Injection formulation of ibudilast

Abstract

An injectable pharmaceutical composition is comprised of a buffered aqueous solution comprising (a) from about 5% w / v to about 15% w / v of sulfobutyl ether-beta-cyclodextrin (SBE-beta-CD), and from about 0.05% w / v to about 0.5% w / v of isobutadilast, or (b) from about 5% w / v to about 25% w / v of polyoxyethylated castor oil, and from about 1% w / v to about 5% w / v of isobutadilast.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 388,834, filed on July 13, 2022, the contents of which are incorporated herein by reference in their entirety. Background Art

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

[0003] Ibudilast has been widely used in Japan to relieve symptoms associated with ischemic stroke or bronchial asthma. In recent clinical trials, its use in the treatment of multiple sclerosis (MS), an inflammatory disease of the central nervous system, has been explored (News.Medical.Net; Pharmaceutical News, August 2, 2005). As disclosed in the publication, this clinical trial is expected to treat "relapsing-remitting MS", but progressive multiple sclerosis is not mentioned. In U.S. Patent No. US 6,395,747, ibudilast is disclosed for the treatment of multiple sclerosis, which is generally understood to be relapsing-remitting multiple sclerosis, rather than progressive multiple sclerosis. U.S. Patent Application Publication No. US20060160843 discloses that ibudilast is used to treat intermittent and short-term pain, but this pain is not related to progressive neurodegenerative diseases. However, US Pat. No. 9,314,452 discloses ibudilast as a treatment for amyotrophic lateral sclerosis (a progressive neurodegenerative disease). Similarly, US Pat. No. 8,138,201 discloses ibudilast for the treatment of primary progressive multiple sclerosis and / or secondary progressive multiple sclerosis.

[0004] In the late stages of the disease, patients may not be able to swallow pills, limiting their drug treatment options. An injectable formulation of ibudilast is ideal to improve dosing until patients are able to accept oral doses of ibudilast. The technology disclosed in the present invention meets this need. Summary of the invention

[0005] In one aspect, the present invention provides a pharmaceutical composition consisting of a buffered aqueous solution comprising 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. In certain embodiments, the buffered aqueous solution comprises disodium hydrogen phosphate (Na2HPO4) and sodium dihydrogen phosphate (NaH2PO4). In certain embodiments, the content of Na2HPO4 in the buffered aqueous solution is about 0.2% w / v, and the content of NaH2PO4 in the buffered aqueous solution is about 0.06% w / v. In certain embodiments, the content of SBE-β-CD in the buffered aqueous solution is about 10% w / v. In certain embodiments, the content of ibudilast in the buffered aqueous solution is about 0.1% w / v.

[0006] On the other hand, the present invention provides a pharmaceutical composition consisting of the following components: about 10% w / v sulfobutyl ether-β-cyclodextrin (SBE-β-CD), about 0.2% w / v disodium hydrogen phosphate, about 0.06% w / v sodium dihydrogen phosphate, about 0.1% w / v ibudilast and an appropriate amount of water.

[0007] On the other hand, the present invention provides a pharmaceutical composition consisting of a buffered aqueous solution comprising about 5% w / v to about 25% w / v of polyoxyethylene castor oil and about 1% w / v to about 5% w / v of ibudilast. In certain embodiments, the buffered aqueous solution comprises about 10% w / v to about 20% w / v of polyoxyethylene castor oil. In certain embodiments, the buffered aqueous solution also comprises about 20% w / v to about 60% w / v of propylene glycol. In certain embodiments, the content of propylene glycol in the buffered aqueous solution is about 40% w / v. In certain embodiments, the polyoxyethylene castor oil is polyoxyethylene-35 castor oil. In certain embodiments, the buffered aqueous solution includes disodium hydrogen phosphate (Na2HPO4) and sodium dihydrogen phosphate (NaH2PO4). In certain embodiments, the content of Na2HPO4 in the buffered aqueous solution is about 0.2% w / v, and the content of NaH2PO4 in the buffered aqueous solution is about 0.06% w / v. In certain embodiments, the content of ibudilast in the buffered aqueous solution is about 2% w / v. In certain embodiments, the pharmaceutical composition is an injectable composition.

[0008] On the other hand, the present invention provides a pharmaceutical composition, which is composed of the following ingredients: about 10% w / v polyoxyethylene castor oil; about 40% w / v propylene glycol; about 0.2% w / v disodium hydrogen phosphate; about 0.06% w / v sodium dihydrogen phosphate; about 2% w / v ibudilast; and an appropriate amount of water. In certain embodiments, the pharmaceutical composition is an injectable composition.

[0009] On the other hand, the present invention provides a pharmaceutical composition, which is composed of the following ingredients: about 20% w / v polyoxyethylene castor oil; about 0.2% w / v disodium hydrogen phosphate; about 0.06% w / v sodium dihydrogen phosphate; about 2% w / v ibudilast; and an appropriate amount of water. In certain embodiments, the pharmaceutical composition is an injectable composition.

[0010] On the other hand, the present invention provides a method for treating a neurodegenerative disease or dysfunction in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition of the present invention. In certain embodiments, the neurodegenerative disease or dysfunction is: Alzheimer's disease, Alzheimer's type senile dementia, Pick's disease (lobar atrophy), a syndrome of progressive dementia and other significant neurological abnormalities, Huntington's disease, multiple system atrophy with dementia and ataxia and / or Parkinson's disease manifestations, progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome), diffuse Lewy body disease, cortical dentate nigral degeneration, Hallerwarden-Spatz disease, progressive familial myoclonic epilepsy, gradual onset of Symptoms of abnormal posture and movement, Parkinson's disease, striatonigral degeneration, progressive supranuclear palsy, torsion dystonia (torsion spasm; dystonia deformans), spasmodic torticollis and other restrictive movement disorders, 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 ), muscle weakness and atrophy syndromes without sensory changes (motor neuron diseases), 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, muscle weakness and atrophy syndromes with sensory changes (progressive neuromuscular atrophy; chronic familial polyneuropathy), Charcot-Marie-Tooth, hypertrophic interstitial polyneuropathy (Deferine-Sottas) or other forms of chronic progressive neuropathies, progressive vision loss syndromes, retinitis pigmentosa (retinitis pigmentosa), hereditary optic atrophy (Leber disease), Parkinson's disease and other extrapyramidal diseases, progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome), torsion dystonia (torsion spasm;dystonia 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, Azores (Machado-Joseph disease), familial progressive neurodegenerative diseases, familial amyotrophic lateral sclerosis, spinal muscular atrophy, familial spastic paraplegia, hereditary biochemical disorders, congenital multiple arthrogryposis, progressive juvenile bulbar palsy (Fazio-Londe), infantile form (Werdnig-Hoffman disease), childhood or adolescent onset (Woh Favart-Kugelberg-Welander disease), degenerative cervical spondylosis, familial HTLV-1 myelopathy, isolated FSP or complex 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 syndrome, kuru, fatal familial insomnia, Alper disease, primary progressive or secondary progressive multiple sclerosis, but not including relapsing remitting multiple sclerosis, frontotemporal dementia, Wilson disease, progressive neuropathic pain, ischemia due to stroke, traumatic brain injury, or spinal cord injury.

[0011] In another aspect, the present invention provides a method of treating cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition disclosed herein.

[0012] In another aspect, the present invention provides a method for preventing cancer metastasis in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition disclosed herein.

[0013] In another aspect, the present invention provides a method for reducing cancer metastasis in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition disclosed herein.

[0014] In another aspect, the present invention provides a method of minimizing cancer metastasis in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition disclosed herein.

[0015] In another aspect, the present invention provides a method for preventing cancer recurrence in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition disclosed herein.

[0016] In another aspect, the present invention provides a method for reducing cancer recurrence in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition disclosed herein.

[0017] In another aspect, the present invention provides a method for minimizing the risk of cancer recurrence or delaying cancer recurrence in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition disclosed herein.

[0018] In some embodiments, the cancer is: a. Cancer of the circulatory system selected from the group consisting of angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyoma, myofibroma, lipoma and teratoma, mediastinal carcinoma and pleural carcinoma or vascular tumors; b. Cancer of the respiratory tract selected from the group consisting of: nasal cavity and middle ear cancer, paranasal sinus cancer, laryngeal cancer, tracheal cancer, bronchial and lung cancer, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), bronchogenic carcinoma, squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma, alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, enchondromatous hamartoma or mesothelioma; c. a cancer of the gastrointestinal system selected from the group consisting of squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma, carcinoma, ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma, adenocarcinoma, carcinoid tumor, Kaposi's sarcoma, hemangioma, lipoma, neurofibroma, fibroma, tubular adenoma, villous adenoma, hamartoma or leiomyoma; d. Cancer of the genitourinary tract selected from the group consisting of adenocarcinoma, Wilm's tumor, lymphoma, leukemia, squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, adenocarcinoma, prostatic sarcoma, seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, or lipoma; e. Cancer of the hepatobiliary and pancreatic system selected from the group consisting of hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, pheochromocytoma, insulinoma, VIP tumor, islet cell tumor, pancreatic exocrine tumor and pancreatic neuroendocrine tumor; f. Bone cancer selected from the group consisting of osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteocartilaginous exostosis), benign enchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma or giant cell tumor; g. Cancer of the nervous system selected from the group consisting of primary central nervous system lymphoma, osteoma, hemangioma, granuloma, xanthomas, osteitis deformans, meningioma, meningiosarcoma, gliomatosis, astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, spinal neurofibromas, meningiomas, gliomas or sarcomas; h. cancer of the reproductive system selected from the group consisting of endometrial cancer, cervical cancer, preneoplastic cervical atypical hyperplasia, ovarian cancer, serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, granulosa theca cell tumor, Sertoli cell-Leydig cell tumor, dysgerminoma, malignant teratoma, vulvar squamous cell carcinoma, vulvar intraepithelial carcinoma, vulvar adenocarcinoma, vulvar fibrosarcoma, vulvar melanoma, vaginal clear cell carcinoma, vaginal squamous cell carcinoma, vaginal botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube cancer, placental cancer, uterine cancer, penile cancer, prostate cancer, or testicular cancer; i. a cancer of the blood system selected from the group consisting of: bone marrow, acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disease, multiple myeloma, myelodysplastic syndrome, Hodgkin's disease or non-Hodgkin's lymphoma; j. Oral cancer selected from: lip cancer, tongue cancer, gum cancer, floor of mouth cancer, palate cancer, parotid gland cancer, salivary gland cancer, tonsil cancer, oropharyngeal cancer, nasopharyngeal cancer, pyriform sinus cancer or hypopharyngeal cancer; k. Skin cancer selected from the group consisting of malignant melanoma, cutaneous melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, and keloid; or l. A cancer selected from the group consisting of adrenal cancer, neuroblastoma, connective and soft tissue cancer, retroperitoneal and peritoneal cancer, eye cancer, intraocular melanoma, adnexal cancer, breast cancer, head and / or neck cancer, anal cancer, thyroid cancer, parathyroid cancer, adrenal cancer, cancer of the endocrine glands and related structures, secondary and unspecified malignancies of the lymph nodes, secondary malignancies of the respiratory and digestive systems, or secondary malignancies of other sites.

[0019] On the other hand, the present invention provides a method for treating an autoimmune disease in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition disclosed herein. In some embodiments, the autoimmune disease comprises rheumatoid arthritis, IgA nephropathy, vascular disease 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, or idiopathic pulmonary fibrosis.

[0020] In another aspect, the present invention provides a method for treating a microbial infection in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition disclosed herein. In some embodiments, the microbial infection is caused by a virus, a bacterium, a fungus, or a combination of any two or more thereof.

[0021] In another aspect, the present invention provides a method of treating sepsis and / or septic shock in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition disclosed herein.

[0022] On the other hand, the present invention provides a method for treating severe viral pneumonia in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition disclosed herein. In some embodiments, severe viral pneumonia is associated with a respiratory viral infection. 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.

[0023] On the other hand, the present invention provides a method for treating mild to severe acute respiratory distress syndrome (ARDS) in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition disclosed herein, wherein the patient's positive end-expiratory pressure (PEEP) is ≥5cm H2O; and PaO2 / FiO2<300mm Hg. In some embodiments, the patient's positive end-expiratory pressure (PEEP) is ≥5cm H2O; and PaO2 / FiO2<200mm Hg. In some embodiments, ARDS is associated with respiratory viral infection. 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.

[0024] In another aspect, the present invention provides a method of treating fragile X syndrome in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition disclosed herein.

[0025] On the other hand, the present invention provides a method for treating acute lung injury in a patient in need, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition disclosed in the present invention. In some embodiments, lung injury is caused by aspiration, trauma, pancreatitis, blood transfusion, or inhalation of smoke or inhalation of toxic chemicals. In some embodiments, lung injury is caused by a chemical selected from chlorine, mustard gas, phosgene, Lewis agent, hydrogen chloride, sulfur dioxide, hydrogen sulfide, nitrogen dioxide, ammonia, hydrofluoric acid, ozone, methyl isocyanate, and any two or more combinations thereof. In some embodiments, lung injury includes chemical burns, pulmonary edema, laryngeal edema, apoptosis of lung tissue, pneumonia (caused by infection), pneumonia (caused by causes other than infection), bronchitis, bronchiolitis, fibrosis, acute respiratory distress syndrome, airway spasm, or any two or more combinations thereof. DETAILED DESCRIPTION

[0026] Unless otherwise indicated, the practice of the present disclosure will employ conventional methods of chemistry, biochemistry, and pharmacology within the skill of the art. These techniques are explained in detail in the literature. See, for example, ALLehninger, 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, LLL Limbird, A. Gilman, 11th Ed., 2005, The Merck Manual, 18th edition, 2007, and The Merck Manual of Medical Information 2003.

[0027] All publications cited herein, including internet articles, the FDA Orange Book (available on the FDA website), books, manuals, journal articles, patents and patent applications, whether supra or infra, are hereby incorporated by reference in their entirety. definition

[0028] Before describing the present invention in detail, it should be understood that the present invention is not limited to a particular mode of administration, patient population, etc., as such may vary as will be apparent from the remainder of the description of the invention.

[0029] It must be noted that, as used in this specification and the claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a drug" includes a single drug as well as two or more of the same or different drugs, reference to "an optional excipient" refers to a single optional excipient as well as two or more of the same or different optional excipients, etc. The term "qs" is an abbreviation for "quantum satis", which means "appropriate amount".

[0030] In describing and claiming the present invention, the following terminology will be used in accordance with the definitions described below.

[0031] “Optional” or “optionally” means that the subsequently described event may or may not occur, so that the description includes instances where the event occurs and instances where it does not.

[0032] "Pharmaceutically acceptable excipients or carriers" refer to excipients that may be optionally included in the compositions of the present invention and that do not cause significant adverse toxicological effects to patients.

[0033] "Pharmaceutically acceptable salts" include, but are not limited to, amino acid salts, salts prepared with inorganic acids, such as chlorides, sulfates, phosphates, diphosphates, bromides and nitrates, or salts prepared from the corresponding inorganic acid forms of any of the above, such as hydrochlorides, etc., or salts prepared with organic acids, such as malate, maleate, fumarate, tartrate, succinate, ethylsuccinate, citrate, acetate, lactate, methanesulfonate, benzoate, ascorbate, p-toluenesulfonate, palmitate, salicylate and stearate, as well as propionate lauryl sulfate, gluconate and lactobionate. Similarly, salts containing pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium and ammonium (including substituted ammonium).

[0034] As used herein, "active molecules" or "active agents" include any agent, drug, compound, substance or mixture composition that has been shown to provide certain pharmacological effects (usually beneficial) in vivo or in vitro. It includes foods, food supplements, nutrients, health products, drugs, vaccines, antibodies, vitamins and other beneficial substances. As used herein, the term also includes 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.

[0035] "Substantially" or "essentially" means nearly all or completely, for example, 95% or more of a given amount.

[0036] The terms "subject", "individual" or "patient" are used interchangeably in the present invention and refer to vertebrates, preferably mammals. Mammals include, but are not limited to, mice, rodents, rats, monkeys, humans, farm animals, dogs, cats, sports animals, and pets. In some embodiments, the subject, individual or patient refers to a human.

[0037] The term "pharmaceutically effective amount" or "therapeutically effective amount" of a composition or medicament provided herein refers to an amount of a composition or medicament that is non-toxic but sufficient to provide a desired response (e.g., to alleviate or reverse any disease or dysfunction described herein). The exact amount required will vary from subject to subject, depending on the species, age, and overall condition of the subject, the severity of the condition being treated, the specific drug used, the mode of administration, etc. Based on the information provided herein, one of ordinary skill in the art can use routine experiments to determine the appropriate "effective" amount in any individual case.

[0038] The term "about" will be understood by those of ordinary skill in the art, and the term will vary to some extent depending on the context in which it is used. If the use of the term is unclear to those of ordinary skill in the art given the context in which it is used, "about" means a maximum of plus or minus 10% of the particular term. For example, in some embodiments, it will mean plus or minus 5% of the particular term. The numerical values ​​of certain ranges given in the present invention are preceded by the term "about". The present invention uses the term "about" to provide textual support for the exact number that follows and the close or approximate number that follows the term. When determining whether a number is close to or approximate to a specifically listed number, the close or approximate unlisted number can be a number that, in the context in which the number is presented, provides a substantially equivalent form of the specifically listed number.

[0039] As used herein, the term "treatment" or "treating" refers to any treatment of a disease or condition or related disorder of a patient, including inhibiting the disease or condition, i.e., inhibiting or suppressing the development of clinical symptoms. "Treatment" or "treatment" also includes preventing the development of one or more symptoms of a disease or reversing the symptoms of a disease. For the purposes of various aspects and embodiments of the present invention, beneficial or desired clinical results include, but are not limited to, reducing, alleviating or alleviating one or more manifestations or negative effects of any disease or condition described herein, improving one or more clinical results, reducing the scope of any disease or condition described herein, delaying or slowing the progression of any disease or condition described herein, alleviating, alleviating or stabilizing the state of any disease or condition described herein, and other beneficial results described herein.

[0040] In certain aspects, the term "treatment" refers to alleviation of a clinical outcome. The term "clinical outcome" refers to any clinical observation or measurement related to a patient's response to a treatment.

[0041] Other purposes, 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, although indicating specific embodiments of the present disclosure, are given by way of illustration only, because various changes and modifications within the spirit and scope of the present disclosure will become apparent to those skilled in the art based on the detailed description.

[0042] The terms "one", "a kind of" and "the" and similar referents are to be understood as covering the singular and the plural when describing elements herein (especially in the following claims), unless otherwise stated herein or the context clearly contradicts it. The recording of the numerical range herein is only a shorthand method for individually citing each individual numerical value within the range, unless otherwise stated herein, and each individual numerical value is included in the specification in a separately listed manner. All methods described herein can be performed in any suitable order, unless otherwise stated herein or the context clearly contradicts it. Any and all examples or exemplary language (e.g., "for example") provided herein are only used to better illustrate the implementation method and do not limit the scope of the claims, unless otherwise stated. Any language in the specification should not be interpreted as indicating that any undeclared element is essential.

[0043] The present invention discloses an injectable dosage form of ibudilast. More specifically, the dosage form is a pharmaceutical composition consisting of a buffered aqueous solution comprising: (a) 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, or (b) about 5% w / v to about 25% w / v of polyoxyethylene castor oil, and about 1% w / v to about 5% w / v of ibudilast. Ibudilast

[0044] The method disclosed herein is based on the administration of the molecule ibudilast. Ibudilast is a small molecule drug (molecular weight 230.3) having the following structure.

[0045] Ibudilast can also be found under ChemBank ID 3227, CAS#50847-11-5 and Beilstein Manual Reference 5-24-03-00396. Its molecular formula is C 14 H 18 N2O. Ibudilast is also known by a variety of 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 aliases for ibudilast include Ibudilastum (Latin), BRN 0656579, KC-404, and MN-166. Its brand name is References to ibudilast in this disclosure are intended to include any and all pharmaceutically acceptable salt forms, prodrug forms (eg, corresponding ketals), solvates, etc. thereof, as long as they are suitable for their intended administration formulations.

[0046] Ibudilast is an inhibitor of macrophage inhibitory factor (MIF). Ibudilast is also a selective inhibitor of cyclic nucleotide phosphodiesterases (PDEs) 3A, 4, 10A1 and 11A1 (Gibson et al., Eur J Pharmacol 538:39-42, 2006), and is reported to have leukotriene D4 and PAF antagonist activity. Ibudilast has potent anti-inflammatory effects and is unique compared to other PDE inhibitors and anti-inflammatory agents. PDEs catalyze the hydrolysis of phosphate bonds bound to the 3'-carbon to generate the corresponding 5'-nucleotide monophosphates. Therefore, they regulate the cellular concentration of cyclic nucleotides. Since many extracellular receptors for hormones and neurotransmitters use cyclic nucleotides as second messengers, PDEs also regulate the response of cells to these extracellular signals. There are at least eight types of PDEs: Ca 2+ / Calmodulin-dependent PDEs (PDE1), cGMP-stimulated PDEs (PDE2), cGMP-inhibited PDEs (PDE3), cAMP-specific PDEs (PDE4), cGMP-binding PDEs (PDE5), photoreceptor PDEs (PDE6), high-affinity cAMP-specific PDEs (PDE7), and high-affinity cGMP-specific PDEs (PDE9). Ibudilast inhibits inflammation by acting on inflammatory cells (such as glial cells), thereby inhibiting the release of proinflammatory mediators and neuroactive mediators. Ibudilast can also inhibit the production of proinflammatory cytokines (IL-1β, TNF-α) and can enhance the production of anti-inflammatory cytokines (IL-4, IL-10).Another publication of the most recent biological reference:Obernolte,R.,et al.(1993)“The cDNA of a human lymphocyte cyclic-AMPphosphodiesterase(PDE IV)reveals a multigene family”Gene 129:239-247;Rile,G.,et al.(2001)“Potentiation of ibudilast inhibition of platelet aggregation in the presence of endothelial cells”Thromb.Res.102:239-246;Souness,JE,et al actions ofibudilast on eosinophil thromboxane generation and airways smooth muscletone”Br.J.Pharmacol.111:1081-1088;Suzumura,A.,et al CNS”Brain Res.837:203-212;Takuma,K.,et al.(2001)“Ibudilast attenuates astrocyte apoptosis via cyclic GMP signalingpathway in an in vitro reperfusion model”Br.J.Pharmacol.133:841-848.ibudilast exhibits good CNS penetration:Sanftner et al Xenobiotica 2009 39:964–977.

[0047] As mentioned above, any one or more drugs mentioned in the present disclosure, in particular ibudilast, are meant to cover any and all enantiomers, mixtures of enantiomers (including racemic mixtures), prodrugs, pharmaceutically acceptable salt forms, hydrates (e.g., monohydrates, dihydrates, etc.), solvates, different physical forms (e.g., crystalline solids, amorphous solids), metabolites, etc., where applicable. Pharmaceutical composition

[0048] In one aspect, the invention features a pharmaceutical composition consisting of a buffered aqueous solution comprising about 5% w / v to about 15% w / v sulfobutyl ether-β-cyclodextrin (SBE-β-CD) and about 0.05% w / v to about 0.5% w / v ibudilast.

[0049] In some embodiments, the buffered aqueous solution comprises about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15% w / v SBE-β-CD. In some embodiments, the buffered aqueous solution comprises about 5% w / v to about 13% w / v SBE-β-CD, about 5% w / v to about 11% w / v SBE-β-CD, about 8% w / v to about 15% w / v SBE-β-CD, or about 8% w / v to about 13% w / v SBE-β-CD.

[0050] In another aspect, the present invention describes a pharmaceutical composition consisting of a buffered aqueous solution comprising about 5% w / v to about 25% w / v of polyoxyethylene castor oil and about 1% w / v to about 5% w / v of ibudilast.

[0051] 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 polyoxyethylene castor oil. In some embodiments, the buffered aqueous solution comprises about 5% w / v to about 20% w / v polyoxyethylene castor oil. In some embodiments, the buffered aqueous solution comprises about 10% w / v to about 20% w / v polyoxyethylene castor oil. In some embodiments, the buffered aqueous solution comprises about 10% w / v to about 25% w / v polyoxyethylene castor oil.

[0052] In some embodiments, the polyoxyl castor oil is polyoxyl-35 castor oil.

[0053] In some embodiments, the buffered aqueous solution further comprises about 20% w / v to about 60% w / v propylene glycol. This includes 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 propylene glycol. In some embodiments, the buffered aqueous solution further comprises about 20% w / v to about 55% w / v, about 20% w / v to about 50% w / v, about 20% w / v to about 45% w / v, about 20% w / v to about 40% w / v, about 20% w / v to about 35% w / v, about 20% w / v to about 30% w / v, about 25% w / v to about 60% w / v, about 25% w / v to about 55% w / v, about 2 5% w / v to about 50% w / v, about 25% w / v to about 45% w / v, about 25% w / v to about 40% w / v, about 25% w / v to about 35% w / v, about 30% w / v to about 60% w / v, about 30% w / v to about 55% w / v, about 30% w / v to about 50% w / v, about 30% w / v to about 45% w / v, or about 30% w / v to about 40% w / v of propylene glycol.

[0054] In some embodiments, the buffered aqueous solution comprises disodium hydrogen phosphate (Na2HPO4) and sodium dihydrogen phosphate (NaH2PO4). In some embodiments, the content of Na2HPO4 in the buffered aqueous solution is about 0.2% w / v, and the content of NaH2PO4 in the buffered aqueous solution is about 0.06% w / v.

[0055] In some embodiments, the amount of ibudilast in the buffered aqueous solution is 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 all increments therein. In some embodiments, ibudilast is present in an aqueous buffered solution at a level 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.

[0056] In some embodiments, ibudilast is present in an aqueous buffered solution at 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 all increments therein. In some embodiments, ibudilast is present in an aqueous buffered 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.

[0057] In another aspect, the invention features a pharmaceutical composition comprising, consisting essentially of, or consisting of: About 10% w / v SBE-β-CD; About 0.2% w / v disodium hydrogen phosphate; About 0.06% w / v sodium dihydrogen phosphate; about 0.1% w / v ibudilast; and Appropriate amount of water.

[0058] In another aspect, the invention features a pharmaceutical composition comprising, consisting essentially of, or consisting of: About 10% w / v polyoxyethylene castor oil; About 40% w / v propylene glycol; About 0.2% w / v disodium hydrogen phosphate; About 0.06% w / v sodium dihydrogen phosphate; about 2% w / v ibudilast; and Appropriate amount of water.

[0059] In another aspect, the invention features a pharmaceutical composition comprising, consisting essentially of, or consisting of: About 20% w / v polyoxyethylene castor oil; About 0.2% w / v disodium hydrogen phosphate; About 0.06% w / v sodium dihydrogen phosphate; about 2% w / v ibudilast; and Appropriate amount of water. Treatment

[0060] On the other hand, any of the compositions described herein can be used to treat any one or more of the diseases or functional disorders described herein. Therefore, a method of using a therapeutically effective amount of the compositions described herein to treat one or more of the diseases or functional disorders described herein is another aspect of the present disclosure.

[0061] In some embodiments, the disease or dysfunction is a neurodegenerative disease, a genetic biochemical disorder, a progressive neurodegenerative disease or a symptom thereof. Exemplary neurodegenerative diseases / dysfunctions include, but are not limited to, Alzheimer's disease, Alzheimer's type senile dementia or Pick's disease (lobar atrophy), multiple sclerosis, neurodegenerative diseases including syndromes with progressive dementia combined with other significant neurological abnormalities, progressive neurodegenerative diseases that primarily affect adults, including progressive neurodegenerative forms of Huntington's disease, multiple system atrophy in which dementia is combined with ataxia and / or Parkinson's disease manifestations, progressive supranuclear palsy (Steele-Richardson-Olszewski), diffuse Lewy body disease, or cortical dentate nucleus substantia nigra degeneration. Other patients may have progressive neurodegenerative disorders that primarily affect young adults and children, including Hallervorden-Spatz disease and progressive familial myoclonic epilepsy, progressive neurodegenerative disorders that include syndromes with gradual onset of postural and movement abnormalities, or include Parkinson's disease, striatonigral degeneration, progressive supranuclear palsy, torsion dystonia (torsion spasm; dystonia deformans), spasmodic torticollis and other restrictive movement disorders, familial tremor or Gilles de la Tourette syndrome, progressive ataxia syndromes, cerebellar degeneration or spinocerebellar degeneration, cerebellar cortical degeneration or olivopontocerebellar atrophy (OPCA), spinocerebellar degeneration (including spinocerebellar degeneration (Friedreich's ataxia and related disorders)). Neurodegenerative diseases / disorders include, but are not limited to, central autonomic nervous system failure (Shy-Drager syndrome), muscle weakness and atrophy syndrome 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, muscle weakness and atrophy syndrome with sensory changes (progressive neuromuscular atrophy; chronic familial polyneuropathy), Charcot-Marie-Tooth, hypertrophic interstitial polyneuropathy (Dejerine-Sottas) or other forms of chronic progressive neuropathies, progressive neurodegenerative diseases including progressive visual loss syndrome.Neurodegenerative diseases / disorders include, but are not limited to, retinitis pigmentosa (retinitis pigmentosa), or hereditary optic atrophy (Leber's disease), motor neuron disease and progressive ataxia; glaucoma; retinal detachment; sporadic progressive neurodegenerative diseases, multifocal motor neuropathy with conduction block, motor neuropathy with paraproteinemia, motor-predominant peripheral neuropathy, olivopontocerebellar atrophy, Azores disease (Machado-Joseph disease), familial progressive neurodegenerative diseases, such as familial amyotrophic lateral sclerosis, spinal muscular atrophy, familial spastic paraplegia, hereditary biochemical diseases, arthrogryposis multiplex congenita, or progressive juvenile bulbar palsy (Fazio-Londe). Examples of hereditary biochemical diseases include superoxide dismutase deficiency, hexosaminidase A and B deficiency, or androgen receptor mutations (Kennedy syndrome). Progressive neurodegenerative diseases include viral and prion diseases, such as HTLV-1-associated myelopathy, progressive multifocal leukoencephalopathy, Creutzfeldt-Jakob disease, Gerstmann syndrome, kuru, fatal familial insomnia, or Alper disease.

[0062] "Progressive neurodegenerative disease" means any neurodegenerative disease that is progressive (i.e., symptoms become worse compared to baseline levels) or has such progressive characteristics. Thus, a progressive state means that symptoms gradually or rapidly worsen over time. Examples of progressive neurodegenerative diseases include Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, and progressive multiple sclerosis excluding relapsing / remitting multiple sclerosis.

[0063] In some embodiments, the disease or dysfunction is an ocular disease / dysfunction or injury associated with a neurodegenerative disease / dysfunction or a neuro-ophthalmologic disorder. In certain embodiments, the ocular disease / dysfunction or injury is retinal damage. In certain embodiments, the ocular disease / dysfunction or injury is macular damage. In certain embodiments, the ocular disease / dysfunction or injury is macular thinning. In certain embodiments, the neurodegenerative disease / dysfunction is progressive multiple sclerosis. Exemplary neuro-ophthalmologic disorders include, but are not limited to, papilledema and idiopathic intracranial hypertension (IIH); anterior ischemic optic neuropathy (AION); optic neuritis; ocular motor cranial neuropathy; and Horner's syndrome.

[0064] In some embodiments, the disease or dysfunction is alcoholism and depression and / or dysphoria. Examples include alcohol use disorder (AUD) which may be accompanied by depression or dysphoria. In certain embodiments, depression is mild depression, moderate depression, or severe depression. In certain embodiments, dysphoria is high dysphoria, moderate dysphoria, or mild dysphoria.

[0065] In some embodiments, the disease or dysfunction is glioblastoma, recurrent glioblastoma, or symptoms associated therewith. In some embodiments, the disease or dysfunction is glioblastoma. In some embodiments, the disease or dysfunction is recurrent glioblastoma.

[0066] For treating glioblastoma or recurrent glioblastoma, in some embodiments, the patient is a human patient. In some embodiments, the patient has an extra copy of the epidermal growth factor receptor (EGFR) gene or expresses abnormally high levels of EGFR. In some embodiments, abnormally high levels of EGFR refer to EGFR levels in cancer patients that are higher than EGFR levels in cancer-free individuals. In some embodiments, the patient lacks heterozygosity for chromosome 10. In some embodiments, the patient shows chromosome 7 amplification. In some embodiments, the patient has a mutant gene selected from TP53, PDGFRA, IDH1, PTEN, and NF1. In some embodiments, the patient expresses NEFL, GABRA1, SYT1, or SLC12A5.

[0067] In some embodiments, the disease or dysfunction is multiple sclerosis or progressive multiple sclerosis. There are four recognized types of multiple sclerosis: (1) relapsing / remitting multiple sclerosis (RR-type multiple sclerosis), (2) secondary progressive multiple sclerosis (SP-type multiple sclerosis), (3) progressive relapsing multiple sclerosis (PR-type multiple sclerosis), and (4) primary progressive multiple sclerosis (PP-type multiple sclerosis). RR-type multiple sclerosis is not within the scope of the present patent claims, but other forms of multiple sclerosis, namely SP-type multiple sclerosis, PR-type multiple sclerosis, and PP-type multiple sclerosis are considered to be an aspect of the present invention. In all types of progressive MS, whether or not there are relapses, function is lost over time.

[0068] Relapsing / remitting MS (RR MS) is characterized by relapses (also called exacerbations), during which new symptoms may develop and old symptoms may reappear or worsen. Relapses are followed by remissions, during which people may fully or partially recover from the deficits they experienced during the relapse. Relapses may last for days, weeks, or months, and recovery may be slow and gradual or almost instantaneous. The vast majority of people with MS are initially diagnosed with RR MS. MS is usually diagnosed in people's twenties or thirties, although it can be diagnosed earlier or later. About twice as many women as men have the disease.

[0069] In "secondary progressive MS (SP-MS)", people who initially have relapsing-remitting MS begin to experience a gradual deterioration in neurological function, with or without relapses. Many people with RRMS enter the secondary progressive stage of the disease after several years. This stage is characterized by a gradual worsening of the disease between relapses. In the early stages of RPMS, people may still experience a few relapses, but over time these relapses coalesce into a general progression of the disease. People often do not return to their previous level of function after a relapse. People with RPMS may have periods of milder symptoms and periods of more severe symptoms, but there is no real recovery other than some relief after a relapse. After 10 years, 50% of people with RRMS will develop into the secondary progressive form. After 25 to 30 years, this number rises to 90%.

[0070] Progressive-relapsing MS (PR-MS) shows a marked progression in disability from the time symptoms first appear, but with significant relapses that may or may not be related to recovery from an acute attack. This type of MS is progressive from the start, with relapses. There is marked recovery immediately after a relapse, but between relapses, symptoms gradually worsen.

[0071] Primary progressive MS (PP MS) is characterized by a gradual progression of disease from the onset of disease, without periods of remission or relapse. There may be periods of slowing of disease activity, and as with secondary progressive, people may have periods of milder symptoms and periods of more severe symptoms. PP MS differs from relapsing / remitting and secondary progressive MS in that onset is usually in the 30s or 40s, it affects men and women equally, and initial disease activity occurs in the spinal cord rather than the brain. PP MS often migrates to the brain, but is less likely to damage brain areas than relapsing / remitting or secondary progressive forms—for example, people with PP MS are less likely to have cognitive problems.

[0072] In some embodiments, progressive multiple sclerosis has progressed 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 progressive disease from the onset of disease, allowing for occasional plateaus and temporary mild improvements, but without significant relapses. 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 progressive disease, with or without occasional relapses, mild remissions, and plateaus.

[0073] In some embodiments, the disease or disorder is cancer.

[0074] In some embodiments, the disease or disorder is uveal melanoma.

[0075] 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.

[0076] In some embodiments, the disease or disorder is Fragile X syndrome.

[0077] In some embodiments, the disease or disorder is an autoimmune disorder. Non-limiting examples of autoimmune disorders include rheumatoid arthritis, IgA nephropathy, vascular disease 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.

[0078] In some embodiments, the disease or dysfunction is a microbial infection. In some embodiments, the microbial infection is caused by a virus, a bacterium, a fungus, or a combination of two or more thereof.

[0079] In some embodiments, the disease or disorder is sepsis and / or septic shock.

[0080] In some embodiments, the disease or dysfunction is severe viral pneumonia. In some embodiments, severe viral pneumonia is associated with a respiratory viral infection. 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.

[0081] In some embodiments, the disease or dysfunction is mild to severe acute respiratory distress syndrome (ARDS), wherein the patient has a positive end-expiratory pressure (PEEP) ≥ 5 cm H2O; and PaO2 / FiO2 < 300 mm Hg. In some embodiments, the patient has a positive end-expiratory pressure (PEEP) ≥ 5 cm H2O; and PaO2 / FiO2 < 200 mm Hg. In some embodiments, ARDS is associated with a respiratory viral infection. 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.

[0082] In some embodiments, the disease or dysfunction is acute lung injury. In some embodiments, the lung injury is caused by aspiration, trauma, pancreatitis, blood transfusion or inhalation of smoke or inhalation of toxic chemicals. In some embodiments, the lung injury is caused by a chemical selected from chlorine, mustard gas, phosgene, Lewis agent, hydrogen chloride, sulfur dioxide, hydrogen sulfide, nitrogen dioxide, ammonia, hydrofluoric acid, ozone, methyl isocyanate and any two or more combinations thereof. In some embodiments, the lung injury includes chemical burns, pulmonary edema, laryngeal edema, apoptosis of lung tissue, pneumonia (caused by infection), pneumonia (caused by reasons other than infection), bronchitis, bronchiolitis, fibrosis, acute respiratory distress syndrome, airway spasm or a combination of two or more thereof.

[0083] In some embodiments, the disease or dysfunction is lung injury caused by a chemical substance. In some embodiments, the lung injury is caused by a chemical selected from chlorine, mustard gas, phosgene, Lewis agent, hydrogen chloride, sulfur dioxide, hydrogen sulfide, nitrogen dioxide, ammonia, hydrofluoric acid, ozone, methyl isocyanate, and two or more combinations thereof. In some embodiments, the lung injury includes chemical burns, pulmonary edema, laryngeal edema, apoptosis of lung tissue, pneumonia (caused by infection), pneumonia (caused by causes other than infection), bronchitis, bronchiolitis, fibrosis, acute respiratory distress syndrome, airway spasm, or a combination of two or more thereof.

[0084] In another aspect, any of the compositions described herein are used in a method of preventing cancer metastasis in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the composition described herein.

[0085] In another aspect, any of the compositions described herein are used in a method of reducing cancer metastasis in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the composition described herein.

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

[0087] In another aspect, any of the compositions described herein are used in a method of preventing cancer recurrence in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the composition described herein.

[0088] In another aspect, any of the compositions described herein are used in a method of reducing cancer recurrence in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the composition described herein.

[0089] In another aspect, any of the compositions described herein are used in a method of minimizing the risk of or delaying cancer recurrence in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the composition described herein.

[0090] In another aspect, any of the compositions described herein are used in a method of inhibiting myeloid-derived suppressor cells (MDSCs) in a patient diagnosed with or afflicted with cancer, the method comprising administering to the patient a therapeutically effective amount of a composition described herein.

[0091] In another aspect, any of the compositions described herein are used in a method of reducing immunosuppression in a patient diagnosed with or afflicted with cancer, the method comprising administering to the patient a therapeutically effective amount of a composition described herein.

[0092] In another aspect, any of the compositions described herein are used in a method of reducing the number of regulatory T cells in a patient diagnosed with or afflicted with cancer, the method comprising administering to the patient a therapeutically effective amount of the composition described herein.

[0093] In another aspect, any of the compositions described herein is used in a method for 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.

[0094] In some embodiments, the cancer is selected from the group consisting of angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyosarcoma, myxoma, fibroma, lipoma and teratoma, mediastinal cancer and pleural cancer, vascular tumors of the circulatory system; selected from the group consisting of nasal cavity and middle ear cancer, paranasal sinus cancer, laryngeal cancer, tracheal cancer, bronchial and lung cancer, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), bronchogenic carcinoma, squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma, alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma and mesothelioma of the respiratory tract; selected from the group consisting of squamous cell carcinoma, adenocarcinoma, smooth muscle adenocarcinoma, Wilms' tumor, lymphoma, leukemia, squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, adenocarcinoma, prostatic sarcoma, seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, stromal cell carcinoma, fibroma, fibroadenomas, adenocarcinoid tumors, adenocarcinomas, fibroid tumors, adenomatous tumors, and lipomas; a genitourinary tract cancer selected from the group consisting of adenocarcinoma, Wilms' tumor, lymphoma, leukemia, squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, adenocarcinoma, prostatic sarcoma, seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, and lipoma; Cancers of the hepatobiliary and pancreatic systems selected from hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, pheochromocytoma, insulinoma, VIP tumor, islet cell tumor, pancreatic exocrine tumors (e.g. adenocarcinoma, acinar cell carcinoma, intraductal papillary mucinous tumor, adenocarcinoma with aggressive mucinous cystic tumor) and pancreatic neuroendocrine tumors (e.g. gastrinoma, glucagonoma, insulinoma, somatostatinoma, VIP tumor (VIP), non-functional islet cell tumor); selected from bone sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant Bone cancers among lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteocartilaginous exostosis), benign enchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumor; cancers of the nervous system selected from primary central nervous system lymphoma, osteoma, hemangioma, granuloma, xanthomas, osteitis deformans, meningioma, meningiosarcoma, gliomatosis, astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, spinal neurofibromas, meningiomas, gliomas and sarcomas;Reproductive system cancer selected from endometrial cancer, cervical cancer, preneoplastic cervical atypical hyperplasia, ovarian cancer, serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, granulosa cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma, vulvar squamous cell carcinoma, vulvar intraepithelial carcinoma, vulvar adenocarcinoma, vulvar fibrosarcoma, vulvar melanoma, vaginal clear cell carcinoma, vaginal squamous cell carcinoma, vaginal botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube cancer, placental cancer, uterine cancer, penile cancer, prostate cancer and testicular cancer; hematological cancer selected from bone marrow, acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disease, multiple myeloma, myelodysplastic syndrome, Hodgkin's disease and non-Hodgkin's lymphoma; selected from lip cancer, tongue cancer, gum cancer, oral cancer Oral cancer selected from the group consisting of malignant melanoma, cutaneous melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma and keloid; or selected from the group consisting of adrenal cancer, neuroblastoma, connective tissue and soft tissue cancer, retroperitoneal and peritoneal cancer, eye cancer, intraocular melanoma, uveal melanoma, adnexal cancer, breast cancer, head and / or neck cancer, anal cancer, thyroid cancer, parathyroid cancer, adrenal cancer, cancer of endocrine glands and related structures, secondary and unspecified malignancies of lymph nodes, secondary malignancies of the respiratory and digestive systems and secondary malignancies of other sites. In some embodiments, the cancer is glioblastoma multiforme (GBM). In some embodiments, the cancer is not glioblastoma multiforme (GBM). ;

[0095] In another aspect, any of the compositions described herein is used in a method of inhibiting myeloid-derived suppressor cells (MDSCs) in a patient diagnosed with or suffering from a microbial infection, the method comprising administering to the patient a therapeutically effective amount of a composition described herein.

[0096] In another aspect, any of the compositions described herein are used in a method of 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 a composition described herein.

[0097] In another aspect, any of the compositions described herein is used in a method of reducing the number of regulatory T cells in a patient diagnosed with or suffering from a microbial infection, the method comprising administering to the patient a therapeutically effective amount of the composition described herein.

[0098] In another aspect, any of the compositions described herein is used in 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.

[0099] In another aspect, any of the compositions described herein is used in a method of inhibiting myeloid-derived suppressor cells (MDSCs) in a patient diagnosed with or suffering from sepsis, the method comprising administering to the patient a therapeutically effective amount of a composition described herein.

[0100] In another aspect, any of the compositions described herein are used in a method of reducing immunosuppression in a patient diagnosed with or suffering from sepsis, the method comprising administering to the patient a therapeutically effective amount of a composition described herein.

[0101] In another aspect, any of the compositions described herein are 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 a composition described herein.

[0102] In another aspect, any of the compositions described herein is used in a method for 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. Dosage

[0103] On the other hand, the present disclosure relates to the administration of ibudilast or a pharmaceutically acceptable salt thereof by injection. In some embodiments, the administration of injection 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 administration of injection is subcutaneous injection, intramuscular injection, intrathecal injection, intraperitoneal injection or intraocular injection. dose

[0104] The therapeutic dose can be determined empirically and will vary depending on the specific condition being treated, the subject, and the efficacy and toxicity of each active ingredient in the composition. The actual dose 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 specific combination administered.

[0105] The therapeutically effective amount can be determined by those skilled in the art and adjusted according to the needs of the specific case. Generally speaking, the total daily dose of a therapeutically effective amount of ibudilast or a pharmaceutically acceptable salt thereof will be within an approximate range.

[0106] In some embodiments, the 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, the therapeutically effective amount of ibudilast or a pharmaceutically acceptable salt thereof is at least about 50 mg.

[0107] 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 In some embodiments, the therapeutically effective amount of ibudilast or a pharmaceutically acceptable salt thereof is about 10 mg to about 100 mg.

[0108] 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.

[0109] 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. In some embodiments, the therapeutically effective amount of ibudilast or a pharmaceutically acceptable salt thereof is at least about 50 mg / day.

[0110] 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 200 mg / day, 10 mg / day to about 300 mg / day, 10 mg / day to about 400 mg / day, 10 mg / day to about 500 mg / day, 10 mg / day to about 600 mg / day, 10 mg / day to about 700 mg / day, 10 mg / day to about 800 mg / day, 10 mg / day to about 900 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, 2 0 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 In some embodiments, the therapeutically effective amount of ibudilast or a pharmaceutically acceptable salt thereof is about 10 mg / day to about 100 mg / day.

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

[0112] According to dosage and specific treatment condition, administration can be once, twice, three times or four times a day, and the administration duration can be from one day to several days, weeks, months or even years, and can even last for a lifetime of the patient. Exemplary dosage regimen will last at least about one 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, dosage regimen lasts at least about 12, 24, 36, 48, 60, 72, 84 or 96 weeks. In some embodiments, dosage regimen lasts about 12, 24, 36, 48, 60, 72, 84 or 96 weeks. In some embodiments, the dosing regimen continues for at least about 1 year, 2 years, 3 years, 4 years, or 5 years. In some embodiments, the dosing regimen continues for about 1 year, 2 years, 3 years, 4 years, or 5 years.

[0113] In fact, the unit dose of any given composition or active agent of the present disclosure can be administered in a variety of dosing schedules, depending on the judgment of the clinician, the needs of the patient, etc. Those of ordinary skill in the art will know the specific dosing schedule, or can use conventional methods to determine the specific dosing schedule by experiment. Exemplary dosing schedules include, but are not limited to, five times a day, four times a day, three times a day, twice a day, once a day, once every other day, three times a week, twice a week, once a week, twice a month, once a month, etc. Other active agents

[0114] The preparation (or kit) according to the present disclosure may contain one or more other active agents in addition to ibudilast or its pharmaceutically acceptable salt. In some embodiments, one or more other therapeutic agents have a different mechanism of action from ibudilast. Such active ingredients can be found in the FDA Orange Book, Goodman & Gilman's "Pharmacological Basis of Therapeutics" (J. Griffith Hardman, LL Limbird, A. Gilman, 11th edition, 2005), "The Merck Manual" (18th edition, 2007) and "The Merck Manual of Medical Information" (2003). Reagent test kit

[0115] The present disclosure also provides a kit, which comprises any one of the compositions of the present disclosure and is accompanied by instructions for use.

[0116] For example, the kit includes ibudilast or a pharmaceutically acceptable salt thereof and instructions for use. Ibudilast or a pharmaceutically acceptable salt thereof can be packaged in any suitable manner for administration, and when considered together with the instructions for administration, the package should clearly indicate the manner of administration of each pharmaceutical component.

[0117] For example, for an illustrative kit comprising ibudilast or a pharmaceutically acceptable salt thereof, the kit may be organized by any appropriate time period (e.g., by day). As an example, for day 1, a representative kit may include a unit dose of ibudilast or a pharmaceutically acceptable salt thereof. If each drug is administered twice a day, then corresponding to day 1, the kit may include two rows of unit doses of ibudilast or a pharmaceutically acceptable salt thereof, respectively, and instructions for administration time. Alternatively, if ibudilast or a pharmaceutically acceptable salt thereof is different in administration time or quantity, this will be reflected in the packaging and instructions. Based on the above, various embodiments may be easily conceived, and of course depend on the specific combination of drugs used for treatment in addition to ibudilast or a pharmaceutically acceptable salt thereof, its corresponding dosage form, recommended dose, expected patient population, etc. The packaging may be in any form commonly used for pharmaceutical packaging, and may utilize a variety of features, such as different colors, packaging, tamper-proof packaging, blister packaging, desiccant, etc.

[0118] It should be understood that although the present disclosure has been described in conjunction with preferred specific embodiments, 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 belongs. Example

[0119] Example 1: Initial solubility screening using different excipients

[0120] The solubility of ibudilast was evaluated using the excipients shown in the table below. *After shaking for 2 h, more ibudilast was added and the ibudilast concentration was increased to 50 mg / mL; solubility may be higher. **Very viscous; data unreliable. ***Completely dissolved after 24 hours; solubility may be higher.

[0121] Example 2: Subsequent Solubility Evaluation

[0122] The solubility of ibudilast was evaluated using aqueous and non-aqueous co-solvent mixtures, increasing concentrations of surfactant, or combinations of surfactant and co-solvent as shown in the table below. *Due to the high viscosity of the solvent, the amount added is less than 5mL

[0123] Example 3: Solution Screening, Part 1

[0124] Based on the initial solubility screening results and subsequent solubility assessments, seven formulations were evaluated. All seven formulations contained 25 mg / mL of ibudilast and 15 mM sodium phosphate buffer with a target pH of 7.5. Formulation 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 (1 mL) Formulation 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 (1 mL) Formulation 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 (1 mL) Formulation 4: Kolliphor ELP (250 mg / mL), Na2HPO4·2H2O (1.9941 mg / mL), NaH2PO4·2H2O (0.5923 mg / mL), ibudilast (25 mg / mL), water (1 mL) Formulation 5: Montanox 80 (300 mg / mL), Na2HPO4·2H2O (1.9941 mg / mL), NaH2PO4·2H2O (0.5923 mg / mL), ibudilast (25 mg / mL), water (1 mL) Formulation 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 (1 mL) Formulation 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 (1 mL)

[0125] Each solution was prepared in 50 mL quantities using a volumetric flask. Before adding ibudilast, the solvent was transferred to a beaker for better homogenization. After ibudilast was dissolved, the solution was transferred back to the volumetric flask and water was added to reach the final volume. Finally, the solution was divided into two 20 mL vials and subsequently placed at room temperature or 2-8°C for several days. Dilution tests were performed in 0.9% NaCl solutions (2 mL of the formulation solution was diluted in 50 mL or 100 mL of saline solution). Formulations 1, 2, and 3 were also prepared without buffer to evaluate the effect of the buffer on solubility.

[0126] Formulation 1 (buffered), Formulation 2 (buffered), Formulation 3 (with or without buffer), and Formulation 5 showed solubility issues during formulation preparation. The remaining formulations were tested for dilution. Formulations 4 and 6 were clear solutions after dilution in 50 and 100 mL of saline solution; the other formulations (Formulation 1 without buffer, Formulation 2 without buffer, and Formulation 7) showed solubility issues after dilution testing.

[0127] Example 4: Solution Screening, Part 2

[0128] Based on the results of the solution screening in Part 1, the potential impact of the buffer was further investigated in detail for Formulations 4 and 6. Additionally, other formulations (8A, 8B, 9, 10, 11, 12, and 13) involving surfactants with alternative solvents and with or without buffer were investigated. Formulation 4A: Kolliphor ELP (250 mg / mL), Na2HPO4·2H2O (1.9941 mg / mL), NaH2PO4·2H2O (0.5923 mg / mL), ibudilast (25 mg / mL), water (1 mL) Formulation 4B: Kolliphor ELP (250 mg / mL), ibudilast (25 mg / mL), water (1 mL) Formulation 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) Formulation 6B: propylene glycol (500 mg / mL), glycerol (100 mg / mL), Kolliphor ELP (100 mg / mL), ibudilast (25 mg / mL), water (q.s. 1 mL) Formulation 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) Formulation 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) Formulation 9: Kolliphor ELP (200 mg / mL), Na2HPO4·2H2O (1.9941 mg / mL), NaH2PO4·2H2O (0.5923 mg / mL), ibudilast (20 mg / mL), water (1 mL) Formulation 10: Kolliphor ELP (100 mg / mL), Na2HPO4·2H2O (1.9941 mg / mL), NaH2PO4·2H2O (0.5923 mg / mL), ibudilast (10 mg / mL), water (1 mL) Formulation 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) Formulation 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) Formulation 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)

[0129] Prepare 50 mL of Formulation 9 and Formulation 10: Melt Kolliphor ELP at 55°C and weigh in a beaker. Add Ibudilast to Formulation 9 and Formulation 10 and stir under magnetic stirring for 1.5 hours. Add hot water (40°C) to give a viscous solution for Formulation 9, but homogenization occurs after only 10 minutes for Formulation 10. Add buffer solution under magnetic stirring until complete homogenization for Formulation 9 (1.5 hours) and Formulation 10 (10 minutes). Transfer the solutions to their respective volumetric flasks and add more water to the final volume at room temperature.

[0130] Prepare 50 mL of Formulations 11, 12, and 13: Melt Kolliphor ELP at 55°C and weigh in a beaker. Add propylene glycol to the beaker and homogenize under magnetic stirring for a few minutes to obtain a milky solution. Add ibudilast to Formulations 11 (1 hour, milky solution), Formulation 12 (1 hour, milky solution), and Formulation 13 (1.5 hours, milky solution) under magnetic stirring. Add buffer solution under magnetic stirring at room temperature until Formulations 11, 12, and 13 (10 minutes each) are completely homogenized. Transfer the solutions to their respective volumetric flasks and add more water to the final volume at room temperature.

[0131] Kolliphor ELP used in up to 25% water formed a very viscous gel that took time to dissolve. Formulation 11 had a high viscosity at t=0 (14.65 mPa s) and was difficult to filter. Formulations 9, 10, 12, and 13 had lower viscosities at t=0: 7.33 mPa s (formulation 9), 2.12 mPa s (formulation 10), 6.60 mPa s (formulation 12), and 9.66 mPa s (formulation 13). Formulation 10 was slightly milky at t=0 and t=20 h, while formulations 9, 11, 12, and 13 were clear solutions at t=0 and t=20 h.

[0132] Formulations 9-13 without buffer were also evaluated. Formulations 11-13 without buffer had a milky white color that dissipated upon heating, but a small amount of precipitate remained.

[0133] Further stability studies were performed on Formulations 9 and 13 (each containing 20 mg / mL of ibudilast). At different temperatures (2-8°C or 60°C), buffered solutions (less than 0.4 pH unit change) showed better pH stability over 10 days relative to non-buffered solutions (up to 2 pH unit change). Flocculation / precipitation was also observed for Formulation 9 at t=10 days (60°C). Three weeks of stability testing also showed similar results.

[0134] Example 5: Solution Screening, Part 3

[0135] Other aqueous formulations were evaluated. Formulation 14: SBE-β-CD (100 mg / mL), ibudilast (1 mg / mL), water (1 mL) Formulation 15: SBE-β-CD (100 mg / mL), Na2HPO4·2H2O (2.0284 mg / mL), NaH2PO4·2H2O (0.5622 mg / mL), ibudilast (1 mg / mL), water (1 mL) Formulation 16: propylene glycol (3 mg / mL), ethanol (80 mg / mL), ibudilast (1 mg / mL), water (1 mL) Formulation 17: PEG 400 (100 mg / mL), ethanol (50 mg / mL), ibudilast (1 mg / mL), water (1 mL) Formulation 18: PEG 400 (100 mg / mL), ethanol (30 mg / mL), ibudilast (1 mg / mL), water (1 mL) Formulation 19: PEG 400 (100 mg / mL), ethanol (80 mg / mL), ibudilast (1 mg / mL), water (1 mL) Formulation 20: PEG 400 (100 mg / mL), ethanol (100 mg / mL), ibudilast (1 mg / mL), water (1 mL) Formulation 21: PEG 400 (75 mg / mL), ethanol (100 mg / mL), ibudilast (1 mg / mL), water (1 mL) Formulation 22: PEG 400 (150 mg / mL), ethanol (80 mg / mL), ibudilast (1 mg / mL), water (1 mL) Formulation 23: PEG 400 (150 mg / mL), ethanol (50 mg / mL), ibudilast (1 mg / mL), water (1 mL) Formulation 24: PEG 400 (150 mg / mL), ethanol (100 mg / mL), ibudilast (1 mg / mL), water (1 mL) Formulation 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 (1 mL) Formulation 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 (1 mL) Formulation 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 (1 mL)

[0136] All formulations were clear solutions at T0 and were stored at room temperature and at 2-8°C for subsequent use. At both storage temperatures, only four formulations remained clear solutions after 48 hours and 7 days: two formulations prepared with 10% SBE-β-CD (buffered formulation 15 and non-buffered formulation 14), and two formulations prepared with 10% ethanol and 15% PEG 400 (buffered formulation 26 and non-buffered formulation 24). All other formulations began to precipitate after 24 hours or 48 hours of storage at 2-8°C. The pH values ​​of formulations 14, 15, 24, and 26 were all between 6.3 and 8, with the pH of the buffered formulations being closer to the target pH of the infusion product (approximately 7.5).

[0137] In terms of osmolarity, the two formulations prepared using SBE-β-CD were close to isotonic, with an osmolarity value of 267 mOsm / kg for the non-buffered formulation (Formulation 14) and 302 mOsm / kg for the buffered formulation (Formulation 15). The osmolarity value was higher for the formulation containing the PEG 400 / ethanol cosolvent.

[0138] Formulations 14, 15, and 24 were further evaluated in short-term stress studies to assess their physical and chemical stability during storage for 4 weeks at different conditions (i.e., 2-8°C, 25°C / 60% RH, 40°C / 75% RH, and 60°C). Preliminary shear stress studies and freeze-thaw studies were also performed. Formulation 15 performed better than formulations 14 and 24.

[0139] Example 6: Phase I trial: single dose, safety, tolerability and pharmacokinetics in healthy volunteers to test the absorption rate and extent of ibudilast extended release oral or parenteral formulations.

[0140] The subjects participated in two different parts of this study. Part A is a crossover, open-label, single-center Phase I study in 12 healthy volunteers. Subjects who meet the study eligibility and provide informed consent will be randomized into two sequences according to one of the following treatment regimens in Part A. sequence Week 1 Week 2 Week 3 1 ERC after eating ERC fasting IRC fasting 2 ERC fasting ERC after eating IRC fasting ERC = extended-release capsule; IRC = intermediate-release capsule (commercially available) Part B: Subjects received a single dose of 10 mg of ibudilast (prepared according to Formulation 15) intravenously at a constant rate over 4 hours (1 mg / mL).

[0141] During each dosing treatment period, subjects checked into the research facility the night before dosing and remained there for 32 hours after dosing. Subjects returned to the research facility for outpatient visits on each of the remaining pharmacokinetic sampling days (48 hours, 72 hours, 96 hours, and 168 hours after treatment). Subjects were discharged 168 hours after the start of study drug infusion.

[0142] During each treatment period, blood samples (approximately 2 mL per sample) were collected before dosing, and at 0.5, 1, 2 (at the end of the infusion), 4, 6, 8, 10, 12, 24, 32, 48, 72, 96, and 168 hours after the start of the infusion. Ibudilast was detected using a validated liquid chromatography-tandem mass spectrometry (LC / MS / MS) method.

[0143] The pharmacokinetic data for intravenous administration are as follows:

[0144] The pharmacokinetic data of intermediate-release capsules (single dose 50 mg) are as follows:

[0145] Certain embodiments

[0146] Embodiment 1: A pharmaceutical composition consisting of a buffered aqueous solution comprising about 5% w / v to about 15% w / v sulfobutyl ether-β-cyclodextrin (SBE-β-CD) and about 0.05% w / v to about 0.5% w / v ibudilast.

[0147] Embodiment 2: The pharmaceutical composition of Embodiment 1, wherein the buffered aqueous solution comprises disodium hydrogen phosphate (Na2HPO4) and sodium dihydrogen phosphate (NaH2PO4).

[0148] Embodiment 3: The pharmaceutical composition of Embodiment 2, wherein the content of Na2HPO4 in the buffered aqueous solution is about 0.2% w / v, and the content of NaH2PO4 in the buffered aqueous solution is about 0.06% w / v.

[0149] Embodiment 4: The pharmaceutical composition of any one of Embodiments 1-3, wherein the content of SBE-β-CD in the buffered aqueous solution is about 10% w / v.

[0150] Embodiment 5: The pharmaceutical composition of any one of Embodiments 1-4, wherein the content of ibudilast in the buffered aqueous solution is about 0.1% w / v.

[0151] Embodiment 6: A pharmaceutical composition consisting of the following ingredients: About 10% w / v SBE-β-CD; About 0.2% w / v disodium hydrogen phosphate; About 0.06% w / v sodium dihydrogen phosphate; About 0.1% w / v of ibudilast; Appropriate amount of water.

[0152] Embodiment 7: A pharmaceutical composition consisting of a buffered aqueous solution comprising about 5% w / v to about 25% w / v of polyoxyethylene castor oil and about 1% w / v to about 5% w / v of ibudilast.

[0153] Embodiment 8: The pharmaceutical composition of Embodiment 7, wherein the buffered aqueous solution comprises about 10% w / v to about 20% w / v polyoxyethylene castor oil.

[0154] Embodiment 9: The pharmaceutical composition of Embodiment 7 or Embodiment 8, wherein the buffered aqueous solution further comprises about 20% w / v to about 60% w / v propylene glycol.

[0155] Embodiment 10: The pharmaceutical composition of Embodiment 9, wherein the content of propylene glycol in the buffered aqueous solution is about 40% w / v.

[0156] Embodiment 11: The pharmaceutical composition of any one of Embodiments 7-10, wherein the polyoxyethylene castor oil is polyoxyethylene-35 castor oil.

[0157] Embodiment 12: The pharmaceutical composition of any one of Embodiments 7-11, wherein the buffered aqueous solution comprises disodium hydrogen phosphate (Na2HPO4) and sodium dihydrogen phosphate (NaH2PO4).

[0158] Embodiment 13: The pharmaceutical composition of Embodiment 12, wherein the content of Na2HPO4 in the buffered aqueous solution is about 0.2% w / v, and the content of NaH2PO4 in the buffered aqueous solution is about 0.06% w / v.

[0159] Embodiment 14: The pharmaceutical composition of any one of Embodiments 7-13, wherein the content of ibudilast in the buffered aqueous solution is about 2% w / v.

[0160] Embodiment 15: A pharmaceutical composition consisting of the following ingredients: About 10% w / v polyoxyethylene castor oil; About 40% w / v propylene glycol; About 0.2% w / v disodium hydrogen phosphate; About 0.06% w / v sodium dihydrogen phosphate; about 2% w / v ibudilast; and Appropriate amount of water.

[0161] Embodiment 16: A pharmaceutical composition consisting of the following ingredients: About 20% w / v polyoxyethylene castor oil; About 0.2% w / v disodium hydrogen phosphate; About 0.06% w / v sodium dihydrogen phosphate; about 2% w / v ibudilast; and Appropriate amount of water.

[0162] Embodiment 17: The pharmaceutical composition of any one of Embodiments 1-16, wherein the pharmaceutical composition is an injectable composition.

[0163] Embodiment 18: A method of treating a neurodegenerative disease or disorder in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition of any one of Embodiments 1-17.

[0164] Embodiment 19: The method of embodiment 18, wherein the neurodegenerative disease or dysfunction is: Alzheimer's disease, Alzheimer's type senile dementia, Pick's disease (lobar atrophy), a syndrome with progressive dementia and other significant neurological abnormalities, Huntington's disease, multiple system atrophy with dementia combined with ataxia and / or Parkinson's disease manifestations, progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome), diffuse Lewy body disease, cortical dentate nigral degeneration, Hallerwarden-Spatz disease, progressive familial myoclonus epilepsy, gradual onset of postural and motor abnormalities, Parkinson's disease, striatonigral degeneration, progressive supranuclear palsy, torsion dystonia (torsion spasm; dystonia deformans), spasmodic torticollis and other restrictive movement disorders, 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-Dra ger syndrome), muscle weakness and wasting syndromes 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, muscle weakness and wasting syndromes with sensory changes (progressive neuromuscular atrophy; chronic familial polyneuropathy), Charcot-Marie-Tooth, hypertrophic interstitial polyneuropathy (Deferine-Sottas) or other forms of chronic progressive neuropathies, progressive vision loss syndromes, retinitis pigmentosa (retinitis pigmentosa), hereditary optic atrophy (Leber disease), Parkinson's disease and other extrapyramidal diseases, progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome), torsion dystonia (torsion spasm;dystonia deformans), focal dystonia, motor neuron disease, progressive ataxia, primary lateral sclerosis, multifocal motor neuropathy with conduction block, motor neuropathy with paraproteinemia, predominantly motor peripheral neuropathy, olivopontocerebellar atrophy, Azores (Machado-Joseph disease), familial progressive neurodegenerative disorders, familial amyotrophic lateral sclerosis, spinal muscular atrophy, familial spastic paraplegia, inherited biochemical disorders, arthrogryposis multiplex congenita or progressive juvenile bulbar palsy (Fazio-Londe), infantile form (Werdnig-Hoffman disease), or childhood or adolescent onset (Woh Favart-Kugelberg-Welander disease), degenerative cervical spondylosis, familial HTLV-1 myelopathy, isolated FSP or complex 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 syndrome, kuru, fatal familial insomnia, Alper disease, primary progressive or secondary progressive multiple sclerosis, but not including relapsing remitting multiple sclerosis, frontotemporal dementia, Wilson disease, progressive neuropathic pain, ischemia due to stroke, traumatic brain injury, or spinal cord injury.

[0165] Embodiment 20: A method of treating cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition according to any one of Embodiments 1-17.

[0166] Embodiment 21: A method of preventing cancer metastasis in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition of any one of Embodiments 1-17.

[0167] Embodiment 22: A method of reducing cancer metastasis in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition of any one of Embodiments 1-17.

[0168] Embodiment 23: A method of minimizing cancer metastasis in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition of any one of Embodiments 1-17.

[0169] Embodiment 24: A method of preventing cancer recurrence in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition of any one of Embodiments 1-17.

[0170] Embodiment 25: A method of reducing cancer recurrence in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition of any one of Embodiments 1-17.

[0171] Embodiment 26: A method of minimizing the risk of or delaying cancer recurrence in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition according to any one of Embodiments 1-17.

[0172] Embodiment 27: The method of any one of Embodiments 20-26, wherein the cancer is: a. Cancer of the circulatory system selected from angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyoma, myofibroma, lipoma and teratoma, mediastinal carcinoma and pleural carcinoma or vascular tumors; b. Cancer of the respiratory tract selected from the group consisting of nasal cavity and middle ear cancer, paranasal sinus cancer, laryngeal cancer, tracheal cancer, bronchial and lung cancer, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), bronchogenic carcinoma, squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma, alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, enchondromatous hamartoma or mesothelioma; c. a cancer of the gastrointestinal system selected from the group consisting of squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma, carcinoma, ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma, adenocarcinoma, carcinoid tumor, Kaposi's sarcoma, hemangioma, lipoma, neurofibroma, fibroma, tubular adenoma, villous adenoma, hamartoma or leiomyoma; d. a cancer of the genitourinary tract selected from adenocarcinoma, Wilm's tumor, lymphoma, leukemia, squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, adenocarcinoma, prostatic sarcoma, seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor or lipoma; e. Cancer of the hepatobiliary and pancreatic system selected from hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, pheochromocytoma, insulinoma, VIP tumor, islet cell tumor, pancreatic exocrine tumor and pancreatic neuroendocrine tumor; f. Bone cancer selected from the group consisting of osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteocartilaginous exostosis), benign enchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma or giant cell tumor; g. Cancer of the nervous system selected from the group consisting of primary central nervous system lymphoma, osteoma, hemangioma, granuloma, xanthomas, osteitis deformans, meningioma, meningiosarcoma, gliomatosis, astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, spinal neurofibromas, meningiomas, gliomas or sarcomas; h. a cancer of the reproductive system selected from the group consisting of endometrial cancer, cervical cancer, preneoplastic cervical atypical hyperplasia, ovarian cancer, serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, granulosa theca cell tumor, Sertoli cell-Leydig cell tumor, dysgerminoma, malignant teratoma, vulvar squamous cell carcinoma, vulvar intraepithelial carcinoma, vulvar adenocarcinoma, vulvar fibrosarcoma, vulvar melanoma, vaginal clear cell carcinoma, vaginal squamous cell carcinoma, vaginal botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube cancer, placental cancer, uterine cancer, penile cancer, prostate cancer, or testicular cancer; i. a cancer of the hematologic system selected from the group consisting of bone marrow, acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disease, multiple myeloma, myelodysplastic syndrome, Hodgkin's disease, or non-Hodgkin's lymphoma; j. Oral cancer selected from the group consisting of lip cancer, tongue cancer, gum cancer, floor of mouth cancer, palate cancer, parotid gland cancer, salivary gland cancer, tonsil cancer, oropharyngeal cancer, nasopharyngeal cancer, pyriform sinus cancer, or hypopharyngeal cancer; k. a skin cancer selected from the group consisting of malignant melanoma, cutaneous melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma and keloid; or l. A cancer selected from the group consisting of adrenal cancer, neuroblastoma, connective and soft tissue cancer, retroperitoneal and peritoneal cancer, eye cancer, intraocular melanoma, adnexal cancer, breast cancer, head and / or neck cancer, anal cancer, thyroid cancer, parathyroid cancer, adrenal cancer, cancer of the endocrine glands and related structures, secondary and unspecified malignancies of the lymph nodes, secondary malignancies of the respiratory and digestive systems, or secondary malignancies of other sites.

[0173] Embodiment 28: A method of treating an autoimmune disorder in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition of any one of Embodiments 1-17.

[0174] Embodiment 29: The method of embodiment 28, wherein the autoimmune dysfunction comprises: rheumatoid arthritis, IgA nephropathy, vascular disease 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 or idiopathic pulmonary fibrosis.

[0175] Embodiment 30: A method of treating a microbial infection in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition according to any one of Embodiments 1-17.

[0176] Embodiment 31: The method of Embodiment 30, wherein the microbial infection is caused by viruses, bacteria, fungi, or a combination of any two or more thereof.

[0177] Embodiment 32: A method of treating sepsis and / or septic shock in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition of any one of Embodiments 1-17.

[0178] Embodiment 33: A method of treating severe viral pneumonia in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition according to any one of Embodiments 1-17.

[0179] Embodiment 34: The method of Embodiment 33, wherein the severe viral pneumonia is associated with a respiratory viral infection.

[0180] Embodiment 35: The method of Embodiment 34, wherein the respiratory virus is selected from influenza virus, respiratory syncytial virus, coronavirus, rhinovirus, adenovirus and parainfluenza virus.

[0181] Embodiment 36: The method of Embodiment 35, wherein the coronavirus is COVID-19.

[0182] Embodiment 37: A method for treating mild to severe acute respiratory distress syndrome (ARDS) in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition as described in any one of Embodiments 1-17, wherein the patient has a positive end-expiratory pressure (PEEP) ≥ 5 cm H2O; and PaO2 / FiO2 < 300 mm Hg.

[0183] Embodiment 38: The method of Embodiment 37, wherein the patient's positive end-expiratory pressure (PEEP) is ≥ 5 cm H2O; and PaO2 / FiO2 is < 200 mm Hg.

[0184] Embodiment 39: The method of Embodiment 37 or Embodiment 38, wherein the ARDS is associated with a respiratory viral infection.

[0185] Embodiment 40: The method of Embodiment 39, wherein the respiratory virus is selected from influenza virus, respiratory syncytial virus, coronavirus, rhinovirus, adenovirus and parainfluenza virus.

[0186] Embodiment 41: The method of Embodiment 40, wherein the coronavirus is COVID-19.

[0187] Embodiment 42: A method of treating fragile X syndrome in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition according to any one of embodiments 1-17.

[0188] Embodiment 43: A method of treating acute lung injury in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition according to any one of Embodiments 1-17.

[0189] Embodiment 44: The method of Embodiment 43, wherein the lung injury is caused by aspiration, trauma, pancreatitis, blood transfusion, or inhalation of smoke or inhalation of toxic chemicals.

[0190] Embodiment 45: The method of Embodiment 43, wherein the lung injury is caused by a chemical selected from the group consisting of chlorine, mustard gas, phosgene, Lewis agent, hydrogen chloride, sulfur dioxide, hydrogen sulfide, nitrogen dioxide, ammonia, hydrofluoric acid, ozone, methyl isocyanate, and any two or more combinations thereof.

[0191] Embodiment 46: The method of any one of Embodiments 43-45, wherein the lung injury comprises: chemical burns, pulmonary edema, laryngeal edema, lung tissue apoptosis, pneumonia (caused by infection), pneumonia (caused by reasons other than infection), bronchitis, bronchiolitis, fibrosis, acute respiratory distress syndrome, airway spasm, or a combination of any two or more thereof.

[0192] Although the present disclosure supports a definition referring to alternatives only and "and / or," the term "or" used in the claims is used to mean "and / or" unless explicitly stated to refer to alternatives only or the alternatives are mutually exclusive.

[0193] While particular embodiments have been illustrated and described, it will be appreciated that modifications and changes may be made thereto in accordance with ordinary skill in the art without departing from the broader aspects of the technology as defined by the following claims.

[0194] The embodiments described in the present invention can be appropriately implemented in the absence of any elements or limitations not specifically disclosed in the present invention. Thus, for example, the terms "comprising", "including", "containing", etc. should be understood broadly and without limitation. In addition, the terms and expressions used in the present disclosure are used as descriptive terms rather than restrictive terms, and the use of such terms and expressions is not intended to exclude any equivalents of the features shown and described or parts thereof, but it should be recognized that various modifications can be made within the scope of the claimed technology. In addition, the term "essentially consisting of..." will be understood to include those specifically listed elements and those additional elements that will not have a substantial impact on the basic and novel features of the claimed technology. The phrase "consisting of..." excludes any unspecified elements.

[0195] The present invention is not limited to the specific embodiments described in this application. It will be appreciated by those skilled in the art that many modifications and variations may be made without departing from its spirit and scope. In addition to the methods and compositions listed in the present invention, it will be apparent to those skilled in the art from the foregoing description that functionally equivalent methods and compositions within the scope of the present invention are within the scope of the present invention. Such modifications and variations are intended to fall within the scope of the appended claims. The present invention is limited only by the terms of the appended claims and the full scope of the equivalents of these claims. It should be understood that the present invention is not limited to specific methods, reagents, compounds, compositions or biological systems, and these factors may vary. It should also be understood that the terms used herein are only used to describe specific embodiments and are not intended to be limiting.

[0196] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0197] As will be appreciated by those skilled in the art, for any and all purposes, particularly in providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily considered to fully describe and enable the same range to be decomposed into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be easily decomposed into a lower third, a middle third, and an upper third, etc. All language, such as "at most," "at least," "greater than," "less than," etc., can also be understood by those skilled in the art to include the listed numbers and refer to ranges that can subsequently be decomposed into subranges as described above. Finally, as will be appreciated by those skilled in the art, ranges include each individual member.

[0198] All publications, patent applications, issued patents, and other documents mentioned in this specification are incorporated herein by reference, as if each individual publication, patent application, issued patent, or other document was expressly and individually indicated to be incorporated by reference in its entirety. Definitions contained in the cited text are excluded to the extent they conflict with definitions in the present invention.

[0199] Other embodiments are set forth in the claims.

Claims

1. A pharmaceutical composition consisting of a buffered aqueous solution comprising 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.

2. The pharmaceutical composition according to claim 1, wherein The buffered aqueous solution comprises disodium hydrogen phosphate (Na2HPO4) and sodium dihydrogen phosphate (NaH2PO4).

3. The pharmaceutical composition according to claim 2, wherein The content of Na2HPO4 in the buffered aqueous solution is about 0.2% w / v, and the content of NaH2PO4 in the buffered aqueous solution is about 0.06% w / v.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein The content of SBE-β-CD in the buffered aqueous solution is about 10% w / v.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein The content of ibudilast in the buffered aqueous solution is about 0.1% w / v.

6. A pharmaceutical composition consisting of the following ingredients: About 10% w / v SBE-β-CD; About 0.2% w / v disodium hydrogen phosphate; About 0.06% w / v sodium dihydrogen phosphate; About 0.1% w / v of ibudilast; Appropriate amount of water.

7. A pharmaceutical composition consisting of a buffered aqueous solution comprising about 5% w / v to about 25% w / v of polyoxyethylene castor oil and about 1% w / v to about 5% w / v of ibudilast.

8. The pharmaceutical composition according to claim 7, wherein The buffered aqueous solution contains about 10% w / v to about 20% w / v polyoxyethylene castor oil.

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

10. The pharmaceutical composition according to claim 9, wherein The content of propylene glycol in the buffered aqueous solution is about 40% w / v.

11. The pharmaceutical composition according to any one of claims 7 to 10, wherein The polyoxyethylene castor oil is polyoxyethylene-35 castor oil.

12. The pharmaceutical composition according to any one of claims 7 to 11, wherein The buffered aqueous solution includes disodium hydrogen phosphate (Na2HPO4) and sodium dihydrogen phosphate (NaH2PO4).

13. The pharmaceutical composition according to claim 12, wherein The content of Na2HPO4 in the buffered aqueous solution is about 0.2% w / v, and the content of NaH2PO4 in the buffered aqueous solution is about 0.06% w / v.

14. The pharmaceutical composition according to any one of claims 7 to 13, wherein The content of ibudilast in the aqueous buffer solution is about 2% w / v.

15. A pharmaceutical composition consisting of the following ingredients: About 10% w / v polyoxyethylene castor oil; About 40% w / v propylene glycol; About 0.2% w / v disodium hydrogen phosphate; About 0.06% w / v sodium dihydrogen phosphate; about 2% w / v ibudilast; and Appropriate amount of water.

16. A pharmaceutical composition consisting of the following ingredients: About 20% w / v polyoxyethylene castor oil; About 0.2% w / v disodium hydrogen phosphate; About 0.06% w / v sodium dihydrogen phosphate; about 2% w / v ibudilast; and Appropriate amount of water.

17. The pharmaceutical composition according to any one of claims 1 to 16, wherein the pharmaceutical composition is an injectable composition.

18. A method of treating a neurodegenerative disease or disorder in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition of any one of claims 1-17.

19. The method according to claim 18, wherein: The neurodegenerative diseases or functional disorders are: Alzheimer's disease, Alzheimer's type senile dementia, Pick's disease (lobar atrophy), a syndrome with progressive dementia and other significant neurological abnormalities, Huntington's disease, multiple system atrophy with dementia and ataxia and / or Parkinson's disease manifestations, progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome), diffuse Lewy body disease, cortical dentate nigral degeneration, Hallervorden-Spatz disease, progressive familial myoclonic epilepsy, gradual onset of postural and Movement disorders, Parkinson's disease, striatonigral degeneration, progressive supranuclear palsy, torsion dystonia (torsion spasm; dystonia deformans), spasmodic torticollis and other restrictive movement disorders, 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), Muscle weakness and wasting syndromes 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, muscle weakness and wasting syndromes with sensory changes (progressive neuromuscular atrophy; chronic familial polyneuropathy), Charcot-Marie-Tooth, hypertrophic interstitial polyneuropathy (Deferine-Sottas) or other forms of chronic progressive neuropathies, progressive vision loss syndromes, retinitis pigmentosa (retinitis pigmentosa), hereditary optic atrophy (Leber disease), Parkinson's disease and other extrapyramidal diseases, progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome), torsion dystonia (torsion spasm;dystonia deformans), focal dystonia, motor neuron disease, progressive ataxia, primary lateral sclerosis, multifocal motor neuropathy with conduction block, motor neuropathy with paraproteinemia, predominantly motor peripheral neuropathy, olivopontocerebellar atrophy, Azores (Machado-Joseph disease), familial progressive neurodegenerative disorders, familial amyotrophic lateral sclerosis, spinal muscular atrophy, familial spastic paraplegia, inherited biochemical disorders, arthrogryposis multiplex congenita or progressive juvenile bulbar palsy (Fazio-Londe), infantile form (Werdnig-Hoffman disease), or childhood or adolescent onset (Woh Favart-Kugelberg-Welander disease), degenerative cervical spondylosis, familial HTLV-1 myelopathy, isolated FSP or complex 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 syndrome, kuru, fatal familial insomnia, Alper disease, primary progressive or secondary progressive multiple sclerosis, but not including relapsing remitting multiple sclerosis, frontotemporal dementia, Wilson disease, progressive neuropathic pain, ischemia due to stroke, traumatic brain injury, or spinal cord injury.

20. A method of treating cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition of any one of claims 1-17.

21. A method of preventing cancer metastasis in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition of any one of claims 1-17.

22. A method of reducing cancer metastasis in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition of any one of claims 1-17.

23. A method of minimizing cancer metastasis in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition of any one of claims 1-17.

24. A method of preventing cancer recurrence in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition of any one of claims 1-17.

25. A method of reducing cancer recurrence in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition of any one of claims 1-17.

26. A method of minimizing the risk of or delaying the recurrence of cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition of any one of claims 1-17.

27. The method according to any one of claims 20 to 26, wherein: The cancer is: a. Cancer of the circulatory system selected from angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyoma, myofibroma, lipoma and teratoma, mediastinal carcinoma and pleural carcinoma or vascular tumors; b. Cancer of the respiratory tract selected from the group consisting of nasal cavity and middle ear cancer, paranasal sinus cancer, laryngeal cancer, tracheal cancer, bronchial and lung cancer, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), bronchogenic carcinoma, squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma, alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, enchondromatous hamartoma or mesothelioma; c. a cancer of the gastrointestinal system selected from the group consisting of squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma, carcinoma, ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma, adenocarcinoma, carcinoid tumor, Kaposi's sarcoma, hemangioma, lipoma, neurofibroma, fibroma, tubular adenoma, villous adenoma, hamartoma or leiomyoma; d. a cancer of the genitourinary tract selected from adenocarcinoma, Wilm's tumor, lymphoma, leukemia, squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, adenocarcinoma, prostatic sarcoma, seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor or lipoma; e. Cancer of the hepatobiliary and pancreatic system selected from hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, pheochromocytoma, insulinoma, VIP tumor, islet cell tumor, pancreatic exocrine tumor and pancreatic neuroendocrine tumor; f. Bone cancer selected from the group consisting of osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteocartilaginous exostosis), benign enchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma or giant cell tumor; g. Cancer of the nervous system selected from the group consisting of primary central nervous system lymphoma, osteoma, hemangioma, granuloma, xanthomas, osteitis deformans, meningioma, meningiosarcoma, gliomatosis, astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, spinal neurofibromas, meningiomas, gliomas or sarcomas; h. a cancer of the reproductive system selected from the group consisting of endometrial cancer, cervical cancer, preneoplastic cervical atypical hyperplasia, ovarian cancer, serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, granulosa theca cell tumor, Sertoli cell-Leydig cell tumor, dysgerminoma, malignant teratoma, vulvar squamous cell carcinoma, vulvar intraepithelial carcinoma, vulvar adenocarcinoma, vulvar fibrosarcoma, vulvar melanoma, vaginal clear cell carcinoma, vaginal squamous cell carcinoma, vaginal botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube cancer, placental cancer, uterine cancer, penile cancer, prostate cancer, or testicular cancer; i. a cancer of the hematologic system selected from the group consisting of bone marrow, acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disease, multiple myeloma, myelodysplastic syndrome, Hodgkin's disease, or non-Hodgkin's lymphoma; j. Oral cancer selected from the group consisting of lip cancer, tongue cancer, gum cancer, floor of mouth cancer, palate cancer, parotid gland cancer, salivary gland cancer, tonsil cancer, oropharyngeal cancer, nasopharyngeal cancer, pyriform sinus cancer, or hypopharyngeal cancer; k. a skin cancer selected from the group consisting of malignant melanoma, cutaneous melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma and keloid; or l. A cancer selected from the group consisting of adrenal cancer, neuroblastoma, connective and soft tissue cancer, retroperitoneal and peritoneal cancer, eye cancer, intraocular melanoma, adnexal cancer, breast cancer, head and / or neck cancer, anal cancer, thyroid cancer, parathyroid cancer, adrenal cancer, cancer of the endocrine glands and related structures, secondary and unspecified malignancies of the lymph nodes, secondary malignancies of the respiratory and digestive systems, or secondary malignancies of other sites.

28. A method of treating an autoimmune disorder in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition of any one of claims 1-17.

29. The method of claim 28, wherein the autoimmune disorder comprises: Rheumatoid arthritis, IgA nephropathy, vascular disease 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, or idiopathic pulmonary fibrosis.

30. A method of treating a microbial infection in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition according to any one of claims 1-17.

31. The method according to claim 30, wherein: The microbial infection is caused by viruses, bacteria, fungi or a combination of any two or more thereof.

32. A method of treating sepsis and / or septic shock in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition of any one of claims 1-17.

33. A method of treating severe viral pneumonia in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition as described in any one of claims 1-17.

34. The method of claim 33, wherein: Severe viral pneumonia is associated with respiratory viral infections.

35. The method of claim 34, wherein: The respiratory virus is selected from the group consisting of influenza virus, respiratory syncytial virus, coronavirus, rhinovirus, adenovirus and parainfluenza virus.

36. The method of claim 35, wherein: The coronavirus is COVID-19.

37. A method for treating mild to severe acute respiratory distress syndrome (ARDS) in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition according to any one of claims 1 to 17, wherein The patient's positive end-expiratory pressure (PEEP) is ≥5 cm H2O; and PaO2 / FiO2 is <300 mm Hg.

38. The method of claim 37, wherein: The patient's positive end-expiratory pressure (PEEP) is ≥5cm H2O; and PaO2 / FiO2 is <200mm Hg.

39. The method according to claim 37 or 38, wherein: ARDS is associated with respiratory viral infections.

40. The method of claim 39, wherein: The respiratory virus is selected from the group consisting of influenza virus, respiratory syncytial virus, coronavirus, rhinovirus, adenovirus and parainfluenza virus.

41. The method of claim 40, wherein: The coronavirus is COVID-19.

42. A method of treating fragile X syndrome in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition of any one of claims 1-17.

43. A method of treating acute lung injury in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition as described in any one of claims 1-17.

44. The method of claim 43, wherein: The lung injury described is caused by aspiration, trauma, pancreatitis, blood transfusion, or inhalation of smoke or inhalation of toxic chemicals.

45. The method of claim 43, wherein: The lung injury is caused by a chemical selected from chlorine, mustard gas, phosgene, Lewis agent, hydrogen chloride, sulfur dioxide, hydrogen sulfide, nitrogen dioxide, ammonia, hydrofluoric acid, ozone, methyl isocyanate, and any two or more combinations thereof.

46. ​​The method according to any one of claims 43 to 45, wherein: The lung injury includes: chemical burns, pulmonary edema, laryngeal edema, lung tissue apoptosis, pneumonia (caused by infection), pneumonia (caused by reasons other than infection), bronchitis, bronchiolitis, fibrosis, acute respiratory distress syndrome, airway spasm, or a combination of two or more thereof.

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