodiments, ibudilast is present in the buffered aqueous solution in an amount of about 2% w / v. In some embodiments, the pharmaceutical composition is an injectable composition.

[0010] In another aspect, a pharmaceutical composition comprising about 10% w / v of polyoxyl castor oil; about 40% w / v of propylene glycol; about 0.2% w / v of disodium phosphate; about 0.06% w / v of sodium dihydrogen phosphate; about 2% w / v of ibudilast; and a suitable amount of water is provided herein. In some embodiments, the pharmaceutical composition is an injectable composition.

[0011] In another aspect, a pharmaceutical composition comprising about 20% w / v of polyoxyl castor oil; about 0.2% w / v of disodium phosphate; about 0.06% w / v of sodium dihydrogen phosphate; about 2% w / v of ibudilast; and a suitable amount of water is provided herein. In some embodiments, the pharmaceutical composition is an injectable composition.

[0012] In another aspect, provided herein is a method of treating a neurodegenerative disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition disclosed herein. In some embodiments, the neurodegenerative disease or disorder is Alzheimer's disease, Alzheimer-type senile dementia, Pick's disease (lobar atrophy), a syndrome combining progressive dementia with other prominent neurological abnormalities, Huntington's disease, multiple system atrophy combining dementia with ataxia and / or the onset of Parkinson's disease symptoms, progressive supranuclear palsy (Steel-Richardson-Olszewski), diffuse Lewy body disease, corticodentate degeneration, Hallervorden-Spatz disease, progressive familial myoclonic epilepsy, symptoms of gradually developing postural and movement abnormalities, paralysis agitans (Parkinson's disease), striatonigral degeneration, progressive supranuclear palsy, torsion dystonia (torsion spasm; dystonia musculorum deformans), spasmodic torticollis and other restrictive dyskinesias, familial tremor, Gilles de la Tourette syndrome, progressive ataxia, cerebellar degeneration, spinocerebellar degeneration, cerebellar cortical degeneration, olivopontocerebellar atrophy (OPCA), spinocerebellar degeneration (Friedreich's ataxia and related disorders), central autonomic nervous system failure (Shy-Drager syndrome), a syndrome of muscle weakness and wasting without sensory changes (motor neuron disease), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, infantile spinal muscular atrophy (Werdnig-Hoffmann), juvenile spinal muscular atrophy (Wohlfart-Kugelberg-Welander), other forms of familial spinal muscular atrophy, primary lateral sclerosis, hereditary spastic paraplegia, a syndrome combining muscle weakness and wasting with sensory changes (progressive neuropathic muscular atrophy;Chronic familial polyneuropathy, Charcot-Marie-Tooth disease, hypertrophic interstitial polyneuropathy (Déjerine-Sottas), or various forms of chronic progressive neuropathy, progressive vision loss syndrome, retinal pigment degeneration (retinitis pigmentosa), hereditary optic atrophy (Leber's disease), Parkinson's disease and other extrapyramidal disorders, progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome), torsion dystonia (torsion spasm, dystonia musculorum deformans), focal dystonia, motor neuron disease, progressive ataxia, primary lateral sclerosis, multifocal motor neuropathy with conduction block, motor neuropathy with paraproteinemia, motor-predominant peripheral neuropathy, olivopontocerebellar atrophy, Azorean (Machado-Joseph) disease, familial progressive neurodegenerative disease, familial amyotrophic lateral sclerosis, spinal muscular atrophy, familial spastic paraparesis, hereditary biochemical disorders, multiple joint contractures, or progressive juvenile bulbar palsy (Fazio-Londe), infantile (Werdnig-Hoffmann disease), childhood onset or adolescence (Wohlfart-Kugelberg-Welander disease), degenerative cervical myelopathy, familial HTLV-1 myelopathy, isolated FSP or associated FSP, superoxide dismutase deficiency, hexosaminidase A and B deficiency, androgen receptor mutation (Kennedy syndrome), viral and prion diseases, myelopathy, progressive multifocal leukoencephalopathy, Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker disease, kuru, fatal familial insomnia, Alpers' disease, primary progressive or secondary progressive multiple sclerosis that does not relapse, relapsing-remitting multiple sclerosis, frontotemporal dementia, Wilson's disease, progressive neuropathic pain, stroke, traumatic brain injury, or ischemia caused by spinal cord injury.;

[0013] In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition disclosed herein.

[0014] In another aspect, provided herein is a method of preventing cancer metastasis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition disclosed herein.

[0015] In another aspect, provided herein is a method of ameliorating cancer metastasis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition disclosed herein.

[0016] In another aspect, provided herein is a method of minimizing cancer metastasis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition disclosed herein.

[0017] In another aspect, provided herein is a method of preventing cancer recurrence in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition disclosed herein.

[0018] In another aspect, provided herein is a method of ameliorating cancer recurrence in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition disclosed herein.

[0019] In another aspect, provided herein is a method of minimizing the risk of cancer recurrence or delaying cancer recurrence in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition disclosed herein.

[0020] In some embodiments, the cancer is: a. a circulatory system cancer selected from angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma and teratoma, cancers of the mediastinum and pleura, and hemangioma tumors; b. Cancers of the nasal cavity and middle ear, cancers of the paranasal sinuses, cancers of the larynx, cancers of the trachea, cancers of the bronchi and lungs, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), bronchiogenic carcinoma, squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma, alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroma, and mesothelioma; c. Squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma, carcinoma, ductal adenocarcinoma of the breast, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, bipoma, adenocarcinoma, carcinoid tumor, Kaposi's sarcoma, hemangioma, lipoma, neurofibroma, fibroma, tubular adenoma, villous adenoma, chondroma, and leiomyoma; d. Adenocarcinoma, Wilms tumor (nephroblastoma), lymphoma, leukemia, squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, adenocarcinoma, sarcoma of the prostate, seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, and lipoma; e. Cancers of the hepatobiliary and pancreatic systems selected from liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, pheochromocytoma, insulinoma, vasoactive intestinal peptide tumor, pancreatic islet cell tumor, pancreatic exocrine tumor, and pancreatic neuroendocrine tumor; f. Cancers of the bone selected from osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteoma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; g. Cancers of the nervous system selected from primary CNS lymphoma, osteoma, hemangioma, granuloma, xanthoma, Paget's disease of bone, meningioma, meningiosarcoma, gliosis, astrocytoma, medulloblastoma, glioma, epithelioma, germ cell tumor (pinealoma), oligodendroglioma, schwannoma, retinoblastoma, congenital tumor, spinal neurofibroma, meningioma, glioma, and sarcoma; h. A cancer of the reproductive system selected from endometrial cancer, cervical cancer, pre-tumor cervical dysplasia, ovarian cancer, serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, granulosa-theca cell tumor, Sertoli-Leydig cell tumor, undifferentiated embryonal cell tumor, malignant teratoma, squamous cell carcinoma of the vulva, intraepithelial carcinoma of the vulva, adenocarcinoma of the vulva, fibrosarcoma of the vulva, melanoma of the vulva, clear cell carcinoma of the vagina, squamous cell carcinoma of the vagina, squamous cell sarcoma of the vagina (fetal rhabdomyosarcoma), tubal placental cancer, uterine cancer, penile cancer, prostate cancer, and testicular cancer; i. A cancer of the hematological system selected from myeloid, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes, Hodgkin's disease and non-Hodgkin lymphoma; j. A cancer of the oral cavity selected from lip cancer, tongue cancer, gum cancer, cancer of the floor of the mouth, palate cancer, parotid gland cancer, salivary gland cancer, tonsil cancer, cancer of the oropharynx, cancer of the nasopharynx, nasal cavity cancer, and cancer of the hypopharynx; k. A cancer of the skin selected from malignant melanoma, cutaneous melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma and keloid carcinoma; or l. A cancer selected from adrenal cancer, neuroblastoma, cancers of connective tissue and soft tissue, cancers of the retroperitoneum and peritoneum, eye cancer, intraocular melanoma, cancers of the adnexa, breast cancer, head and neck cancer, anal cancer, thyroid cancer, parathyroid cancer, adrenal cancer, cancers of the endocrine glands and related structures, secondary and unknown malignant neoplasms of lymph nodes, secondary malignant neoplasms of the respiratory and digestive systems, and secondary malignant neoplasms of other sites.

[0021] In another aspect, provided herein is a method of treating an autoimmune disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition disclosed herein. In some embodiments, the autoimmune disorder is rheumatoid arthritis, IgA nephropathy, vascular diseases associated with kidney diseases, systemic lupus erythematosus (SLE), Wegener's granulomatosis, relapsing polychondritis, atopic dermatitis, psoriasis, sarcoidosis, Behcet's disease, Vogt-Koyanagi-Harada disease, uveitis or idiopathic pulmonary fibrosis.

[0022] In another aspect, provided herein is a method of treating a microbial infection in a subject in need of treatment for the microbial infection, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition disclosed herein. In some embodiments, the microbial infection is caused by a virus, bacterium, fungus, or any combination of two or more thereof.

[0023] In another aspect, provided herein is a method of treating sepsis and / or septic shock in a subject in need of treatment for sepsis and / or septic shock, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition disclosed herein.

[0024] In another aspect, provided herein is a method of treating severe virus-induced pneumonia in a subject in need of treatment for severe virus-induced pneumonia, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition disclosed herein. In some embodiments, the severe virus-induced pneumonia is associated with an infection by a respiratory virus. In some embodiments, the respiratory virus is selected from influenza virus, respiratory syncytial virus, coronavirus, rhinovirus, adenovirus, and parainfluenza virus. In some embodiments, the coronavirus is COVID-19.

[0025] In another aspect, a method of treating mild to severe acute respiratory distress syndrome (ARDS) in a subject in need of treatment for mild to severe acute respiratory distress syndrome (ARDS), the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition disclosed herein, wherein the subject has an end-expiratory positive pressure (PEEP) of ≧5 cm H2O; and a PaO2 / FiO2 < 300 mmHg is provided herein. In some embodiments, the subject has an end-expiratory positive pressure (PEEP) of ≧5 cm H2O; and a PaO2 / FiO2 < 200 mmHg. In some embodiments, the ARDS is associated with infection by a respiratory virus. In some embodiments, the respiratory virus is selected from influenza virus, respiratory syncytial virus, coronavirus, rhinovirus, adenovirus, and parainfluenza virus. In some embodiments, the coronavirus is COVID-19.

[0026] In another aspect, a method of treating fragile X syndrome in a subject in need of treatment for fragile X syndrome, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition disclosed herein is provided herein.

[0027] In another aspect, a method of treating acute lung injury in a subject in need of treatment for acute lung injury, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition disclosed herein is provided herein. In some embodiments, the lung injury is induced by aspiration, trauma, pancreatitis, transfusion, or inhalation of smoke or toxic chemicals. In some embodiments, the lung injury is induced by a chemical selected from chlorine, sulfur mustard gas, phosgene, lewisite, hydrogen chloride, sulfur dioxide, hydrogen sulfide, nitrogen dioxide, ammonia, hydrofluoric acid, ozone, methyl isocyanate, and combinations of two or more thereof. In some embodiments, the lung injury comprises chemical burns, pulmonary edema, laryngeal edema, lung tissue apoptosis, pneumonia, pneumonitis, bronchitis, bronchiolitis, fibrosis, acute respiratory distress syndrome, airway spasm, or combinations of two or more thereof.

Mode for Carrying Out the Invention

[0028] In the practice of the present disclosure, unless otherwise indicated, conventional methods of chemistry, biochemistry, and pharmacology are used within the skill of the art. Such techniques are well described in the literature. For example, see A.L. Lehninger, Biochemistry (Worth Publishers, Inc., current addition); Morrison and Boyd, Organic Chemistry (Allyn and Bacon, Inc., current addition); J. March, Advanced Organic Chemistry (McGraw Hill, current addition); Remington: The Science and Practice of Pharmacy, A. Gennaro, Ed., 20th Ed.; FDA’s Orange Book, Goodman & Gilman The Pharmacological Basis of Therapeutics, J. Griffith Hardman, L.L. Limbird, A. Gilman, 11th Ed., 2005, The Merck Manual, 18th edition, 2007, and The Merck Manual of Medical Information 2003.

[0029] All publications cited in this specification, including Internet articles, FDA Orange Book (available on the FDA website), books, handbooks, magazine articles, patents, and patent applications, are hereby incorporated by reference in their entirety, whether supra or infra.

[0030] Definitions Before describing the present disclosure in detail, it is to be understood that the present disclosure is not limited to a particular mode of administration, patient population, etc., and thus can be varied as will be apparent from the accompanying specification and drawings.

[0031] As used in this specification and the appended claims, it should be noted that the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a drug" includes a single drug and two or more of the same or different drugs, and reference to "an optional excipient" refers to a single optional excipient and two or more of the same or different optional excipients, etc. The term "q.s." is an abbreviation of "quantum satis" and means "as much as is sufficient".

[0032] In the description and claims of this disclosure, the following terms are used according to the definitions set forth below.

[0033] "Optional" or "optionally" means that the subsequently described circumstance may or may not occur, and as a result, the description includes both the case where the circumstance occurs and the case where it does not occur.

[0034] "Pharmaceutically acceptable excipient or carrier" optionally refers to an excipient that may be included in the compositions of the present disclosure and that does not cause significant toxicological adverse effects in a patient.

[0035] "Pharmaceutically acceptable salts" include, but are not limited to, amino acid salts, salts prepared with inorganic acids such as chlorides, sulfates, phosphates, diphosphates, bromides and nitrates, or salts prepared from any corresponding inorganic acid form of the foregoing, such as hydrochloride, etc., or salts prepared with organic acids such as malates, maleates, fumarates, tartrates, succinates, ethylsuccinates, citrates, acetates, lactates, methanesulfonates, benzoates, ascorbates, para-toluenesulfonates, palmoates, salicylates and stearates, as well as estolates, gluceptates and lactobionates. Similarly, salts containing pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium and ammonium (including substituted ammonium).

[0036] The "active molecule" or "active agent" described herein includes any agent, drug, compound, composition or mixture that provides some pharmacological, often beneficial, effects that can be demonstrated in vivo or in vitro. This includes foods, nutraceuticals, nutrients, dietary supplements, drugs, vaccines, antibodies, vitamins, and other beneficial agents. As used herein, these terms further include any physiologically or pharmacologically active substance that produces a local or systemic effect in a patient. In a specific embodiment, the active molecule or active agent may include ibudilast or a pharmaceutically acceptable salt thereof.

[0037] "Substantially" or "essentially" means almost entirely or completely, e.g., 90% or more, or 95% or more, of a given amount.

[0038] The terms "subject", "individual" or "patient" are used interchangeably herein and refer to a vertebrate, preferably a mammal. Mammals include, but are not limited to, mice, rodents, rats, monkeys, humans, livestock, dogs, cats, sports animals and pets. In some embodiments, the subject, individual or patient is human-based.

[0039] The term "pharmacologically effective amount" or "therapeutically effective amount" of a composition or agent provided herein refers to a non-toxic but sufficient amount of the composition or agent to provide a desired response such as reduction or recovery of any disease or disorder described herein. The exact amount required varies from subject to subject and depends on factors such as the species, age and general condition of the subject, the severity of the condition being treated, the particular drug(s) used, the mode of administration, etc. The appropriate "effective" amount in any individual case can be determined by one of ordinary skill in the art using routine experimentation based on the information provided herein.

[0040] The term "about" is understood by those of ordinary skill in the art and varies to some extent depending on the context in which it is used. Considering the context in which it is used, when a term that is not clear to those of ordinary skill in the art is used, "about" means plus or minus 10% of the particular term. For example, in some embodiments, it means plus or minus 5% of the particular term. A particular range is indicated herein by a numerical value preceded by the term "about". The term "about" is used herein to provide literal support for the exact number that it precedes, and for numbers that are close to or approximate the number that the term precedes. When determining whether a number is close to or approximates a specifically recited number, a number that is not described as being close to or approximate may, in the context in which it is presented, be a number that provides a substantial equivalent of the specifically recited number.

[0041] As used herein, the term "treatment" or "treating" means any treatment of a disease or condition or related disorder in a patient, including inhibition of the disease or condition, i.e., arrest or suppression of the onset of clinical symptoms. "Treatment" or "treating" also includes preventing the onset of one or more symptoms of a disease and reversing the same. For purposes of the various aspects and embodiments of the present disclosure, beneficial or desired clinical results include, but are not limited to, reduction, alleviation, or improvement of one or more symptom manifestations or negative effects of any disease or disorder described herein, improvement of one or more clinical outcomes, reduction in the degree of any disease or disorder described herein, delay or slowing of the progression of any disease or disorder described herein, improvement, alleviation, or stabilization of the condition of any disease or disorder described herein, and other beneficial results described herein.

[0042] In some aspects, the term "treating" refers to improvement of a clinical outcome. The term "clinical outcome" refers to any clinical observation or measurement related to a patient's response to treatment.

[0043] Other objects, features, and advantages of the present disclosure will become apparent from the following detailed description. However, it should be understood that the detailed description and specific examples, while indicating specific embodiments of the present disclosure, are given by way of illustration only, since various changes and modifications within the spirit and scope of the present disclosure will become apparent to those skilled in the art from this detailed description.

[0044] The use of the terms "a", "an", "the", and similar referents in the context of describing an element (especially in the context of the following claims) shall be construed to include both the singular and the plural unless otherwise indicated herein or clearly contradicted by the context. The recitation of a range of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, and each separate value is incorporated herein as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by the context. The use of any and all examples or exemplary language provided herein (e.g., "such as") is merely intended to better clarify the embodiments and is not limiting of the claims unless otherwise specifically recited. No language in this specification should be construed as indicating any non-claimed element as essential.

[0045] Injectable dosage forms of ibudilast are described herein. More particularly, the dosage form is a pharmaceutical composition comprising a buffered aqueous solution comprising (a) about 5% w / v to about 15% w / v of sulfobutylether-β-cyclodextrin (SBE-β-CD) and about 0.05% w / v to about 0.5% w / v of ibudilast, or (b) about 5% w / v to about 25% w / v of polyoxyl castor oil, and about 1% w / v to about 5% w / v of ibudilast. ibudilast

[0046] The methods of the present disclosure are based on the administration of the molecule ibudilast. Ibudilast is a small molecule drug (molecular weight 230.3) having the structure shown below.

Chemical formula

[0047] The ibudilast illustration is also found in ChemBank ID 3227, CAS number 50847-11-5, and Beilstein Handbook reference number 5-24-03-00396. Its molecular formula corresponds to C 14 H 18 N2O. 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. The trade name is KETAS (registered trademark). As referred to herein, ibudilast is meant to include any and all pharmaceutically acceptable salt forms, prodrug forms (e.g., the corresponding ketal), solvates, etc. that are suitable for use in the intended formulation for administration.

[0048] Ibudilast is an inhibitor of macrophage migration 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 also been reported to have leukotriene D4 and PAF antagonist activities. Its profile appears to be uniquely and effectively anti-inflammatory compared to other PDE inhibitors and anti-inflammatory agents. PDE catalyzes the hydrolysis of the phosphoester bond on the 3'-carbon to produce the corresponding 5'-nucleotide monophosphate. Thus, they regulate the cellular concentration of cyclic nucleotides. Since the extracellular receptors of many hormones and neurotransmitters utilize cyclic nucleotides as second messengers, PDE also regulates the cellular response to these extracellular signals. There are at least eight classes of PDE: 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); and high-affinity cGMP-specific PDE (PDE9). Ibudilast acts to suppress inflammation through its action on inflammatory cells (e.g., glial cells), resulting in the suppression of the release of both pro-inflammatory mediators and neuroactive mediators. Ibudilast may also suppress the production of pro-inflammatory cytokines (IL-1β, TNF-α) and enhance the production of anti-inflammatory cytokines (IL-4, IL-10).The related references mentioned above include the following: 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, J.E., 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 shows good CNS permeability; Sanftner et al. Xenobiotica, (2009) 39:964-977.

[0049] As described above, any reference to one or more of the drugs described herein, particularly ibudilast, where applicable, means including all possible enantiomers, racemic mixtures, prodrugs, pharmaceutically acceptable salt forms, hydrates (e.g., monohydrate, dihydrate, etc.), solvates, different physical forms (e.g., crystalline solid, amorphous solid), metabolite mixtures of enantiomers, etc.

[0050] Pharmaceutical composition In one aspect, a pharmaceutical composition is described herein that consists of a buffered aqueous solution containing about 5% w / v to about 15% w / v of sulfobutyl ether-β-cyclodextrin (SBE-β-CD) and about 0.05% w / v to about 0.5% w / v of ibudilast.

[0051] In some embodiments, the buffered aqueous solution contains about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15% w / v of SBE-β-CD. In some embodiments, the buffered aqueous solution contains about 5% w / v to about 13% w / v of SBE-β-CD, about 5% w / v to about 11% w / v of SBE-β-CD, about 8% w / v to about 15% w / v of SBE-β-CD, or about 8% w / v to about 13% w / v of SBE-β-CD.

[0052] In another aspect, a pharmaceutical composition is provided herein that consists of a buffered aqueous solution containing about 5% w / v to about 25% w / v of polyoxyl castor oil and about 1% w / v to about 5% w / v of ibudilast.

[0053] In some embodiments, the buffered aqueous solution comprises about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25% w / v of polyoxyl castor oil. In some embodiments, the buffered aqueous solution comprises from about 5% w / v to about 20% w / v of polyoxyl castor oil. In some embodiments, the buffered aqueous solution comprises from about 10% w / v to about 20% w / v of polyoxyl castor oil. In some embodiments, the buffered aqueous solution comprises from about 10% w / v to about 25% w / v of polyoxyl castor oil.

[0054] In some embodiments, the polyoxyl castor oil is polyoxyl-35 castor oil.

[0055] In some embodiments, the buffered aqueous solution further comprises from about 20% w / v to about 60% w / v of propylene glycol. This includes from about 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, or 60% w / v of propylene glycol. In some embodiments, the buffered aqueous solution further comprises from about 20% w / v to about 55% w / v, from about 20% w / v to about 50% w / v, from about 20% w / v to about 45% w / v, from about 20% w / v to about 40% w / v, from about 20% w / v to about 35% w / v, from about 20% w / v to about 30% w / v, from about 25% w / v to about 60% w / v, from about 25% w / v to about 55% w / v, from about 25% w / v to about 50% w / v, from about 25% w / v to about 45% w / v, from about 25% w / v to about 40% w / v, from about 25% w / v to about 35% w / v, from about 30% w / v to about 60% w / v, from about 30% w / v to about 55% w / v, from about 30% w / v to about 50% w / v, from about 30% w / v to about 45% w / v, or from about 30% w / v to about 40% w / v of propylene glycol.

[0056] In some embodiments, the buffered aqueous solution contains disodium phosphate (Na2HPO4) and sodium dihydrogen phosphate (NaH2PO4). In some embodiments, Na2HPO4 is present in the buffered aqueous solution in an amount of about 0.2% w / v, and NaH2PO4 is present in the buffered aqueous solution in an amount of about 0.06% w / v.

[0057] In some embodiments, ibudilast is present in the buffered aqueous solution in an amount of about 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.2%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.3%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.4%, 0.41%, 0.42%, 0.43%, 0.44%, 0.45%, 0.46%, 0.47%, 0.48%, 0.49% or 0.5% w / v (including increments therein). In some embodiments, ibudilast is present in the buffered aqueous solution in an amount of about 0.05% w / v to about 0.4% w / v, about 0.05% w / v to about 0.3% w / v, about 0.05% w / v to about 0.2% w / v, about 0.05% w / v to about 0.1% w / v, about 0.1% w / v to about 0.5% w / v, about 0.1% w / v to about 0.4% w / v, about 0.1% w / v to about 0.3% w / v or about 0.1% w / v to about 0.2% w / v.

[0058] In some embodiments, ibudilast is present in a buffered aqueous solution in an amount of about 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, or 5% w / v (including increments therein). In some embodiments, ibudilast is present in a buffered aqueous solution in an amount of about 1% w / v to about 4% w / v, about 1% w / v to about 3% w / v, about 1% w / v to about 2% w / v, about 2% w / v to about 5% w / v, about 2% w / v to about 4% w / v or about 2% w / v to about 3% w / v.

[0059] In another aspect, about 10% w / v of SBE-β-CD; about 0.2% w / v of disodium phosphate; about 0.06% w / v of sodium dihydrogen phosphate; about 0.1% w / v of ibudilast; and a suitable amount of water A pharmaceutical composition comprising, consisting essentially of, or consisting of the foregoing is described herein.

[0060] In another aspect, about 10% w / v of polyoxyl castor oil; about 40% w / v of propylene glycol; about 0.2% w / v of disodium phosphate; about 0.06% w / v of sodium dihydrogen phosphate; about 2% w / v of ibudilast; and a suitable amount of water A pharmaceutical composition comprising, consisting essentially of, or consisting of the foregoing is described herein.

[0061] In another aspect, about 20% w / v of polyoxyl castor oil; About 0.2% w / v of disodium phosphate; About 0.06% w / v of sodium dihydrogen phosphate; About 2% w / v of ibudilast; and An appropriate amount of water A pharmaceutical composition comprising, consisting essentially of, or consisting of the foregoing is described herein.

[0062] Method of treatment In another aspect, any one of the compositions described herein is used to treat any one or more of the diseases or disorders described herein. Accordingly, a method of treating one or more of the diseases or disorders described herein using a therapeutically effective amount of a composition described herein is another aspect of the disclosure.

[0063] In some embodiments, the disease or disorder is a neurodegenerative disease, a hereditary biochemical disorder, a progressive neurodegenerative disease, or a symptom thereof. Exemplary neurodegenerative diseases / disorders include Alzheimer's disease, Alzheimer's type senile dementia, or Pick's disease (lobar atrophy), multiple sclerosis, a neurodegenerative disease including a syndrome combining progressive dementia and other prominent neurological abnormalities, a progressive neurodegenerative disease including mainly the progressive neurodegenerative form of Huntington's disease, multiple system atrophy combining dementia and ataxia and / or the onset of Parkinson's disease symptoms, progressive supranuclear palsy (Steel-Richardson-Olszewski), diffuse Lewy body disease, or cortical dentate nigral degeneration, but are not limited thereto. Further subjects may be suffering from progressive neurodegenerative diseases that mainly affect young adults and children, including Hallervorden-Spatz disease and progressive familial myoclonic epilepsy, a progressive neurodegenerative disease including a syndrome of gradually developing postural and movement abnormalities, or a disease including tremor paralysis (Parkinson's disease), striatonigral degeneration, progressive supranuclear palsy, torsion dystonia (torsion spasm; dystonia musculorum deformans), spasmodic torticollis and other restricted dyskinesias, familial tremor, or Gilles de la Tourette syndrome, progressive ataxia, cerebellar degeneration or spinocerebellar degeneration, cerebellar cortical degeneration or the syndrome of olivopontocerebellar atrophy (OPCA), spinocerebellar degeneration including spinocerebellar degeneration (Friedreich's ataxia and related disorders). Neurodegenerative diseases / disorders include central autonomic nervous system failure (Shy-Drager syndrome), a syndrome of muscle weakness and wasting without sensory changes (motor neuron disease), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, infantile spinal muscular atrophy (Werdnig-Hoffmann), juvenile spinal muscular atrophy (Wohlfart-Kugelberg-Welander), or other forms of familial spinal muscular atrophy, primary lateral sclerosis or hereditary spastic paraplegia, a syndrome combining muscle weakness and wasting and sensory changes (progressive neuronal muscular atrophy; chronic familial polyneuropathy), peroneal muscular atrophy (Charcot-Marie-Tooth), hypertrophic interstitial polyneuropathy (Dejerine-Sottas), or various forms of chronic progressive polyneuropathy, a progressive neurodegenerative disease including a syndrome of progressive vision loss, but are not limited thereto.Neurodegenerative diseases / disorders include, but are not limited to, retinitis pigmentosa (RP) or hereditary optic atrophy (Leber's disease), motor neuron diseases and progressive ataxia; glaucoma; retinal detachment; sporadic progressive neurodegenerative diseases, multifocal motor neuropathy with conduction block, motor neuropathy with paraproteinemia, motor-predominant peripheral neuropathy, olivopontocerebellar atrophy, Azorean (Machado-Joseph) disease, familial progressive neurodegenerative diseases, such as familial amyotrophic lateral sclerosis, spinal muscular atrophy, familial spastic paraplegia, hereditary biochemical disorders, multiple joint contractures, or progressive juvenile bulbar palsy (Fazio-Londe). Examples of hereditary biochemical disorders are superoxide dismutase deficiency, hexosaminidase A and B deficiency, or androgen receptor mutations (Kennedy syndrome). Viral and prion diseases such as HTLV-1 associated myelopathy, progressive multifocal leukoencephalopathy, Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker disease, kuru, fatal familial insomnia, or Alpers disease may be included in progressive neurodegenerative diseases.

[0064] "Progressive neurodegenerative disease" means any neurodegenerative disease that is in a progressive state (i.e., worsening compared to a baseline level) or has such progressive characteristics. Thus, a progressive state is a worsening of symptoms over time and can be abrupt or gradual. Examples of progressive neurodegenerative diseases include Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, and progressive forms of multiple sclerosis other than relapsing / remitting multiple sclerosis.

[0065] In some embodiments, the disease or disorder is an eye disease / disorder or injury associated with a neurodegenerative disease / disorder or a neuro-ophthalmic disorder. In some embodiments, the eye disease / disorder or injury is a retinal injury. In some embodiments, the eye disease / disorder or injury is a macular injury. In some embodiments, the eye disease / disorder or injury is macular thinning. In some embodiments, the neurodegenerative disease / disorder is progressive multiple sclerosis. Exemplary neuro-ophthalmic disorders include, but are not limited to, papilledema and idiopathic intracranial hypertension (IIH); anterior ischemic optic neuropathy (AION); optic neuritis; ocular motor neuropathy; and Horner syndrome.

[0066] In some embodiments, the disease or disorder is alcohol dependence 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 higher dysphoria, moderate dysphoria, or lower dysphoria.

[0067] In some embodiments, the disease or disorder is glioblastoma, recurrent glioblastoma or related symptoms thereof. In some embodiments, the disease or disorder is glioblastoma. In some embodiments, the disease or disorder is recurrent glioblastoma.

[0068] To treat 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 refer to higher levels of EGRF in cancer patients compared to lower levels of EGFR in individuals without cancer. In some embodiments, the patient lacks heterozygosity on chromosome 10. In some embodiments, the patient exhibits chromosome 7 amplification. In some embodiments, the patient has a mutant gene selected from the group consisting of TP53, PDGFRA, IDH1, PTEN, and NF1. In some embodiments, the patient expresses NEFL, GABRA1, SYT1, or SLC12A5.

[0069] 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 the other forms of multiple sclerosis, namely SP multiple sclerosis, PR multiple sclerosis, and PP multiple sclerosis, are considered to be an aspect of the present invention. In all types of progressive MS, there is loss of function over time, regardless of relapses.

[0070] Relapsing / remitting multiple sclerosis (RRMS) is characterized by relapses (also known as exacerbations), during which new symptoms may appear and old symptoms may reappear or worsen. After a relapse, a remission period follows, during which the person recovers completely or partially from the deficits acquired during the relapse. Relapses can last for days, weeks, or months, and recovery can be slow and progressive or almost instantaneous. Most people with multiple sclerosis are initially diagnosed with the relapsing / remitting form. This is typically the case when they are in their 20s or 30s, although diagnoses are known to be quite early or late. Approximately twice as many women as men exhibit this diversity.

[0071] In "secondary progressive multiple sclerosis (SPMS)", people who initially had relapsing-remitting multiple sclerosis begin to develop a progressive worsening of neurological function, with or without relapses. After several years, many people who have experienced relapsing / remitting multiple sclerosis transition into the secondary progressive phase of the disease. This is characterized by a progressive worsening of the disease during relapses. In the early stages of secondary progressive MS, a person may still experience several relapses, but over time, these merge into the general progression. People often do not return to their previous functional levels after a relapse. People with secondary progressive MS may experience good days and bad days or good weeks and bad weeks, but there is no actual recovery except for some remission after a relapse episode. After 10 years, 50% of people with relapsing / remitting multiple sclerosis will develop secondary progression. By 25 to 30 years, this number has risen to 90%.

[0072] "Progressive relapsing multiple sclerosis (PRMS) shows a clear progression in the level of disability from the time the symptoms first begin, but is accompanied by clear relapse episodes that may or may not be associated with some recovery after an acute episode. This form of multiple sclerosis follows a course from onset to progression, interrupted by relapses. There is significant recovery immediately after a relapse, but there is a progressive worsening of symptoms during the relapse.

[0073] Primary progressive multiple sclerosis (PP multiple sclerosis) is characterized by a progressive course without remission or recurrence from the onset of the disease. There may be periods of disease activity leveling off, and as in the case of secondary progressive, there can be good days and bad days or good weeks and bad weeks. PP multiple sclerosis typically has an onset in the late 30s or early 40s, with men being as likely as women to develop it, and initial disease activity is in the spinal cord and not the brain, which is different from relapsing / remitting MS and secondary progressive MS. Primary progressive multiple sclerosis often spreads to the brain, but is less likely to damage brain regions than relapsing / remitting or secondary progressive. For example, people with primary progressive MS are less likely to develop cognitive problems.

[0074] In some embodiments, progressive multiple sclerosis is progressing beyond relapsing-remitting multiple sclerosis. In some embodiments, 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 tolerated, but no clear relapses tolerated. In some embodiments, progressive multiple sclerosis is secondary progressive multiple sclerosis. In some embodiments, secondary progressive multiple sclerosis is characterized by an initial relapsing-remitting course followed by progression, with or without occasional relapses, mild remissions, and plateaus.

[0075] In some embodiments, the disease or disorder is cancer.

[0076] In some embodiments, the disease or disorder is uveal melanoma.

[0077] 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.

[0078] In some embodiments, the disease or disorder is fragile X syndrome.

[0079] In some embodiments, the disease or disorder is an autoimmune disorder. Non-limiting examples of autoimmune disorders include rheumatoid arthritis, IgA nephropathy, vasculopathy associated with kidney disease, systemic lupus erythematosus (SLE), Wegener's granulomatosis, relapsing polychondritis, atopic dermatitis, psoriasis, sarcoidosis, Behcet's disease, Vogt-Koyanagi-Harada disease, uveitis, and idiopathic pulmonary fibrosis.

[0080] In some embodiments, the disease or disorder is a microbial infection. In some embodiments, the microbial infection is caused by a virus, a bacterium, a fungus, or any combination of two or more thereof.

[0081] In some embodiments, the disease or disorder is sepsis and / or septic shock.

[0082] In some embodiments, the disease or disorder is severe virus-induced pneumonia. In some embodiments, the severe virus-induced pneumonia is associated with an infection by a respiratory virus. In some embodiments, the respiratory virus is selected from influenza virus, respiratory syncytial virus, coronavirus, rhinovirus, adenovirus, and parainfluenza virus. In some embodiments, the coronavirus is COVID-19.

[0083] In some embodiments, the disease or disorder is mild to severe acute respiratory distress syndrome (ARDS), and the subject has an end-expiratory positive pressure (PEEP) of ≧5 cm H2O; and a PaO2 / FiO2 < 300 mmHg. In some embodiments, the subject has an end-expiratory positive pressure (PEEP) of ≧5 cm H2O; and a PaO2 / FiO2 < 200 mmHg. In some embodiments, the ARDS is associated with an infection by a respiratory virus. In some embodiments, the respiratory virus is selected from influenza virus, respiratory syncytial virus, coronavirus, rhinovirus, adenovirus, and parainfluenza virus. In some embodiments, the coronavirus is COVID-19.

[0084] In some embodiments, the disease or disorder is acute lung injury. In some embodiments, the lung injury is induced by aspiration, trauma, pancreatitis, transfusion, or inhalation of smoke or toxic chemicals. In some embodiments, the lung injury is induced by a chemical selected from chlorine, sulfur mustard gas, phosgene, lewisite, hydrogen chloride, sulfur dioxide, hydrogen sulfide, nitrogen dioxide, ammonia, hydrofluoric acid, ozone, methyl isocyanate, and combinations of two or more thereof. In some embodiments, the lung injury includes chemical burns, pulmonary edema, laryngeal edema, lung tissue apoptosis, pneumonia, pneumonitis, bronchitis, bronchiolitis, fibrosis, acute respiratory distress syndrome, airway spasm, or combinations of two or more thereof.

[0085] In some embodiments, the disease or disorder is chemically induced lung injury. In some embodiments, the lung injury is induced by a chemical selected from chlorine, sulfur mustard gas, phosgene, lewisite, hydrogen chloride, sulfur dioxide, hydrogen sulfide, nitrogen dioxide, ammonia, hydrofluoric acid, ozone, methyl isocyanate, and combinations of two or more thereof. In some embodiments, the lung injury includes chemical burns, pulmonary edema, laryngeal edema, lung tissue apoptosis, pneumonia, pneumonitis, bronchitis, bronchiolitis, fibrosis, acute respiratory distress syndrome, airway spasm, or combinations of two or more thereof.

[0086] In another aspect, any one of the compositions described herein is used in a method of preventing cancer metastasis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the composition described herein.

[0087] In another aspect, any one of the compositions described herein is used in a method of improving cancer metastasis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the composition described herein.

[0088] In another aspect, any one of the compositions described herein is used in a method for minimizing cancer metastasis in a subject in need of minimizing cancer metastasis, the method comprising administering to the subject a therapeutically effective amount of the composition described herein.

[0089] In another aspect, any one of the compositions described herein is used in a method for preventing cancer recurrence in a subject in need of preventing cancer recurrence, the method comprising administering to the subject a therapeutically effective amount of the composition described herein.

[0090] In another aspect, any one of the compositions described herein is used in a method for improving cancer recurrence in a subject in need of improving cancer recurrence, the method comprising administering to the subject a therapeutically effective amount of the composition described herein.

[0091] In another aspect, any one of the compositions described herein is used in a method for minimizing the risk of cancer recurrence or delaying cancer recurrence in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the composition described herein.

[0092] In another aspect, any one of the compositions described herein is used in a method for suppressing myeloid-derived suppressor cells (MDSC) in a patient diagnosed with cancer or suffering from cancer, the method comprising administering to the patient a therapeutically effective amount of the composition described herein.

[0093] In another aspect, any one of the compositions described herein is used in a method for reducing immunosuppression in a patient diagnosed with cancer or suffering from cancer, the method comprising administering to the patient a therapeutically effective amount of the composition described herein.

[0094] In another aspect, 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, the method comprising administering to the patient a therapeutically effective amount of the composition described herein.

[0095] In another aspect, any one of the compositions described herein is used in a method of increasing the number of CD4+ T cells in a patient diagnosed with or suffering from cancer, the method comprising administering to the patient a therapeutically effective amount of the composition described herein.

[0096] In some embodiments, the cancer is a circulatory system cancer selected from angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma and teratoma, cancers of the mediastinum and pleura, and hemangioma; cancers of the airway selected from cancers of the nasal cavity and middle ear, cancers of the paranasal sinuses, cancers of the larynx, cancers of the trachea, cancers of the bronchi and lungs, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), bronchiogenic carcinoma, squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma, alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroma, and mesothelioma; cancers of the gastrointestinal system selected from squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma, carcinoma, leiomyosarcoma, ductal adenocarcinoma of the breast, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, bipoma, adenocarcinoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma, adenocarcinoma, tubular adenoma, villous adenoma, chondroma and leiomyosarcoma; cancers of the urogenital 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, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, and lipoma; cancers of the hepatobiliary and pancreatic systems selected from liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, pheochromocytoma, insulinoma, vasoactive intestinal peptide tumor, pancreatic islet cell tumor (e.g., adenocarcinoma, acinar cell carcinoma, intraductal papillary mucinous neoplasm, mucinous cystic neoplasm with invasive adenocarcinoma) and pancreatic neuroendocrine tumor (e.g., gastrinoma, glucagonoma, insulinoma, somatostatinoma, VIPoma (vasoactive intestinal peptide), non-functional pancreatic islet cell tumor); cancers 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, osteoma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumor;A cancer of the nervous system selected from primary CNS lymphoma, osteoma, hemangioma, granuloma, xanthoma, Paget's disease of bone, meningioma, meningosarcoma, gliosis, astrocytoma, medulloblastoma, glioma, epithelioma, germ cell tumor (pinealoma), oligodendroglioma, schwannoma, retinoblastoma, congenital tumor, spinal neurofibroma, meningioma, glioma, and sarcoma; a cancer of the reproductive system selected from endometrial cancer, cervical cancer, pre-cancerous cervical dysplasia, ovarian cancer, serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, granulosa-theca cell tumor, Sertoli-Leydig cell tumor, undifferentiated germ cell tumor, malignant teratoma, squamous cell carcinoma of the vulva, intraepithelial carcinoma of the vulva, adenocarcinoma of the vulva, fibrosarcoma of the vulva, melanoma of the vulva, clear cell carcinoma of the vagina, squamous cell carcinoma of the vagina, squamous cell sarcoma of the vagina (fetal rhabdomyosarcoma), placental cancer of the fallopian tube, uterine cancer, penile cancer, prostate cancer, and testicular cancer; a cancer of the hematopoietic system selected from myeloid, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes, Hodgkin's disease and non-Hodgkin lymphoma; a cancer of the oral cavity selected from lip cancer, tongue cancer, gingival cancer, cancer of the floor of the mouth, palate cancer, parotid gland cancer, salivary gland cancer, tonsil cancer, cancer of the oropharynx, cancer of the nasopharynx, nasal cavity cancer, and cancer of the hypopharynx; a cancer of the skin selected from malignant melanoma, cutaneous melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma and keroid carcinoma; or a cancer selected from adrenal cancer, neuroblastoma, cancer of connective tissue and soft tissue, cancer of the retroperitoneum and peritoneum, eye cancer, intraocular melanoma, uveal melanoma, cancer of the adnexa, breast cancer, head and neck cancer, anal cancer, thyroid cancer, parathyroid cancer, adrenal cancer, cancer of the endocrine glands and related structures, secondary and unknown malignant neoplasms of lymph nodes, secondary malignant neoplasms of the respiratory and digestive systems, and secondary malignant neoplasms of other sites. In some embodiments, the cancer is glioblastoma multiforme (GBM). In some embodiments, the cancer is not glioblastoma multiforme (GBM).;

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

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

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

[0100] In another aspect, any one of the compositions described herein is a method for increasing the number of CD4+ T cells in a patient diagnosed with or suffering from a microbial infection, the method comprising administering to the patient a therapeutically effective amount of the composition described herein and is used in the method.

[0101] In another aspect, any one of the compositions described herein is a method for suppressing myeloid-derived suppressor cells (MDSC) in a patient diagnosed with or suffering from sepsis, the method comprising administering to the patient a therapeutically effective amount of the composition described herein and is used in the method.

[0102] In another aspect, any one of the compositions described herein is a method for reducing immunosuppression in a patient diagnosed with or suffering from sepsis, the method comprising administering to the patient a therapeutically effective amount of the composition described herein and is used in the method.

[0103] In another aspect, 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, the method comprising administering to the patient a therapeutically effective amount of the composition described herein.

[0104] In another aspect, any one of the compositions described herein is used in a method of increasing the number of CD4+ T cells in a patient diagnosed with or suffering from sepsis, the method comprising administering to the patient a therapeutically effective amount of the composition described herein.

[0105] Route of Administration In another aspect, the present disclosure is directed to injectable administration of ibudilast or a pharmaceutically acceptable salt thereof. In some embodiments, the injectable administration is intravenous administration. In some embodiments, the intravenous administration provides an infusion of ibudilast or a pharmaceutically acceptable salt thereof. In some embodiments, the intravenous administration provides a bolus of ibudilast or a pharmaceutically acceptable salt thereof. In some embodiments, the injectable administration is subcutaneous, intramuscular, intrathecal, intraperitoneal or intraocular injection.

[0106] Dosage The therapeutic amount can be determined empirically and will vary depending on the particular condition being treated, the subject, and the effectiveness and toxicity of each active agent contained in the composition. The actual dosage administered will vary depending on the age, weight and general condition of the subject, the severity of the condition being treated, the judgment of the medical professional, and the particular combination being administered.

[0107] The therapeutically effective amount can be determined by one of ordinary skill in the art and adjusted to meet the requirements of each particular case. Generally, the therapeutically effective amount of ibudilast or a pharmaceutically acceptable salt thereof will be in the approximate range from the total daily dose.

[0108] In some embodiments, a therapeutically effective amount of ibudilast or a pharmaceutically 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, a therapeutically effective amount of ibudilast or a pharmaceutically acceptable salt thereof is at least about 50 mg.

[0109] In some embodiments, the therapeutically effective amount of ibudilast or a pharmaceutically acceptable salt thereof is from 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 20 mg, 10 mg to about 30 mg, 10 mg to about 40 mg, 10 mg to about 50 mg, 10 mg to about 60 mg, 10 mg to about 70 mg, 10 mg to about 80 mg, 10 mg to about 90 mg, 10 mg to about 100 mg, 10 mg to about 150 mg, 10 mg to about 200 mg, 20 mg to about 30 mg, 20 mg to about 40 mg, 20 mg to about 50 mg, 20 mg to about 60 mg, 20 mg to about 70 mg, 20 mg to about 80 mg, 20 mg to about 90 mg, 20 mg to about 100 mg, 20 mg to about 250 mg, 20 mg to about 200 mg, 30 mg to about 40 mg, 30 mg to about 50 mg, 30 mg to about 60 mg, 30 mg to about 70 mg, 30 mg to about 80 mg, 30 mg to about 90 mg, 30 mg to about 100 mg, 30 mg to about 250 mg, 30 mg to about 200 mg, 40 mg to 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 pharmaceutically acceptable salt thereof is from about 10 mg to about 100 mg.

[0110] In some embodiments, the therapeutically effective amount of ibudilast or a pharmaceutically 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 pharmaceutically acceptable salt thereof is about 50 mg.

[0111] In some embodiments, the therapeutically effective amount of ibudilast or a pharmaceutically 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 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 pharmaceutically acceptable salt thereof is at least about 50 mg / day.

[0112] In some embodiments, the therapeutically effective amount of ibudilast or a pharmaceutically 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, 10 mg / day to about 30 mg / day, 10 mg / day to about 40 mg / day, 10 mg / day to about 50 mg / day, 10 mg / day to about 60 mg / day, 10 mg / day to about 70 mg / day, 10 mg / day to about 80 mg / day, 10 mg / day to about 90 mg / day, 10 mg / day to about 100 mg / day, 10 mg / day to about 150 mg / day, 10 mg / day to about 200 mg / day, 20 mg / day to about 30 mg / day, 20 mg / day to about 40 mg / day, 20 mg / day to about 50 mg / day, 20 mg / day to about 60 mg / day, 20 mg / day to about 70 mg / day, 20 mg / day to about 80 mg / day, 20 mg / day to about 90 mg / day, 20 mg / day to about 100 mg / day, 20 mg / day to about 250 mg / day, 20 mg / day to about 200 mg / day, 30 mg / day to about 40 mg / day, 30 mg / day to about 50 mg / day, 30 mg / day to about 60 mg / day, 30 mg / day to about 70 mg / day, 30 mg / day to about 80 mg / day, 30 mg / day to about 90 mg / day, 30 mg / day to about 100 mg / day, 30 mg / day to about 250 mg / day, 30 mg / day to about 200 mg / day, 40 mg / day to about 50 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 pharmaceutically acceptable salt thereof is from about 10 mg / day to about 100 mg / day.

[0113] In some embodiments, a therapeutically effective amount of ibudilast or a pharmaceutically 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, a therapeutically effective amount of ibudilast or a pharmaceutically acceptable salt thereof is about 50 mg / day.

[0114] Depending on the dosage and the exact condition being treated, administration can be once, twice, three times, or four times daily over a period of one day to several days, weeks, months, or even years, and can even be over the patient's lifetime. Exemplary dosing regimens continue 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 for a period of at least about 12, 24, 36, 48, 60, 72, 84, or 96 weeks. In some embodiments, the dosing regimen is for a period of about 12, 24, 36, 48, 60, 72, 84, or 96 weeks. In some embodiments, the dosing regimen is for a period of at least about 1 year, 2 years, 3 years, 4 years or 5 years. In some embodiments, the dosing regimen is for a period of about 1 year, 2 years, 3 years, 4 years or 5 years.

[0115] In fact, the unit dose of any given composition or active agent of the present disclosure can be administered according to various dosing schedules depending on the judgment of the clinician, the needs of the patient, etc. Specific dosing schedules are known to those skilled in the art or can be determined experimentally using routine methods. Exemplary dosing schedules include, but are not limited to, administration 5 times a day, 4 times a day, 3 times a day, 2 times a day, 1 time a day, every other day, 3 times a week, 2 times a week, 1 time a week, 2 times a month, 1 time a month, etc.

[0116] 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 a pharmaceutically acceptable salt thereof. In some embodiments, one or more other therapeutic agents have a mechanism of action different from that of ibudilast. Such active ingredients can be found in the FDA’s Orange Book, Goodman&Gilman The Pharmacological Basis of Therapeutics, J.Griffith Hardman, L.L.Limbird, A.Gilman, 11th Ed., 2005, The Merck Manual, 18th edition, 2007, and The Merck Manual of Medical Information 2003.

[0117] Kit Also provided herein is a kit containing any one of the compositions of the present disclosure and accompanied by instructions for use.

[0118] For example, the kit includes ibudilast or a pharmaceutically acceptable salt thereof together with instructions for use. Ibudilast or a pharmaceutically acceptable salt thereof can be packaged in any suitable manner for administration as long as the packaging clearly indicates the manner in which the drug component is to be administered when considered together with the instructions for administration.

[0119] For example, in an exemplary kit containing ibudilast or a pharmaceutically acceptable salt thereof, the kit can be formulated for any suitable period, for example, daily. As an example, on the first day, a representative kit can include the respective unit dosages of ibudilast or a pharmaceutically acceptable salt thereof. When each drug is administered twice daily, corresponding to the first day, two columns of unit dosage forms of ibudilast or a pharmaceutically acceptable salt thereof can be included in the kit together with instructions regarding the timing of administration. Alternatively, if ibudilast or a pharmaceutically acceptable salt thereof differs in terms of the timing or amount of administration, this will be reflected in the packaging and instructions. Various embodiments as described above can be easily envisioned, which will of course depend on, in addition to ibudilast or a pharmaceutically acceptable salt thereof used for treatment, the specific combination of drugs, their corresponding dosage forms, the recommended dosages, the intended patient population, etc. The packaging can be in any form commonly used for pharmaceutical packaging and can utilize any of several features such as different colors, wrapping, tamper-proof packaging, blister packs, desiccants, etc.

[0120] The present disclosure has been described in conjunction with preferred specific embodiments, but it should be understood that the foregoing description and the following examples are intended to illustrate rather than 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 the present disclosure pertains.

Example

[0121] Example 1. Initial Solubility Screening Using Various Excipients

[0122] The solubility of ibudilast was evaluated using the excipients shown in the following table.

Table 1

[0123] Example 2. Follow-up solubility evaluation

[0124] The solubility of ibudilast was evaluated using co-solvent mixtures with and without water, increased surfactant concentrations, or combinations of surfactants and co-solvents as shown in the following table.

Table 2

[0125] Example 3. Solution screening, Part 1

[0126] Based on the results of the initial solubility screening and follow-up solubility evaluation, seven formulation concepts were evaluated. All seven concepts targeted pH 7.5 and contained 25 mg / mL of ibudilast and 15 mM of sodium phosphate buffer. · Concept 1: Propylene glycol (500 mg / mL), ethanol (250 mg / mL), Na2HPO4·2H2O (1.9941 mg / mL), NaH2PO4·2H2O (0.5923 mg / mL), ibudilast (25 mg / mL), water (q.s. 1 mL) · Concept 2: Ethanol (250 mg / mL), glycerol (150 mg / mL), PEG 400 (150 mg / mL), Na2HPO4·2H2O (1.9941 mg / mL), NaH2PO4·2H2O (0.5923 mg / mL), ibudilast (25 mg / mL), water (q.s. 1 mL) · Concept 3: Propylene glycol (400 mg / mL), glycerol (150 mg / mL), PEG 400 (250 mg / mL), Na2HPO4·2H2O (1.9941 mg / mL), NaH2PO4·2H2O (0.5923 mg / mL), ibudilast (25 mg / mL), water (q.s. 1 mL) ·Concept 4: Kolliphor ELP (250 mg / mL), Na2HPO4·2H2O (1.9941 mg / mL), NaH2PO4·2H2O (0.5923 mg / mL), ibudilast (25 mg / mL), water (q.s. 1 mL) ·Concept 5: Montanox 80 (300 mg / mL), Na2HPO4·2H2O (1.9941 mg / mL), NaH2PO4·2H2O (0.5923 mg / mL), ibudilast (25 mg / mL), water (q.s. 1 mL) ·Concept 6: Propylene glycol (500 mg / mL), glycerol (100 mg / mL), Kolliphor ELP (100 mg / mL), Na2HPO4·2H2O (1.9941 mg / mL), NaH2PO4·2H2O (0.5923 mg / mL), ibudilast (25 mg / mL), water (q.s. 1 mL) ·Concept 7: Propylene glycol (500 mg / mL), glycerol (100 mg / mL), Montanox 80 (100 mg / mL), Na2HPO4·2H2O (1.9941 mg / mL), NaH2PO4·2H2O (0.5923 mg / mL), ibudilast (25 mg / mL), water (q.s. 1 mL)

[0127] Each solution was prepared on a 50 mL scale using a volumetric flask. Before adding ibudilast, the medium was transferred to a beaker for better homogenization. After ibudilast solubilization, the solution was returned to the volumetric flask and water was added to obtain the final volume. The final solution was divided into two 20 mL vials for follow-up over several days at room temperature or 2 - 8°C. A dilution test was performed with 0.9% NaCl solution (2 mL of the concept formulation diluted with 50 or 100 mL of the saline solution). Concepts 1, 2, and 3 were also formulated without buffer to evaluate the effect of the buffer on solubility.

[0128] Concept 1 (with buffer), Concept 2 (with buffer), Concept 3 (with or without buffer), and Concept 5 demonstrated solubility problems during formulation preparation. The remaining concepts were presented for dilution testing. Concepts 4 and 6 showed clear solutions after dilution with 50 and 100 mL of saline; the other concepts (Concept 1 without buffer, Concept 2 without buffer, and Concept 7) showed solubility problems after the dilution test.

[0129] Example 4. Solution Screening, Part 2

[0130] Based on the results of the solution screening, in Part 1, Concepts 4 and 6 investigated the potential effects of the buffer more thoroughly. Additional concepts (8A, 8B, 9, 10, 11, 12, 13) containing surfactants were also investigated regardless of the presence or absence of alternative solvents and buffers. · Concept 4A: Kolliphor ELP (250 mg / mL), Na2HPO4·2H2O (1.9941 mg / mL), NaH2PO4·2H2O (0.5923 mg / mL), ibudilast (25 mg / mL), water (q.s. 1 mL) · Concept 4B: Kolliphor ELP (250 mg / mL), ibudilast (25 mg / mL), water (q.s. 1 mL) · Concept 6A: Propylene glycol (500 mg / mL), glycerol (100 mg / mL), Kolliphor ELP (100 mg / mL), Na2HPO4·2H2O (1.9941 mg / mL), NaH2PO4·2H2O (0.5923 mg / mL), ibudilast (25 mg / mL), water (q.s. 1 mL) · Concept 6B: Propylene glycol (500 mg / mL), glycerol (100 mg / mL), Kolliphor ELP (100 mg / mL), ibudilast (25 mg / mL), water (q.s. 1 mL) · Concept 8A: Ethanol (100 mg / mL), Kolliphor ELP (250 mg / mL), Na2HPO4·2H2O (1.9941 mg / mL), NaH2PO4·2H2O (0.5923 mg / mL), ibudilast (25 mg / mL), water (q.s. 1 mL) · Concept 8B: Ethanol (100 mg / mL), Kolliphor ELP (250 mg / mL), Na2HPO4·2H2O (1.9941 mg / mL), NaH2PO4·2H2O (0.5923 mg / mL), Ibudilast (25 mg / mL), Water (q.s. 1 mL) · Concept 9: Kolliphor ELP (200 mg / mL), Na2HPO4·2H2O (1.9941 mg / mL), NaH2PO4·2H2O (0.5923 mg / mL), Ibudilast (20 mg / mL), Water (q.s. 1 mL) · Concept 10: Kolliphor ELP (100 mg / mL), Na2HPO4·2H2O (1.9941 mg / mL), NaH2PO4·2H2O (0.5923 mg / mL), Ibudilast (10 mg / mL), Water (q.s. 1 mL) · Concept 11: Propylene Glycol (500 mg / mL), Kolliphor ELP (100 mg / mL), Na2HPO4·2H2O (1.9941 mg / mL), NaH2PO4·2H2O (0.5923 mg / mL), Ibudilast (20 mg / mL), Water (q.s. 1 mL) · Concept 12: Propylene Glycol (500 mg / mL), Kolliphor ELP (50 mg / mL), Na2HPO4·2H2O (1.9941 mg / mL), NaH2PO4·2H2O (0.5923 mg / mL), Ibudilast (10 mg / mL), Water (q.s. 1 mL) · Concept 13: Propylene Glycol (400 mg / mL), Kolliphor ELP (100 mg / mL), Na2HPO4·2H2O (1.9941 mg / mL), NaH2PO4·2H2O (0.5923 mg / mL), Ibudilast (20 mg / mL), Water (q.s. 1 mL)

[0131] Regarding Concepts 9 and 10 on a 50 mL scale: Kolliphor ELP was melted at 55 °C and then weighed into a beaker. Ibuprofen was added to both Concepts 9 and 10 under magnetic stirring for 1.5 hours. Heated water (40 °C) was added to obtain a viscous solution for Concept 9, while homogenization occurred for Concept 10 only after 10 minutes. A buffer solution was added under magnetic stirring until complete homogenization for Concept 9 (1.5 hours) and Concept 10 (10 minutes). After transferring the solution to each volumetric flask, additional water was added at room temperature to bring the final volume to the mark.

[0132] Regarding Concepts 11, 12, and 13 on a 50 mL scale: Kolliphor ELP was melted at 55 °C and then weighed into a beaker. Propylene glycol was added to the beaker and homogenized for several minutes under magnetic stirring to obtain a milky white solution. Ibuprofen was added to Concepts 11 (1 hour, milky white solution), 12 (1 hour, milky white solution), and 13 (1.5 hours, milky white solution) under magnetic stirring. A buffer solution was added under magnetic stirring at room temperature until complete homogenization for Concepts 11, 12, and 13 (10 minutes each). After transferring the solution to each volumetric flask, additional water was added at room temperature to bring the final volume to the mark.

[0133] When using Kolliphor ELP in up to 25% water, a very viscous gel was obtained and solubilization took time. Concept 11 had a high viscosity (14.65 mPa s) at t = 0, making filtration difficult. The viscosity values for Concepts 9, 10, 12, and 13 were lower at t = 0: 7.33 mPa s (Concept 9), 2.12 mPa s (Concept 10), 6.60 mPa s (Concept 12), and 9.66 mPa s (Concept 13). Concept 10 was slightly milky at t = 0 and t = 20 hours, while Concepts 9, 11, 12, and 13 were clear solutions at t = 0 and t = 20 hours.

[0134] The formulations of Concepts 9 - 13 without buffer were also evaluated. Concepts 11 - 13 without buffer had some precipitate remaining and exhibited a milky white color that dissolved upon heating.

[0135] Concepts 9 and 13, each containing 20 mg / mL of ibudilast, were investigated in further stability studies. The buffer solutions showed better pH stability (change less than 0.4 pH units) over 10 days at various temperatures (2 - 8°C or 60°C) than the non - buffered counterparts (change up to 2 pH units). Coagulation / precipitation was also observed for Concept 9 at t = 10 days (60°C). The 3 - week stability test demonstrated similar results.

[0136] Example 5. Solution Screening, Part 3

[0137] Additional aqueous formulations were evaluated. · Concept 14: SBE - β - CD (100 mg / mL), ibudilast (1 mg / mL), water (q.s. 1 mL) · Concept 15: SBE - β - CD (100 mg / mL), Na2HPO4·2H2O (2.0284 mg / mL), NaH2PO4·2H2O (0.5622 mg / mL), ibudilast (1 mg / mL), water (q.s. 1 mL) · Concept 16: Propylene glycol (3 mg / mL), ethanol (80 mg / mL), ibudilast (1 mg / mL), water (q.s. 1 mL) · Concept 17: PEG 400 (100 mg / mL), ethanol (50 mg / mL), ibudilast (1 mg / mL), water (q.s. 1 mL) · Concept 18: PEG 400 (100 mg / mL), ethanol (30 mg / mL), ibudilast (1 mg / mL), water (q.s. 1 mL) · Concept 19: PEG 400 (100 mg / mL), ethanol (80 mg / mL), ibudilast (1 mg / mL), water (q.s. 1 mL) · Concept 20: PEG 400 (100 mg / mL), ethanol (100 mg / mL), ibudilast (1 mg / mL), water (q.s. 1 mL) · Concept 21: PEG 400 (75 mg / mL), ethanol (100 mg / mL), ibudilast (1 mg / mL), water (q.s. 1 mL) · Concept 22: PEG 400 (150 mg / mL), ethanol (80 mg / mL), ibudilast (1 mg / mL), water (q.s. 1 mL) ·Concept 23: PEG 400 (150 mg / mL), ethanol (50 mg / mL), ibudilast (1 mg / mL), water (q.s. 1 mL) ·Concept 24: PEG 400 (150 mg / mL), ethanol (100 mg / mL), ibudilast (1 mg / mL), water (q.s. 1 mL) ·Concept 25: PEG 400 (100 mg / mL), ethanol (100 mg / mL), Na2HPO4·2H2O (2.0284 mg / mL), NaH2PO4·2H2O (0.5622 mg / mL), ibudilast (1 mg / mL), water (q.s. 1 mL) ·Concept 26: PEG 400 (150 mg / mL), ethanol (100 mg / mL), Na2HPO4·2H2O (2.0284 mg / mL), NaH2PO4·2H2O (0.5622 mg / mL), ibudilast (1 mg / mL), water (q.s. 1 mL) ·Concept 27: PEG 400 (75 mg / mL), ethanol (100 mg / mL), Na2HPO4·2H2O (2.0284 mg / mL), NaH2PO4·2H2O (0.5622 mg / mL), ibudilast (1 mg / mL), water (q.s. 1 mL)

[0138] All concepts were stored for follow-up at RT and 2 - 8°C using a clear solution at T0. Only four concepts remained clear solutions after 48 hours and 7 days at both storage temperatures: two concepts prepared with 10% SBE-β-CD (Concept 15 buffered and Concept 14 unbuffered), and two concepts formulated with 10% EtOH and 15% PEG 400 (Concept 26 buffered and Concept 24 unbuffered). All other concepts began to precipitate after 24 hours or 48 hours of storage at 2 - 8°C. The pH values of Concepts 14, 15, 24, and 26 were all between 6.3 and 8, and the buffered versions had pH values closer to the target pH of the injectable product (around 7.5).

[0139] With respect to weight osmolality, the two concepts prepared using SBE-β-CD were near isotonicity, with values of 267 mOsm / kg for the non-buffered one (Concept 14) and 302 mOsm / kg for the buffered one (Concept 15). The weight osmolality values were higher for the concepts using the PEG 400 / ethanol co-solvent.

[0140] Concepts 14, 15, and 24 were further evaluated in short stress studies to assess the physical and chemical stability during storage under different conditions (i.e., 2 - 8 °C, 25 °C / 60% RH, 40 °C / 75% RH, and 60 °C) over a 4-week period. Preliminary shear stress studies and freeze / thaw studies were also conducted. Concept 15 was superior to Concepts 14 and 24.

[0141] Example 6. Phase 1, single-dose, safety, tolerability, and pharmacokinetic study to investigate the absorption rate and extent of absorption of an ibudilast sustained-release oral or parenteral formulation in healthy volunteers

[0142] Subjects participated in two different parts of this study: · Part A was a crossover, non-blind, single-site, Phase 1 study in 12 healthy volunteers. Subjects who met the study eligibility criteria and provided informed consent were randomized into two sequences according to one of the following treatments in Part A.

Table 3

[0143] During each dosing procedure, the subjects checked into the research facility the night before dosing and stayed at the facility until 32 hours after dosing. The subjects returned to the research facility for outpatient visits on each of the remaining PK sampling days (48, 72, 96, and 168 hours after treatment). The subjects were released from the study 168 hours after the start of the study drug infusion.

[0144] In each treatment, blood samples (approximately 2 mL per sample) were collected before dosing and at 0.5, 1, 2 (end of infusion), 4, 6, 8, 10, 12, 24, 32, 48, 72, 96, and 168 hours after the start of infusion. The blood samples were assayed for ibudilast using a validated liquid chromatography / tandem mass spectrometry (LC / MS / MS) method.

[0145] The pharmacokinetic data for intravenous injection were as follows:

Table 4

[0146] The pharmacokinetic data for the intermediate release capsule (single dose of 50 mg) were as follows:

Table 5

[0147] Certain embodiments

[0148] Embodiment 1. A pharmaceutical composition comprising a buffered aqueous solution containing about 5% w / v to about 15% w / v of sulfobutyl ether-β-cyclodextrin (SBE-β-CD) and about 0.05% w / v to about 0.5% w / v of ibudilast.

[0149] Embodiment 2. The pharmaceutical composition according to Embodiment 1, wherein the buffered aqueous solution contains disodium phosphate (Na2HPO4) and sodium dihydrogen phosphate (NaH2PO4).

[0150] Embodiment 3. The pharmaceutical composition according to Embodiment 2, wherein Na2HPO4 is present in a buffer aqueous solution in an amount of about 0.2% w / v and NaH2PO4 is present in a buffer aqueous solution in an amount of about 0.06% w / v.

[0151] Embodiment 4. The pharmaceutical composition according to any one of Embodiments 1 to 3, wherein SBE-β-CD is present in a buffer aqueous solution in an amount of about 10% w / v.

[0152] Embodiment 5. The pharmaceutical composition according to any one of Embodiments 1 to 4, wherein ibudilast is present in a buffer aqueous solution in an amount of about 0.1% w / v.

[0153] Embodiment 6. About 10% w / v of SBE-β-CD; About 0.2% w / v of disodium phosphate; About 0.06% w / v of sodium dihydrogen phosphate; About 0.1% w / v of ibudilast; and An appropriate amount of water A pharmaceutical composition comprising.

[0154] Embodiment 7. A pharmaceutical composition comprising a buffer aqueous solution containing about 5% w / v to about 25% w / v of polyoxyl castor oil and about 1% w / v to about 5% w / v of ibudilast.

[0155] Embodiment 8. The pharmaceutical composition according to Embodiment 7, wherein the buffer aqueous solution contains about 10% w / v to about 20% w / v of polyoxyl castor oil.

[0156] Embodiment 9. The pharmaceutical composition according to Embodiment 7 or Embodiment 8, wherein the buffer aqueous solution further contains about 20% w / v to about 60% w / v of propylene glycol.

[0157] Embodiment 10. The pharmaceutical composition according to Embodiment 9, wherein propylene glycol is present in a buffer aqueous solution in an amount of about 40% w / v.

[0158] Embodiment 11. The pharmaceutical composition according to any one of Embodiments 7 to 10, wherein the polyoxyl castor oil is polyoxyl-35 castor oil.

[0159] Embodiment 12. The pharmaceutical composition according to any one of Embodiments 7 to 11, wherein the buffer aqueous solution contains disodium phosphate (Na2HPO4) and sodium dihydrogen phosphate (NaH2PO4).

[0160] Embodiment 13. The pharmaceutical composition according to Embodiment 12, wherein Na2HPO4 is present in the buffer aqueous solution in an amount of about 0.2% w / v and NaH2PO4 is present in the buffer aqueous solution in an amount of about 0.06% w / v.

[0161] Embodiment 14. The pharmaceutical composition according to any one of Embodiments 7 to 13, wherein ibudilast is present in the buffer aqueous solution in an amount of about 2% w / v.

[0162] Embodiment 15. About 10% w / v of polyoxyl castor oil; About 40% w / v of propylene glycol; About 0.2% w / v of disodium phosphate; About 0.06% w / v of sodium dihydrogen phosphate; About 2% w / v of ibudilast; and An appropriate amount of water A pharmaceutical composition comprising the above.

[0163] Embodiment 16. About 20% w / v of polyoxyl castor oil; About 0.2% w / v of disodium phosphate; About 0.06% w / v of sodium dihydrogen phosphate; About 2% w / v of ibudilast; and An appropriate amount of water A pharmaceutical composition comprising the above.

[0164] Embodiment 17. The pharmaceutical composition according to any one of Embodiments 1 to 16, which is an injectable composition.

[0165] Embodiment 18. A method for treating a neurodegenerative disease or disorder in a subject in need of treatment for a neurodegenerative disease or disorder, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition according to any one of Embodiments 1 to 17.

[0166] Embodiment 19. The neurodegenerative disease or disorder is Alzheimer's disease, Alzheimer's type senile dementia, Pick's disease (lobar atrophy), a syndrome combining progressive dementia with other prominent neurological abnormalities, Huntington's disease, multiple system atrophy combining dementia with the onset of ataxia and / or Parkinson's disease symptoms, progressive supranuclear palsy (Steel-Richardson-Olszewski), diffuse Lewy body disease, corticodentate degeneration, Hallervorden-Spatz disease, progressive familial myoclonic epilepsy, symptoms of gradually developing postural and movement abnormalities, paralysis agitans (Parkinson's disease), striatonigral degeneration, progressive supranuclear palsy, torsion dystonia (torsion spasm; dystonia musculorum deformans), spasmodic torticollis and other restrictive dyskinesias, essential tremor, Gilles de la Tourette syndrome, progressive ataxia, cerebellar degeneration, spinocerebellar degeneration, cerebellar cortical degeneration, olivopontocerebellar atrophy (OPCA), spinocerebellar degeneration (Friedreich's ataxia and related disorders), central autonomic nervous system failure (Shy-Drager syndrome), a syndrome of muscle weakness and wasting without sensory changes (motor neuron disease), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, infantile spinal muscular atrophy (Werdnig-Hoffmann), juvenile spinal muscular atrophy (Wohlfart-Kugelberg-Welander), other forms of familial spinal muscular atrophy, primary lateral sclerosis, hereditary spastic paraplegia, a syndrome combining muscle weakness and wasting with sensory changes (progressive neuropathic amyotrophy;Chronic familial polyneuropathy, Charcot-Marie-Tooth disease, hypertrophic interstitial polyneuropathy (Déjerine-Sottas), or various forms of chronic progressive neuropathy, progressive vision loss syndrome, retinitis pigmentosa, hereditary optic atrophy (Leber's disease), Parkinson's disease and other extrapyramidal disorders, progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome), torsion dystonia (torsion spasm, dystonia musculorum deformans), focal dystonia, motor neuron disease, progressive ataxia, primary lateral sclerosis, multifocal motor neuropathy with conduction block, motor neuropathy with paraproteinemia, motor-predominant peripheral neuropathy, olivopontocerebellar atrophy, Azorean (Machado-Joseph) disease, familial progressive neurodegenerative disease, familial amyotrophic lateral sclerosis, spinal muscular atrophy, familial spastic paraparesis, hereditary biochemical disorder, multiple joint contractures, or progressive juvenile bulbar palsy (Fazio-Londe), infantile (Werdnig-Hoffmann disease), childhood onset or adolescence (Wohlfart-Kugelberg-Welander disease), degenerative cervical myelopathy, familial HTLV-1 myelopathy, isolated FSP or associated FSP, superoxide dismutase deficiency, hexosaminidase A and B deficiency, androgen receptor mutation (Kennedy syndrome), viral and prion diseases, myelopathy, progressive multifocal leukoencephalopathy, Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker disease, kuru, fatal familial insomnia, Alpers disease, primary progressive or secondary progressive multiple sclerosis that does not relapse, relapsing-remitting multiple sclerosis, frontotemporal dementia, Wilson's disease, progressive neuropathic pain, stroke, traumatic brain injury, or ischemia caused by spinal cord injury, the method according to Embodiment 18.;

[0167] Embodiment 20. A method for treating cancer in a subject in need of cancer treatment, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition according to any one of Embodiments 1 to 17.

[0168] Embodiment 21. A method for preventing cancer metastasis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition according to any one of Embodiments 1 to 17.

[0169] Embodiment 22. A method for improving cancer metastasis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition according to any one of Embodiments 1 to 17.

[0170] Embodiment 23. A method for minimizing cancer metastasis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition according to any one of Embodiments 1 to 17.

[0171] Embodiment 24. A method for preventing cancer recurrence in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition according to any one of Embodiments 1 to 17.

[0172] Embodiment 25. A method for improving cancer recurrence in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition according to any one of Embodiments 1 to 17.

[0173] Embodiment 26. A method for minimizing the risk of cancer recurrence or delaying cancer recurrence in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition according to any one of Embodiments 1 to 17.

[0174] Embodiment 27. The cancer is a. a cancer of the circulatory system selected from angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma and teratoma, cancers of the mediastinum and pleura, and hemangioma tumors; b. Cancers of the nasal cavity and middle ear, cancers of the paranasal sinuses, cancers of the larynx, cancers of the trachea, cancers of the bronchi and lungs, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), bronchiogenic carcinoma, squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma, alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, and mesothelioma; c. Squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma, carcinoma, ductal adenocarcinoma of the breast, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, bipoma, adenocarcinoma, carcinoid tumor, Kaposi's sarcoma, hemangioma, lipoma, neurofibroma, fibroma, tubular adenoma, villous adenoma, hamartoma, and leiomyoma selected from gastrointestinal cancers; d. Adenocarcinoma, Wilms tumor (nephroblastoma), lymphoma, leukemia, squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, adenocarcinoma, sarcoma of the prostate, seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, and lipoma selected from genitourinary cancers; e. Liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, pheochromocytoma, insulinoma, vasoactive intestinal peptide tumor, pancreatic islet cell tumor, pancreatic exocrine tumor, and pancreatic neuroendocrine tumor selected from hepatobiliary and pancreatic cancers; f. Osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, periosteal tumor (osteochondral exostosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor selected from bone cancers; g. Primary CNS lymphoma, osteoma, hemangioma, granuloma, xanthoma, Paget's disease of bone, meningioma, meningiosarcoma, gliosis, astrocytoma, medulloblastoma, glioma, epithelioma, germ cell tumor (pinealoma), oligodendroglioma, schwannoma, retinoblastoma, congenital tumor, spinal neurofibroma, meningioma, glioma, and sarcoma selected from nervous system cancers; h. A cancer of the reproductive system selected from endometrial cancer, cervical cancer, pre-tumor cervical dysplasia, ovarian cancer, serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, granulosa-theca cell tumor, Sertoli-Leydig cell tumor, undifferentiated embryonal cell tumor, malignant teratoma, vulvar squamous cell carcinoma, vulvar intraepithelial carcinoma, vulvar adenocarcinoma, vulvar fibrosarcoma, vulvar melanoma, vaginal clear cell carcinoma, vaginal squamous cell carcinoma, vaginal squamous cell sarcoma (fetal rhabdomyosarcoma), tubal placental cancer, uterine cancer, penile cancer, prostate cancer, and testicular cancer; i. A cancer of the hematological system selected from myeloid, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes, Hodgkin's disease and non-Hodgkin lymphoma; j. A 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, oropharyngeal cancer, nasopharyngeal cancer, nasal cavity cancer, and hypopharyngeal cancer; k. A cancer of the skin selected from malignant melanoma, cutaneous melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, and keloid cancer; or l. A cancer selected from adrenal cancer, neuroblastoma, cancers of connective and soft tissues, retroperitoneal and peritoneal cancers, eye cancer, intraocular melanoma, cancers of the adnexa, breast cancer, head and neck cancer, anal cancer, thyroid cancer, parathyroid cancer, adrenal cancer, cancers of endocrine glands and related structures, secondary and unknown malignant neoplasms of lymph nodes, secondary malignant neoplasms of the respiratory and digestive systems, and secondary malignant neoplasms of other sites The method according to any one of Embodiments 20 to 26.

[0175] Embodiment 28. A method for treating an autoimmune disorder in a subject in need of treatment for an autoimmune disorder, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition according to any one of Embodiments 1 to 17.

[0176] Embodiment 29. The method according to embodiment 28, wherein the autoimmune disorder is rheumatoid arthritis, IgA nephropathy, vasculopathy associated with kidney disease, systemic lupus erythematosus (SLE), Wegener's granulomatosis, relapsing polychondritis, atopic dermatitis, psoriasis, sarcoidosis, Behçet's disease, Vogt-Koyanagi-Harada disease, uveitis and idiopathic pulmonary fibrosis.

[0177] Embodiment 30. A method for treating a microbial infection in a subject in need of treatment for a microbial infection, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition according to any one of embodiments 1 to 17.

[0178] Embodiment 31. The method according to embodiment 30, wherein the microbial infection is caused by a virus, a bacterium, a fungus, or any combination of two or more thereof.

[0179] Embodiment 32. A method for treating sepsis and / or septic shock in a subject in need of treatment for sepsis and / or septic shock, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition according to any one of embodiments 1 to 17.

[0180] Embodiment 33. A method for treating severe virus-induced pneumonia in a subject in need of treatment for severe virus-induced pneumonia, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition according to any one of embodiments 1 to 17.

[0181] Embodiment 34. The method according to embodiment 33, wherein the severe virus-induced pneumonia is associated with an infection by a respiratory virus.

[0182] Embodiment 35. The method according to embodiment 34, wherein the respiratory virus is selected from influenza virus, respiratory syncytial virus, coronavirus, rhinovirus, adenovirus, and parainfluenza virus.

[0183] Embodiment 36. The method according to embodiment 35, wherein the coronavirus is COVID-19.

[0184] Embodiment 37. A method for treating mild to severe acute respiratory distress syndrome (ARDS) in a subject in need of treatment for mild to severe acute respiratory distress syndrome (ARDS), the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition according to any one of Embodiments 1 to 17, wherein the subject has an end-expiratory positive pressure (PEEP) of ≧ 5 cm H2O; and a PaO2 / FiO2 < 300 mmHg.

[0185] Embodiment 38. The method according to Embodiment 37, wherein the subject has an end-expiratory positive pressure (PEEP) of ≧ 5 cm H2O; and a PaO2 / FiO2 < 200 mmHg.

[0186] Embodiment 39. The method according to Embodiment 37 or Embodiment 38, wherein the ARDS is related to infection by a respiratory virus.

[0187] Embodiment 40. The method according to Embodiment 39, wherein the respiratory virus is selected from influenza virus, respiratory syncytial virus, coronavirus, rhinovirus, adenovirus, and parainfluenza virus.

[0188] Embodiment 41. The method according to Embodiment 40, wherein the coronavirus is COVID-19.

[0189] Embodiment 42. A method for treating fragile X syndrome in a subject in need of treatment for fragile X syndrome, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition according to any one of Embodiments 1 to 17.

[0190] Embodiment 43. A method for treating acute lung injury in a subject in need of treatment for acute lung injury, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition according to any one of Embodiments 1 to 17.

[0191] Embodiment 44. The method according to Embodiment 43, wherein the lung injury is induced by aspiration, trauma, pancreatitis, blood transfusion, or inhalation of smoke or toxic chemicals.

[0192] Embodiment 45. The method according to embodiment 43, wherein the lung injury is induced by a chemical substance selected from chlorine, sulfur mustard gas, phosgene, Lewisite, hydrogen chloride, sulfur dioxide, hydrogen sulfide, nitrogen dioxide, ammonia, hydrofluoric acid, ozone, methyl isocyanate, and combinations of two or more thereof.

[0193] Embodiment 46. The method according to any one of embodiments 43 to 45, wherein the lung injury includes chemical burns, pulmonary edema, laryngeal edema, lung tissue apoptosis, pneumonia, pneumonitis, bronchitis, bronchiolitis, fibrosis, acute respiratory distress syndrome, airway spasm, or combinations of two or more thereof.

[0194] The use of the term "or" in the claims is used to mean "and / or" unless explicitly indicated to refer only to alternatives or unless the alternatives are mutually exclusive, but the present disclosure supports definitions that refer only to alternatives and "and / or".

[0195] It should be understood that while certain embodiments have been illustrated and described, changes and modifications can be made by those skilled in the art without departing from the broader aspects of the technology defined in the claims below.

[0196] The embodiments illustratively described in this specification can be appropriately practiced without any one or more elements or one or more limitations not specifically disclosed herein. Thus, for example, terms such as "comprising", "including", "containing", etc. shall be read broadly and without limitation. Further, the terms and expressions used in this specification are used as terms of explanation rather than limitation, and in the use of such terms and expressions, there is no intention to exclude equivalents of the features shown and described or parts thereof, but it is recognized that various modifications are possible within the scope of the claimed technology. Further, the phrase "consisting essentially of" is understood to include the specifically recited elements and additional elements that do not substantially affect the basic and novel features of the claimed technology. The phrase "consisting of" excludes any element not specified.

[0197] The present disclosure should not be limited to the specific embodiments described in this application. As will be apparent to those skilled in the art, many modifications and variations can be made without departing from the spirit and scope thereof. In addition to those listed herein, functionally equivalent methods and compositions within the scope of the present disclosure will be apparent to those skilled in the art from the foregoing description. Such modifications and variations are intended to be included within the scope of the appended claims. The present disclosure should be limited only by the terms of the appended claims, and such claims are accompanied by the full scope of equivalents to which the rights are entitled. It should be understood that the present disclosure is not limited to a particular method, reagent, compound, composition, or biological system and can of course vary. It should also be understood that the terms used herein are for the purpose of describing particular embodiments only and are not intended to be limiting.

[0198] Furthermore, if a feature or aspect of the present disclosure is described with respect to a Markush group, those skilled in the art will recognize that the present disclosure is also described with respect to any individual member or subgroup of members of the Markush group.

[0199] As will be understood by those skilled in the art, for all purposes, and particularly with respect to providing a written description, all ranges disclosed herein include any and all possible subranges and combinations of those subranges. Each of the recited ranges can be readily recognized as being fully described and enabled to be divided into at least equal halves, thirds, quarters, fifths, tenths, etc. of the same range. By way of non-limiting example, each range discussed herein can be readily divided into lower thirds, middle thirds, upper thirds, etc. Also, as will be understood by those skilled in the art, all language such as "up to," "at least," "greater than," "less than," etc. includes the recited number and refers to ranges that can later be divided into the subranges as discussed above. Finally, as will be understood by those skilled in the art, ranges include individual members.

[0200] All publications, patent applications, issued patents, and other documents referred to herein are incorporated herein by reference as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions contained in the incorporated text by reference are excluded to the extent they conflict with the definitions in the present disclosure.

[0201] Other embodiments are described in the following claims.

Claims

1. An injectable pharmaceutical composition comprising a buffered aqueous solution containing 5% w / v to 15% w / v sulfobutyl ether-β-cyclodextrin (SBE-β-CD) and 0.05% w / v to 0.5% w / v ibudilast.

2. The aforementioned buffer aqueous solution contains disodium phosphate (Na ２ HPO ４ ) and sodium dihydrogen phosphate (NaH ２ PO ４ The injectable pharmaceutical composition according to claim 1, comprising )

3. The Na ２ HPO ４ However, it is present in the buffer aqueous solution in an amount of 0.2% w / v, and the NaH ２ PO ４ The injectable pharmaceutical composition according to claim 2, wherein the substance is present in the buffer aqueous solution in an amount of 0.06% w / v.

4. The injectable pharmaceutical composition according to any one of claims 1 to 3, wherein the SBE-β-CD is present in the buffer aqueous solution in an amount of 10% w / v.

5. The injectable pharmaceutical composition according to any one of claims 1 to 3, wherein the ibu dilast is present in the buffer aqueous solution in an amount of 0.1% w / v.

6. 10% w / v SBE-β-CD; 0.2% w / v disodium phosphate; 0.06% w / v sodium dihydrogen phosphate; 0.1% w / v ibudilast; and an appropriate amount of water A pharmaceutical composition for injection consisting of the following.

7. A pharmaceutical composition for injection comprising a buffered aqueous solution containing 5% w / v to 25% w / v polyoxyl castor oil and 1% w / v to 5% w / v ibudilast.

8. The injectable pharmaceutical composition according to claim 7, wherein the buffer aqueous solution contains 10% w / v to 20% w / v polyoxyl castor oil.

9. The pharmaceutical composition for injection according to claim 7 or 8, wherein the buffer aqueous solution further comprises 20% w / v to 60% w / v propylene glycol.

10. The injectable pharmaceutical composition according to claim 9, wherein the propylene glycol is present in the buffer aqueous solution at an amount of 40% w / v.

11. The injectable pharmaceutical composition according to claim 7 or 8, wherein the polyoxyl castor oil is polyoxyl-35 castor oil.

12. The buffer aqueous solution contains disodium phosphate (Na ２ HPO ４ ), and sodium dihydrogen phosphate (NaH ２ PO ４ ), and the pharmaceutical composition for injection according to claim 7 or 8.

13. The Na ２ HPO ４ However, it is present in the buffer aqueous solution in an amount of 0.2% w / v, and the NaH ２ PO ４ The pharmaceutical composition for injection according to claim 12, wherein the buffer aqueous solution contains the substance in an amount of 0.06% w / v.

14. The injectable pharmaceutical composition according to claim 7 or 8, wherein the ibu dilast is present in the buffer aqueous solution in an amount of 2% w / v.

15. 10% w / v polyoxyl castor oil; 40% w / v propylene glycol; 0.2% w / v disodium phosphate; 0.06% w / v sodium dihydrogen phosphate; 2% w / v ibudilast; and an appropriate amount of water A pharmaceutical composition for injection consisting of the following.

16. 20% w / v polyoxyl castor oil; 0.2% w / v disodium phosphate; 0.06% w / v sodium dihydrogen phosphate; 2% w / v ibudilast; and an appropriate amount of water A pharmaceutical composition for injection consisting of the following.