WO2024103012A1 - Polycyclic compounds for use in neurodegenerative conditions - Google Patents
Polycyclic compounds for use in neurodegenerative conditions Download PDFInfo
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- WO2024103012A1 WO2024103012A1 PCT/US2023/079395 US2023079395W WO2024103012A1 WO 2024103012 A1 WO2024103012 A1 WO 2024103012A1 US 2023079395 W US2023079395 W US 2023079395W WO 2024103012 A1 WO2024103012 A1 WO 2024103012A1
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Definitions
- Riluzole is the first treatment for ALS approved by the U.S. FDA in 1995. Riluzole works by blocking the release of glutamate, too much of which is believed to injure nerve cells.
- Edaravone is the second (and only other) drug approved for ALS. It was approved in Japan and South Korea in 2015. In the U.S, the drug received Orphan Drug Designation from the FDA by 2016, followed by the EU’s EMA. In 2017, the FDA approved RADICAVA® (intravenous formulation of Edaravone). Edaravone is a synthetic free radical scavenger and works by decreasing oxidative stress, another potential cause of nerve cell death in ALS.
- Dermatosclerosis a chronic hardening and shrinking of the connective tissues of any organ of the body, including the skin, heart, esophagus, kidney, or lung.
- the skin may be thickened, hard, and rigid, and pigmented patches may occur.
- the two main types are systemic scleroderma and localized scleroderma.
- the milder forms are most often seen in women between the ages of 30 and 50; the more severe forms usually affect men, blacks, and older persons.
- systemic sclerosis It is estimated the incidence of systemic sclerosis in the United States is approximately 20 cases per million population, and its prevalence is approximately 276 cases per million population (Jimenez, Drugs & Diseases, Rheumatology, Scleroderma, emedicine.medscape.com/article/331864 (2022)).
- An increase in systemic sclerosis incidence and prevalence has occurred over the last 50 years.
- Systemic sclerosis occurs worldwide, although its reported prevalence varies significantly in different countries; with higher prevalence rates reported in Europe and the Americas in comparison to East Asia. Obtaining an exact estimate of prevalence is challenging given that systemic sclerosis is often misdiagnosed. Additionally, ethnic and geographical clustering may contribute to the variability in terms of frequency. However, it appears that there is a higher frequency among black individuals.
- the method includes administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof: wherein R 1 is ( CO 2 )-, CO 2 (C 1 -C 6 alkyl), or CO 2 H; R 2 is CO 2 (C 1 -C 6 alkyl), CO 2 H, or (CO 2 )-; R 3 is independently selected at each occurrence from H, C(O)C 1 -C 6 alkyl, or C 1 -C 6 alkyl; X is a cation; and n is 0, 1, or 2.
- Another aspect of the present application relates to a pharmaceutical composition for the treatment of a neurodegenerative disease including a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof.
- a further aspect of the present application relates to a method of treating a fibrotic condition or disease in a subject in need thereof. The method includes administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof.
- Another aspect of the present application relates to a pharmaceutical composition for the treatment of a fibrotic condition or disease comprising a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof.
- Figure 1A is flowchart showing the treatment of hCD14+ monocytes for the inhibition of lipopolysaccharide stimulated IL-12 p70 and TNF- ⁇ production in human dendritic cells of Example 5.
- Figure 1B is a plot of the inhibition of lipopolysaccharide stimulated IL-12 p70 production in human dendritic cells treated with the compound described herein.
- Figure 1C is a plot of the inhibition of lipopolysaccharide stimulated TNF- ⁇ production in human dendritic cells treated with the compound described herein.
- Figure 2A is flowchart showing the treatment of human peripheral CD3+ T cells for the inhibition of IL-2, IL-4 and TNF- ⁇ production of Example 6.
- Figure 2B is a plot of the inhibition of the IL-2, IL-4 and TNF- ⁇ production in human CD3 + T stimulated with stimulated with anti-CD3/anti-CD28 or PMA/Ionomycin upon treatment with the compound described herein.
- Figure 2C is a plot of the cell viability of human peripheral CD3+ T cells treated with the compounds described herein as described in Example 6.
- Figure 3 is a plot of the reduction of the reactive oxygen species in human vascular endothelial cells treated with the compounds described herein as described in Example 7.
- the present application provides chemical entities (e.g., a compound or a pharmaceutically acceptable salt, and/or hydrate, and/or solvate, and/or co-crystal, and/or drug combination of the compound) with strong antioxidant properties. These chemical entities are useful, e.g., for treating a condition, disease or disorder in which increased (e.g., excessive) oxidative stress, immune response, and/or inflammation is associated with the pathology and/or symptoms and/or progression of the condition, disease or disorder in a subject (e.g., a human).
- the present application also provides compositions containing the same, as well as methods of using and making the same.
- R 1 is (CO 2 )-, CO 2 (C 1 -C 6 alkyl), or CO 2 H
- R 2 is CO 2 (C 1 -C 6 alkyl), CO 2 H, or (CO 2 )-
- R 3 is independently selected at each occurrence from H, C(O)C 1 -C 6 alkyl, or C 1 -C 6 alkyl
- X is a cation
- n is 0, 1, or 2.
- about means a range extending to +/- 10% of the specified value. In embodiments, about means the specified value.
- B. Chemical Definitions [0031] The following chemical functional group definitions are provided to give guidance in understanding their meaning and scope. Those skilled in the art will recognize that these functional groups are being used in a manner consistent with practice of the chemical arts. Any of the following chemical functional groups may be optionally substituted as defined below and each chemical functional group below may itself be an optional substitution.
- An “alkylcarbonyl” or “alkanoyl” group refers to an alkyl group attached to the parent molecular moiety through a carbonyl group. Examples of such groups include, without limitation, methylcarbonyl and ethylcarbonyl.
- an “arylcarbonyl” or “aroyl” group refers to an aryl group attached to the parent molecular moiety through a carbonyl group.
- examples of such groups include, without limitation, benzoyl and naphthoyl.
- generic examples of acyl groups include alkanoyl, aroyl, heteroaroyl, and so on.
- Specific examples of acyl groups include, without limitation, formyl, acetyl, acryloyl, benzoyl, trifluoroacetyl and the like.
- alkenyl refers to a straight- chain or branched-chain hydrocarbon radical having one or more double bonds and containing from 2 to 20 carbon atoms.
- the alkenyl may comprise from 2 to 6 carbon atoms, or from 2 to 4 carbons, either of which may be referred to as “lower alkenyl.”
- Alkenyl can include any number of carbons, such as C 2 , C 23 , C 24 , C 25 , C 26 , C 27 , C 28 , C 29 , C 210 , C 3 , C 34 , C 35 , C 36 , C 4 , C 45 , C 46 , C 5 , C 56 , and C 6 , and so on up to 20 carbon atoms.
- Alkenyl groups can have any suitable number of double bonds, including, but not limited to, 1, 2, 3, 4, 5 or more.
- alkenyl groups include, but are not limited to, vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3- hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexatrienyl.
- Alkenyl groups can be substituted or unsubstituted. Unless otherwise specified, the term “alkenyl” may include “alkenylene” groups.
- alkoxy refers to an alkyl ether radical, wherein the term alkyl is as defined below. Alkoxy groups may have the general formula: alkyl-O-. As for alkyl group, alkoxy groups can have any suitable number of carbon atoms, such as C 16 . Alkoxy groups include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2butoxy, isobutoxy, secbutoxy, tertbutoxy, pentoxy, hexoxy, and the like.
- alkoxy groups can be further optionally substituted as defined herein.
- alkyl as used herein, alone or in combination, (sometimes abbreviated Alk) refers to a straight-chain or branched-chain alkyl radical containing from 1 to 20 carbon atoms. In certain embodiments, the alkyl may comprise from 1 to 10 carbon atoms. In further embodiments, the alkyl may comprise from 1 to 6 carbon atoms, or from 1 to 4 carbon atoms.
- Alkyl can include any number of carbons, such as C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 110 , C 23 , C 24 , C 25 , C 26 , C 34 , C 35 , C 36 , C 45 , C 46 and C 56 .
- C 16 alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secbutyl, tertbutyl, pentyl, isopentyl, hexyl, etc.
- Alkyl can also refer to alkyl groups having up to 20 carbons atoms, such as, but not limited to heptyl, octyl, nonyl, decyl, etc. Alkyl groups can be substituted or unsubstituted.
- alkylene refers to a saturated aliphatic group derived from a straight or branched chain saturated hydrocarbon attached at two or more positions, such as methylene (--CH 2 --). Unless otherwise specified, the term “alkyl” may include “alkylene” groups. When the alkyl is methyl, it may be represented structurally as CH3, Me, or just a single bond terminating with no end group substitution.
- aryl as used herein, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused.
- aryl embraces aromatic radicals such as benzyl, phenyl, naphthyl, anthracenyl, phenanthryl, indanyl, indenyl, annulenyl, azulenyl, tetrahydronaphthyl, and biphenyl.
- benzo and benz as used herein, alone or in combination, refer to the divalent radical C 6 H 4 - derived from benzene.
- Examples include benzothiophene and benzimidazole.
- cycloalkyl or, alternatively, “carbocycle,” as used herein, alone or in combination, refers to a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl radical wherein each cyclic moiety contains from 3 to 12 carbon atom ring members and which may optionally be a benzo fused ring system which is optionally substituted as defined herein.
- a cycloalkyl may comprise from from 3 to 7 carbon atoms, or from 5 to 7 carbon atoms.
- cycloalkyl radicals examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, octahydronaphthyl, 2,3-dihydro-1H- indenyl, adamantyl and the like.
- “Bicyclic” and “tricyclic” as used herein are intended to include both fused ring systems, such as decahydronaphthalene, octahydronaphthalene as well as the multicyclic (multicentered) saturated or partially unsaturated type.
- ether typically refers to an oxy group bridging two moieties linked at carbon atoms.
- “Ether” may also include polyethers, such as, for example, --RO(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 OR', --RO(CH 2 ) 2 O(CH 2 ) 2 OR', -- RO(CH 2 ) 2 OR', and --RO(CH 2 ) 2 OH.
- the term “oxo,” as used herein, alone or in combination, refers to O.
- any one of the positions that is understood to have a hydrogen may also exist or understood to be isotopically enriched.
- any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Obtaining 100% deuteration at any relevant site of a compound in an amount of milligram or greater can be difficult. Therefore, it is understood that some percentage of hydrogen may still be present, even though a deuterium atom is specifically shown in a chemical structure.
- a chemical structure contains a “D”
- the compound represented by the structure is deuterium-enriched at the site represented by “D.”
- a position is designated specifically as “H” or “hydrogen,” the position is understood to have hydrogen at its natural abundance isotopic composition.
- a position is designated specifically as “D” or “deuterium,” the position is understood to have deuterium at an abundance that is at least 3340 times greater than the natural abundance of deuterium, which is 0.015% (i.e., the term “D” or “deuterium” indicates at least 50.1% incorporation of deuterium).
- a benzene ring may be optionally exist as –C 6 D 5 , -C 6 DH 4 , -C 6 D 2 H 3 , -C 6 D 3 H 2 , and -C 6 D 4 H.
- a cyclohexyl group may optionally exist as –C 6 D 11 .
- the composite group alkylamido would represent an alkyl group attached to the parent molecule through an amido group
- the term alkoxyalkyl would represent an alkoxy group attached to the parent molecule through an alkyl group.
- R or the term R' appearing by itself and without a number designation, unless otherwise defined, refers to a moiety selected from the group consisting of hydrogen, hydroxyl, halogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl and heterocycloalkyl, any of which may be optionally substituted.
- Each such R and R' groups should be understood to be optionally substituted as defined herein.
- Each incidence of R and R’ should be understood to be independent.
- an unsymmetrical group such as -- C(O)N(R)-- may be attached to the parent moiety at either the carbon or the nitrogen.
- Asymmetric centers, axial asymmetry (non-interchanging rotamers), or the like may exist in the compounds of the various embodiments disclosed herein. Such chirality may be designated by the symbols “R” or “S,” depending on the configuration of substituents around the chiral carbon atom or the relevant axis. It should be understood that embodiments encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric, and epimeric forms, d-isomers and l-isomers, and mixtures thereof.
- bonds refers to a covalent linkage between two atoms, or two moieties when the atoms joined by the bond are considered part of larger substructure. A bond may be single, double, or triple unless otherwise specified.
- Salts of Compounds can exist as pharmaceutically acceptable salts, including acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable salts may be of utility in the preparation and purification of the compound in question. Basic addition salts may also be formed and be pharmaceutically acceptable. For a more complete discussion of the preparation and selection of salts, refer to Pharmaceutical Salts: Properties, Selection, and Use (Stahl, P. Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002).
- each of the compounds disclosed herein, and each embodiment of the compounds set forth herein include pharmaceutically acceptable salts of such compounds.
- pharmaceutically acceptable salt represents salts or zwitterionic forms of the compounds disclosed herein which are water or oil-soluble or dispersible and pharmaceutically acceptable as defined herein.
- the salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound in the form of the free base with a suitable acid.
- Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethansulfonate (isethionate), lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2- naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phen
- basic groups in the compounds of the various embodiments disclosed herein can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides.
- acids which can be employed to form pharmaceutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric.
- Salts can also be formed by coordination of the compounds with an alkali metal or alkaline earth ion.
- the various embodiments disclosed herein contemplates sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein, and the like.
- Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxyl group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine.
- the cations of pharmaceutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, and N,N'-dibenzylethylenediamine.
- nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine,
- ALS Amyotrophic lateral sclerosis
- ALS includes all of the classifications of ALS known in the art, including, but not limited to classical ALS (typically affecting both lower and upper motor neurons), Primary Lateral Sclerosis (PLS, typically affecting only the upper motor neurons), Progressive Bulbar Palsy (PBP or Bulbar Onset, a version of ALS that typically begins with difficulties swallowing, chewing and speaking), Progressive Muscular Atrophy (PMA, typically affecting only the lower motor neurons) and familial ALS (a genetic version of ALS).
- classical ALS typically affecting both lower and upper motor neurons
- PPS Primary Lateral Sclerosis
- PBP or Bulbar Onset Progressive Bulbar Palsy
- PMA Progressive Muscular Atrophy
- familial ALS a genetic version of ALS
- Alzheimer's disease or “AD” are terms understood in the art and used herein to denote a progressive neurodegenerative disease characterized by dementia and defined by the American Psychiatric Association (in DSM IV) as the development of multiple cognitive deficits that includes memory impairment.
- DSM IV American Psychiatric Association
- MS Multiple sclerosis
- MS includes all of the classifications of MS known in the art, including, but not limited Relapsing-remitting (RRMS) (typically characterized by partial or total recovery after attacks (also called exacerbations, relapses, or flares)), Secondary progressive (SPMS) (generally characterized by fewer relapses, with an increase in disability and symptoms), and Primary progressive (PPMS) (generally characterized by progression of symptoms and disability without remission).
- RRMS Relapsing-remitting
- SPMS Secondary progressive
- PPMS Primary progressive
- a “fibrotic disease” is one involving the formation of excess fibrous connective tissue in an organ and/or tissue.
- fibrotic diseases herein include: systemic sclerosis (scleroderma), keloids, hypertrophic scars, burn scars, liver fibrosis, liver cirrhosis, pulmonary hypertension, pulmonary fibrosis (including idiopathic pulmonary fibrosis, IPF), cardiac fibrosis, kidney fibrosis, hepatic fibrosis, etc.
- the fibrotic disease is systemic sclerosis.
- Systemic sclerosis SSc
- scleroderma is a complex and heterogeneous disease with skin and tissue fibrosis, vascular alterations, and autoantibodies against various cellular antigens being amongst its principal features.
- autoimmune disorder refers to disease, disorders or conditions in which the body's immune system, which normally fights infections and viruses, is misdirected and attacks the body's own normal, healthy tissue.
- the phrase “effective amount” means an amount of compound that, when administered to a subject in need of such treatment, is sufficient to (i) treat a disease or disorder associated with oxidative stress (e.g., neurodegenerative diseases and/or fibrotic diseases and conditions), (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease, condition, or disorder, or (iii) delay the onset of one or more symptoms of the particular disease, condition, or disorder described herein.
- oxidative stress e.g., neurodegenerative diseases and/or fibrotic diseases and conditions
- a “therapeutically effective amount” of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition.
- a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition.
- a therapeutically effective amount can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and/or enhances the therapeutic efficacy of another therapeutic agent.
- a therapeutically effective amount is an amount sufficient for inhibition of neurodegenerative diseases and fibrotic diseases and conditions.
- patient and/or “subject” relates to a human or non-human mammalian patient (e.g., mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, and/or primates) suffering from a disease or condition associated with oxidative stress (e.g., neurodegenerative diseases and fibrotic diseases and conditions) and thus in need of such treatment, preferably the patient is a human person.
- the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented.
- a “mammal” includes humans and both domestic animals such as laboratory animals and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wildlife and the like.
- domestic animals such as laboratory animals and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wildlife and the like.
- non-domestic animals such as wildlife and the like.
- terms “treat” or “treatment” refer to therapeutic or palliative measures.
- Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease or disorder or condition, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. II. COMPOUNDS A.
- R 1 is (CO 2 )-, CO 2 (C 1 -C 6 alkyl), or CO 2 H
- R 2 is CO 2 (C 1 -C 6 alkyl), CO 2 H, or (CO 2 )-
- R 3 is independently selected at each occurrence from H, C(O)C 1 -C 6 alkyl, or C 1 -C 6 alkyl
- X is a cation
- n is 0, 1, or 2.
- the compound of Formula (I) is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof: wherein R 1 is (CO 2 )-, CO 2 (C 1 -C 6 alkyl), or CO 2 H; R 2 is CO 2 (C 1 -C 6 alkyl), CO 2 H, or (CO 2 )-; R 3 is independently selected at each occurrence from H, C(O)C 1 -C 6 alkyl, or C 1 -C 6 alkyl; X is a cation; and n is 0, 1, or 2.
- compound of Formula (I) is a compound of Formula (III) or a pharmaceutically acceptable salt or solvate thereof: wherein R 1 is (CO 2 )-, CO 2 (C 1 -C 6 alkyl), or CO 2 H; R 2 is CO 2 (C 1 -C 6 alkyl), CO 2 H, or (CO 2 )-; R 3 is independently selected at each occurrence from H, C(O)C 1 -C 6 alkyl, or C 1 -C 6 alkyl; X is a cation; and n is 0, 1, or 2.
- R 1 is (CO 2 )-, CO 2 Me, or CO 2 H;
- R 2 is CO 2 Me, CO 2 H, or (CO 2 )-;
- R 3 is H; and
- X is Mg 2+ , Na + , K + , Ca 2+ , aluminum, arginine, choline, diethanolamine, ethanolamine, lithium, histidine, lysine, procaine, or zinc.
- R 1 is (CO 2 )-;
- R 2 is (CO 2 )-;
- R 3 is H; and
- X is Mg 2+ ; and n is 1.
- R 1 is CO 2 Me; R 2 is CO 2 Me; R 3 is H; and n is 0.
- R 1 is CO 2 H; R 2 is CO 2 H; R 3 is H; and n is 0.
- exemplary compounds described herein include, but are not limited to,
- the compound of Formula (I) includes one or more of
- the compound of Formula (I) includes two or more of
- the compound of Formula (I) is [0078] In some embodiments, the compound of Formula (I) is [0079] In some embodiments, the compound of Formula (I) is [0080] In some embodiments, the compound of Formula (I) is [0081] In some embodiments, the compound of Formula (I) is [0082] In some embodiments, the compound of Formula (I) is [0083] In some embodiments, the compound of Formula (I) is [0084] In some embodiments, the compound of Formula (I) is [0085] In some embodiments, the compound of Formula (I) is [0086] In some embodiments, the compound of Formula (I) is [0087] In some embodiments, the compound of Formula (I) is [0088] In some embodiments, the compound of Formula (I) is [0089] In some embodiments, the compound of Formula (I) is [0090] In some embodiments, the compound of Formula (I) is [0091] In some embodiments, the compound of Formula (I) is [0080] In some embodiments
- the compounds of the present application may be extracted, separated and purified from Salvia miltiorrhiza, also known as Danshen, a natural herb. Because of the polyphenol structure of the compounds of Formula (I), these compounds have a strong reducibility, approximately 500-1000 times that of Vitamin E. Consequently, they are easily oxidized during the separation and purification process, and the natural metal ions are easily cleaved, resulting in the collapse of the compound structure. Therefore, the separation, purification and protection process must be done under conditions to prevent oxidation. Standard extracts of MLB obtained from Salvia miltiorrhiza often include impurities such as rosmarinic acid and lithospermic acid. These impurities can constitute 20% or more of the compositions.
- lithospermate or salts thereof e.g., magnesium lithospermate B
- the isolation of lithospermate or salts thereof is usually achieved through column chromatography using an adsorbent (stationary phase), such as silica gel.
- adsorbent stationary phase
- Alternative methods of extraction are also known in the art including polar and non-polar extraction techniques.
- One exemplary technique for forming obtaining Magnesium Lithospermate B includes extracting a Salvia miltiorrhiza plant material with an alcohol-water solution.
- the alcohol-water solution can be concentrated to give a Salvia miltiorrhiza liquid extract. Then the liquid extract is separated liquid via chromatography on macroporous absorption resin with a second alcohol-water solution used for elution. The addition of magnesium salts may be used in the extraction solution to help increase the yield of the product.
- Neurodegenerative diseases are generally characterized by a degeneration of neurons in either the brain or the nervous system of an individual.
- Misfolding can in some cases cause protein aggregation which can further give rise to discrete deposits extracellularly (e.g., plaques) or intracellularly (e.g., inclusions in the cytosol or nucleus).
- Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and prion diseases are characterized by neural deposits of misfolded aggregated protein. Neurodegenerative diseases also pose major challenges to our aging population and health care system.
- Sporadic AD, ALS, and Parkinson's disease/Lewy body dementia are all associated with neural accumulation of pathological multimers of misfolded polypeptides (these could potentially be fibrils, protofilaments, and amorphous aggregates), including the amyloid-beta (Abeta) fragment of the amyloid precursor protein (APP) in AD; superoxide dismutase-1 (SOD1) in ALS, AD, and PD, and alpha-synuclein in PD and LBD.
- Abeta amyloid-beta fragment of the amyloid precursor protein (APP) in AD
- SOD1 superoxide dismutase-1
- alpha-synuclein in PD and LBD.
- FAP familial amyloidotic polyneuropathy
- a method of treating a neurodegenerative disease in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof: wherein R 1 is (CO 2 )-, CO 2 (C 1 -C 6 alkyl), or CO 2 H; R 2 is CO 2 (C 1 -C 6 alkyl), CO 2 H, or (CO 2 )-; R 3 is independently selected at each occurrence from H, C(O)C 1 -C 6 alkyl, or C 1 -C 6 alkyl; X is a cation; and n is 0, 1, or 2.
- the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, or multiple sclerosis.
- Alzheimer's Disease [0102] AD is a common dementing (disordered memory and cognition) neurodegenerative disease associated with brain accumulation of extracellular plaques composed predominantly of the Abeta (1-40), Abeta (1-42) and Abeta (1-43) peptides, all of which are proteolytic products of APP.
- neurofibrillary tangles composed principally of abnormally phosphorylated tau protein (a neuronal microtubule-associated protein), accumulate intracellularly in dying neurons.
- Familial forms of AD can be caused by mutations in the APP gene, or in the presenilin 1 or 2 genes (St George-Hyslop & Petit, C R Biol.328(2):119-30 (2005)), the protein products of which are implicated in the processing of APP to Abeta.
- Apolipoprotein E allelic variants also influence the age at onset of both sporadic and familial forms of AD (Puglielli et al., Nat Neurosci. 6:345-51(2003)).
- Abeta, tau and phosphorylated tau has been detected in the blood and CSF of AD patients and in normal controls (Mehta et al., Arch Neurol. 57:100-5 (2000); Clark et al., Arch Neurol.
- the neurodegenerative disease to be treated is Alzheimer's disease.
- Parkinson's Disease [0103] PD is a neurodegenerative movement disorder, second only to AD in prevalence (approx. 350 per 100,000 population). It is clinically characterized by rigidity, slowness of movement, and tremor. Most cases of Parkinson's disease are sporadic, but both sporadic and familial forms of the disease are characterized by intracellular Lewy bodies in dying neurons of the substantia nigra, a population of midbrain neurons (approx. 60,000) that are selectively decimated in PD.
- Lewy bodies are predominantly composed of alpha-synuclein (Iwatsubo T., J Neurol 250 Suppl 3:III11-4 (2003)). Mutations in, and duplication of, the gene encoding alpha-synuclein have been found in patients with familial Parkinson's disease (Eriksen et al., Neuron 40:453-6 (2003)). Another gene associated with autosomal recessive PD is parkin, which is involved in alpha-synuclein degradation (Eriksen et al., Neuron 40:453-6 (2003)).
- LBD Lewy body disease
- AD Lewy body disease
- a dementing syndrome associated with parkinsonian tone changes, hallucinations, and rapid symptom fluctuation McKeith et al., Lancet Neurol 3:19- 28(2004)
- LBD may be the second most common form of neurodegenerative dementia after AD, accounting for 20 to 30 percent of cases among persons over the age of 60 years.
- the neurodegenerative disease to be treated is Parkinson's disease.
- Huntington's Disease [0104]
- Huntington's disease (HD) is a fatal neurodegenerative disorder with an autosomal dominant mode of inheritance. The disease is associated with a triad of motor, behavioral, and cognitive symptoms.
- chorea Motor disturbances are the defining feature of the disease, with chorea the most evident motor symptom. Although useful for diagnosis, chorea is a poor marker of disease severity. Rather, disability and disease severity best correlate with negative motor features such as impairment in fine motor skills, bradykinesia, and gross motor coordination skills, including speech difficulties, gait, and postural dysfunction.
- a disrupted dopaminergic signaling has been implicated in a number of neurological and psychiatric conditions, and there is considerable clinical and preclinical evidence suggesting that dopaminergic functions are also compromised in HD.
- the neurodegenerative disease to be treated is Huntington's disease.
- ALS Amyotrophic Lateral Sclerosis
- ALS Amyotrophic Lateral Sclerosis
- ALS Amyotrophic lateral sclerosis
- the neurodegenerative disease to be treated is amyotrophic lateral sclerosis.
- SOD1 superoxide dismutase 1
- the ALS is familial ALS.
- the ALS is sporadic ALS.
- ALS is characterized by progressive manifestations of dysfunction of both lower and upper motor neurons.
- Lower motor neurons connect the brainstem and spinal cord to muscle fibres. Their dysfunction leads to muscle atrophy, cramps and fasciculations (small, local, involuntary muscle contraction).
- Upper motor neurons originate in motor region of the cerebral cortex or the brainstem and carry motor information down to motor neurons that are directly responsible for stimulating the target muscle.
- mutated genes in ALS can be roughly divided into two groups (Brown et al,, N Engl J Med 377:162-72 (2017)).
- One group of mutated genes generate aggregates of misfolded protein and form prion-like assembly
- another group of mutated genes cause neuroinflammation through activation of NF-kB, interferon-b and TNF-a pathways.
- Both prion-like self-assembly and neuroinflammation causes neurotoxicity and motor neuron degradation.
- the compounds of Formula (I) can be administered individually or in combination with functional electrical stimulation (FES) and/or neuromodulation systems, to improve the nerve functions of subjects.
- FES functional electrical stimulation
- the compounds of Formula (I) may be administered sequentially or simultaneously with the FES and neuromodulation systems.
- Functional electrical stimulation FES
- FES can be used to activate nerves innervating muscle affected by paralysis resulting from spinal cord injury, head injury, stroke and other neurological disorders, or muscle affected by foot drop and gait disorders.
- FES is also used to stimulate muscles as an orthotic substitute, e.g., replace a brace or support in scoliosis management.
- the compounds disclosed herein are capable of significantly dilating tiny blood vessels and capillaries, thereby improving microcirculation, especially in the blood supply around central and peripheral nerves.
- the compounds described herein are highly reducable (about 1000 times that of vitamin E) providing a strong antioxidant effect, which may significantly reduce oxidative stress damage caused by hypoxia resulting from nerve atrophy related to breathing and oxygen exchange, as well as reducing local inflammation.
- the compounds described herein possess significant anti-fibrotic effects.
- the compounds described herein are powerful regulation of calcium ion channels and potassium ion channels, which helps to improve the membrane surface action potential of nerve cells, regulate nerve excitability, and enhance muscle contractility.
- the strong and specific organ distribution of the compounds described herein help to improve the quality of life of the patients.
- MS Multiple sclerosis
- attack areas of white matter of the central nervous system, known as plaques, become inflamed. Inflammation of these areas of plaque is followed by destruction of myelin, the fatty substance that forms a sheath or covering that insulates nerve cell fibers in the brain and spinal cord. Myelin facilitates the smooth, high-speed transmission of electrochemical messages between the brain, spinal cord, and the rest of the body.
- MS damage to the myelin sheath can slow or completely block the transmission of these electrochemical messages, which can result in diminished or lost bodily function.
- the most common course of MS manifests itself as a series of attacks, which are followed by either complete or partial remission, during which the symptoms lessen only to return at some later point in time. This type of MS is commonly referred to as “relapsing- remitting MS.”
- Another form of MS called “primary-progressive MS,” is characterized by a gradual decline into the disease state, with no distinct remissions and only temporary plateaus or minor relief from the symptoms.
- a third form of MS starts as a relapsing-remitting course, but later deteriorates into a primary-progressive course of MS.
- the neurodegenerative disease to be treated is multiple sclerosis.
- the MS is relapsing-remitting MS.
- the MS is primary-progressive MS.
- the symptoms of MS can be mild or severe, acute or of a long duration, and may appear in various combinations.
- These symptoms can include vision problems such as blurred or double vision, red-green color distortion, or even blindness in one eye, muscle weakness in the extremities, coordination and balance problems, muscle spasticity, muscle fatigue, paresthesias, fleeting abnormal sensory feelings such as numbness, prickling, or “pins and needles” sensations, and in the worst cases, partial or complete paralysis.
- vision problems such as blurred or double vision, red-green color distortion, or even blindness in one eye
- muscle weakness in the extremities coordination and balance problems
- muscle spasticity muscle fatigue
- paresthesias fleeting abnormal sensory feelings such as numbness, prickling, or “pins and needles” sensations
- cognitive impairments such as for example, poor concentration, attention, memory and/or judgment.
- cognitive symptoms occur when lesions develop in those areas of the brain that are responsible for information processing.
- the treatment of MS results in a reduction of any one of these symptoms.
- the treatment of neurodegenerative disease includes reducing motor neuron degeneration in the subject. Additionally, the treating may delay the progress of the neurodegenerative disease in the subject.
- the method described herein include administering to the subject a secondary therapy.
- the secondary therapy may be administered simultaneously, concurrently, or sequentially with the compound of Formula (I).
- the secondary therapy can be tailored to the specific condition being treated.
- the compounds of Formula (I) may be administered orally, parenterally, sublingually, buccally, intravenously, or in any combination thereof. In some embodiments, the compounds of Formula (I) are administered orally.
- the compounds of Formula (I) may be formulated into easier to administer dosages, such as dissolvable thin films. In some cases it may be necessary or beneficial to administer the compounds of Formula (I) intravenously.
- Fibrotic Disease In an aspect, provided herein is a method of treating a fibrotic condition or disease a subject in need thereof comprising administering to said subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof: wherein R 1 is (CO 2 )-, CO 2 (C 1 -C 6 alkyl), or CO 2 H; R 2 is CO 2 (C 1 -C 6 alkyl), CO 2 H, or (CO 2 )-; R 3 is independently selected at each occurrence from H, C(O)C 1 -C 6 alkyl, or C 1 -C 6 alkyl; X is a cation; and n is 0, 1, or 2.
- R 1 is (CO 2 )-, CO 2 (C 1 -C 6 alkyl), or CO 2 H
- R 2 is CO 2 (C 1 -C 6 alkyl), CO 2 H, or (CO 2 )-
- R 3 is independently selected at each occurrence from H, C(O)
- Fibrotic diseases which may be treated according to the methods described herein include, for example, hepatic fibrosis (alcoholic, viral, autoimmune, metabolic and hereditary chronic disease), renal fibrosis (e.g., resulting from chronic inflammation, infections or type II diabetes), pulmonary fibrosis (idiopathic or resulting from environmental insults including toxic particles, sarcoidosis, asbestosis, hypersensitivity pneumonitis, bacterial infections including tuberculosis, medicines, etc.), interstitial fibrosis, systemic scleroderma (autoimmune disease in which many organs become fibrotic), macular degeneration (fibrotic disease of the eye), pancreatic fibrosis (resulting from, for example, alcohol abuse and chronic inflammatory disease of the pancreas), fibrosis of the spleen (from sickle cell anemia, other blood disorders) cardiac fibrosis (resulting from infection, inflammation and hypertrophy), mediastinal fibrosis, myelofibrosis, endomyocardi
- Fibrotic Disease – Fibrotic skin conditions Skin fibrosis (i.e., skin fibrosis or dermal fibrosis) is characterized by excessive scarring of the skin and often resulting from the pathological wound healing responses. There are a wide variety of fibrotic skin diseases and conditions: keloids, hypertrophic scars, scleroderma, nephrogenic fibrotic skin disease, mixed connective tissue disease, sclerosing mucoedema, scleredema disease, and eosinophilic fasciitis.
- Also contemplated herein is a method to treat such fibrotic skin diseases and conditions by administering a subject experiencing the conditions a compound of Formula (I).
- Exposure to chemical substances or physical factors (mechanical trauma, burn wounds) is also a potential cause of fibrotic skin diseases. Skin fibrosis can be driven by immune, autoimmune and inflammatory mechanisms. The balance of collagen production and degradation by fibroblasts plays a key role in the pathophysiology of the fibrotic process in the skin.
- scarring that is part of the wound healing process and accompanies fibrosis is particularly undesirable from a cosmetic standpoint, especially when the scarring is formed on other exposed parts of the face and/or body.
- Scleroderma refers to skin fibrosis; sclera means hard and derma means skin.
- skin fibrosis can have significant health problems, especially when it is part of systemic scleroderma.
- Systemic scleroderma refers to a connective tissue disease with autoimmune etiology. Limited-skin scleroderma is limited to skin on the face and on the feet, while diffuse-skin scleroderma covers more skin and may spread to internal organs.
- D. Fibrotic Disease - Systematic scleroderma [0123] Scleroderma is a fibrotic disorder characterized by a thickening and induration of the skin caused by the overproduction of new collagen by fibroblasts in skin and other organs.
- Scleroderma may occur as a local or systemic disease.
- Systemic scleroderma may affect a number of organs.
- Systemic sclerosis is characterized by formation of hyalinized and thickened collagenous fibrous tissue, with thickening of the skin and adhesion to underlying tissues, especially of the hands and face.
- the disease may also be characterized by dysphagia due to loss of peristalsis and submucosal fibrosis of the esophagus, dyspnea due to pulmonary fibrosis, myocardial fibrosis, and renal vascular changes. (Stedman's Medical Dictionary, 26 th Edition, Williams & Wilkins, 1995)).
- the fibrotic condition or disease to be treated is systemic scleroderma. In some embodiments, the fibrotic condition or disease to be treated is local scleroderma. In some embodiments, the treatment of a subject for systemic and/or local scleroderma results in a reduction of collagenous fibrous tissue.
- Scleroderma is mainly an immunological reaction in which the skin attracts lymph cells which stimulate the production of collagen.
- scleroderma Because the symptoms of scleroderma often mimic those of other diseases such as bursitis, osteoarthritis, rheumatoid arthritis, and other collagen disorders, it is difficult to diagnose. There is no test specific for confirmation of a diagnosis of scleroderma, but x-rays, skin biopsies, and tests for antinuclear antibodies, gamma globulin, sedimentation rate, and latex fixation can provide evidence that the disease is present.
- the patient with systemic sclerosis has been classified according to the American College of Rheumatology (formerly, the American Rheumatism Association) criteria for the classification of systemic scleroderma based on: major criterion: proximal diffuse (truncal) sclerosis (skin tightness, thickening, and non-pitting induration); and minor criteria: (1) sclerodactyly (only fingers and/or toes), (2) digital pitting scars or loss of substance of the digital finger pads (pulp loss), and (3) bilateral basilar pulmonary fibrosis, wherein a patient with systemic sclerosis should fulfill the major criterion or two of the three minor criteria.
- major criterion proximal diffuse (truncal) sclerosis (skin tightness, thickening, and non-pitting induration)
- minor criteria (1) sclerodactyly (only fingers and/or toes), (2) digital pitting scars or loss of substance of the digital finger pads (pulp loss), and (3) bilateral basil
- Systemic autoimmunity encompasses autoimmune conditions in which autoreactivity is not limited to a single organ or organ system.
- autoimmune diseases including autoimmune skin disease manifestations such as systemic lupus erythematosus (SLE), systemic sclerosis (scleroderma), pemphigus, vitiligo, dermatitis herpetiformis, psoriasis, etc.
- the fibrotic condition or disease to be treated is autoimmune skin disorder.
- Cutaneous SLE is a common systemic autoimmune disorder that includes specific skin manifestations such as “butterfly” rash, photosensitive rash dermatitis, and discoid lesions as well as vasculitis and alopecia.
- SLE is characterized by the presence of antinuclear antibodies (ANAs) and is associated with chronic inflammation.
- ANAs antinuclear antibodies
- Scleroderma or systemic sclerosis
- Scleroderma is marked by inflammation, followed by deposition of ANAs in skin and viscera.
- Scleroderma is characterized by a marked reduction in circulation in peripheral arteries of distal fingertips (often stimulated by cold temperatures) known as Reynauld's phenomenon.
- Pemphigus comprises a group of autoimmune blistering diseases characterized by autoantibody induced epidermal cell-cell detachment (acantholysis). Pemphigus manifests clinically with flaccid blisters and skin erosions.
- Vitiligo is a skin depigmentation disorder that may be associated with other autoimmune disorders such as the autoimmune polyendocrine syndrome type I. Vitiligo is characterized by the presence of anti-melanocyte autoantibodies, skin infiltration of CD4+ and CD8+ T lymphocytes and overexpression of type I cytokine profiles.
- Dermatitis herpetiformis (DH) is a lifelong very pruritic, polymorphic blisteric skin disease associated with gluten sensitivity. The predominant autoantigen in DH is tissue transglutaminase, found in the intestine and the skin.
- Psoriasis is a common autoimmune skin disease with a genetic basis affecting 1-3% of the Caucasian population.
- the compounds and methods described herein are capable of treating a cutaneous scar associated with an autoimmune skin disorder.
- the autoimmune skin disorder is selected from the group consisting of systemic lupus erythematosus (SLE), systemic sclerosis (scleroderma), pemphigus, vitiligo, dermatitis herpetiformis, psoriasis, or a combination thereof.
- the autoimmune skin disorder is systemic lupus erythematosus (SLE).
- the autoimmune skin disorder is systemic sclerosis (scleroderma).
- the autoimmune skin disorder is pemphigus.
- the autoimmune skin disorder is vitiligo.
- the autoimmune skin disorder is dermatitis herpetiformis.
- the autoimmune skin disorder is psoriasis.
- F. Fibrotic Disease - Pulmonary fibrosis [0135] Lung fibrosis, also referred to as pulmonary fibrosis, is a serious medical condition that involves scarring of the lung tissue. This condition occurs when the alveoli and interstitial tissue of the lungs become inflamed and develop scars on the tissue in an attempt to repair themselves.
- Pulmonary fibrosis involves gradual exchange of normal lung parenchyma with fibrotic tissue (fibrous scar). The replacement of normal lung with scar tissue causes irreversible decrease in oxygen diffusion capacity.
- the fibrotic condition or disease to be treated is pulmonary fibrosis.
- Pulmonary fibrosis can be caused by many conditions which includes chronic inflammatory processes (sarcoidosis, Wegener's granulomatosis), infections, environmental agents (asbestos, silica, exposure to certain gases), exposure to ionizing radiation (such as radiation therapy to treat tumors of the chest), chronic conditions (lupus), and certain medications (e.g.
- Idiopathic Pulmonary Fibrosis is characterized by chronic inflammation of the alveolar walls with progressive fibrosis, of unknown etiology. IPF, or cryptogenic fibrosing alveolitis, causes 50 to 60% of cases of idiopathic interstitial lung disease. In some embodiments, the fibrotic disease to be treated is idiopathic pulmonary fibrosis.
- COPD chronic obstructive pulmonary disease
- COPD is another form of lung fibrosis (Gosker et al. (2003) Eur. Respir. J.
- CF Cystic fibrosis
- CF is also another form of lung fibrosis. CF is an autosomal recessive genetic disorder that affects most critically the lungs, and also the pancreas, liver, and intestine.
- cystic fibrosis refers to the characteristic scarring (fibrosis) and cyst formation within the pancreas, first recognized in the 1930s. Difficulty breathing is the most serious symptom and results from frequent lung infections that are treated with antibiotics and other medications. Other symptoms (including sinus infections, poor growth, and infertility) affect other parts of the body. CF is caused by a mutation in the gene for the protein cystic fibrosis transmembrane conductance regulator (CFTR). This protein is required to regulate the components of sweat, digestive fluids, and mucus.
- CFTR cystic fibrosis transmembrane conductance regulator
- CFTR regulates the movement of chloride and sodium ions across epithelial membranes, such as the alveolar epithelia located in the lungs.
- epithelial membranes such as the alveolar epithelia located in the lungs.
- Most people without CF have two working copies of the CFTR gene, and both copies must be missing for CF to develop, due to the disorder's recessive nature.
- CF develops when neither copy works normally (as a result of mutation) and therefore has autosomal recessive inheritance.
- the basic pathological features of the fibrotic lesions include excessive collagen deposition.
- the fibrotic disease to be treated is cystic fibrosis. [0140] Fibrotic diseases are associated with excess collagen production.
- the method includes contacting the cells with a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof.
- the cells are mammalian calls.
- the cells are human cells.
- the contacting is in vitro.
- the contacting is in vivo.
- the contacting is in vivo, wherein the method includes administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof to a subject having a disease or disorder described herein.
- the term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
- “contacting” a cell with a compound provided herein includes the administration of a compound provided herein to a subject, such as a human, having, for example cells associated with an excess of collagen, as well as, for example, introducing a compound provided herein into a sample containing mammalian cells.
- the method described herein include administering to the subject a secondary or additional therapy.
- the secondary therapy may be administered simultaneously, concurrently, or sequentially with the compound of Formula (I).
- the secondary therapy can be tailored to the specific condition being treated.
- the compounds of Formula (I) are administered topically. This method of administration may be particularly advantageous for the treatment of fibrotic skin conditions.
- the compounds of Formula (I) are administered intravenously.
- the compounds of Formula (I) are administered as an injection.
- administration should be used with care as fibrotic diseases are often associated with hardening of the skin. For example, patients with scleroderma have especially thick skin that is hard to penetrate with a needle. Injections and venipunctures can be quite painful and should be done with as much care and dispatch as possible. The site of venipuncture for intravenous therapy should be monitored frequently, especially for infiltration, which can cause a painful swelling and pressure for weeks.
- a method for reducing inflammation in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof.
- inflammation is reduced in the brain of the subject.
- a method for reducing expression of inflammatory cytokines in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof.
- expression of inflammatory cytokines is reduced in the brain of the subject.
- a method for inhibiting or reducing formation of reactive oxygen species in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof.
- a method for inhibiting formation of reactive oxygen species in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof.
- a method reducing inhibiting formation of reactive oxygen species in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof.
- the subject has a neurodegenerative disease (e.g., the neurodegenerative diseases disclosed herein).
- the subject has a fibrotic condition or disease (e.g., the fibrotic conditions and diseases described herein).
- IV. COMPOSITIONS [0149]
- the compounds according Formula (I) are formulated as pharmaceutically acceptable compositions that contain a Formula (I) compound in an amount effective to treat a particular disease or condition of interest upon administration of the pharmaceutical composition to a mammal (e.g., a neurodegenerative disease and/or a fibrotic disease or condition).
- compositions as described herein can comprise a compound of Formula (I) in combination with a pharmaceutically acceptable carrier, diluent or excipient.
- the pharmaceutical compositions described herein are formulated for the treatment of a neurodegenerative disease (e.g., the neurodegenerative diseases disclosed herein).
- the pharmaceutical compositions described herein are formulated for the treatment of a fibrotic condition or disease (e.g., the fibrotic conditions and diseases described herein).
- a “pharmaceutically acceptable carrier, diluent or excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
- compositions described herein can be prepared by combining a compound described herein with an appropriate pharmaceutically acceptable carrier, diluent or excipient, and may be formulated into preparations in solid, semisolid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols.
- Typical routes of administering such pharmaceutical compositions include, without limitation, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal, and intranasal.
- parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
- Pharmaceutical compositions described herein are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient.
- Compositions that will be administered to a subject or patient take the form of one or more dosage units, where for example, a tablet may be a single dosage unit, and a container of a compound described herein in aerosol form may hold a plurality of dosage units.
- Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy and Science, 2000).
- composition to be administered will, in any event, contain a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, for treatment of a disease or condition of interest in accordance with the teachings herein.
- a pharmaceutical composition described herein may be in the form of a solid or liquid.
- the carrier(s) are particulate, so that the compositions are, for example, in tablet or powder form.
- the carrier(s) may be liquid, with the compositions being, for example, an oral syrup, injectable liquid or an aerosol, which is useful in, for example, inhalatory administration.
- the pharmaceutical composition When intended for oral administration, the pharmaceutical composition is preferably in either solid or liquid form, where semisolid, semiliquid, suspension and gel forms are included within the forms considered herein as either solid or liquid.
- the pharmaceutical composition may be formulated into a powder, granule, compressed tablet, pill, capsule, oral thin film, wafer or the like form. Such a solid composition will typically contain one or more inert diluents or edible carriers.
- binders such as carboxymethylcellulose, ethyl cellulose, microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, Primogel, corn starch and the like; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; a flavoring agent such as peppermint, methyl salicylate or orange flavoring; and a coloring agent.
- the compound of Formula (I) is formulated into a granule, tablet, capsule, or oral film.
- the pharmaceutical composition when in the form of a capsule, for example, a gelatin capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or oil.
- a liquid carrier such as polyethylene glycol or oil.
- the pharmaceutical composition may be in the form of a liquid, for example, an elixir, syrup, solution, emulsion, suspension or sterile aqueous solution.
- the liquid may be for oral administration or for delivery by injection, as two examples.
- preferred composition contain, in addition to the present compounds, one or more of a sweetening agent, preservatives, dye/colorant and flavor enhancer.
- liquid pharmaceutical compositions described herein may include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer’s solution, isotonic sodium chloride, fixed oils such as synthetic mono or diglycerides which may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as
- parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
- Physiological saline is a preferred adjuvant.
- Pharmaceutical preparation suitable for injectable use may include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the composition must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
- Sterile injectable solutions can be prepared by incorporating the therapeutic agent in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
- dispersions are prepared by incorporating the therapeutic agent into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above.
- the methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient (i.e., the therapeutic agent) plus any additional desired ingredient from a previously sterile-filtered solution thereof.
- a liquid pharmaceutical composition intended for either parenteral or oral administration should contain an amount of a compound described herein such that a suitable dosage will be obtained.
- the pharmaceutical composition is an oral film (e.g., a thin film that dissolves when placed under a patient’s tongue). This formulation provides the advantages for patients with neurodegenerative diseases who may have problems swallowing and that lack mobility to take oral medication by themselves. Sublingual films deliver a convenient, quick-dissolving therapeutic dose contained within a film matrix that does not need to be crushed or injected by patients.
- the thin films may be formulated to a variety of different profiles (e.g., immediate release (IR), sustained release (SR), delayed release (DR), modified release (MR), extended release (XR), and controlled release (CR)).
- IR immediate release
- SR sustained release
- DR delayed release
- MR modified release
- XR extended release
- CR controlled release
- Oral thin film “Oral thin film,” “OTF,” “oral dissolving film,” “oral dissolvable film,” “oral drug strip” or “oral strip” refers to a product used to administer active ingredients via absorption in the mouth (buccally or sublingually), the stomach (gastrically), and/or via the small intestines (enterically).
- the OTF is edible and pharmaceutically acceptable.
- a film is prepared typically using hydrophilic polymers that rapidly dissolves on the tongue or buccal cavity, delivering the active ingredient to the systemic circulation via dissolution when contact with liquid is made.
- the OTF (or more appropriately “thin film” or “TF”) can also be used to adhere to mucosal tissue (e.g., at least one of mouth, nose, eye, vagina, and rectum), thereby locally delivering the active ingredient.
- mucosal tissue e.g., at least one of mouth, nose, eye, vagina, and rectum
- OTF oral thin film
- Oral films may be made using techniques known in the art.
- the thin film (e.g., an oral dissolvable film) includes: (a) solvent, (b) binder, (c) optionally a lipid, (d) optionally an emulsifier, (e) a compound of Formula (I) as described herein, (f) optionally a flavoring agent, (g) optionally a sweetener, (h) optionally a dye or pigment, (i) an optional powder coating on at least one external surface, and (j) optionally a preservative.
- the thin film includes: (a) about 2-24 wt. % solvent, (b) about 40-50 wt. % binder, (c) about 0-22 wt.
- % wt. % lipid (d) about 3-22 wt. % emulsifier, (e) up to about 65 wt. % compound of Formula (I) as described herein, (f) about 0-10 wt. % flavoring agent, (g) about 0-40 wt. % sweetener, (h) about 0-1.0 wt. % dye or pigment, (i) about 0-20 wt. % powder coating on at least one external surface, and (j) about 0-0.1 wt. % preservative.
- the compound of Formula (I) can optionally be at least partially encapsulated by the lipid, when present.
- Binder refers to any material or substance that holds or draws other materials together to form a cohesive whole. Liquid binders are added to a dry substance in order to draw it together in such a way that it maintains a uniform consistency. The binder can also add mucoadhesion to the OTF. [0164]
- the thin film described herein can optionally further include a mucoadhsesive agent. The mucoadhesive agent, when placed in the oral cavity in contact with the mucosa therein, adheres to the mucosa.
- the mucoadhesive agent is especially effective in transmucosal delivery of the active ingredient, as the mucoadhesive agent permits a close and extended contact of the composition with the mucosal surface by promoting adherence of the composition or drug to the mucosa, and facilitates the release of the active ingredient from the composition.
- the mucoadhesive agent can be a polymeric compound, such as a cellulose derivative but it may be also a natural gum, alginate, pectin, or such similar polymer.
- the concentration of the mucoadhesive agent in the coating, such as a powder matrix coating may be adjusted to vary the length of time that the film adheres to the mucosa or to vary the adhesive forces generated between the film and mucosa.
- the mucoadhesive agent may adhere to oral mucosa or to mucosa or tissue in other parts of the body, including the mouth, nose, eyes, vagina, and rectum.
- Mucoadhesive agents include, e.g., carboxymethylcellulose, polyvinyl alcohol, polyvinyl pyrrolidone (povidone), sodium alginate, methyl cellulose, hydroxyl propyl cellulose, hydroxypropylmethyl cellulose, polyethylene glycols, carbopol, polycarbophil, carboxyvinyl copolymers, propylene glycol alginate, alginic acid, methyl methacrylate copolymers, tragacanth gum, guar gum, karaya gum, ethylene vinyl acetate, dimenthylpolysiloxanes, polyoxyalkylene block copolymers, pectin, chitosan, carrageenan, xanthan gum, gellan gum, locust bean gum, and
- Lipid refers to a group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E, and K), monoglycerides, diglycerides, triglycerides, phospholipids, and others.
- the compounds are hydrophobic or amphiphilic small molecules. The amphiphilic nature of some lipids allows them to form structures such as vesicles, liposomes, or membranes in an aqueous environment.
- Biological lipids originate entirely or in part from two distinct types of biochemical subunits or “building-blocks”: ketoacyl and isoprene groups.
- lipids may be divided into eight categories: fatty acids, glycerolipids, glycerophospholipids, sphingolipids, saccharolipids, and polyketides (derived from condensation of ketoacyl subunits); and sterol lipids and prenol lipids (derived from condensation of isoprene subunits).
- fatty acids glycerolipids, glycerophospholipids, sphingolipids, saccharolipids, and polyketides (derived from condensation of ketoacyl subunits); and sterol lipids and prenol lipids (derived from condensation of isoprene subunits).
- fatty acids glycerolipids
- glycerophospholipids glycerophospholipids
- sphingolipids derived from condensation of ketoacyl subunits
- saccharolipids derived from condensation of ketoacyl subunits
- polyketides derived from condensation of ketoacyl subunits
- Liposomes are spherical, lipid bilayer vesicles made from amphiphilic lipids. Typically these are phospholipids that are comprised of a glycerin core with two fatty acid esters, and a phosphate group bound to an additional polar group. These phospholipids thus have two lipophilic tails and a single hydrophilic head. Single fatty acid chains with a single hydrophilic head, like typical soap and detergent molecules, will preferentially form unilayer micelles and not bilayer liposomal structures.
- Liposomes can be unilamellar, with a single lipid bilayer making a single sphere. They can also form various multilamellar structures. Multilamellar structures can be concentric spheres, or a sphere containing multiple unilamellar spheres within. All combinations of the above have been documented.
- a pharmaceutical composition comprising a compound of Formula I is formulated into a cream, gel, liquid, aerosol, hydrogel, dressing, granule, compressed tablet, pill, or capsule.
- the pharmaceutical composition may be intended for topical administration, in which case the carrier may suitably comprise a solution, emulsion, ointment or gel base.
- the base may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, bee wax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers.
- Thickening agents may be present in a pharmaceutical composition for topical administration. If intended for transdermal administration, the composition may include a transdermal patch or iontophoresis device.
- Administration topically to a subject generally includes the direct laying on or spreading of the pharmaceutical composition on the epidermal or epithelial tissue of the subject, or transdermally via a “patch”.
- Such compositions include, for example, lotions, creams, solutions, gels, emulsions and solids.
- Topical compositions may comprise an effective amount, usually about 0.01% to about 10% (w/w), or from about 0.1% to about 5% (w/w), or from about 1% to about 5% (w/w), of a compound described herein.
- Suitable carriers for topical administration typically remain in place on the skin as a continuous film, and resist being removed by perspiration or immersion in water.
- the carrier is organic in nature and capable of having dispersed or dissolved therein the therapeutic agent.
- the carrier may include pharmaceutically acceptable emollients, emulsifiers, thickening agents, solvents and the like.
- the carrier may include vernix.
- Topical formulation includes one or more excipients such as, but not limited to, protectives, adsorbents, demulcents, emollients, preservatives, antioxidants, moisturizers, buffering agents, solubilizing agents, skin-penetration agents, and surfactants.
- Suitable protectives and adsorbents include, but are not limited to, dusting powders, zinc sterate, collodion, dimethicone, silicones, zinc carbonate, aloe vera gel and other aloe products, vitamin E oil, allatoin, glycerin, petrolatum, and zinc oxide.
- Suitable demulcents include, but are not limited to, benzoin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and polyvinyl alcohol.
- Suitable emollients include, but are not limited to, animal and vegetable fats and oils, myristyl alcohol, alum, and aluminum acetate.
- Suitable preservatives include, but are not limited to, quaternary ammonium compounds, such as benzalkonium chloride, benzethonium chloride, cetrimide, dequalinium chloride, and cetylpyridinium chloride; mercurial agents, such as phenylmercuric nitrate, phenylmercuric acetate, and thimerosal; alcoholic agents, for example, chlorobutanol, phenylethyl alcohol, and benzyl alcohol; antibacterial esters, for example, esters of parahydroxybenzoic acid; and other anti-microbial agents such as chlorhexidine, chlorocresol, benzoic acid and polymyxin.
- quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimide, dequalinium chloride, and cetylpyridinium chloride
- mercurial agents such as phenylmercuric nitrate, phenyl
- Suitable antioxidants include, but are not limited to, ascorbic acid and its esters, sodium bisulfite, butylated hydroxytoluene, butylated hydroxyanisole, tocopherols, and chelating agents like EDTA and citric acid.
- Suitable moisturizers include, but are not limited to, glycerin, sorbitol, polyethylene glycols, urea, and propylene glycol.
- Suitable buffering agents include, but are not limited to, acetate buffers, citrate buffers, phosphate buffers, lactic acid buffers, and borate buffers.
- Suitable solubilizing agents include, but are not limited to, quaternary ammonium chlorides, cyclodextrins, benzyl benzoate, lecithin, and polysorbates.
- Suitable skin-penetration agents include, but are not limited to, ethyl alcohol, isopropyl alcohol, octylphenylpolyethylene glycol, oleic acid, polyethylene glycol 400, propylene glycol, N-decylmethylsulfoxide, fatty acid esters (e.g., isopropyl myristate, methyl laurate, glycerol monooleate, and propylene glycol monooleate); and N-methylpyrrolidone.
- the pharmaceutical composition may include various materials, which modify the physical form of a solid or liquid dosage unit.
- the composition may include materials that form a coating shell around the active ingredients.
- the materials that form the coating shell are typically inert, and may be selected from, for example, sugar, shellac, and other enteric coating agents.
- the active ingredients may be encased in a gelatin capsule.
- the pharmaceutical composition in solid or liquid form may include an agent that binds to the compound and thereby assists in the delivery of the compound. Suitable agents that may act in this capacity include, for example, a liposome.
- the pharmaceutical composition may consist of dosage units that can be administered as an aerosol.
- aerosol is used to denote a variety of systems ranging from those of colloidal nature to systems consisting of pressurized packages. Delivery may be by a liquefied or compressed gas or by a suitable pump system that dispenses the active ingredients. Aerosols of compounds may be delivered in single phase, biphasic, or triphasic systems in order to deliver the active ingredient(s). Delivery of the aerosol includes the necessary container, activators, valves, subcontainers, and the like, which together may form a kit. One skilled in the art, without undue experimentation may determine preferred aerosols. [0176] The pharmaceutical compositions may be prepared by any methodology well known in the pharmaceutical art.
- a pharmaceutical composition intended to be administered by injection can be prepared by combining a compound described herein with sterile, distilled water so as to form a solution.
- a surfactant may be added to facilitate the formation of a homogeneous solution or suspension.
- Surfactants are compounds that noncovalently interact with the compound described herein so as to facilitate dissolution or homogeneous suspension of the compound in the aqueous delivery system.
- active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
- the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
- the selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof) the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts. A.
- Lipid nanoparticles [0180] In accordance with the methods and pharmaceutical formulations disclosed herein, in some embodiments, the compound of Formula (I) is formulated into lipid nanoparticles. [0181] In an aspect, provided herein is a pharmaceutical composition including lipids nanoparticle-based compositions (e.g., liposomes, solid lipid particles, oil-in-water emulsions, etc.), and their use in methods of delivering compounds of Formula (I) to a subject. Lipid nanoparticle present many advantages, including increased epidermal penetration of active ingredients may be achieved when incorporated into lipid nanoparticles than when they are applied to the skin in the form of a solution or an emulsion.
- lipids nanoparticle-based compositions e.g., liposomes, solid lipid particles, oil-in-water emulsions, etc.
- lipid nanoparticles may increase the intracellular permeability and absorption rate of the compound of Formula (I) by approximately 30% more than the standard delivery mechanisms.
- Some embodiments disclosed herein relate to particle compositions and/or lipid- based particle compositions for delivering the compounds described herein.
- the particle is a lipid particle.
- the particles are nano- scale particles.
- the particles are micro-scale particles.
- the particle is a liposome (e.g., is a liposome).
- the particles comprise one or more of a phospholipid component, a non-phospholipid lipid component (e.g., medium and/or long chain triglyceride component), a sterol component, and/or water.
- the lipid nanoparticles include an active ingredient (e.g., a therapeutic agent, e.g., a compound of Formula (I)).
- the process of synthesizing lipid nanoparticles in the present disclosure may include homogenization techniques such as hot high pressure homogenization technique, cold high pressure homogenization technique, melt emulsification ultrasound (ultrasonication) homogenization technique, high shear homogenization and/or ultrasound technique, microemulsion technique, emulsification-solvent evaporation technique, solvent displacement or injection technique, emulsification-solvent diffusion technique, phase inversion technique, film ultrasonication dispersion technique, and multiple emulsion technique.
- homogenization techniques such as hot high pressure homogenization technique, cold high pressure homogenization technique, melt emulsification ultrasound (ultrasonication) homogenization technique, high shear homogenization and/or ultrasound technique, microemulsion technique, emulsification-solvent evaporation technique, solvent displacement or injection technique, emulsification-solvent diffusion technique, phase inversion technique, film ultrasonication dispersion technique, and multiple emulsion technique.
- the lipids in the nanoparticle compositions in this disclosure may include fatty acids, triglycerides triacylglycerols, acylglycerols, fats, waxes, cholesterol, sphingolipids, glycerides, sterides, cerides, glycolipids, sulfolipids, lipoproteins, chylomicrons and the derivatives of these lipids. Additionally, simpler lipids may be used and include medium chained triglycerides, hemp seed oil, safflower oil and sesame oil. Simpler lipids used in forming the phospholipid nanoparticles of this disclosure should be biocompatible, GRAS listed and non-toxic as nanoparticles.
- the lipid nanoparticles may be manufactured with biocompatible, physiological and GRAS structural materials and excipients that degrade quickly into non-toxic compounds that are easily eliminated through physiologic metabolic pathways and endogenous enzymes.
- the lipid matrix degradation occurs mostly by lipases whereas only non-enzymatic hydrolytic processes degrade a minor part.
- Lipid carriers prepared with several lipids and emulsifying agents have shown low toxicity in humans.
- the lipids are selected from triglycerides, diglycerides, monoglycerides, fatty acids, phospholipids, steroids, and waxes.
- Surfactants are important excipients frequently used in nanoparticulate systems as stabilizers and solulibilizers.
- the lipid nanoparticles include an emulsifier selected from the group consisting of anionic emulsifiers, cationic emulsifiers, nonionic emulsifiers or zwitterionic emulsifiers.
- the emulsifier is at least one selected from the group consisting of soy lecithin, egg lecithin, phosphatidylcholine; ethylene oxide copolymers, propylene oxide copolymers, poloxamers, sorbitan ethylene oxide/propylene oxide copolymers, polysorbate 20, polysorbate 60, polysorbate 80, sorbitan esters, span 20, span 40, span 60, span 80, alkyllaryl polyether alcohol polymers, tyloxapol, bile salts, cholate, glycocholate, taurocholate, taurodeoxycholate, gemini surfactants and alcohols.
- the emulsifiers are Polysorbate 80 and Soya Lecithin.
- the lipid is a glyceride.
- Exemplary glycerides include, but are not limited to, glyceryl behenate, tricaprin, trilaurin, trimyristin, tripalmitin, tristearin, 1,2-dioctanoyl-sn-glycerol, 1,2-didecanoyl-sn-glycerol, 1,2-dilauroyl-sn-glycerol, 1,2- dimyristoyl-sn-glycerol, 1,2-dipalmitoyl-sn-glycerol, 1-palmitoyl-2-oleoyl-sn-glycerol, 1- stearoyl-2-linoleoyl-sn-glycerol, 1-stearoyl-2-arachidonoyl-sn-glycerol, 1-stearoyl-2-
- the lipid nanoparticles include an oil phase.
- oils phase include, but are not limited to, propylene glycol esters, medium chain mono-, di-, or triglycerides, long chain fatty acids, edible oils, or a mixture thereof.
- the oil phase is selected from commercially available oils including, but not limited to, CAPTEX® 100 (Propylene Glycol Dicaprate), CAPTEX® 300 (Glyceryl Tricaprylate/Tricaprate), CAPTEX® 355 (Glyceryl Tricaprylate/Tricaprate), MIGLYOL® 810 (Caprylic/Capric Triglyceride), MIGLYOL® 812 (Caprylic/Capric Triglyceride), MIGLYOL® 818 (Caprylic/Capric/Linoleic Triglyceride), MIGLYOL® 829 (Caprylic/Capric/Succinic Triglyceride), and DYNACERIN® 660 (Oleyl Erucate), CAPRYOLTM 90, CAPTEX® 200 (Propylene Glycol Dicaprylocaprate) and MIGLYOL® 840 (Propylene Glycol Dicaprylate/Dicaprate), and the like.
- CAPTEX® 100 Propy
- the oil phase is selected from a group comprising edible oils.
- the edible oil may include, but is not limited to, soyabean oil, castor oil, cottonseed oil, Arachis oil, sesame oil, sweet orange oil, canola oil, sunflower seed oil, peanut oil, rapeseed oil, and oleic acid.
- the lipid nanoparticles may be formed in a water and oil emulsion. Accordingly, the nanoparticles may include water.
- the lipid nanoparticles include a compound of Formula (I) ranging in concentration from 0.01% to 90%.
- the lipid nanoparticles may include a compound of Formula (I) at a concentration of about 0.01%, about 0.1%, about 1%, about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, or about 80%, up to about 0.1%, about 1%, about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90%.
- the lipid nanoparticles include a lipid, an emulsifier, and a stabilizer.
- Nanoparticle size is extremely important to the biological properties and functioning of nanoparticle carriers.
- Nanoparticles with diameters ranging from 20 nm to 200 nm typically demonstrate the most prolonged circulation times. Whereas smaller nanoparticle sizes and a lipid structured nanoparticle composition can facilitate easier passage across cell membranes, enhancing cellular uptake and greater delivery to intracellular targets.
- particle size or “particle diameter” refers to the mean diameter of the particles in a sample, as measured by dynamic light scattering (DLS), multiangle light scattering (MALS), nanoparticle tracking analysis, or comparable techniques. It will be understood that a dispersion of lipid nanoparticles as described herein will not be of uniform size but can be described by the average diameter and, optionally, the polydispersity index.
- the lipid nanoparticles have a mean diameter between 10 nm and 1000 nm (e.g., between 10 nm, 20 nm, 30 nm, 40 nm, 50 nm, 60 nm, 70 nm, 80 nm, 90 nm, 100 nm, 110 nm, 120 nm, 130 nm, 140 nm, 150 nm, 160 nm, 170 nm, 180 nm, 190 nm, 200 nm, 250 nm, 300 nm, 350 nm, 400 nm, 450 nm, 500 nm, 550 nm, 600 nm, 700 nm, 800 nm, or 900 nm, up to 20 nm, 30 nm, 40 nm, 50 nm, 60 nm, 70 nm, 80 nm, 90 nm, 100 nm, 110 nm, 120 nm, 130 nm, 150
- the mean diameter is between 100 nm and 300 nm. In some embodiments, the mean diameter is between 150 nm and 200 nm.
- the particles may each be substantially the same shape and/or size, in which case the population is “monodisperse”. For example, the particles may have a distribution of particle sizes such that no more than about 5% or about 10% of the particles have a particle size greater than about 10% greater than the average particle size of the particles, and in some cases, such that no more than about 8%, about 5%, about 3%, about 1%, about 0.3%, about 0.1%, about 0.03%, or about 0.01% have a particle size greater than about 10% greater than the average particle size of the particles.
- the lipid nanoparticles have a polydispersity index of 0.25 or less (e.g., 0.25, 0.24, 0.23, 0.22, 0.21, 0.20, 0.19, 0.18, 0.17, 0.16, 0.15, 0.14, 0.13, 0.12, 0.11, 0.10, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01, or less), as measured by dynamic light scattering (DLS).
- DLS dynamic light scattering
- the compound of Formula (I) is encapsulated in the lipid nanoparticles.
- the compound of Formula (I) encapsulation efficiency is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 92%, at least 94%, at least 95%, at least 96%, at least 97%, or at least 98%, e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or greater).
- the nanoparticles and pharmaceutical formulations may be further converted into powder form by removal of the water there from, e.g., by lyophilization at a suitable temperature-time profile.
- the powder is easily reconstituted by addition of water, saline or buffer.
- cryoprotectants may be added to formulations if so desired (e.g., mannitol, sucrose, trehalose, glycine).
- the lyophilized powder may be suspended in an aqueous formulation prior to administration.
- the subject is administered a second/ additional therapeutic agent beyond the compound of Formula (I).
- the multiple therapeutic agents may be administered in any order or even simultaneously. If simultaneously, the multiple therapeutic agents may be provided in a single, unified form, or in multiple forms (by way of example only, either as a single pill or as two separate pills). One of the therapeutic agents may be given in multiple doses, or both may be given as multiple doses. If not simultaneous, the timing between the multiple doses may be any duration of time ranging from a few minutes to four weeks.
- pharmaceutical combination refers to a pharmaceutical therapy resulting from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
- fixed combination means that a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent, are both administered to a subject simultaneously in the form of a single composition or dosage.
- non-fixed combination means that a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent are formulated as separate compositions or dosages such that they may be administered to a subject in need thereof simultaneously, concurrently or sequentially with variable intervening time limits, wherein such administration provides effective levels of the two or more compounds in the body of the subject.
- cocktail therapies e.g., the administration of three or more active ingredients.
- the subject when the subject is being treated for a neurodegenerative disease such as ALS, the subject may also be administered standard therapeutics for the treatment of ALS.
- Additional therapies that can be used in conjunction with the compound of Formula (I), may comprise one or more drug(s) that ameliorate(s) symptoms of ALS, one or more drug(s) that could be used for palliative treatment of ALS or one or more drug(s) currently evaluated in the frame of clinical trials for treating of ALS.
- Such drugs include, but are not limited to, AEOL 10150, arimoclomol, AVP-923, botulinum toxin type B (Myobloc), ceftriaxone, celastrol, celecoxib, cistanche total glycosides, coenzyme Q10, copaxone, creatine, creatinine, dronabinol, erythropoietin, escitalopram (Lexapro), glatiramer acetate, granulocyte-colony stimulating factor (G-CSF), growth hormone (Somatropin), GSK1223249, indinavir, insulin-like growth factor-1 (IGF-I), IGF-1-AAV, KNS-760704, leteprinim, leuprolide, levetiracetam, MCI-186, mecobalamin, minocycline, modafinil, Naaladase inhibitor, N-Acetylcysteine, NBQX, nimesulide, n
- the subject when the subject is being treated for a neurodegenerative disease such as MS, the subject may also be administered standard therapeutics for the treatment of MS.
- the RRMS treatments include the following: interferon class, IFN-beta-1a (REBIF® and AVONEX®) and IFN- beta-1b (BETASERON®); glatiramer acetate (COPAXONE®), a polypeptide; natalizumab (TYSABRI®); and mitoxantrone (NOVANTRONE®), a cytotoxic agent.
- pulmonary fibrosis drugs have been used with varying degrees of success, including corticosteroids, methotrexate, cyclophosphamide, azathioprine, and intravenous (IV) immunoglobulin.
- corticosteroids methotrexate
- cyclophosphamide azathioprine
- IV intravenous immunoglobulin.
- the benefits of currently approved treatments are relatively modest ( ⁇ 30%) for relapse rate and prevention of disability in RRMS as suggested by two meta-analyses (Filippini et al. Lancet 361:545-52 (2003)).
- the subject when the subject is being treated for a fibrotic disease such as pulmonary fibrosis, the subject may also be administered standard therapeutics for the treatment of pulmonary fibrosis.
- idiopathic pulmonary fibrosis/pulmonary fibrosis can be treated with a combination of a compound of Formula (I) and one or more of the following drugs: pirfenidone (pirfenidone was approved for use in 2011 in Europe under the brand name Esbriet®), prednisone, azathioprine, N-acetylcysteine, interferon- ⁇ 1b, and anti-inflammatory agents such as corticosteroids.
- Prednisone is the usual treatment for idiopathic pulmonary fibrosis but it can be treated with other immunosuppressive therapies with the objective of reduction of inflammation that is the prelude to lung fibrosis.
- a compound of Formula (I) can be used to treat idiopathic pulmonary fibrosis/pulmonary fibrosis in combination with any of the following methods: oxygen therapy, pulmonary rehabilitation and surgery.
- the pharmaceutical compositions also include an anti- inflammatory agent, an analgesic agent, an anti-infective agent, or a combination thereof. Such compositions may be used in the treatment of fibrotic condition or diseases.
- the additional agent is an anti-inflammatory agent.
- the anti-inflammatory agent is a steroidal anti- inflammatory agent.
- steroidal anti-inflammatory agent refers to any one of numerous compounds containing a 17-carbon 4-ring system and includes the sterols, various hormones (as anabolic steroids), and glycosides.
- Representative examples of steroidal anti-inflammatory drugs include, without limitation, corticosteroids such as hydrocortisone, hydroxyltriamcinolone, alpha-methyl dexamethasone, dexamethasone- phosphate, beclomethasone dipropionates, clobetasol valerate, desonide, desoxymethasone, desoxycorticosterone acetate, dexamethasone, dichlorisone, diflucortolone valerate, fluadrenolone, fluclorolone acetonide, flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortine butylesters, fluocortolone, fluprednidene (fluprednylidene
- the anti-inflammatory agent is a nonsteroidal anti-inflammatory agent.
- non-steroidal anti-inflammatory agent refers to a large group of agents that are aspirin-like in their action, including, but not limited to, ibuprofen (Advil®), naproxen sodium (Aleve®), and acetaminophen (Tylenol®).
- non-steroidal anti-inflammatory agents include, without limitation, oxicams, such as piroxicam, isoxicam, tenoxicam, sudoxicam, and CP-14,304; disalcid, benorylate, trilisate, safapryn, solprin, diflunisal, and fendosal; acetic acid derivatives, such as diclofenac, fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac, zidometacin, acematacin, fentiazac, zomepirac, clindanac, oxepinac, felbinac, and ketorolac; fenamates, such as mefenamic, meclofenamic, flufenamic, niflumic, and tolfenamic acids; propionic acid
- the anti-inflammatory agent includes, without limitation, Transforming Growth Factor- beta3 (TGF- ⁇ 3), an anti-Tumor Necrosis Factor- alpha (TNF-a) agent, or a combination thereof.
- TGF- ⁇ 3 Transforming Growth Factor- beta3
- TNF-a anti-Tumor Necrosis Factor- alpha
- the additional agent is an analgesic agent.
- the analgesic agent relives pain by elevating the pain threshold without disturbing consciousness or altering other sensory modalities.
- the analgesic agent is a non-opioid analgesic.
- Non-opioid analgesics are natural or synthetic substances that reduce pain but are not opioid analgesics. Examples of non-opioid analgesics include, but are not limited to, etodolac, indomethacin, sulindac, tolmetin, nabumetone, piroxicam, acetaminophen, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, naproxen, naproxen sodium, oxaprozin, aspirin, choline magnesium trisalicylate, diflunisal, meclofenamic acid, mefenamic acid, and phenylbutazone.
- the analgesic is an opioid analgesic.
- opioid analgesics are natural or synthetic substances that bind to opioid receptors in the central nervous system, producing an agonist action.
- opioid analgesics include, but are not limited to, codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, propoxyphene, buprenorphine, butorphanol, dezocine, nalbuphine, and pentazocine.
- the additional agent is an anti-infective agent.
- the anti-infective agent is an antibiotic agent.
- antibiotic agent as used herein means any of a group of chemical substances having the capacity to inhibit the growth of, or to destroy bacteria, and other microorganisms, used chiefly in the treatment of infectious diseases.
- antibiotic agents include, but are not limited to, Penicillin G; Methicillin; Nafcillin; Oxacillin; Cloxacillin; Dicloxacillin; Ampicillin; Amoxicillin; Ticarcillin; Carbenicillin; Mezlocillin; Azlocillin; Piperacillin; Imipenem; Aztreonam; Cephalothin; Cefaclor; Cefoxitin; Cefuroxime; Cefonicid; Cefmetazole; Cefotetan; Cefprozil; Loracarbef; Cefetamet; Cefoperazone; Cefotaxime; Ceftizoxime; Ceftriaxone; Ceftazidime; Cefepime; Cefixime; Cefpodoxime; Cefsulodin; Fleroxacin; Nalidixic acid; Norfloxacin; Ciprofloxacin; Ofloxacin; Enoxacin ; Lomefloxacin; Cinoxacin; Doxycycline;
- Anti-bacterial antibiotic agents include, but are not limited to, penicillins, cephalosporins, carbacephems, cephamycins, carbapenems, monobactams, aminoglycosides, glycopeptides, quinolones, tetracyclines, macrolides, and fluoroquinolones.
- additional therapeutic agents include, but are not limited to, rose hip oil, vitamin E, 5-fluorouracil, bleomycin, onion extract, pentoxifylline, prolyl-4- hydroxylase, verapamil, tacrolimus, tamoxifen, tretinoin, colchicine, a calcium antagonist, tranilst, zinc, an antibiotic, and a combination thereof.
- compositions including a compound of Formula (I) or a pharmaceutically acceptable salt thereof can be formulated in a unit dosage form, each dosage containing from about 5 mg to about 1,000 mg (1 g), more usually about 100 mg to about 500 mg, of the active ingredient.
- unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other subjects, each unit containing a predetermined quantity of active material (i.e., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
- the compositions provided herein contain from about 100 mg to about 500 mg of the active ingredient.
- the compositions provided herein contain from about 50 mg to about 500 mg of the active ingredient. In some embodiments, the compositions provided herein contain about 10 mg, about 20 mg, about 30 mg, about 80 mg, about 100 mg or about 160 mg of the active ingredient. [0216] In some embodiments, the compositions provided herein contain from about 500 mg to about 1,000 mg of the active ingredient. [0217]
- the daily dosage of the compound of Formula (I) or a pharmaceutically acceptable salt thereof can be varied over a wide range from 1.0 to 10,000 mg per adult human per day, or higher, or any range therein.
- compositions are preferably provided in the form of tablets or oral thin films containing, 10.0, 15.0, 25.0, 50.0, 100, 150, 160, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated.
- An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.1 mg/kg to about 1000 mg/kg of body weight per day, or any range therein.
- the range is from about 0.5 to about 500 mg/kg of body weight per day, or any range therein.
- the range can be from about 0.1 to about 50.0 mg/kg of body weight per day, or any amount or range therein.
- the range can be from about 0.1 to about 15.0 mg/kg of body weight per day, or any range therein. In yet another example, the range can be from about 0.5 to about 7.5 mg/kg of body weight per day, or any amount to range therein.
- Pharmaceutical compositions containing a compound of Formula (I) or a pharmaceutically acceptable salt thereof can be administered on a regimen of 1 to 4 times per day or in a single daily dose. [0218] In accordance with any of the methods disclosed herein, in some embodiments, the compound of Formula (I) is administered in a dose of about 200 to 400 mg per day. The dose may be in a single fixed dose, or alternatively in multiple doses.
- the compound of Formula (I) may be administered once per day, twice per day, or three times per day.
- the compound of Formula (I) is administered in a dose of about 10 to 200 mg per day in a single dose.
- the dose may be 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, or 200 mg per day.
- the active compound may be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. Optimal dosages to be administered can be readily determined by those skilled in the art.
- the amount of the compound actually administered will usually be determined by a physician, and will vary according to the relevant circumstances, including the mode of administration, the actual compound administered, the strength of the preparation, the condition to be treated, and the advancement of the disease condition.
- factors associated with the particular subject being treated including subject response, age, weight, diet, time of administration and severity of the subject’s symptoms, will result in the need to adjust dosages.
- the compounds provided herein can be administered in an amount ranging from about 1 mg/kg to about 100 mg/kg.
- the compound provided herein can be administered in an amount of about 1 mg/kg to about 20 mg/kg, about 5 mg/kg to about 50 mg/kg, about 10 mg/kg to about 40 mg/kg, about 15 mg/kg to about 45 mg/kg, about 20 mg/kg to about 60 mg/kg, or about 40 mg/kg to about 70 mg/kg.
- such administration can be once-daily or twice-daily (BID) administration.
- BID twice-daily
- kits useful for example, in the treatment of a neurodegenerative disease, which include one or more containers containing a pharmaceutical composition including an effective amount of a compound provided herein.
- kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art.
- kits useful, for example, in the treatment of fibrotic condition or disease which include one or more containers containing a pharmaceutical composition including an effective amount of a compound provided herein.
- kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art.
- Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components can also be included in the kit.
- NLC Nanostructured Lipid Carriers
- Glyceryl distearate/glyceryl palmitostearate and triglycerides of capric/caprylic acids are used as solid and liquid lipids, respectively. Both lipids are generally recognized as safe excipients with high biocompatibility and low cytotoxicity, which are advantageous for brain delivery.
- a mixture of mono-, di- and triglycerides, glyceryl distearate/glyceryl palmitostearate form crystals with many imperfections, providing more space to load the compounds of Formula (I) and to avoid its expulsion.
- Polysorbate 80 and poloxamer 188 are used as nonionic surfactants, as they have very low toxicity and produce particles with smaller sizes, which are advantageous for enhancing brain uptake.
- Polysorbate 80 and poloxamer 188 are known to increase drug transport to the brain by coating on the surface of the nanocarriers.
- the NCL formulations and placebo control are prepared according to the concentrations disclosed in Table 1. Table 1.
- the physicochemical properties of the NLCs of Table 1 are disclosed in Table 2: Table 2.
- Mean diameter, polydispersity index (PDI), zeta potential (ZP), and encapsulation efficiency (EE) of NLC formulations (mean ⁇ SD) Cold High Pressure Homogenization [0228]
- the lipid and compound of Formula (I) are melted together and rapidly cooled under liquid nitrogen forming solid lipid micro particles.
- a pre-suspension is formed by homogenization of the particles in a cold surfactant solution.
- the pre-suspension is further homogenized in a high pressure homogenization apparatus at or below room temperature at predetermined homogenization conditions to produce the NLCs.
- the control placebo NLCs are prepared in a similar way, without the addition of the compounds of Formula (I). Characterization of the NLCs [0229] The mean particle size and the polydispersity Index (PDI) are measured using dynamic light scattering (DLS). The zeta potential (ZP) is measured using electrophoretic light scattering (ELS). During the analysis, the cell temperature is kept at 25°C, and the scattering angle is 90°. Prior to the measurements, the samples are diluted with double distilled water for increased accuracy. Encapsulation Efficiency (EE) [0230] The encapsulation efficiency (%) of the NLC formulated with the compound of Formula (I) is assessed using high-performance liquid chromatography (HPLC).
- HPLC high-performance liquid chromatography
- the NLC samples are stored in closed glass vials at both 5 ⁇ 1°C and 25 ⁇ 1°C.
- the particle size, polydispersity index, and zeta potential is measured at day 0, 1 month, 2 months, and 3 months.
- Transmission Electron Microscopy (TEM) [0232] The morphology of the NLCs is examined by transmission electron microscopy (TEM). The TEM images show the NLCs to be spherical with a uniform shape and with smooth surfaces, and confirm the sizes measured by DLS.
- DSC Differential Scanning Calorimetry
- DSC Differential Scanning Calorimetry
- DSC Differential scanning calorimetry
- the NLCs show a homogeneous size distribution with a mean diameter between 165 and 200nm which corresponds to the required size for brain drug delivery.
- the polydispersity index (PDI) is a measure of the uniformity of particle size distribution.
- the PDI of the both the NCL placebo and Formula (I)-loaded NLCs is below 0.3, indicating a fairly narrow and homogeneous size distribution with low variability.
- the zeta potential (ZP) measures the overall surface charge of a particle and is an indicator to predict stability over time.
- the zeta potential of the NLC Placebo and Formula (I)-loaded NLCs is equal or great than I 30 I mV, which demonstrates electrostatic stability and low propensity to aggregate.
- Example 2 Ex vivo Skin Diffusion Studies
- Formulations of NCLs for topical administration are prepared according to Example 1.
- the skin diffusion studies are conducted to analyze the diffusion and skin accumulation of the compounds of Formula (I). The studies are preformed using a similar protocol as defined by Gokce et al. (Resveratrol-loaded solid lipid nanoparticles versus nanostructured lipid carriers - evaluation of antioxidant potential for dermal applications. International Journal of Nanomedicine, 2012:71844, which is hereby incorporated by reference in its entirety).
- Formula (I)-loaded NLCs show superior permeability and skin retention, with their sizes below 200nm, PDI below 0.3 and ZP greater than 30.
- Ex vivo skin diffusion studies show that compounds of Formula (I) alone are unable to permeate skin tissue, but NLCs enable the penetration/accumulation of Formula (I) into both the epidermis and dermis.
- Discussion [0238] Localized scleroderma starts with skin lesions caused by inflammation, followed by excessive, dense collagen deposition and an increase in the number of fibroblasts leading to skin tissue thickening, consequently, topical administration of drugs cannot efficiently penetrate into the depths of the skin through the pathological tissue.
- nanostructured lipid carriers have the following advantages: i. Being non-toxic and non-irritating. ii. Increased stability of the drug. iii. Improved drug loading because NLCs are prepared by a blend of solid and liquid lipids to yield a non-crystalline amorphous lipid core, which allows higher drug load. iv. Enhance permeation of drugs because NLCs have small size, strong adhesive properties, and easily produce an occlusion effect by forming a film on the skin, thereby preventing water loss from the skin, increasing penetration of the drug, and leading to a controlled release of the drug. v.
- Example 3 Efficacy in ALS Animal Model [0239] The gene coding for copper-zinc superoxide dismutase (SOD1) is a frequently mutated gene in familial ALS patients (20% familial cases). Transgenic mice overexpressing human SOD1 have similar phenotypes and pathologies to those seen in human ALS. SOD1G93A transgenic mice are chosen for the present study.
- Female and male mice are given either saline or drug solutions at 12 and 13 weeks of age (disease onset), respectively, for four weeks.
- Motor performances (defined below) is tested at the beginning (0 weeks) and every two weeks of the experiments.
- Grip strength test [0244] The mouse is lightly placed on the center of the grip plate, prompting the animal to grasp the grip plate, and then gently pulled by the tail. Each animal is tested three times and the maximum value of the three results is taken as the evaluation value. After the start of the formal experiment, the mice are tested every two weeks.
- Hanging wire test [0245] The wire lid of the common cage is used to assess limb grip strength. The mouse is placed in the center of the wire lid (21 cm ⁇ 21 cm), which is then turned upside down for up to 90 s. The length of time the mouse holds on to the wire is recorded. Mice are trained for 3 days before testing. The holding time of each mouse is measured twice and the average value is taken as the result. This experiment is conducted every two weeks.
- Climbing-pole test is used to assess the movement and coordination of the mouse.
- a homemade wooden rod is used, which is approximately 50 cm long and approximately 1 cm in diameter, wrapped with gauze to increase friction.
- the mouse is placed face down on the top of the vertical pole, and the descent time from the top of the pole to the bottom platform is recorded.
- Prior to testing each mouse is trained for 3 consecutive days, twice a day, with a maximum cut-off value of 15 s.
- the experimental procedure is repeated three times and the average climb time of each mouse is calculated as an evaluation value. This experiment is conducted every two weeks.
- mice are anesthetized with 1% sodium pentobarbital; the chest is then opened and 0.01 M phosphate buffered saline (PBS, pH 7.2) is perfused through the heart.
- PBS phosphate buffered saline
- the lumbar segments of the spinal cord (L4-L5) is dissected, fixed in 4% paraformaldehyde and embedded in paraffin.
- Approximately 200 of 10 ⁇ m serial cross- sections of the spinal cord are collected. Every fourth section is placed on a slide, and 7 nonconsecutive different sections are selected for Nissl staining. Microscopic examination and counting of motor neurons is performed on one side of the anterior horn of the spinal cord.
- mice are anesthetized and perfused with 0.01 M PBS (pH 7.2) via the heart. From one hind limb, the gastrocnemius muscle is carefully dissected, weighed, photographed, and then fixed in 4% paraformaldehyde (pH 7.4) for 48 h. After fixation, the tissue is dehydrated with ethanol and embedded in paraffin.
- Example 4 Efficacy in Localized Scleroderma Anti-fibrotic Cell Studies
- primary fibroblasts cell line are cultured using DMEM containing 10% FBS.
- the evaluation indicators include: (1) CCK8, EdU: monitor cell proliferation; (2) Flow type: detection of apoptosis; (3) Transwell: monitor cell migration; and (4) qRT-PCR; (5) Western bloting: monitor the expression of fibroblast inflammatory factors.
- the anti-fibrotic activity of the Formula (I)-loaded NLCs is assessed using the bleomycin-induced scleroderma model on eight-week-old CH3/He female mice.
- mice dorsal skin is shaved with a razor, in a diameter of about 1 cm.
- bleomycin 100ul (0.2mg/ml)
- the animals in the treatment group are topically treated with the Formula (I)-loaded NLCs in the evening from Day 15 until Day 28.
- the evaluation indicators include: (1) observation with the naked eye: the skin becomes harder and thicker; (2) HE staining: observe the degree of skin fibrosis and dermal thickness; (3) Mason tricolor staining: observe the changes of collagen fibers in lung tissue and whether the skin collagen fibers are neatly arranged; (4) immunohistochemical staining: detect the expression and distribution of inflammatory factors in diseased skin tissue and analyze it with skin fibrosis indicators; (5) Western blotting: expression of fibroblast inflammatory factors. [0252] All animal experiments are carried out according to guidelines and protocols approved by the ethics committee.
- Example 5 Inhibition of Cytokine Production in Human Dendritic Cells
- Human CD14+ monocytes were differentiated with granulocyte macrophage colony-stimulating factor (GM-CSF) (100 ng/ml) and interleukin 4 (IL-4) (40 ng/ml) for 5 days.
- GM-CSF granulocyte macrophage colony-stimulating factor
- IL-4 interleukin 4
- the cells were then treated with various concentrations of the compounds disclosed herein (0, 10, 20, 40, 80 or 160 uM) for 2h before stimulating cells with oxidized low-density lipoprotein (ox-LDL) (10-50 ug/ml) or Lipopolysaccharide (LPS) (1-100 ng/ml) for another 24 h.
- ox-LDL oxidized low-density lipoprotein
- LPS Lipopolysaccharide
- the cell culture supernatants were analyzed for IL-1b, IL-6, IL-12 & TNF-a levels using multiplex Meso Scale Discovery (MSD) cytokine kits.
- the cell pellets were analyzed for cell viability using Celltiter-glo.
- the compounds described herein produced a dosed dependent inhibition of LPS stimulated IL-12 & TNF- ⁇ production in human dendritic cells. No effect on cell viability was observed.
- Example 6 Inhibition of Cytokine Production in Human CD3+ T Cells
- Human peripheral CD3+ T cells at 1 ⁇ 10 6 /ml were pretreated with various concentrations of the compounds described herein (0, 10, 20, 40, 80, or 160 uM) or a positive control (5 uM Cyclosporin A) for 2 hr and then stimulated with phorbol-12-myristate-13- acetate (PMA) (5 ng/ml)/ Ionomycin (1 uM) or anti-CD3 (plate coated at 2 ug/ml)/anti-CD28 (soluble at 2 ug/ml) for another 24h.
- PMA phorbol-12-myristate-13- acetate
- Ionomycin (1 uM
- anti-CD3 plate coated at 2 ug/ml
- anti-CD28 soluble at 2 ug/ml
- the cell culture supernatants were analyzed for IL-2, IL-4, IFN-g & TNF-a levels by multiplex MSD kits.
- the compounds of Formula (I) produced a dosed dependent inhibition of anti-CD3/anti-CD28 or PMA/Ionomycin stimulated IL-2, IL-4 and TNF- ⁇ production in human CD3 + T cells.
- Figure 2C shows the cell viability results of the CD3+ T cells.
- Example 7 Evaluation of the Anti-oxidative Activity of Compounds of Formula (I) in Human Vascular Endothelial Cells
- Human vascular endothelial cells were pretreated with various concentrations of compounds of Formula (I) (0, 1, 10, 20, 40 or 80 uM) or a positive control (Edaravone) for 30 min, followed by treatment with H2O2 (100 uM) for another 15 min or 30 mM glucose for another 1 hr.
- the intracellular reactive oxygen species (ROS) levels were analyzed by flow cytometry. As shown in Figure 3 the compounds of Formula (I) significantly reduced the ROS level at 20-200 fold lower concentrations than Edaravone.
- the compounds of Formula (I) share a similar antioxidant mechanism of Edaravone, but display superior antioxidant effects.
- Example 8 Efficacy in ALS Humans [0258] The compounds of Formula (I) are administered to a human subject in a therapeutically effective amount as described herein.
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present application relates to compounds of Formula (I), as defined herein, and pharmaceutically acceptable salts or solvates thereof for use in the treatment of neurodegenerative diseases and fibrotic conditions and diseases. The present application also describes pharmaceutical compositions comprising a compound of Formula (I), and pharmaceutically acceptable salts thereof.
Description
POLYCYCLIC COMPOUNDS FOR USE IN NEURODEGENERATIVE CONDITIONS CROSS REFERENCE TO RELATED APPLICATIONS [0001] The present application claims priority to U.S. Provisional Patent Application No.63/383,434 entitled “Polycyclic Compounds for Use in Neurodegenerative Conditions” filed November 11, 2022, which is hereby incorporated by reference in its entirety. BACKGROUND [0002] Few treatments are currently available for the neurodegenerative condition ALS, also known as motor neuron disease and Lou Gehrig’s disease. The incidence of ALS worldwide is about one in 50,000 people per year, equating to about 5,760 to 6,400 new diagnoses annually (Longinetti & Fang, Curr Opin Neurol. 32(5): 771–776 (2019)). Typically, people are diagnosed between the age of 50 and 70. Statistics show that only half of those with ALS live at least three years after diagnosis, 25% survive at least five years and up to 10% live ten years or more beyond their diagnosis. [0003] The condition, which causes death of motor neurons in the brain and spinal cord eventually leading to paralysis and early death from respiratory failure, has impacted high- profile figures, including the famed physicist Stephen Hawking and generated mainstream media attention in recent years. [0004] As of May 2022, the U.S. FDA has approved five medical treatments of ALS, three of which are in different dosage forms of Riluzole: EXSERVAN™ (oral film of Riluzole), RILUTEK® (tablets of Riluzole), TIGLUTIK® (oral suspension of Riluzole). The remaining 2 treatments are in different dosage forms of Edaravone: RADICAVA® (intravenous formulation of Edaravone) and RADICAVA ORS® (oral suspension formulation of Edaravone). [0005] Sanofi’s Riluzole is the first treatment for ALS approved by the U.S. FDA in 1995. Riluzole works by blocking the release of glutamate, too much of which is believed to injure nerve cells. While this approval was a welcome development, it was a very limited step
forward. Riluzole brings only a very modest benefit for ALS patients, prolonging survival rate between 2 and 3 months. [0006] Edaravone is the second (and only other) drug approved for ALS. It was approved in Japan and South Korea in 2015. In the U.S, the drug received Orphan Drug Designation from the FDA by 2016, followed by the EU’s EMA. In 2017, the FDA approved RADICAVA® (intravenous formulation of Edaravone). Edaravone is a synthetic free radical scavenger and works by decreasing oxidative stress, another potential cause of nerve cell death in ALS. Unfortunately, like Riluzole, the drug does not stop or cure the disease but modestly slows its progression in a small group of patients with early-stage ALS. Treatment with RADICAVA®, an intravenous formulation of edaravone, is expensive and requires daily hour-long IV infusions for ten days in a two-week period. This cycle must then be repeated after a two-week break. [0007] Neurodegenerative conditions are often associated with oxidative stress. Additional conditions often associated with oxidative stress include fibrotic conditions and diseases such as multiple sclerosis, systematic scleroderma (systemic sclerosis), pulmonary fibrosis, and dermatosclerosis. [0008] Dermatosclerosis, a chronic hardening and shrinking of the connective tissues of any organ of the body, including the skin, heart, esophagus, kidney, or lung. The skin may be thickened, hard, and rigid, and pigmented patches may occur. The two main types are systemic scleroderma and localized scleroderma. The milder forms are most often seen in women between the ages of 30 and 50; the more severe forms usually affect men, blacks, and older persons. It is estimated the incidence of systemic sclerosis in the United States is approximately 20 cases per million population, and its prevalence is approximately 276 cases per million population (Jimenez, Drugs & Diseases, Rheumatology, Scleroderma, emedicine.medscape.com/article/331864 (2022)). An increase in systemic sclerosis incidence and prevalence has occurred over the last 50 years. Systemic sclerosis occurs worldwide, although its reported prevalence varies significantly in different countries; with higher prevalence rates reported in Europe and the Americas in comparison to East Asia. Obtaining an exact estimate of prevalence is challenging given that systemic sclerosis is often misdiagnosed. Additionally, ethnic and geographical clustering may contribute to the variability in terms of frequency. However, it appears that there is a higher frequency among black individuals.
[0009] The most popular method for treating fibrotic conditions, such as skin fibrosis, is the use of immunosuppressive therapy. The rationale is that autoimmune etiology causes inflammation aspects of the disease and subsequent tissue damage and fibrosis. Drugs studied included methotrexate, mycophenolate mofetil, cyclophosphamide, and cyclosporine. Although some improvement in immunosuppressive therapy has been observed, concerns regarding drug safety and the lack of established clinical data and verifiable efficacy still exist. [0010] Despite the best efforts, there is a crucial unmet medical need to treat neurodegenerative conditions and fibrotic conditions and diseases. BRIEF SUMMARY [0011] It has now been found that certain derivatives of magnesium lithospermate B can function as antioxidants and anti-inflammatory agents useful in the treatment of diseases and conditions associated with oxidative stress including neurodegenerative diseases and fibrotic diseases and conditions. [0012] Accordingly, provided herein is a method of treating a neurodegenerative disease in a subject in need thereof. The method includes administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof: wherein
R1 is ( CO2)-, CO2(C1-C6 alkyl), or CO2H; R2 is CO2(C1-C6 alkyl), CO2H, or (CO2)-;
R3 is independently selected at each occurrence from H, C(O)C1-C6 alkyl, or C1-C6 alkyl; X is a cation; and n is 0, 1, or 2. [0013] Another aspect of the present application relates to a pharmaceutical composition for the treatment of a neurodegenerative disease including a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof. [0014] A further aspect of the present application relates to a method of treating a fibrotic condition or disease in a subject in need thereof. The method includes administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof. [0015] Another aspect of the present application relates to a pharmaceutical composition for the treatment of a fibrotic condition or disease comprising a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof. BRIEF DESCRIPTION OF THE DRAWINGS [0016] Figure 1A is flowchart showing the treatment of hCD14+ monocytes for the inhibition of lipopolysaccharide stimulated IL-12 p70 and TNF-α production in human dendritic cells of Example 5. [0017] Figure 1B is a plot of the inhibition of lipopolysaccharide stimulated IL-12 p70 production in human dendritic cells treated with the compound described herein. [0018] Figure 1C is a plot of the inhibition of lipopolysaccharide stimulated TNF-α production in human dendritic cells treated with the compound described herein. [0019] Figure 2A is flowchart showing the treatment of human peripheral CD3+ T cells for the inhibition of IL-2, IL-4 and TNF-α production of Example 6. [0020] Figure 2B is a plot of the inhibition of the IL-2, IL-4 and TNF-α production in human CD3+ T stimulated with stimulated with anti-CD3/anti-CD28 or PMA/Ionomycin upon treatment with the compound described herein. [0021] Figure 2C is a plot of the cell viability of human peripheral CD3+ T cells treated with the compounds described herein as described in Example 6.
[0022] Figure 3 is a plot of the reduction of the reactive oxygen species in human vascular endothelial cells treated with the compounds described herein as described in Example 7. DETAILED DESCRIPTION [0023] The present application provides chemical entities (e.g., a compound or a pharmaceutically acceptable salt, and/or hydrate, and/or solvate, and/or co-crystal, and/or drug combination of the compound) with strong antioxidant properties. These chemical entities are useful, e.g., for treating a condition, disease or disorder in which increased (e.g., excessive) oxidative stress, immune response, and/or inflammation is associated with the pathology and/or symptoms and/or progression of the condition, disease or disorder in a subject (e.g., a human). The present application also provides compositions containing the same, as well as methods of using and making the same. [0024] Disclosed herein is a class of compounds useful for treating diseases associated with oxidative stress and/or an abnormal autoimmune response, defined by structural Formula (I):
wherein R1 is (CO2)-, CO2(C1-C6 alkyl), or CO2H; R2 is CO2(C1-C6 alkyl), CO2H, or (CO2)-; R3 is independently selected at each occurrence from H, C(O)C1-C6 alkyl, or C1-C6 alkyl; X is a cation; and n is 0, 1, or 2.
I. DEFINITIONS A. General Definitions [0025] Before the present invention is further described, it is to be understood that this invention is not strictly limited to particular embodiments described, as such may of course vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the claims. [0026] It must be noted that as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. It should further be understood that as used herein, the term “a” entity or “an” entity refers to one or more of that entity. For example, a nucleic acid molecule refers to one or more nucleic acid molecules. As such, the terms “a”, “an”, “one or more” and “at least one” can be used interchangeably. Similarly the terms “comprising”, “including” and “having” can be used interchangeably. [0027] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates, which may need to be independently confirmed. [0028] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination. All combinations of the embodiments are specifically embraced by the present invention and are disclosed herein just as if each and every combination was
individually and explicitly disclosed. In addition, all sub-combinations are also specifically embraced by the present invention and are disclosed herein just as if each and every such sub- combination was individually and explicitly disclosed herein. [0029] It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation. [0030] As used herein, the term “about” means a range of values including the specified value, which a person of ordinary skill in the art would consider reasonably similar to the specified value. In embodiments, about means within a standard deviation using measurements generally acceptable in the art. In embodiments, about means a range extending to +/- 10% of the specified value. In embodiments, about means the specified value. B. Chemical Definitions [0031] The following chemical functional group definitions are provided to give guidance in understanding their meaning and scope. Those skilled in the art will recognize that these functional groups are being used in a manner consistent with practice of the chemical arts. Any of the following chemical functional groups may be optionally substituted as defined below and each chemical functional group below may itself be an optional substitution. [0032] The term “acyl,” as used herein, alone or in combination, refers to a carbonyl (C=O) attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, or any other moiety were the atom attached to the carbonyl is carbon. An “acetyl” group, which is a type of acyl, refers to a (--C(=O)CH3) group. An “alkylcarbonyl” or “alkanoyl” group refers to an alkyl group attached to the parent molecular moiety through a carbonyl group. Examples of such groups include, without limitation, methylcarbonyl and ethylcarbonyl. Similarly, an “arylcarbonyl” or “aroyl” group refers to an aryl group attached to the parent molecular moiety through a carbonyl group. Examples of such groups include, without limitation, benzoyl and naphthoyl. Accordingly, generic examples of acyl groups include alkanoyl, aroyl, heteroaroyl, and so on. Specific examples of acyl groups include, without limitation, formyl, acetyl, acryloyl, benzoyl, trifluoroacetyl and the like.
[0033] The term “alkenyl,” as used herein, alone or in combination, refers to a straight- chain or branched-chain hydrocarbon radical having one or more double bonds and containing from 2 to 20 carbon atoms. In certain embodiments, the alkenyl may comprise from 2 to 6 carbon atoms, or from 2 to 4 carbons, either of which may be referred to as “lower alkenyl.” The term “alkenylene” refers to a carbon-carbon double bond system attached at two or more positions such as ethenylene (--CH=CH--). Alkenyl can include any number of carbons, such as C2, C23, C24, C25, C26, C27, C28, C29, C210, C3, C34, C35, C36, C4, C45, C46, C5, C56, and C6, and so on up to 20 carbon atoms. Alkenyl groups can have any suitable number of double bonds, including, but not limited to, 1, 2, 3, 4, 5 or more. Examples of alkenyl groups include, but are not limited to, vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3- hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexatrienyl. Alkenyl groups can be substituted or unsubstituted. Unless otherwise specified, the term “alkenyl” may include “alkenylene” groups. [0034] The term “alkoxy,” as used herein, alone or in combination, refers to an alkyl ether radical, wherein the term alkyl is as defined below. Alkoxy groups may have the general formula: alkyl-O-. As for alkyl group, alkoxy groups can have any suitable number of carbon atoms, such as C16. Alkoxy groups include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2butoxy, isobutoxy, secbutoxy, tertbutoxy, pentoxy, hexoxy, and the like. The alkoxy groups can be further optionally substituted as defined herein. [0035] The term “alkyl,” as used herein, alone or in combination, (sometimes abbreviated Alk) refers to a straight-chain or branched-chain alkyl radical containing from 1 to 20 carbon atoms. In certain embodiments, the alkyl may comprise from 1 to 10 carbon atoms. In further embodiments, the alkyl may comprise from 1 to 6 carbon atoms, or from 1 to 4 carbon atoms. Alkyl can include any number of carbons, such as C12, C13, C14, C15, C16, C17, C18, C19, C110, C23, C24, C25, C26, C34, C35, C36, C45, C46 and C56. For example, C16 alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secbutyl, tertbutyl, pentyl, isopentyl, hexyl, etc. Alkyl can also refer to alkyl groups having up to 20 carbons atoms, such as, but not limited to heptyl, octyl, nonyl, decyl, etc. Alkyl groups can be substituted or unsubstituted. The term “alkylene,” as used herein, alone or in combination, refers to a saturated aliphatic group derived from a straight or branched chain saturated hydrocarbon attached at two or more positions, such as methylene (--CH2--). Unless otherwise specified,
the term “alkyl” may include “alkylene” groups. When the alkyl is methyl, it may be represented structurally as CH3, Me, or just a single bond terminating with no end group substitution. [0036] The term “aryl,” as used herein, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused. The term “aryl” embraces aromatic radicals such as benzyl, phenyl, naphthyl, anthracenyl, phenanthryl, indanyl, indenyl, annulenyl, azulenyl, tetrahydronaphthyl, and biphenyl. [0037] The terms “benzo” and “benz,” as used herein, alone or in combination, refer to the divalent radical C6H4- derived from benzene. Examples include benzothiophene and benzimidazole. [0038] The term “carbonyl,” as used herein, when alone includes formyl [--C(=O)H] and in combination is a --C(=O)-- group. [0039] The term “carboxyl” or “carboxyl,” as used herein, refers to --C(=O)OH, O- carboxy, C-carboxy, or the corresponding “carboxylate” anion, such as is in a carboxylic acid salt. An “O-carboxy” group refers to a RC(=O)O-- group, where R is as defined herein. A “C-carboxy” group refers to a --C(=O)OR groups where R is as defined herein. [0040] The term “cycloalkyl,” or, alternatively, “carbocycle,” as used herein, alone or in combination, refers to a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl radical wherein each cyclic moiety contains from 3 to 12 carbon atom ring members and which may optionally be a benzo fused ring system which is optionally substituted as defined herein. In some embodiments, a cycloalkyl may comprise from from 3 to 7 carbon atoms, or from 5 to 7 carbon atoms. Examples of such cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, octahydronaphthyl, 2,3-dihydro-1H- indenyl, adamantyl and the like. “Bicyclic” and “tricyclic” as used herein are intended to include both fused ring systems, such as decahydronaphthalene, octahydronaphthalene as well as the multicyclic (multicentered) saturated or partially unsaturated type. The latter type of isomer is exemplified in general by, bicyclo[1.1.1]pentane, camphor, adamantane, and bicyclo[3.2.1]octane.
[0041] The term “ester,” as used herein, alone or in combination, refers to a carboxyl group bridging two moieties linked at carbon atoms (--CRR’C(=O)OCRR’--), where each R and R’ are independent and defined herein. [0042] The term “ether,” as used herein, alone or in combination, typically refers to an oxy group bridging two moieties linked at carbon atoms. “Ether” may also include polyethers, such as, for example, --RO(CH2)2O(CH2)2O(CH2)2OR', --RO(CH2)2O(CH2)2OR', -- RO(CH2)2OR', and --RO(CH2)2OH. [0043] The term “hydroxy,” as used herein, alone or in combination, refers to OH. [0044] The terms “oxy” or “oxa,” as used herein, alone or in combination, refer to --O--. [0045] The term “oxo,” as used herein, alone or in combination, refers to =O. [0046] In embodiments, any one of the positions that is understood to have a hydrogen may also exist or understood to be isotopically enriched. In the compounds described herein, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Obtaining 100% deuteration at any relevant site of a compound in an amount of milligram or greater can be difficult. Therefore, it is understood that some percentage of hydrogen may still be present, even though a deuterium atom is specifically shown in a chemical structure. Thus, when a chemical structure contains a “D,” the compound represented by the structure is deuterium-enriched at the site represented by “D.” Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen,” the position is understood to have hydrogen at its natural abundance isotopic composition. Also unless otherwise stated, when a position is designated specifically as “D” or “deuterium,” the position is understood to have deuterium at an abundance that is at least 3340 times greater than the natural abundance of deuterium, which is 0.015% (i.e., the term “D” or “deuterium” indicates at least 50.1% incorporation of deuterium). In embodiments, a benzene ring may be optionally exist as –C6D5, -C6DH4, -C6D2H3, -C6D3H2, and -C6D4H. In embodiments, a cyclohexyl group may optionally exist as –C6D11. [0047] Any definition herein may be used in combination with any other definition to describe a composite structural group. By convention, the trailing element of any such definition is that which attaches to the parent moiety. For example, the composite group alkylamido would represent an alkyl group attached to the parent molecule through an amido
group, and the term alkoxyalkyl would represent an alkoxy group attached to the parent molecule through an alkyl group. [0048] The term R or the term R', appearing by itself and without a number designation, unless otherwise defined, refers to a moiety selected from the group consisting of hydrogen, hydroxyl, halogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl and heterocycloalkyl, any of which may be optionally substituted. Each such R and R' groups should be understood to be optionally substituted as defined herein. Each incidence of R and R’ should be understood to be independent. Whether an R group has a number designation or not, every R group, including R, R' and Rn where n = (1, 2, 3, . . . n), every substituent, and every term should be understood to be independent of every other in terms of selection from a group. Should any variable, substituent, or term (e.g. aryl, heterocycle, R, etc.) occur more than one time in a formula or generic structure, its definition at each occurrence is independent of the definition at every other occurrence. Those of skill in the art will further recognize that certain groups may be attached to a parent molecule or may occupy a position in a chain of elements from either end as written. Thus, by way of example only, an unsymmetrical group such as -- C(O)N(R)-- may be attached to the parent moiety at either the carbon or the nitrogen. [0049] Asymmetric centers, axial asymmetry (non-interchanging rotamers), or the like may exist in the compounds of the various embodiments disclosed herein. Such chirality may be designated by the symbols “R” or “S,” depending on the configuration of substituents around the chiral carbon atom or the relevant axis. It should be understood that embodiments encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric, and epimeric forms, d-isomers and l-isomers, and mixtures thereof. Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art. Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art. Additionally, the compounds of the various embodiments disclosed herein may exist as geometric isomers. The various embodiments disclosed herein includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof. Additionally, compounds may exist as tautomers,
including keto-enol tautomers; all tautomeric isomers are embraced by the embodiments disclosed herein. [0050] Additionally, the compounds of the various embodiments disclosed herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the various embodiments disclosed herein. [0051] The term “bond” refers to a covalent linkage between two atoms, or two moieties when the atoms joined by the bond are considered part of larger substructure. A bond may be single, double, or triple unless otherwise specified. A dashed line between two atoms in a drawing of a molecule indicates that an additional bond may be present or absent at that position. Salts of Compounds [0052] The compounds disclosed herein can exist as pharmaceutically acceptable salts, including acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable salts may be of utility in the preparation and purification of the compound in question. Basic addition salts may also be formed and be pharmaceutically acceptable. For a more complete discussion of the preparation and selection of salts, refer to Pharmaceutical Salts: Properties, Selection, and Use (Stahl, P. Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002). It is understood that each of the compounds disclosed herein, and each embodiment of the compounds set forth herein, include pharmaceutically acceptable salts of such compounds. [0053] The term “pharmaceutically acceptable salt,” as used herein, represents salts or zwitterionic forms of the compounds disclosed herein which are water or oil-soluble or dispersible and pharmaceutically acceptable as defined herein. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound in the form of the free base with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethansulfonate (isethionate), lactate, maleate, malonate, DL-mandelate,
mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2- naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, phosphonate, picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate, tartrate, L- tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para- toluenesulfonate (p-tosylate), and undecanoate. Also, basic groups in the compounds of the various embodiments disclosed herein can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. Examples of acids which can be employed to form pharmaceutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. Salts can also be formed by coordination of the compounds with an alkali metal or alkaline earth ion. Hence, the various embodiments disclosed herein contemplates sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein, and the like. [0054] Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxyl group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine. The cations of pharmaceutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, and N,N'-dibenzylethylenediamine. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine C. Treatment-related Definitions [0055] The term “disease” as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder” and “condition” (as in medical condition), in that all reflect an abnormal condition of the body or of one of its parts that impairs normal functioning and is typically manifested by distinguishing signs and symptoms.
[0056] “Amyotrophic lateral sclerosis” or “ALS” are terms understood in the art and as used herein to denote a progressive neurodegenerative disease that affects upper motor neurons (motor neurons in the brain) and/or lower motor neurons (motor neurons in the spinal cord) and results in motor neuron death. As used herein, the term “ALS” includes all of the classifications of ALS known in the art, including, but not limited to classical ALS (typically affecting both lower and upper motor neurons), Primary Lateral Sclerosis (PLS, typically affecting only the upper motor neurons), Progressive Bulbar Palsy (PBP or Bulbar Onset, a version of ALS that typically begins with difficulties swallowing, chewing and speaking), Progressive Muscular Atrophy (PMA, typically affecting only the lower motor neurons) and familial ALS (a genetic version of ALS). [0057] “Alzheimer's disease” or “AD” are terms understood in the art and used herein to denote a progressive neurodegenerative disease characterized by dementia and defined by the American Psychiatric Association (in DSM IV) as the development of multiple cognitive deficits that includes memory impairment. [0058] “Multiple sclerosis” or “MS” are terms understood in the art and as used herein to denote a progressive neurodegenerative disease resulting in destruction of the myelin covering of nerve cells, particularly of the brain and spinal cord. As used herein, “MS” includes all of the classifications of MS known in the art, including, but not limited Relapsing-remitting (RRMS) (typically characterized by partial or total recovery after attacks (also called exacerbations, relapses, or flares)), Secondary progressive (SPMS) (generally characterized by fewer relapses, with an increase in disability and symptoms), and Primary progressive (PPMS) (generally characterized by progression of symptoms and disability without remission). [0059] Herein, a “fibrotic disease” is one involving the formation of excess fibrous connective tissue in an organ and/or tissue. Examples of fibrotic diseases herein include: systemic sclerosis (scleroderma), keloids, hypertrophic scars, burn scars, liver fibrosis, liver cirrhosis, pulmonary hypertension, pulmonary fibrosis (including idiopathic pulmonary fibrosis, IPF), cardiac fibrosis, kidney fibrosis, hepatic fibrosis, etc. In one embodiment, the fibrotic disease is systemic sclerosis. [0060] “Systemic sclerosis” (SSc) or “scleroderma” is a complex and heterogeneous disease with skin and tissue fibrosis, vascular alterations, and autoantibodies against various cellular antigens being amongst its principal features. The clinical manifestations of systemic
sclerosis can range from limited skin involvement to severe internal organ dysfunction. Internal visceral organ pathology is a major factor contributing to the morbidity of this disease, with the kidneys, esophagus, heart, and lungs being the most frequently involved. There are two major subgroups in the commonly accepted classification of SSc: limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc). [0061] The term “autoimmune disorder” as used herein refers to disease, disorders or conditions in which the body's immune system, which normally fights infections and viruses, is misdirected and attacks the body's own normal, healthy tissue. [0062] The phrase “effective amount” means an amount of compound that, when administered to a subject in need of such treatment, is sufficient to (i) treat a disease or disorder associated with oxidative stress (e.g., neurodegenerative diseases and/or fibrotic diseases and conditions), (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease, condition, or disorder, or (iii) delay the onset of one or more symptoms of the particular disease, condition, or disorder described herein. The amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the subject in need of treatment, but can nevertheless be routinely determined by one skilled in the art. [0063] A “therapeutically effective amount” of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and/or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient for inhibition of neurodegenerative diseases and fibrotic diseases and conditions. [0064] The expression “patient” and/or “subject” relates to a human or non-human mammalian patient (e.g., mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, and/or primates) suffering from a disease or condition associated with oxidative stress (e.g., neurodegenerative diseases and fibrotic diseases and conditions) and thus in need of
such treatment, preferably the patient is a human person. In some embodiments, the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented. [0065] Further, a “mammal” includes humans and both domestic animals such as laboratory animals and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wildlife and the like. [0066] As used herein, terms “treat” or “treatment” refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease or disorder or condition, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. II. COMPOUNDS A. Derivatives of Magnesium Lithospermate B [0067] In some embodiments, there are provided compounds of Formula (I) or a pharmaceutically acceptable salt or solvate thereof:
wherein: R1 is (CO2)-, CO2(C1-C6 alkyl), or CO2H; R2 is CO2(C1-C6 alkyl), CO2H, or (CO2)-; R3 is independently selected at each occurrence from H, C(O)C1-C6 alkyl, or C1-C6 alkyl;
X is a cation; and n is 0, 1, or 2. [0068] In some embodiments, the compound of Formula (I) is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof:
wherein R1 is (CO2)-, CO2(C1-C6 alkyl), or CO2H; R2 is CO2(C1-C6 alkyl), CO2H, or (CO2)-; R3 is independently selected at each occurrence from H, C(O)C1-C6 alkyl, or C1-C6 alkyl; X is a cation; and n is 0, 1, or 2. [0069] Alternatively, in some embodiments, compound of Formula (I) is a compound of Formula (III) or a pharmaceutically acceptable salt or solvate thereof: wherein
R1 is (CO2)-, CO2(C1-C6 alkyl), or CO2H;
R2 is CO2(C1-C6 alkyl), CO2H, or (CO2)-; R3 is independently selected at each occurrence from H, C(O)C1-C6 alkyl, or C1-C6 alkyl; X is a cation; and n is 0, 1, or 2. [0070] In some embodiments of the compounds described herein, R1 is (CO2)-, CO2Me, or CO2H; R2 is CO2Me, CO2H, or (CO2)-; R3 is H; and X is Mg2+, Na+, K+, Ca2+, aluminum, arginine, choline, diethanolamine, ethanolamine, lithium, histidine, lysine, procaine, or zinc. [0071] In further embodiments of the compounds described herein, R1 is (CO2)-; R2 is (CO2)-; R3 is H; and X is Mg2+; and n is 1. [0072] In additional embodiments of the compounds described herein, R1 is CO2Me; R2 is CO2Me; R3 is H; and n is 0. [0073] In some embodiments of the compounds described herein, R1 is CO2H; R2 is CO2H; R3 is H; and n is 0.
[0074] As such, exemplary compounds described herein include, but are not limited to,
[0077] In some embodiments, the compound of Formula (I) is
[0078] In some embodiments, the compound of Formula (I) is
[0079] In some embodiments, the compound of Formula (I) is
[0080] In some embodiments, the compound of Formula (I) is
[0081] In some embodiments, the compound of Formula (I) is
[0082] In some embodiments, the compound of Formula (I) is
[0083] In some embodiments, the compound of Formula (I) is
[0084] In some embodiments, the compound of Formula (I) is
[0085] In some embodiments, the compound of Formula (I) is
[0086] In some embodiments, the compound of Formula (I) is
[0087] In some embodiments, the compound of Formula (I) is
[0088] In some embodiments, the compound of Formula (I) is
[0089] In some embodiments, the compound of Formula (I) is
[0090] In some embodiments, the compound of Formula (I) is
[0091] In some embodiments, the compound of Formula (I) is
[0092] In some embodiments, the compound of Formula (I) is
B. Synthesis and isolation [0093] The compounds of the present application may be extracted, separated and purified from Salvia miltiorrhiza, also known as Danshen, a natural herb. Because of the polyphenol structure of the compounds of Formula (I), these compounds have a strong reducibility, approximately 500-1000 times that of Vitamin E. Consequently, they are easily oxidized
during the separation and purification process, and the natural metal ions are easily cleaved, resulting in the collapse of the compound structure. Therefore, the separation, purification and protection process must be done under conditions to prevent oxidation. Standard extracts of MLB obtained from Salvia miltiorrhiza often include impurities such as rosmarinic acid and lithospermic acid. These impurities can constitute 20% or more of the compositions. The compounds and compositions of the present application are purified to over 98% purity. [0094] Conventionally, the isolation of lithospermate or salts thereof (e.g., magnesium lithospermate B) from Salviae miltiorrhizae Radix or the purification of a Salviae miltiorrhizae extract containing such an active ingredient is usually achieved through column chromatography using an adsorbent (stationary phase), such as silica gel. Alternative methods of extraction are also known in the art including polar and non-polar extraction techniques. [0095] One exemplary technique for forming obtaining Magnesium Lithospermate B includes extracting a Salvia miltiorrhiza plant material with an alcohol-water solution. The alcohol-water solution can be concentrated to give a Salvia miltiorrhiza liquid extract. Then the liquid extract is separated liquid via chromatography on macroporous absorption resin with a second alcohol-water solution used for elution. The addition of magnesium salts may be used in the extraction solution to help increase the yield of the product. The compounds described herein may be obtained using methods known in the art, including, but not limited to, those disclosed in US Patent Nos: 8,883,228 to Yan et al.; 10,259,798 to Xuan et al.; 6,267,992 to Li et al.; and US Patent Application Publications US2010/0174097 to Jung et al., and US2017/0137399 to Xuan et al., which are hereby incorporated by reference in their entirety. III. METHODS OF TREATMENT A. Neurodegenerative diseases [0096] Neurodegenerative diseases are generally characterized by a degeneration of neurons in either the brain or the nervous system of an individual. These diseases are debilitating, the damage that they cause is often irreversible, and the outcome in a number of cases is fatal. Oxidative stress may be an important factor for neurodegenerative diseases, and numerous studies have connected both of them together (see for examples: Islam MT, Neurol Res. 73-82 (2017); Singh et al, Molecules. 24(8):1583 (2019); Obrador et al, Int J Mol Sci. 22(12):6352(2021)).
[0097] Proteins can fold into complex and close-packed structures. Folding is not only crucial for biological activity but failure of proteins to fold properly or remain folded can give rise to disease. Misfolding can in some cases cause protein aggregation which can further give rise to discrete deposits extracellularly (e.g., plaques) or intracellularly (e.g., inclusions in the cytosol or nucleus). [0098] Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and prion diseases are characterized by neural deposits of misfolded aggregated protein. Neurodegenerative diseases also pose major challenges to our aging population and health care system. [0099] Sporadic AD, ALS, and Parkinson's disease/Lewy body dementia (PD/LBD) are all associated with neural accumulation of pathological multimers of misfolded polypeptides (these could potentially be fibrils, protofilaments, and amorphous aggregates), including the amyloid-beta (Abeta) fragment of the amyloid precursor protein (APP) in AD; superoxide dismutase-1 (SOD1) in ALS, AD, and PD, and alpha-synuclein in PD and LBD. Additionally familial amyloidotic polyneuropathy (FAP) results from the aggregation of transthyretin to form amyloid deposits. As with prion diseases, mutations in genes encoding these polypeptides are associated with autosomal dominant familial forms of AD, ALS, and PD. [0100] In an aspect, provided herein is a method of treating a neurodegenerative disease in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:
wherein
R1 is (CO2)-, CO2(C1-C6 alkyl), or CO2H; R2 is CO2(C1-C6 alkyl), CO2H, or (CO2)-; R3 is independently selected at each occurrence from H, C(O)C1-C6 alkyl, or C1-C6 alkyl; X is a cation; and n is 0, 1, or 2. [0101] In some embodiments, the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, or multiple sclerosis. Alzheimer's Disease [0102] AD is a common dementing (disordered memory and cognition) neurodegenerative disease associated with brain accumulation of extracellular plaques composed predominantly of the Abeta (1-40), Abeta (1-42) and Abeta (1-43) peptides, all of which are proteolytic products of APP. In addition, neurofibrillary tangles, composed principally of abnormally phosphorylated tau protein (a neuronal microtubule-associated protein), accumulate intracellularly in dying neurons. Familial forms of AD can be caused by mutations in the APP gene, or in the presenilin 1 or 2 genes (St George-Hyslop & Petit, C R Biol.328(2):119-30 (2005)), the protein products of which are implicated in the processing of APP to Abeta. Apolipoprotein E allelic variants also influence the age at onset of both sporadic and familial forms of AD (Puglielli et al., Nat Neurosci. 6:345-51(2003)). Abeta, tau and phosphorylated tau has been detected in the blood and CSF of AD patients and in normal controls (Mehta et al., Arch Neurol. 57:100-5 (2000); Clark et al., Arch Neurol. 60:1696-702(2003); Green, AJ., Neuropathol Appl Neurobiol. 28:427-40(2002)). In some embodiments, the neurodegenerative disease to be treated is Alzheimer's disease. Parkinson's Disease [0103] PD is a neurodegenerative movement disorder, second only to AD in prevalence (approx. 350 per 100,000 population). It is clinically characterized by rigidity, slowness of movement, and tremor. Most cases of Parkinson's disease are sporadic, but both sporadic and familial forms of the disease are characterized by intracellular Lewy bodies in dying neurons of the substantia nigra, a population of midbrain neurons (approx. 60,000) that are selectively decimated in PD. Lewy bodies are predominantly composed of alpha-synuclein (Iwatsubo T., J Neurol 250 Suppl 3:III11-4 (2003)). Mutations in, and duplication of, the gene encoding alpha-synuclein have been found in patients with familial Parkinson's disease (Eriksen et al., Neuron 40:453-6 (2003)). Another gene associated with autosomal recessive PD is parkin,
which is involved in alpha-synuclein degradation (Eriksen et al., Neuron 40:453-6 (2003)). Diffuse cortical Lewy bodies composed of alpha-synuclein are observed in Lewy body disease (LBD), a dementing syndrome associated with parkinsonian tone changes, hallucinations, and rapid symptom fluctuation (McKeith et al., Lancet Neurol 3:19- 28(2004)). LBD may be the second most common form of neurodegenerative dementia after AD, accounting for 20 to 30 percent of cases among persons over the age of 60 years. In some embodiments, the neurodegenerative disease to be treated is Parkinson's disease. Huntington's Disease [0104] Huntington's disease (HD) is a fatal neurodegenerative disorder with an autosomal dominant mode of inheritance. The disease is associated with a triad of motor, behavioral, and cognitive symptoms. Motor disturbances are the defining feature of the disease, with chorea the most evident motor symptom. Although useful for diagnosis, chorea is a poor marker of disease severity. Rather, disability and disease severity best correlate with negative motor features such as impairment in fine motor skills, bradykinesia, and gross motor coordination skills, including speech difficulties, gait, and postural dysfunction. A disrupted dopaminergic signaling has been implicated in a number of neurological and psychiatric conditions, and there is considerable clinical and preclinical evidence suggesting that dopaminergic functions are also compromised in HD. In some embodiments, the neurodegenerative disease to be treated is Huntington's disease. Amyotrophic Lateral Sclerosis (ALS) [0105] Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease which afflicts about 30,000 patients in North America, with 5,000 new cases per year. In ALS, also known as "Lou Gehrig's disease," muscles of the limbs, speech and swallowing, and respiration weaken and atrophy, due to degeneration of motor nerve cells that supply them from the spinal cord and brain. Half of affected patients are dead within 3 years, with survival over 5 years being less than 20%. In some embodiments, the neurodegenerative disease to be treated is amyotrophic lateral sclerosis. [0106] About 20% of familial (inherited) ALS is associated with mutations in the gene encoding superoxide dismutase 1 (SOD1), an intracellular free radical defense enzyme. Intracellular deposits of aggregated misfolded SOD1 have been observed in familial ALS, and also in the more common non-familial (sporadic) ALS, suggesting that SOD1
aggregation may underlie all ALS. In some embodiments, the ALS is familial ALS. In some embodiments, the ALS is sporadic ALS. [0107] Experiments performed in cell culture and mice transgenic for human mutant SOD1 have established that extracellular misfolded SOD1 is highly toxic for motor neurons, in part by activation of killing pathways by local immune cells (microglia). Recently, it has also become clear that misfolded SOD1 is exported from the cell by both secretory and constitutive mechanisms. [0108] ALS is characterized by progressive manifestations of dysfunction of both lower and upper motor neurons. Lower motor neurons connect the brainstem and spinal cord to muscle fibres. Their dysfunction leads to muscle atrophy, cramps and fasciculations (small, local, involuntary muscle contraction). Upper motor neurons originate in motor region of the cerebral cortex or the brainstem and carry motor information down to motor neurons that are directly responsible for stimulating the target muscle. Their dysfunction leads to spasticity (continuous muscle contraction that interfere with gait, movement, and speech) and pathological reflexes (Mitchell & Borasio, Lancet 369, 2031-41 (2007)). The other related motor neuron diseases are usually distinguished by the type of nerve cells impaired, i.e. upper or lower motor neurons: they are known as primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), pseudobulbar palsy and progressive bulbar palsy (PBP). Cognitive and behavioral, as well as sensory, symptoms have also been reported in cases of ALS. In some embodiments, the treatment of ALS results in a decrease of muscle atrophy, cramps and fasciculations. [0109] Genetic studies of ALS has helped to elucidate the biological mechanisms behind the disease. The mutated genes in ALS can be roughly divided into two groups (Brown et al,, N Engl J Med 377:162-72 (2017)). One group of mutated genes generate aggregates of misfolded protein and form prion-like assembly, another group of mutated genes cause neuroinflammation through activation of NF-kB, interferon-b and TNF-a pathways. Id. Both prion-like self-assembly and neuroinflammation causes neurotoxicity and motor neuron degradation. Id. [0110] In some embodiments, the compounds of Formula (I) can be administered individually or in combination with functional electrical stimulation (FES) and/or neuromodulation systems, to improve the nerve functions of subjects. The compounds of Formula (I) may be administered sequentially or simultaneously with the FES and
neuromodulation systems. Functional electrical stimulation (FES) can be used to activate nerves innervating muscle affected by paralysis resulting from spinal cord injury, head injury, stroke and other neurological disorders, or muscle affected by foot drop and gait disorders. FES is also used to stimulate muscles as an orthotic substitute, e.g., replace a brace or support in scoliosis management. [0111] Without wishing to be bound by theory, it is postulated that the compounds of the present application have at least the following major pharmacological properties as its core mechanism of action for treating neurogenerative diseases, including those discussed supra. First, the compounds disclosed herein are capable of significantly dilating tiny blood vessels and capillaries, thereby improving microcirculation, especially in the blood supply around central and peripheral nerves. Second, the compounds described herein are highly reducable (about 1000 times that of vitamin E) providing a strong antioxidant effect, which may significantly reduce oxidative stress damage caused by hypoxia resulting from nerve atrophy related to breathing and oxygen exchange, as well as reducing local inflammation. Third, the compounds described herein possess significant anti-fibrotic effects. Fourth, the compounds described herein are powerful regulation of calcium ion channels and potassium ion channels, which helps to improve the membrane surface action potential of nerve cells, regulate nerve excitability, and enhance muscle contractility. Fifth, the strong and specific organ distribution of the compounds described herein help to improve the quality of life of the patients. For example, the high concentration in the kidney and lung after infusion can help to rapidly reduce the mortality risk caused by pulmonary hypoxia and renal oxidative stress due to the weakened respiratory capacity of the patients. Multiple Sclerosis [0112] Multiple sclerosis (MS) is a chronic disease that is characterized by “attack,” during which areas of white matter of the central nervous system, known as plaques, become inflamed. Inflammation of these areas of plaque is followed by destruction of myelin, the fatty substance that forms a sheath or covering that insulates nerve cell fibers in the brain and spinal cord. Myelin facilitates the smooth, high-speed transmission of electrochemical messages between the brain, spinal cord, and the rest of the body. Damage to the myelin sheath can slow or completely block the transmission of these electrochemical messages, which can result in diminished or lost bodily function.
[0113] The most common course of MS manifests itself as a series of attacks, which are followed by either complete or partial remission, during which the symptoms lessen only to return at some later point in time. This type of MS is commonly referred to as “relapsing- remitting MS.” Another form of MS, called “primary-progressive MS,” is characterized by a gradual decline into the disease state, with no distinct remissions and only temporary plateaus or minor relief from the symptoms. A third form of MS, known as “secondary-progressive MS,” starts as a relapsing-remitting course, but later deteriorates into a primary-progressive course of MS. In some embodiments, the neurodegenerative disease to be treated is multiple sclerosis. In some embodiments, the MS is relapsing-remitting MS. In some embodiments, the MS is primary-progressive MS. [0114] The symptoms of MS can be mild or severe, acute or of a long duration, and may appear in various combinations. These symptoms can include vision problems such as blurred or double vision, red-green color distortion, or even blindness in one eye, muscle weakness in the extremities, coordination and balance problems, muscle spasticity, muscle fatigue, paresthesias, fleeting abnormal sensory feelings such as numbness, prickling, or “pins and needles” sensations, and in the worst cases, partial or complete paralysis. About half of the people suffering from MS also experience cognitive impairments, such as for example, poor concentration, attention, memory and/or judgment. These cognitive symptoms occur when lesions develop in those areas of the brain that are responsible for information processing. In some embodiments, the treatment of MS results in a reduction of any one of these symptoms. [0115] In accordance with the methods described herein, in some embodiments, the treatment of neurodegenerative disease includes reducing motor neuron degeneration in the subject. Additionally, the treating may delay the progress of the neurodegenerative disease in the subject. [0116] In some embodiments, the method described herein include administering to the subject a secondary therapy. The secondary therapy may be administered simultaneously, concurrently, or sequentially with the compound of Formula (I). As will be apparent to those of skill in the art, the secondary therapy can be tailored to the specific condition being treated. [0117] In some embodiments, the compounds of Formula (I) may be administered orally, parenterally, sublingually, buccally, intravenously, or in any combination thereof. In some embodiments, the compounds of Formula (I) are administered orally. However, many subject with reduced motor neuron function have difficulties swallowing pills. As such, the
compounds of Formula (I) may be formulated into easier to administer dosages, such as dissolvable thin films. In some cases it may be necessary or beneficial to administer the compounds of Formula (I) intravenously. B. Fibrotic Disease [0118] In an aspect, provided herein is a method of treating a fibrotic condition or disease a subject in need thereof comprising administering to said subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:
wherein R1 is (CO2)-, CO2(C1-C6 alkyl), or CO2H; R2 is CO2(C1-C6 alkyl), CO2H, or (CO2)-; R3 is independently selected at each occurrence from H, C(O)C1-C6 alkyl, or C1-C6 alkyl; X is a cation; and n is 0, 1, or 2. [0119] Fibrotic diseases which may be treated according to the methods described herein include, for example, hepatic fibrosis (alcoholic, viral, autoimmune, metabolic and hereditary chronic disease), renal fibrosis (e.g., resulting from chronic inflammation, infections or type II diabetes), pulmonary fibrosis (idiopathic or resulting from environmental insults including toxic particles, sarcoidosis, asbestosis, hypersensitivity pneumonitis, bacterial infections including tuberculosis, medicines, etc.), interstitial fibrosis, systemic scleroderma (autoimmune disease in which many organs become fibrotic), macular degeneration (fibrotic disease of the eye), pancreatic fibrosis (resulting from, for example, alcohol abuse and
chronic inflammatory disease of the pancreas), fibrosis of the spleen (from sickle cell anemia, other blood disorders) cardiac fibrosis (resulting from infection, inflammation and hypertrophy), mediastinal fibrosis, myelofibrosis, endomyocardial fibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, fibrotic complications of surgery, especially surgical implants, injection fibrosis fibrotic skin conditions, and secondary conditions and disease states of fibrosis. Secondary conditions and disease states of fibrosis include for example, cirrhosis, diffuse parenchymal lung disease, post-vasectomy pain syndrome and rheumatoid arthritis, among others. C. Fibrotic Disease – Fibrotic skin conditions [0120] Skin fibrosis (i.e., skin fibrosis or dermal fibrosis) is characterized by excessive scarring of the skin and often resulting from the pathological wound healing responses. There are a wide variety of fibrotic skin diseases and conditions: keloids, hypertrophic scars, scleroderma, nephrogenic fibrotic skin disease, mixed connective tissue disease, sclerosing mucoedema, scleredema disease, and eosinophilic fasciitis. Also contemplated herein is a method to treat such fibrotic skin diseases and conditions by administering a subject experiencing the conditions a compound of Formula (I). [0121] Exposure to chemical substances or physical factors (mechanical trauma, burn wounds) is also a potential cause of fibrotic skin diseases. Skin fibrosis can be driven by immune, autoimmune and inflammatory mechanisms. The balance of collagen production and degradation by fibroblasts plays a key role in the pathophysiology of the fibrotic process in the skin. [0122] During skin fibrosis, scarring that is part of the wound healing process and accompanies fibrosis is particularly undesirable from a cosmetic standpoint, especially when the scarring is formed on other exposed parts of the face and/or body. Scleroderma refers to skin fibrosis; sclera means hard and derma means skin. However, skin fibrosis can have significant health problems, especially when it is part of systemic scleroderma. Systemic scleroderma refers to a connective tissue disease with autoimmune etiology. Limited-skin scleroderma is limited to skin on the face and on the feet, while diffuse-skin scleroderma covers more skin and may spread to internal organs.
D. Fibrotic Disease - Systematic scleroderma [0123] Scleroderma is a fibrotic disorder characterized by a thickening and induration of the skin caused by the overproduction of new collagen by fibroblasts in skin and other organs. Scleroderma may occur as a local or systemic disease. Systemic scleroderma may affect a number of organs. Systemic sclerosis is characterized by formation of hyalinized and thickened collagenous fibrous tissue, with thickening of the skin and adhesion to underlying tissues, especially of the hands and face. The disease may also be characterized by dysphagia due to loss of peristalsis and submucosal fibrosis of the esophagus, dyspnea due to pulmonary fibrosis, myocardial fibrosis, and renal vascular changes. (Stedman's Medical Dictionary, 26th Edition, Williams & Wilkins, 1995)). While the exact cause is currently unknown scleroderma is associated with abnormalities involve autoimmunity and alteration of endothelial cell and fibroblast function. In some embodiments, the fibrotic condition or disease to be treated is systemic scleroderma. In some embodiments, the fibrotic condition or disease to be treated is local scleroderma. In some embodiments, the treatment of a subject for systemic and/or local scleroderma results in a reduction of collagenous fibrous tissue. [0124] Scleroderma is mainly an immunological reaction in which the skin attracts lymph cells which stimulate the production of collagen. Because the symptoms of scleroderma often mimic those of other diseases such as bursitis, osteoarthritis, rheumatoid arthritis, and other collagen disorders, it is difficult to diagnose. There is no test specific for confirmation of a diagnosis of scleroderma, but x-rays, skin biopsies, and tests for antinuclear antibodies, gamma globulin, sedimentation rate, and latex fixation can provide evidence that the disease is present. [0125] In one embodiment, the patient with systemic sclerosis has been classified according to the American College of Rheumatology (formerly, the American Rheumatism Association) criteria for the classification of systemic scleroderma based on: major criterion: proximal diffuse (truncal) sclerosis (skin tightness, thickening, and non-pitting induration); and minor criteria: (1) sclerodactyly (only fingers and/or toes), (2) digital pitting scars or loss of substance of the digital finger pads (pulp loss), and (3) bilateral basilar pulmonary fibrosis, wherein a patient with systemic sclerosis should fulfill the major criterion or two of the three minor criteria. See Subcommittee for Scleroderma Criteria of the American Rheumatism Association, Diagnostic and Therapeutic Criteria Committee. Preliminary
criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum 23:581-90 (1980). [0126] In some embodiments, the patient after administration of a compound disclosed herein has shown improvement in their assessment based on the American College of Rheumatology criteria for the classification of systemic scleroderma. E. Fibrotic Disease - Autoimmune skin disorder [0127] Systemic autoimmunity encompasses autoimmune conditions in which autoreactivity is not limited to a single organ or organ system. This definition includes, but is not limited to, autoimmune diseases including autoimmune skin disease manifestations such as systemic lupus erythematosus (SLE), systemic sclerosis (scleroderma), pemphigus, vitiligo, dermatitis herpetiformis, psoriasis, etc. In some embodiments, the fibrotic condition or disease to be treated is autoimmune skin disorder. [0128] Cutaneous SLE is a common systemic autoimmune disorder that includes specific skin manifestations such as “butterfly” rash, photosensitive rash dermatitis, and discoid lesions as well as vasculitis and alopecia. SLE is characterized by the presence of antinuclear antibodies (ANAs) and is associated with chronic inflammation. [0129] Scleroderma (or systemic sclerosis) is marked by inflammation, followed by deposition of ANAs in skin and viscera. Scleroderma is characterized by a marked reduction in circulation in peripheral arteries of distal fingertips (often stimulated by cold temperatures) known as Reynauld's phenomenon. [0130] Pemphigus comprises a group of autoimmune blistering diseases characterized by autoantibody induced epidermal cell-cell detachment (acantholysis). Pemphigus manifests clinically with flaccid blisters and skin erosions. [0131] Vitiligo is a skin depigmentation disorder that may be associated with other autoimmune disorders such as the autoimmune polyendocrine syndrome type I. Vitiligo is characterized by the presence of anti-melanocyte autoantibodies, skin infiltration of CD4+ and CD8+ T lymphocytes and overexpression of type I cytokine profiles. [0132] Dermatitis herpetiformis (DH) is a lifelong very pruritic, polymorphic blisteric skin disease associated with gluten sensitivity. The predominant autoantigen in DH is tissue transglutaminase, found in the intestine and the skin.
[0133] Psoriasis is a common autoimmune skin disease with a genetic basis affecting 1-3% of the Caucasian population. Psoriasis is characterized by hyperkeratosis, epidermal hyperplasia (acanthosis) and inflammation and dilation of dermal capillaries. [0134] According to some embodiments, the compounds and methods described herein are capable of treating a cutaneous scar associated with an autoimmune skin disorder. According to some such embodiments, the autoimmune skin disorder is selected from the group consisting of systemic lupus erythematosus (SLE), systemic sclerosis (scleroderma), pemphigus, vitiligo, dermatitis herpetiformis, psoriasis, or a combination thereof. According to one embodiment, the autoimmune skin disorder is systemic lupus erythematosus (SLE). According to another embodiment, the autoimmune skin disorder is systemic sclerosis (scleroderma). According to another embodiment, the autoimmune skin disorder is pemphigus. According to another embodiment, the autoimmune skin disorder is vitiligo. According to another embodiment, the autoimmune skin disorder is dermatitis herpetiformis. According to another embodiment, the autoimmune skin disorder is psoriasis. F. Fibrotic Disease - Pulmonary fibrosis [0135] Lung fibrosis, also referred to as pulmonary fibrosis, is a serious medical condition that involves scarring of the lung tissue. This condition occurs when the alveoli and interstitial tissue of the lungs become inflamed and develop scars on the tissue in an attempt to repair themselves. Pulmonary fibrosis involves gradual exchange of normal lung parenchyma with fibrotic tissue (fibrous scar). The replacement of normal lung with scar tissue causes irreversible decrease in oxygen diffusion capacity. In some embodiments, the fibrotic condition or disease to be treated is pulmonary fibrosis. [0136] Pulmonary fibrosis can be caused by many conditions which includes chronic inflammatory processes (sarcoidosis, Wegener's granulomatosis), infections, environmental agents (asbestos, silica, exposure to certain gases), exposure to ionizing radiation (such as radiation therapy to treat tumors of the chest), chronic conditions (lupus), and certain medications (e.g. amiodarone, bleomycin, pingyangmycin, busulfan, methotrexate, and nitrofurantoin). [0137] Idiopathic Pulmonary Fibrosis (IPF) is characterized by chronic inflammation of the alveolar walls with progressive fibrosis, of unknown etiology. IPF, or cryptogenic fibrosing alveolitis, causes 50 to 60% of cases of idiopathic interstitial lung disease. In some embodiments, the fibrotic disease to be treated is idiopathic pulmonary fibrosis.
[0138] COPD (chronic obstructive pulmonary disease) is another form of lung fibrosis (Gosker et al. (2003) Eur. Respir. J. 22(2), 280-285) that is caused by smoke irritation of the lung tissue. Tobacco smoking is the most common cause of COPD, with a number of other factors such as air pollution and genetics playing a smaller role. Long-term exposure to these irritants causes an inflammatory response in the lungs resulting in narrowing of the small airways and breakdown of lung tissue known as emphysema. In some embodiments, the fibrotic disease to be treated is chronic obstructive pulmonary disease. [0139] Cystic fibrosis (CF) is also another form of lung fibrosis. CF is an autosomal recessive genetic disorder that affects most critically the lungs, and also the pancreas, liver, and intestine. It is characterized by abnormal transport of chloride and sodium across an epithelium, leading to thick, viscous secretions. The name cystic fibrosis refers to the characteristic scarring (fibrosis) and cyst formation within the pancreas, first recognized in the 1930s. Difficulty breathing is the most serious symptom and results from frequent lung infections that are treated with antibiotics and other medications. Other symptoms (including sinus infections, poor growth, and infertility) affect other parts of the body. CF is caused by a mutation in the gene for the protein cystic fibrosis transmembrane conductance regulator (CFTR). This protein is required to regulate the components of sweat, digestive fluids, and mucus. CFTR regulates the movement of chloride and sodium ions across epithelial membranes, such as the alveolar epithelia located in the lungs. Most people without CF have two working copies of the CFTR gene, and both copies must be missing for CF to develop, due to the disorder's recessive nature. CF develops when neither copy works normally (as a result of mutation) and therefore has autosomal recessive inheritance. Although CF and IPF have different etiologies, the basic pathological features of the fibrotic lesions include excessive collagen deposition. In some embodiments, the fibrotic disease to be treated is cystic fibrosis. [0140] Fibrotic diseases are associated with excess collagen production. Accordingly, also disclosed herein is a method for reducing collagen production in cells. The method includes contacting the cells with a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the cells are mammalian calls. In some embodiments, the cells are human cells. [0141] In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo, wherein the method
includes administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof to a subject having a disease or disorder described herein. [0142] As used herein, the term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, “contacting” a cell with a compound provided herein includes the administration of a compound provided herein to a subject, such as a human, having, for example cells associated with an excess of collagen, as well as, for example, introducing a compound provided herein into a sample containing mammalian cells. [0143] In some embodiments, the method described herein include administering to the subject a secondary or additional therapy. The secondary therapy may be administered simultaneously, concurrently, or sequentially with the compound of Formula (I). As will be apparent to those of skill in the art, the secondary therapy can be tailored to the specific condition being treated. [0144] In some embodiments, the compounds of Formula (I) are administered topically. This method of administration may be particularly advantageous for the treatment of fibrotic skin conditions. In some embodiments, the compounds of Formula (I) are administered intravenously. In further embodiments, the compounds of Formula (I) are administered as an injection. However, such administration should be used with care as fibrotic diseases are often associated with hardening of the skin. For example, patients with scleroderma have especially thick skin that is hard to penetrate with a needle. Injections and venipunctures can be quite painful and should be done with as much care and dispatch as possible. The site of venipuncture for intravenous therapy should be monitored frequently, especially for infiltration, which can cause a painful swelling and pressure for weeks. The skin should be protected from irritation that could lead to breakdown and the introduction of infectious agents. G. Other Methods [0145] In some aspects is provided a method for reducing inflammation in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, inflammation is reduced in the brain of the subject.
[0146] In some aspects is provided a method for reducing expression of inflammatory cytokines in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, expression of inflammatory cytokines is reduced in the brain of the subject. [0147] In some aspects is provided a method for inhibiting or reducing formation of reactive oxygen species in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is provided a method for inhibiting formation of reactive oxygen species in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is provided a method reducing inhibiting formation of reactive oxygen species in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, formation of ROS is reduced or inhibited in the brain of the subject. [0148] In some embodiments, the subject has a neurodegenerative disease (e.g., the neurodegenerative diseases disclosed herein). In some embodiments, the subject has a fibrotic condition or disease (e.g., the fibrotic conditions and diseases described herein). IV. COMPOSITIONS [0149] In one embodiment, the compounds according Formula (I) are formulated as pharmaceutically acceptable compositions that contain a Formula (I) compound in an amount effective to treat a particular disease or condition of interest upon administration of the pharmaceutical composition to a mammal (e.g., a neurodegenerative disease and/or a fibrotic disease or condition). Pharmaceutical compositions as described herein can comprise a compound of Formula (I) in combination with a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, the pharmaceutical compositions described herein are formulated for the treatment of a neurodegenerative disease (e.g., the neurodegenerative diseases disclosed herein). In some embodiments, the pharmaceutical compositions described herein are formulated for the treatment of a fibrotic condition or disease (e.g., the fibrotic conditions and diseases described herein). [0150] In this regard, a “pharmaceutically acceptable carrier, diluent or excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent,
preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals. [0151] The pharmaceutical compositions described herein can be prepared by combining a compound described herein with an appropriate pharmaceutically acceptable carrier, diluent or excipient, and may be formulated into preparations in solid, semisolid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols. Typical routes of administering such pharmaceutical compositions include, without limitation, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal, and intranasal. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. Pharmaceutical compositions described herein are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient. Compositions that will be administered to a subject or patient take the form of one or more dosage units, where for example, a tablet may be a single dosage unit, and a container of a compound described herein in aerosol form may hold a plurality of dosage units. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy and Science, 2000). The composition to be administered will, in any event, contain a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, for treatment of a disease or condition of interest in accordance with the teachings herein. [0152] A pharmaceutical composition described herein may be in the form of a solid or liquid. In one aspect, the carrier(s) are particulate, so that the compositions are, for example, in tablet or powder form. The carrier(s) may be liquid, with the compositions being, for example, an oral syrup, injectable liquid or an aerosol, which is useful in, for example, inhalatory administration. When intended for oral administration, the pharmaceutical composition is preferably in either solid or liquid form, where semisolid, semiliquid, suspension and gel forms are included within the forms considered herein as either solid or liquid.
[0153] As a solid composition for oral administration the pharmaceutical composition may be formulated into a powder, granule, compressed tablet, pill, capsule, oral thin film, wafer or the like form. Such a solid composition will typically contain one or more inert diluents or edible carriers. In addition, one or more of the following may be present: binders such as carboxymethylcellulose, ethyl cellulose, microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, Primogel, corn starch and the like; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; a flavoring agent such as peppermint, methyl salicylate or orange flavoring; and a coloring agent. In some embodiments, the compound of Formula (I) is formulated into a granule, tablet, capsule, or oral film. [0154] When the pharmaceutical composition is in the form of a capsule, for example, a gelatin capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or oil. [0155] The pharmaceutical composition may be in the form of a liquid, for example, an elixir, syrup, solution, emulsion, suspension or sterile aqueous solution. The liquid may be for oral administration or for delivery by injection, as two examples. When intended for oral administration, preferred composition contain, in addition to the present compounds, one or more of a sweetening agent, preservatives, dye/colorant and flavor enhancer. In a composition intended to be administered by injection, one or more of a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer and isotonic agent may be included. [0156] The liquid pharmaceutical compositions described herein, whether they be solutions, suspensions or other like form, may include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer’s solution, isotonic sodium chloride, fixed oils such as synthetic mono or diglycerides which may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Physiological saline is a preferred adjuvant. [0157] Pharmaceutical preparation suitable for injectable use may include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the composition must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. Sterile injectable solutions can be prepared by incorporating the therapeutic agent in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the therapeutic agent into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient (i.e., the therapeutic agent) plus any additional desired ingredient from a previously sterile-filtered solution thereof. [0158] A liquid pharmaceutical composition intended for either parenteral or oral administration should contain an amount of a compound described herein such that a suitable dosage will be obtained. [0159] In some embodiments, the pharmaceutical composition is an oral film (e.g., a thin film that dissolves when placed under a patient’s tongue). This formulation provides the advantages for patients with neurodegenerative diseases who may have problems swallowing and that lack mobility to take oral medication by themselves. Sublingual films deliver a convenient, quick-dissolving therapeutic dose contained within a film matrix that does not need to be crushed or injected by patients. The thin films may be formulated to a variety of different profiles (e.g., immediate release (IR), sustained release (SR), delayed release (DR), modified release (MR), extended release (XR), and controlled release (CR)). [0160] “Oral thin film,” “OTF,” “oral dissolving film,” “oral dissolvable film,” “oral drug strip” or “oral strip” refers to a product used to administer active ingredients via absorption in the mouth (buccally or sublingually), the stomach (gastrically), and/or via the small intestines (enterically). The OTF is edible and pharmaceutically acceptable. A film is prepared typically using hydrophilic polymers that rapidly dissolves on the tongue or buccal cavity, delivering
the active ingredient to the systemic circulation via dissolution when contact with liquid is made. The OTF (or more appropriately “thin film” or “TF”) can also be used to adhere to mucosal tissue (e.g., at least one of mouth, nose, eye, vagina, and rectum), thereby locally delivering the active ingredient. As such, it is appreciated that those of skill in the art understand that reference to a thin film for use with mucosal tissue, such as nose, eye, vagina, and rectum, as an “oral thin film” or OTF is appropriate and acceptable. Oral films may be made using techniques known in the art. [0161] In some embodiments the thin film (e.g., an oral dissolvable film) includes: (a) solvent, (b) binder, (c) optionally a lipid, (d) optionally an emulsifier, (e) a compound of Formula (I) as described herein, (f) optionally a flavoring agent, (g) optionally a sweetener, (h) optionally a dye or pigment, (i) an optional powder coating on at least one external surface, and (j) optionally a preservative. [0162] In some embodiments the thin film includes: (a) about 2-24 wt. % solvent, (b) about 40-50 wt. % binder, (c) about 0-22 wt. % wt. % lipid, (d) about 3-22 wt. % emulsifier, (e) up to about 65 wt. % compound of Formula (I) as described herein, (f) about 0-10 wt. % flavoring agent, (g) about 0-40 wt. % sweetener, (h) about 0-1.0 wt. % dye or pigment, (i) about 0-20 wt. % powder coating on at least one external surface, and (j) about 0-0.1 wt. % preservative. The compound of Formula (I) can optionally be at least partially encapsulated by the lipid, when present. [0163] “Binder” refers to any material or substance that holds or draws other materials together to form a cohesive whole. Liquid binders are added to a dry substance in order to draw it together in such a way that it maintains a uniform consistency. The binder can also add mucoadhesion to the OTF. [0164] The thin film described herein can optionally further include a mucoadhsesive agent. The mucoadhesive agent, when placed in the oral cavity in contact with the mucosa therein, adheres to the mucosa. The mucoadhesive agent is especially effective in transmucosal delivery of the active ingredient, as the mucoadhesive agent permits a close and extended contact of the composition with the mucosal surface by promoting adherence of the composition or drug to the mucosa, and facilitates the release of the active ingredient from the composition. The mucoadhesive agent can be a polymeric compound, such as a cellulose derivative but it may be also a natural gum, alginate, pectin, or such similar polymer. The concentration of the mucoadhesive agent in the coating, such as a powder matrix coating,
may be adjusted to vary the length of time that the film adheres to the mucosa or to vary the adhesive forces generated between the film and mucosa. The mucoadhesive agent may adhere to oral mucosa or to mucosa or tissue in other parts of the body, including the mouth, nose, eyes, vagina, and rectum. Mucoadhesive agents include, e.g., carboxymethylcellulose, polyvinyl alcohol, polyvinyl pyrrolidone (povidone), sodium alginate, methyl cellulose, hydroxyl propyl cellulose, hydroxypropylmethyl cellulose, polyethylene glycols, carbopol, polycarbophil, carboxyvinyl copolymers, propylene glycol alginate, alginic acid, methyl methacrylate copolymers, tragacanth gum, guar gum, karaya gum, ethylene vinyl acetate, dimenthylpolysiloxanes, polyoxyalkylene block copolymers, pectin, chitosan, carrageenan, xanthan gum, gellan gum, locust bean gum, and hydroxyethylmethacrylate copolymers. [0165] “Lipid” refers to a group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E, and K), monoglycerides, diglycerides, triglycerides, phospholipids, and others. The compounds are hydrophobic or amphiphilic small molecules. The amphiphilic nature of some lipids allows them to form structures such as vesicles, liposomes, or membranes in an aqueous environment. Biological lipids originate entirely or in part from two distinct types of biochemical subunits or “building-blocks”: ketoacyl and isoprene groups. Using this approach, lipids may be divided into eight categories: fatty acids, glycerolipids, glycerophospholipids, sphingolipids, saccharolipids, and polyketides (derived from condensation of ketoacyl subunits); and sterol lipids and prenol lipids (derived from condensation of isoprene subunits). [0166] Although the term lipid is sometimes used as a synonym for fats, fats are a subgroup of lipids called triglycerides. Lipids also encompass molecules such as fatty acids and their derivatives (including tri-, di-, monoglycerides, and phospholipids), as well as other sterol- containing metabolites such as cholesterol. [0167] In particular reference to the thin films described herein, the lipids facilitate for the formation of liposomes and micelles. [0168] Liposomes are spherical, lipid bilayer vesicles made from amphiphilic lipids. Typically these are phospholipids that are comprised of a glycerin core with two fatty acid esters, and a phosphate group bound to an additional polar group. These phospholipids thus have two lipophilic tails and a single hydrophilic head. Single fatty acid chains with a single hydrophilic head, like typical soap and detergent molecules, will preferentially form unilayer micelles and not bilayer liposomal structures.
[0169] Liposomes can be unilamellar, with a single lipid bilayer making a single sphere. They can also form various multilamellar structures. Multilamellar structures can be concentric spheres, or a sphere containing multiple unilamellar spheres within. All combinations of the above have been documented. [0170] In certain embodiments, a pharmaceutical composition comprising a compound of Formula I is formulated into a cream, gel, liquid, aerosol, hydrogel, dressing, granule, compressed tablet, pill, or capsule. [0171] The pharmaceutical composition may be intended for topical administration, in which case the carrier may suitably comprise a solution, emulsion, ointment or gel base. The base, for example, may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, bee wax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers. Thickening agents may be present in a pharmaceutical composition for topical administration. If intended for transdermal administration, the composition may include a transdermal patch or iontophoresis device. [0172] Administration topically to a subject generally includes the direct laying on or spreading of the pharmaceutical composition on the epidermal or epithelial tissue of the subject, or transdermally via a “patch”. Such compositions include, for example, lotions, creams, solutions, gels, emulsions and solids. These topical compositions may comprise an effective amount, usually about 0.01% to about 10% (w/w), or from about 0.1% to about 5% (w/w), or from about 1% to about 5% (w/w), of a compound described herein. Suitable carriers for topical administration typically remain in place on the skin as a continuous film, and resist being removed by perspiration or immersion in water. Generally, the carrier is organic in nature and capable of having dispersed or dissolved therein the therapeutic agent. The carrier may include pharmaceutically acceptable emollients, emulsifiers, thickening agents, solvents and the like. The carrier may include vernix. Topical formulation includes one or more excipients such as, but not limited to, protectives, adsorbents, demulcents, emollients, preservatives, antioxidants, moisturizers, buffering agents, solubilizing agents, skin-penetration agents, and surfactants. Suitable protectives and adsorbents include, but are not limited to, dusting powders, zinc sterate, collodion, dimethicone, silicones, zinc carbonate, aloe vera gel and other aloe products, vitamin E oil, allatoin, glycerin, petrolatum, and zinc oxide. Suitable demulcents include, but are not limited to, benzoin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and polyvinyl alcohol. Suitable emollients include,
but are not limited to, animal and vegetable fats and oils, myristyl alcohol, alum, and aluminum acetate. Suitable preservatives include, but are not limited to, quaternary ammonium compounds, such as benzalkonium chloride, benzethonium chloride, cetrimide, dequalinium chloride, and cetylpyridinium chloride; mercurial agents, such as phenylmercuric nitrate, phenylmercuric acetate, and thimerosal; alcoholic agents, for example, chlorobutanol, phenylethyl alcohol, and benzyl alcohol; antibacterial esters, for example, esters of parahydroxybenzoic acid; and other anti-microbial agents such as chlorhexidine, chlorocresol, benzoic acid and polymyxin. Suitable antioxidants include, but are not limited to, ascorbic acid and its esters, sodium bisulfite, butylated hydroxytoluene, butylated hydroxyanisole, tocopherols, and chelating agents like EDTA and citric acid. Suitable moisturizers include, but are not limited to, glycerin, sorbitol, polyethylene glycols, urea, and propylene glycol. Suitable buffering agents include, but are not limited to, acetate buffers, citrate buffers, phosphate buffers, lactic acid buffers, and borate buffers. Suitable solubilizing agents include, but are not limited to, quaternary ammonium chlorides, cyclodextrins, benzyl benzoate, lecithin, and polysorbates. Suitable skin-penetration agents include, but are not limited to, ethyl alcohol, isopropyl alcohol, octylphenylpolyethylene glycol, oleic acid, polyethylene glycol 400, propylene glycol, N-decylmethylsulfoxide, fatty acid esters (e.g., isopropyl myristate, methyl laurate, glycerol monooleate, and propylene glycol monooleate); and N-methylpyrrolidone. [0173] The pharmaceutical composition may include various materials, which modify the physical form of a solid or liquid dosage unit. For example, the composition may include materials that form a coating shell around the active ingredients. The materials that form the coating shell are typically inert, and may be selected from, for example, sugar, shellac, and other enteric coating agents. Alternatively, the active ingredients may be encased in a gelatin capsule. [0174] The pharmaceutical composition in solid or liquid form may include an agent that binds to the compound and thereby assists in the delivery of the compound. Suitable agents that may act in this capacity include, for example, a liposome. [0175] The pharmaceutical composition may consist of dosage units that can be administered as an aerosol. The term aerosol is used to denote a variety of systems ranging from those of colloidal nature to systems consisting of pressurized packages. Delivery may be by a liquefied or compressed gas or by a suitable pump system that dispenses the active
ingredients. Aerosols of compounds may be delivered in single phase, biphasic, or triphasic systems in order to deliver the active ingredient(s). Delivery of the aerosol includes the necessary container, activators, valves, subcontainers, and the like, which together may form a kit. One skilled in the art, without undue experimentation may determine preferred aerosols. [0176] The pharmaceutical compositions may be prepared by any methodology well known in the pharmaceutical art. For example, a pharmaceutical composition intended to be administered by injection can be prepared by combining a compound described herein with sterile, distilled water so as to form a solution. A surfactant may be added to facilitate the formation of a homogeneous solution or suspension. Surfactants are compounds that noncovalently interact with the compound described herein so as to facilitate dissolution or homogeneous suspension of the compound in the aqueous delivery system. [0177] For use in the methods described herein, active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier. [0178] Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. [0179] The selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof) the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts. A. Lipid nanoparticles [0180] In accordance with the methods and pharmaceutical formulations disclosed herein, in some embodiments, the compound of Formula (I) is formulated into lipid nanoparticles. [0181] In an aspect, provided herein is a pharmaceutical composition including lipids nanoparticle-based compositions (e.g., liposomes, solid lipid particles, oil-in-water
emulsions, etc.), and their use in methods of delivering compounds of Formula (I) to a subject. Lipid nanoparticle present many advantages, including increased epidermal penetration of active ingredients may be achieved when incorporated into lipid nanoparticles than when they are applied to the skin in the form of a solution or an emulsion. [0182] The use of lipid nanoparticles may increase the intracellular permeability and absorption rate of the compound of Formula (I) by approximately 30% more than the standard delivery mechanisms. [0183] Some embodiments disclosed herein relate to particle compositions and/or lipid- based particle compositions for delivering the compounds described herein. In some embodiments, the particle is a lipid particle. In some embodiments, the particles are nano- scale particles. In some embodiments, the particles are micro-scale particles. In some embodiments, the particle is a liposome (e.g., is a liposome). In some embodiments, the particles comprise one or more of a phospholipid component, a non-phospholipid lipid component (e.g., medium and/or long chain triglyceride component), a sterol component, and/or water. In some embodiments, the lipid nanoparticles include an active ingredient (e.g., a therapeutic agent, e.g., a compound of Formula (I)). [0184] The process of synthesizing lipid nanoparticles in the present disclosure may include homogenization techniques such as hot high pressure homogenization technique, cold high pressure homogenization technique, melt emulsification ultrasound (ultrasonication) homogenization technique, high shear homogenization and/or ultrasound technique, microemulsion technique, emulsification-solvent evaporation technique, solvent displacement or injection technique, emulsification-solvent diffusion technique, phase inversion technique, film ultrasonication dispersion technique, and multiple emulsion technique. These processes are known in the art and examples thereof are disclosed in U.S. Patent Nos. 10,596,124 to Kaufman; 9,925,149 to Kaufman; 7,775,704 to Hegmann; 8,728,527 to Singh; as well as U.S. Patent Applciation No. 2013/0017239 to Petit et al.; 2020/0315967 to Geldhof, 20170172937 to Repka et al., which are hereby incorporated by reference in their entirety. [0185] The lipids in the nanoparticle compositions in this disclosure may include fatty acids, triglycerides triacylglycerols, acylglycerols, fats, waxes, cholesterol, sphingolipids, glycerides, sterides, cerides, glycolipids, sulfolipids, lipoproteins, chylomicrons and the derivatives of these lipids. Additionally, simpler lipids may be used and include medium chained triglycerides, hemp seed oil, safflower oil and sesame oil. Simpler lipids used in
forming the phospholipid nanoparticles of this disclosure should be biocompatible, GRAS listed and non-toxic as nanoparticles. [0186] The lipid nanoparticles may be manufactured with biocompatible, physiological and GRAS structural materials and excipients that degrade quickly into non-toxic compounds that are easily eliminated through physiologic metabolic pathways and endogenous enzymes. The lipid matrix degradation occurs mostly by lipases whereas only non-enzymatic hydrolytic processes degrade a minor part. Lipid carriers prepared with several lipids and emulsifying agents have shown low toxicity in humans. In some embodiments the lipids are selected from triglycerides, diglycerides, monoglycerides, fatty acids, phospholipids, steroids, and waxes. [0187] Surfactants are important excipients frequently used in nanoparticulate systems as stabilizers and solulibilizers. There are many commercially available surfactants. They have different properties and the same surfactant may have a wide range of applications. The pharmaceutical surfactants lecithin; phosphadylcholine fractions, poloxamer, sodium cholate and polysorbate 80 are well tolerated and non-toxic in nanoparticles. They are unlikely to induce allergic reactions, hypersensitivity or cytokine production. [0188] In some embodiments, the lipid nanoparticles include an emulsifier selected from the group consisting of anionic emulsifiers, cationic emulsifiers, nonionic emulsifiers or zwitterionic emulsifiers. In accordance with one of the embodiment of the present disclosure the emulsifier is at least one selected from the group consisting of soy lecithin, egg lecithin, phosphatidylcholine; ethylene oxide copolymers, propylene oxide copolymers, poloxamers, sorbitan ethylene oxide/propylene oxide copolymers, polysorbate 20, polysorbate 60, polysorbate 80, sorbitan esters, span 20, span 40, span 60, span 80, alkyllaryl polyether alcohol polymers, tyloxapol, bile salts, cholate, glycocholate, taurocholate, taurodeoxycholate, gemini surfactants and alcohols. Preferably, the emulsifiers are Polysorbate 80 and Soya Lecithin. [0189] In some embodiments, the lipid is a glyceride. Exemplary glycerides include, but are not limited to, glyceryl behenate, tricaprin, trilaurin, trimyristin, tripalmitin, tristearin, 1,2-dioctanoyl-sn-glycerol, 1,2-didecanoyl-sn-glycerol, 1,2-dilauroyl-sn-glycerol, 1,2- dimyristoyl-sn-glycerol, 1,2-dipalmitoyl-sn-glycerol, 1-palmitoyl-2-oleoyl-sn-glycerol, 1- stearoyl-2-linoleoyl-sn-glycerol, 1-stearoyl-2-arachidonoyl-sn-glycerol, 1-stearoyl-2- docosahexaenoyl-sn-glycerol, 1-oleoyl-2-acetyl-sn-glycerol, 1,2-di-O-phytanyl-sn-glycerol,
1,2-dipalmitoyl ethylene glycol, 1-2-dioleoyl ethylene glycol, glyceryl monostearate, behenoyl polyoxyl-8 glycerides, glyceryl palmitostearate, 1-O-hexadecyl-sn-glycerol, 1-O- hexadecyl-2-acetyl-sn-glycerol, 1-O-hexadecyl-2-O-methyl-sn-glycerol, 1,2-diacyl-3-O-(α- D-glucopyranosyl)-sn-glycerol, stearoyl macrogol-32 glycerides, stearoyl polyoxyl-32 glycerides, lauroyl macrogol-32 glycerides, lauroyl polyoxyl-32 glycerides, lauroyl macrogol-6 glycerides, lauroyl polyoxyl-6 glycerides, oleoyl macrogol-6 glycerides, oleoyl polyoxyl-6 glycerides, linoleoyl macrogol-6 glycerides, polyglyceryl-3 dioleate, glycerol monolinoleate, glyceryl monolinoleate, glycerol monooleates, diethylene glycol monoethyl ether, glyceryl dibehenate, glycerol distearate, glyceryl distearate, glyceryl dipalmitostearate and linoleoyl polyoxyl-6 glyceride. [0190] In some embodiments, the lipid nanoparticles include an oil phase. Exemplary compounds useful in the oil phase include, but are not limited to, propylene glycol esters, medium chain mono-, di-, or triglycerides, long chain fatty acids, edible oils, or a mixture thereof. In some embodiments, the oil phase is selected from commercially available oils including, but not limited to, CAPTEX® 100 (Propylene Glycol Dicaprate), CAPTEX® 300 (Glyceryl Tricaprylate/Tricaprate), CAPTEX® 355 (Glyceryl Tricaprylate/Tricaprate), MIGLYOL® 810 (Caprylic/Capric Triglyceride), MIGLYOL® 812 (Caprylic/Capric Triglyceride), MIGLYOL® 818 (Caprylic/Capric/Linoleic Triglyceride), MIGLYOL® 829 (Caprylic/Capric/Succinic Triglyceride), and DYNACERIN® 660 (Oleyl Erucate), CAPRYOL™ 90, CAPTEX® 200 (Propylene Glycol Dicaprylocaprate) and MIGLYOL® 840 (Propylene Glycol Dicaprylate/Dicaprate), and the like. In another embodiment, the oil phase is selected from a group comprising edible oils. For example, the edible oil may include, but is not limited to, soyabean oil, castor oil, cottonseed oil, Arachis oil, sesame oil, sweet orange oil, canola oil, sunflower seed oil, peanut oil, rapeseed oil, and oleic acid. [0191] In some embodiments, the lipid nanoparticles may be formed in a water and oil emulsion. Accordingly, the nanoparticles may include water. [0192] In some embodiments, the lipid nanoparticles include a compound of Formula (I) ranging in concentration from 0.01% to 90%. For example, the lipid nanoparticles may include a compound of Formula (I) at a concentration of about 0.01%, about 0.1%, about 1%, about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, or about 80%, up to about 0.1%, about 1%, about 5%, about 10%, about
15%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90%. [0193] In some embodiments, the lipid nanoparticles include a lipid, an emulsifier, and a stabilizer. [0194] Nanoparticle size is extremely important to the biological properties and functioning of nanoparticle carriers. Nanoparticles with diameters ranging from 20 nm to 200 nm typically demonstrate the most prolonged circulation times. Whereas smaller nanoparticle sizes and a lipid structured nanoparticle composition can facilitate easier passage across cell membranes, enhancing cellular uptake and greater delivery to intracellular targets. [0195] The term “particle size” or “particle diameter” refers to the mean diameter of the particles in a sample, as measured by dynamic light scattering (DLS), multiangle light scattering (MALS), nanoparticle tracking analysis, or comparable techniques. It will be understood that a dispersion of lipid nanoparticles as described herein will not be of uniform size but can be described by the average diameter and, optionally, the polydispersity index. In some embodiments, the lipid nanoparticles have a mean diameter between 10 nm and 1000 nm (e.g., between 10 nm, 20 nm, 30 nm, 40 nm, 50 nm, 60 nm, 70 nm, 80 nm, 90 nm, 100 nm, 110 nm, 120 nm, 130 nm, 140 nm, 150 nm, 160 nm, 170 nm, 180 nm, 190 nm, 200 nm, 250 nm, 300 nm, 350 nm, 400 nm, 450 nm, 500 nm, 550 nm, 600 nm, 700 nm, 800 nm, or 900 nm, up to 20 nm, 30 nm, 40 nm, 50 nm, 60 nm, 70 nm, 80 nm, 90 nm, 100 nm, 110 nm, 120 nm, 130 nm, 140 nm, 150 nm, 160 nm, 170 nm, 180 nm, 190 nm, 200 nm, 250 nm, 300 nm, 350 nm, 400 nm, 450 nm, 500 nm, 550 nm, 600 nm, 700 nm, 800 nm, 900 nm, or 1000 nm). In some embodiments the mean diameter is between 100 nm and 300 nm. In some embodiments, the mean diameter is between 150 nm and 200 nm. [0196] In some embodiments, the particles may each be substantially the same shape and/or size, in which case the population is “monodisperse”. For example, the particles may have a distribution of particle sizes such that no more than about 5% or about 10% of the particles have a particle size greater than about 10% greater than the average particle size of the particles, and in some cases, such that no more than about 8%, about 5%, about 3%, about 1%, about 0.3%, about 0.1%, about 0.03%, or about 0.01% have a particle size greater than about 10% greater than the average particle size of the particles. In some cases, no more than about 5% of the particles have a particle size greater than about 5%, about 3%, about 1%, about 0.3%, about 0.1%, about 0.03%, or about 0.01% greater than the average particle size
of the particles. In some embodiments the lipid nanoparticles have a polydispersity index of 0.25 or less (e.g., 0.25, 0.24, 0.23, 0.22, 0.21, 0.20, 0.19, 0.18, 0.17, 0.16, 0.15, 0.14, 0.13, 0.12, 0.11, 0.10, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01, or less), as measured by dynamic light scattering (DLS). [0197] In some embodiments, all or a portion of the compound of Formula (I) is encapsulated in the lipid nanoparticles. In some embodiments, the compound of Formula (I) encapsulation efficiency is at least 80% (e.g., at least 80%, at least 85%, at least 90%, at least 92%, at least 94%, at least 95%, at least 96%, at least 97%, or at least 98%, e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or greater). [0198] The nanoparticles and pharmaceutical formulations may be further converted into powder form by removal of the water there from, e.g., by lyophilization at a suitable temperature-time profile. The powder is easily reconstituted by addition of water, saline or buffer. While not required, it is of course understood that conventional cryoprotectants may be added to formulations if so desired (e.g., mannitol, sucrose, trehalose, glycine). The lyophilized powder may be suspended in an aqueous formulation prior to administration. B. Combinations [0199] In accordance with the methods disclosed herein, in some embodiments, the subject is administered a second/ additional therapeutic agent beyond the compound of Formula (I). These additional therapeutic agents may be administered simultaneously, concurrently, or sequentially with the compound of Formula (I). The additional therapeutic agent should be tailored to the subject’s needs and diseases to be treated. [0200] In any case, the multiple therapeutic agents (at least one of which is a compound of the various embodiments disclosed herein) may be administered in any order or even simultaneously. If simultaneously, the multiple therapeutic agents may be provided in a single, unified form, or in multiple forms (by way of example only, either as a single pill or as two separate pills). One of the therapeutic agents may be given in multiple doses, or both may be given as multiple doses. If not simultaneous, the timing between the multiple doses may be any duration of time ranging from a few minutes to four weeks. [0201] The term “pharmaceutical combination”, as used herein, refers to a pharmaceutical therapy resulting from the mixing or combining of more than one active ingredient and
includes both fixed and non-fixed combinations of the active ingredients. The term “fixed combination” means that a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent, are both administered to a subject simultaneously in the form of a single composition or dosage. The term “non-fixed combination” means that a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent are formulated as separate compositions or dosages such that they may be administered to a subject in need thereof simultaneously, concurrently or sequentially with variable intervening time limits, wherein such administration provides effective levels of the two or more compounds in the body of the subject. These also apply to cocktail therapies, e.g., the administration of three or more active ingredients. [0202] In some embodiments, when the subject is being treated for a neurodegenerative disease such as ALS, the subject may also be administered standard therapeutics for the treatment of ALS. Additional therapies that can be used in conjunction with the compound of Formula (I), may comprise one or more drug(s) that ameliorate(s) symptoms of ALS, one or more drug(s) that could be used for palliative treatment of ALS or one or more drug(s) currently evaluated in the frame of clinical trials for treating of ALS. Such drugs include, but are not limited to, AEOL 10150, arimoclomol, AVP-923, botulinum toxin type B (Myobloc), ceftriaxone, celastrol, celecoxib, cistanche total glycosides, coenzyme Q10, copaxone, creatine, creatinine, dronabinol, erythropoietin, escitalopram (Lexapro), glatiramer acetate, granulocyte-colony stimulating factor (G-CSF), growth hormone (Somatropin), GSK1223249, indinavir, insulin-like growth factor-1 (IGF-I), IGF-1-AAV, KNS-760704, leteprinim, leuprolide, levetiracetam, MCI-186, mecobalamin, minocycline, modafinil, Naaladase inhibitor, N-Acetylcysteine, NBQX, nimesulide, nimodipine, olanzapine, olesoxime (TRO19622), ONO-2506, oxepa, pioglitazone, R(+) pramipexole dihydrochloride monohydrate, olesoxime, oxandrolone, quinidine, phenyl butyrate, SB-509, Scriptaid, sNN0029, somatropine, talampanel, tamoxifen, tauroursodeoxycholic acid, TCH346, testosterone, thalidomide, trehalose, tretinoin, vitamin E, YAM80 or from 17-beta-estradiol, 2-MPPA (2-(3-mercaptopropyl)pentanedioic acid), 3,4-diaminopyridine, 5- hydroxytryptophan, 7-nitroindazole, alpha-lipoic acid, AM1241, aminophylline, angiogenin, anti-human SOD1 antibody, antisense peptide nucleic acid directed against p75(NTR), AP7, apocynin, BAPTA-AM, BDNF, BN82451, cannabinol, cardiotrophin-1, CD4 antibodies, CNTF, colivelin, dietary copper, corticotrophin, cyclophosphamide, Delta(9)-
tetrahydrocannabinol, DHEA, diazepam, dietary zinc, diltiazem, DMPO, DP-109, DP-460, edaravone, EGCG, epigallocatechin gallate, etidronate, FeTCPP, fluvoxamine, folic acid, gabapentin, galectin-1, GDNF, ginseng, GPI-1046, guanidine, HGF, humanin, IFN-alpha, interleukin-3, ivermectin, L-745,870, L-carnitine, L-DOPA, lecithinized SOD, lenalidomide, leupeptin, LIF, L-NAME, lysine acetylsalicylate, melatonin, mepivacaine, methamphetamine, methylcobalamin, MK-801, MnTBAP, modafinil, morphine, Neu2000, NGF, nordihydroguaiaretic acid, nortriptyline, NT3, olmesartan, penicillamine, pentoxifylline, pimozide, polyamine-modified catalase, pramipexole, prednisone, progesterone, promethazine, putrescine-modified catalase, pyruvate, rasagiline, RK35, Ro 28-2653, rofecoxib, RPR 119990, RX77368, SB203580, selegiline, semapimod, sertraline, SS-31, SSR180575, stabilized siRNA against human Cu,Zn-superoxide dismutase (SOD1), tacrolimus, tamsulosin hydrochloride, TAT-modified Bcl-X(L), TGF-beta2, tianeptine, trientine, TR019622, U-74389F, VEGF, vincristine, WHI-P131, WIN55,212-2, WX-340, xaliproden, ZK 187638 and zVAD-fmk. [0203] In some embodiments, when the subject is being treated for a neurodegenerative disease such as MS, the subject may also be administered standard therapeutics for the treatment of MS. Currently, six drugs in four classes are approved in the United States for the treatment of RRMS, whereas no drugs have been approved for PPMS. The RRMS treatments include the following: interferon class, IFN-beta-1a (REBIF® and AVONEX®) and IFN- beta-1b (BETASERON®); glatiramer acetate (COPAXONE®), a polypeptide; natalizumab (TYSABRI®); and mitoxantrone (NOVANTRONE®), a cytotoxic agent. Other drugs have been used with varying degrees of success, including corticosteroids, methotrexate, cyclophosphamide, azathioprine, and intravenous (IV) immunoglobulin. The benefits of currently approved treatments are relatively modest (˜30%) for relapse rate and prevention of disability in RRMS as suggested by two meta-analyses (Filippini et al. Lancet 361:545-52 (2003)). [0204] In some embodiments, when the subject is being treated for a fibrotic disease such as pulmonary fibrosis, the subject may also be administered standard therapeutics for the treatment of pulmonary fibrosis. In some embodiments, idiopathic pulmonary fibrosis/pulmonary fibrosis can be treated with a combination of a compound of Formula (I) and one or more of the following drugs: pirfenidone (pirfenidone was approved for use in 2011 in Europe under the brand name Esbriet®), prednisone, azathioprine, N-acetylcysteine, interferon-γ 1b, and anti-inflammatory agents such as corticosteroids. Prednisone is the usual
treatment for idiopathic pulmonary fibrosis but it can be treated with other immunosuppressive therapies with the objective of reduction of inflammation that is the prelude to lung fibrosis. [0205] In some embodiments, a compound of Formula (I) can be used to treat idiopathic pulmonary fibrosis/pulmonary fibrosis in combination with any of the following methods: oxygen therapy, pulmonary rehabilitation and surgery. [0206] In some embodiments, the pharmaceutical compositions also include an anti- inflammatory agent, an analgesic agent, an anti-infective agent, or a combination thereof. Such compositions may be used in the treatment of fibrotic condition or diseases. [0207] According to some embodiments, the additional agent is an anti-inflammatory agent. According to some such embodiments, the anti-inflammatory agent is a steroidal anti- inflammatory agent. The term "steroidal anti-inflammatory agent", as used herein, refer to any one of numerous compounds containing a 17-carbon 4-ring system and includes the sterols, various hormones (as anabolic steroids), and glycosides. Representative examples of steroidal anti-inflammatory drugs include, without limitation, corticosteroids such as hydrocortisone, hydroxyltriamcinolone, alpha-methyl dexamethasone, dexamethasone- phosphate, beclomethasone dipropionates, clobetasol valerate, desonide, desoxymethasone, desoxycorticosterone acetate, dexamethasone, dichlorisone, diflucortolone valerate, fluadrenolone, fluclorolone acetonide, flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortine butylesters, fluocortolone, fluprednidene (fluprednylidene) acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone acetonide, cortisone, cortodoxone, flucetonide, fludrocortisone, dif uorosone diacetate, fluradrenolone, fludrocortisone, diflorosone diacetate, fluradrenolone acetonide, medrysone, amcinafel, amcinafide, betamethasone and the balance of its esters, chloroprednisone, chlorprednisone acetate, clocortelone, clescinolone, dichlorisone, dif urprednate, fucloronide, flunisolide, fluoromethalone, fluperolone, fluprednisolone, hydrocortisone valerate, hydrocortisone cyclopentylpropionate, hydrocortamate, meprednisone, paramethasone, prednisolone, prednisone, beclomethasone dipropionate, triamcinolone, and mixtures thereof. [0208] According to some other embodiments, the anti-inflammatory agent is a nonsteroidal anti-inflammatory agent. The term "non-steroidal anti-inflammatory agent" as used herein refers to a large group of agents that are aspirin-like in their action, including, but
not limited to, ibuprofen (Advil®), naproxen sodium (Aleve®), and acetaminophen (Tylenol®). Additional examples of non-steroidal anti-inflammatory agents that are usable in the context of the described invention include, without limitation, oxicams, such as piroxicam, isoxicam, tenoxicam, sudoxicam, and CP-14,304; disalcid, benorylate, trilisate, safapryn, solprin, diflunisal, and fendosal; acetic acid derivatives, such as diclofenac, fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac, zidometacin, acematacin, fentiazac, zomepirac, clindanac, oxepinac, felbinac, and ketorolac; fenamates, such as mefenamic, meclofenamic, flufenamic, niflumic, and tolfenamic acids; propionic acid derivatives, such as benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen, indopropfen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, and tiaprofenic; pyrazoles, such as phenylbutazone, oxyphenbutazone, feprazone, azapropazone, and trimethazone. Mixtures of these non- steroidal anti-inflammatory agents also may be employed, as well as the dermato logically acceptable salts and esters of these agents. For example, etofenamate, a flufenamic acid derivative, is particularly useful for topical application. [0209] According to another embodiment, the anti-inflammatory agent includes, without limitation, Transforming Growth Factor- beta3 (TGF-β3), an anti-Tumor Necrosis Factor- alpha (TNF-a) agent, or a combination thereof. [0210] According to some embodiments, the additional agent is an analgesic agent. According to some embodiments, the analgesic agent relives pain by elevating the pain threshold without disturbing consciousness or altering other sensory modalities. According to some such embodiments, the analgesic agent is a non-opioid analgesic. "Non-opioid analgesics" are natural or synthetic substances that reduce pain but are not opioid analgesics. Examples of non-opioid analgesics include, but are not limited to, etodolac, indomethacin, sulindac, tolmetin, nabumetone, piroxicam, acetaminophen, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, naproxen, naproxen sodium, oxaprozin, aspirin, choline magnesium trisalicylate, diflunisal, meclofenamic acid, mefenamic acid, and phenylbutazone. According to some other embodiments, the analgesic is an opioid analgesic. "Opioid analgesics", "opioid", or "narcotic analgesics" are natural or synthetic substances that bind to opioid receptors in the central nervous system, producing an agonist action. Examples of opioid analgesics include, but are not limited to, codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, propoxyphene, buprenorphine, butorphanol, dezocine, nalbuphine, and pentazocine.
[0211] According to another embodiment, the additional agent is an anti-infective agent. In some embodiments, the anti-infective agent is an antibiotic agent. The term "antibiotic agent" as used herein means any of a group of chemical substances having the capacity to inhibit the growth of, or to destroy bacteria, and other microorganisms, used chiefly in the treatment of infectious diseases. Examples of antibiotic agents include, but are not limited to, Penicillin G; Methicillin; Nafcillin; Oxacillin; Cloxacillin; Dicloxacillin; Ampicillin; Amoxicillin; Ticarcillin; Carbenicillin; Mezlocillin; Azlocillin; Piperacillin; Imipenem; Aztreonam; Cephalothin; Cefaclor; Cefoxitin; Cefuroxime; Cefonicid; Cefmetazole; Cefotetan; Cefprozil; Loracarbef; Cefetamet; Cefoperazone; Cefotaxime; Ceftizoxime; Ceftriaxone; Ceftazidime; Cefepime; Cefixime; Cefpodoxime; Cefsulodin; Fleroxacin; Nalidixic acid; Norfloxacin; Ciprofloxacin; Ofloxacin; Enoxacin ; Lomefloxacin; Cinoxacin; Doxycycline; Minocycline; Tetracycline; Amikacin; Gentamicin; Kanamycin; Netilmicin; Tobramycin; Streptomycin; Azithromycin; Clarithromycin; Erythromycin; Erythromycin estolate ; Erythromycin ethyl succinate; Erythromycin glucoheptonate; Erythromycin lactobionate; Erythromycin stearate; Vancomycin; Teicoplanin; Chloramphenicol; Clindamycin; Trimethoprim; Sulfamethoxazole; Nitrofurantoin; Rifampin; Mupirocin; Metronidazole; Cephalexin; Roxithromycin; Co-amoxiclavuanate; combinations of Piperacillin and Tazobactam; and their various salts, acids, bases, and other derivatives. Anti-bacterial antibiotic agents include, but are not limited to, penicillins, cephalosporins, carbacephems, cephamycins, carbapenems, monobactams, aminoglycosides, glycopeptides, quinolones, tetracyclines, macrolides, and fluoroquinolones. [0212] Other examples of additional therapeutic agents include, but are not limited to, rose hip oil, vitamin E, 5-fluorouracil, bleomycin, onion extract, pentoxifylline, prolyl-4- hydroxylase, verapamil, tacrolimus, tamoxifen, tretinoin, colchicine, a calcium antagonist, tranilst, zinc, an antibiotic, and a combination thereof. A. Dosage [0213] The compositions including a compound of Formula (I) or a pharmaceutically acceptable salt thereof can be formulated in a unit dosage form, each dosage containing from about 5 mg to about 1,000 mg (1 g), more usually about 100 mg to about 500 mg, of the active ingredient. The term “unit dosage form” refers to physically discrete units suitable as unitary dosages for human subjects and other subjects, each unit containing a predetermined quantity of active material (i.e., a compound of Formula (I) or a pharmaceutically acceptable
salt thereof) calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. [0214] In some embodiments, the compositions provided herein contain from about 100 mg to about 500 mg of the active ingredient. [0215] In some embodiments, the compositions provided herein contain from about 50 mg to about 500 mg of the active ingredient. In some embodiments, the compositions provided herein contain about 10 mg, about 20 mg, about 30 mg, about 80 mg, about 100 mg or about 160 mg of the active ingredient. [0216] In some embodiments, the compositions provided herein contain from about 500 mg to about 1,000 mg of the active ingredient. [0217] The daily dosage of the compound of Formula (I) or a pharmaceutically acceptable salt thereof can be varied over a wide range from 1.0 to 10,000 mg per adult human per day, or higher, or any range therein. For oral administration, the compositions are preferably provided in the form of tablets or oral thin films containing, 10.0, 15.0, 25.0, 50.0, 100, 150, 160, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.1 mg/kg to about 1000 mg/kg of body weight per day, or any range therein. Preferably, the range is from about 0.5 to about 500 mg/kg of body weight per day, or any range therein. In an example, the range can be from about 0.1 to about 50.0 mg/kg of body weight per day, or any amount or range therein. In another example, the range can be from about 0.1 to about 15.0 mg/kg of body weight per day, or any range therein. In yet another example, the range can be from about 0.5 to about 7.5 mg/kg of body weight per day, or any amount to range therein. Pharmaceutical compositions containing a compound of Formula (I) or a pharmaceutically acceptable salt thereof can be administered on a regimen of 1 to 4 times per day or in a single daily dose. [0218] In accordance with any of the methods disclosed herein, in some embodiments, the compound of Formula (I) is administered in a dose of about 200 to 400 mg per day. The dose may be in a single fixed dose, or alternatively in multiple doses. The compound of Formula (I) may be administered once per day, twice per day, or three times per day. [0219] In other embodiments, the compound of Formula (I) is administered in a dose of about 10 to 200 mg per day in a single dose. The dose may be 10 mg, 20 mg, 30 mg, 40 mg,
50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, or 200 mg per day. [0220] The active compound may be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. Optimal dosages to be administered can be readily determined by those skilled in the art. It will be understood, therefore, that the amount of the compound actually administered will usually be determined by a physician, and will vary according to the relevant circumstances, including the mode of administration, the actual compound administered, the strength of the preparation, the condition to be treated, and the advancement of the disease condition. In addition, factors associated with the particular subject being treated, including subject response, age, weight, diet, time of administration and severity of the subject’s symptoms, will result in the need to adjust dosages. [0221] In some embodiments, the compounds provided herein can be administered in an amount ranging from about 1 mg/kg to about 100 mg/kg. In some embodiments, the compound provided herein can be administered in an amount of about 1 mg/kg to about 20 mg/kg, about 5 mg/kg to about 50 mg/kg, about 10 mg/kg to about 40 mg/kg, about 15 mg/kg to about 45 mg/kg, about 20 mg/kg to about 60 mg/kg, or about 40 mg/kg to about 70 mg/kg. In some embodiments, such administration can be once-daily or twice-daily (BID) administration. [0222] One skilled in the art will recognize that both in vivo and in vitro trials using suitable, known and generally accepted cell and/or animal models are predictive of the ability of a test compound to treat or prevent a given disorder. [0223] One skilled in the art will further recognize that human clinical trials including first- in-human, dose ranging and efficacy trials, in healthy subjects and/or those suffering from a given disorder, can be completed according to methods well known in the clinical and medical arts. [0224] Provided herein are pharmaceutical kits useful, for example, in the treatment of a neurodegenerative disease, which include one or more containers containing a pharmaceutical composition including an effective amount of a compound provided herein. Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically
acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit. [0225] Also provided herein are pharmaceutical kits useful, for example, in the treatment of fibrotic condition or disease, which include one or more containers containing a pharmaceutical composition including an effective amount of a compound provided herein. Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit. EXAMPLES Example 1: Formulations for Intravenous Administration [0226] The compounds of Formula (I) are formed into Nanostructured Lipid Carriers (NLC) (i.e., lipid nanoparticles) using a cold high pressure homogenization method. Glyceryl distearate/glyceryl palmitostearate and triglycerides of capric/caprylic acids are used as solid and liquid lipids, respectively. Both lipids are generally recognized as safe excipients with high biocompatibility and low cytotoxicity, which are advantageous for brain delivery. A mixture of mono-, di- and triglycerides, glyceryl distearate/glyceryl palmitostearate form crystals with many imperfections, providing more space to load the compounds of Formula (I) and to avoid its expulsion. Polysorbate 80 and poloxamer 188 are used as nonionic surfactants, as they have very low toxicity and produce particles with smaller sizes, which are advantageous for enhancing brain uptake. Polysorbate 80 and poloxamer 188 are known to increase drug transport to the brain by coating on the surface of the nanocarriers. The NCL formulations and placebo control are prepared according to the concentrations disclosed in Table 1.
Table 1. Composition of the NLCs
[0227] The physicochemical properties of the NLCs of Table 1 are disclosed in Table 2: Table 2. Mean diameter, polydispersity index (PDI), zeta potential (ZP), and encapsulation efficiency (EE) of NLC formulations (mean ± SD)
Cold High Pressure Homogenization [0228] The lipid and compound of Formula (I) are melted together and rapidly cooled under liquid nitrogen forming solid lipid micro particles. A pre-suspension is formed by homogenization of the particles in a cold surfactant solution. The pre-suspension is further homogenized in a high pressure homogenization apparatus at or below room temperature at predetermined homogenization conditions to produce the NLCs. The control placebo NLCs are prepared in a similar way, without the addition of the compounds of Formula (I). Characterization of the NLCs [0229] The mean particle size and the polydispersity Index (PDI) are measured using dynamic light scattering (DLS). The zeta potential (ZP) is measured using electrophoretic
light scattering (ELS). During the analysis, the cell temperature is kept at 25°C, and the scattering angle is 90°. Prior to the measurements, the samples are diluted with double distilled water for increased accuracy. Encapsulation Efficiency (EE) [0230] The encapsulation efficiency (%) of the NLC formulated with the compound of Formula (I) is assessed using high-performance liquid chromatography (HPLC). Stability Studies [0231] The NLC samples are stored in closed glass vials at both 5 ± 1°C and 25 ± 1°C. The particle size, polydispersity index, and zeta potential is measured at day 0, 1 month, 2 months, and 3 months. Transmission Electron Microscopy (TEM) [0232] The morphology of the NLCs is examined by transmission electron microscopy (TEM). The TEM images show the NLCs to be spherical with a uniform shape and with smooth surfaces, and confirm the sizes measured by DLS. Differential Scanning Calorimetry (DSC) Analysis [0233] Differential scanning calorimetry (DSC) analysis is performed to investigate the melting and crystallization behavior of the NLCs. [0234] The NLCs show a homogeneous size distribution with a mean diameter between 165 and 200nm which corresponds to the required size for brain drug delivery. The polydispersity index (PDI) is a measure of the uniformity of particle size distribution. The PDI of the both the NCL placebo and Formula (I)-loaded NLCs is below 0.3, indicating a fairly narrow and homogeneous size distribution with low variability. The zeta potential (ZP) measures the overall surface charge of a particle and is an indicator to predict stability over time. The zeta potential of the NLC Placebo and Formula (I)-loaded NLCs is equal or great than I 30 I mV, which demonstrates electrostatic stability and low propensity to aggregate. The encapsulation efficiency is 98.8 ± 1% for this formulation. The stability studies suggest that the NLCs remain stable for at least 3 months. Example 2: Ex vivo Skin Diffusion Studies
[0235] Formulations of NCLs for topical administration are prepared according to Example 1. [0236] The skin diffusion studies are conducted to analyze the diffusion and skin accumulation of the compounds of Formula (I). The studies are preformed using a similar protocol as defined by Gokce et al. (Resveratrol-loaded solid lipid nanoparticles versus nanostructured lipid carriers - evaluation of antioxidant potential for dermal applications. International Journal of Nanomedicine, 2012:71844, which is hereby incorporated by reference in its entirety). [0237] Formula (I)-loaded NLCs show superior permeability and skin retention, with their sizes below 200nm, PDI below 0.3 and ZP greater than 30. Ex vivo skin diffusion studies show that compounds of Formula (I) alone are unable to permeate skin tissue, but NLCs enable the penetration/accumulation of Formula (I) into both the epidermis and dermis. Discussion [0238] Localized scleroderma starts with skin lesions caused by inflammation, followed by excessive, dense collagen deposition and an increase in the number of fibroblasts leading to skin tissue thickening, consequently, topical administration of drugs cannot efficiently penetrate into the depths of the skin through the pathological tissue. To address this problem, nanostructured lipid carriers (NLCs) have the following advantages: i. Being non-toxic and non-irritating. ii. Increased stability of the drug. iii. Improved drug loading because NLCs are prepared by a blend of solid and liquid lipids to yield a non-crystalline amorphous lipid core, which allows higher drug load. iv. Enhance permeation of drugs because NLCs have small size, strong adhesive properties, and easily produce an occlusion effect by forming a film on the skin, thereby preventing water loss from the skin, increasing penetration of the drug, and leading to a controlled release of the drug. v. Enable penetration of the drug into the deeper layers of skin tissue, because NLC components, such as lipids and surfactants, interact with the sebum and specific skin lipids and change the natural arrangement of corneocytes, consequently facilitating the release of the encapsulated molecules and their penetration into the deeper layers of skin. Example 3: Efficacy in ALS Animal Model
[0239] The gene coding for copper-zinc superoxide dismutase (SOD1) is a frequently mutated gene in familial ALS patients (20% familial cases). Transgenic mice overexpressing human SOD1 have similar phenotypes and pathologies to those seen in human ALS. SOD1G93A transgenic mice are chosen for the present study. [0240] A similar protocol as defined by Wen et al. (Neuropharmacology. 2021 Jan;182:108380, which is hereby incorporated by reference in its entirety) is used. All animal experiments are carried out according to guidelines and protocols approved by the ethics committee. [0241] B6SJLTg-SOD1*G93A-1Gur/J mice carrying the mutant human SOD1 with a substitution of glycine to alanine in position 93 are purchased from Jackson Laboratories (Bar Harbor, ME, USA). Compounds of Formula (I) are delivered to mice by intraperitoneal injection with dose groups of 80, 120 and 160 mg/kg. [0242] SOD1G93A mice (n = 100) are randomly divided into 5 groups: (a) Saline (n = 20, twice daily); (b) compounds of formula (I) 80 mg/kg (n = 20, twice daily), (c) compounds of formula (I) 120 mg/kg (n = 20, twice daily), (d) compounds of formula (I) 160 mg/kg (n = 20, twice daily), and (e) edaravone 15 mg/kg (n = 20, twice daily). Female and male mice are given either saline or drug solutions at 12 and 13 weeks of age (disease onset), respectively, for four weeks. [0243] Motor performances (defined below) is tested at the beginning (0 weeks) and every two weeks of the experiments. Grip strength test [0244] The mouse is lightly placed on the center of the grip plate, prompting the animal to grasp the grip plate, and then gently pulled by the tail. Each animal is tested three times and the maximum value of the three results is taken as the evaluation value. After the start of the formal experiment, the mice are tested every two weeks. Hanging wire test [0245] The wire lid of the common cage is used to assess limb grip strength. The mouse is placed in the center of the wire lid (21 cm × 21 cm), which is then turned upside down for up to 90 s. The length of time the mouse holds on to the wire is recorded. Mice are trained for 3 days before testing. The holding time of each mouse is measured twice and the average value is taken as the result. This experiment is conducted every two weeks.
Climbing-pole test [0246] The climbing-pole test is used to assess the movement and coordination of the mouse. A homemade wooden rod is used, which is approximately 50 cm long and approximately 1 cm in diameter, wrapped with gauze to increase friction. The mouse is placed face down on the top of the vertical pole, and the descent time from the top of the pole to the bottom platform is recorded. Prior to testing, each mouse is trained for 3 consecutive days, twice a day, with a maximum cut-off value of 15 s. The experimental procedure is repeated three times and the average climb time of each mouse is calculated as an evaluation value. This experiment is conducted every two weeks. Motor neuron survival analysis [0247] At the end of the experiment, mice are anesthetized with 1% sodium pentobarbital; the chest is then opened and 0.01 M phosphate buffered saline (PBS, pH 7.2) is perfused through the heart. The lumbar segments of the spinal cord (L4-L5) is dissected, fixed in 4% paraformaldehyde and embedded in paraffin. Approximately 200 of 10 μm serial cross- sections of the spinal cord are collected. Every fourth section is placed on a slide, and 7 nonconsecutive different sections are selected for Nissl staining. Microscopic examination and counting of motor neurons is performed on one side of the anterior horn of the spinal cord. Only anterior horn cells having diameters of >20 μm with a clearly identifiable nucleus, nucleolus and cytoplasm are counted by two individuals blind to the tissue source. Muscle histology for fibrosis: [0248] Mice are anesthetized and perfused with 0.01 M PBS (pH 7.2) via the heart. From one hind limb, the gastrocnemius muscle is carefully dissected, weighed, photographed, and then fixed in 4% paraformaldehyde (pH 7.4) for 48 h. After fixation, the tissue is dehydrated with ethanol and embedded in paraffin. Serial cross sections (10 μm) are stained with hematoxylin and eosin (H&E) or Masson staining (6–8 mice in each group and two tissue sections for each mouse are used as statistics). H&E-stained images are taken by an inverted microscope, and the muscle fiber areas of two regions in each section are calculated by Image J. Histological images by Masson staining are acquired on a digital scanning microscopy imaging system (M8, Precipoint, Germany) using 20 × and 40 × objectives. The percentage of the blue area to the entire tissue area, which reflects the level of tissue fibrosis, is calculated by MIPAR image analysis software. Example 4: Efficacy in Localized Scleroderma
Anti-fibrotic Cell Studies [0249] To evaluate the anti-fibrotic capacity of the Formula (I)-loaded NLCs, primary fibroblasts cell line are cultured using DMEM containing 10% FBS. The evaluation indicators include: (1) CCK8, EdU: monitor cell proliferation; (2) Flow type: detection of apoptosis; (3) Transwell: monitor cell migration; and (4) qRT-PCR; (5) Western bloting: monitor the expression of fibroblast inflammatory factors. In Vivo Studies [0250] The anti-fibrotic activity of the Formula (I)-loaded NLCs is assessed using the bleomycin-induced scleroderma model on eight-week-old CH3/He female mice. The animals are divided into two groups: the treatment group and the control group. The mice’s dorsal skin is shaved with a razor, in a diameter of about 1 cm. For 28 days, bleomycin (100ul (0.2mg/ml)) is injected subcutaneously into the mice dorsal skin every day at 9:00 a.m. The animals in the treatment group are topically treated with the Formula (I)-loaded NLCs in the evening from Day 15 until Day 28. [0251] The evaluation indicators include: (1) observation with the naked eye: the skin becomes harder and thicker; (2) HE staining: observe the degree of skin fibrosis and dermal thickness; (3) Mason tricolor staining: observe the changes of collagen fibers in lung tissue and whether the skin collagen fibers are neatly arranged; (4) immunohistochemical staining: detect the expression and distribution of inflammatory factors in diseased skin tissue and analyze it with skin fibrosis indicators; (5) Western blotting: expression of fibroblast inflammatory factors. [0252] All animal experiments are carried out according to guidelines and protocols approved by the ethics committee. Example 5: Inhibition of Cytokine Production in Human Dendritic Cells [0253] Human CD14+ monocytes were differentiated with granulocyte macrophage colony-stimulating factor (GM-CSF) (100 ng/ml) and interleukin 4 (IL-4) (40 ng/ml) for 5 days. The cells were then treated with various concentrations of the compounds disclosed herein (0, 10, 20, 40, 80 or 160 uM) for 2h before stimulating cells with oxidized low-density lipoprotein (ox-LDL) (10-50 ug/ml) or Lipopolysaccharide (LPS) (1-100 ng/ml) for another 24 h. The cell culture supernatants were analyzed for IL-1b, IL-6, IL-12 & TNF-a levels
using multiplex Meso Scale Discovery (MSD) cytokine kits. The cell pellets were analyzed for cell viability using Celltiter-glo. [0254] As shown in Figures 1A-C, the compounds described herein produced a dosed dependent inhibition of LPS stimulated IL-12 & TNF-α production in human dendritic cells. No effect on cell viability was observed. Example 6: Inhibition of Cytokine Production in Human CD3+ T Cells [0255] Human peripheral CD3+ T cells at 1×106 /ml were pretreated with various concentrations of the compounds described herein (0, 10, 20, 40, 80, or 160 uM) or a positive control (5 uM Cyclosporin A) for 2 hr and then stimulated with phorbol-12-myristate-13- acetate (PMA) (5 ng/ml)/ Ionomycin (1 uM) or anti-CD3 (plate coated at 2 ug/ml)/anti-CD28 (soluble at 2 ug/ml) for another 24h. The cell culture supernatants were analyzed for IL-2, IL-4, IFN-g & TNF-a levels by multiplex MSD kits. [0256] As shown in Figures 2A-B, the compounds of Formula (I) produced a dosed dependent inhibition of anti-CD3/anti-CD28 or PMA/Ionomycin stimulated IL-2, IL-4 and TNF-α production in human CD3+ T cells. Figure 2C shows the cell viability results of the CD3+ T cells. Example 7: Evaluation of the Anti-oxidative Activity of Compounds of Formula (I) in Human Vascular Endothelial Cells [0257] Human vascular endothelial cells were pretreated with various concentrations of compounds of Formula (I) (0, 1, 10, 20, 40 or 80 uM) or a positive control (Edaravone) for 30 min, followed by treatment with H2O2 (100 uM) for another 15 min or 30 mM glucose for another 1 hr. The intracellular reactive oxygen species (ROS) levels were analyzed by flow cytometry. As shown in Figure 3 the compounds of Formula (I) significantly reduced the ROS level at 20-200 fold lower concentrations than Edaravone. The compounds of Formula (I) share a similar antioxidant mechanism of Edaravone, but display superior antioxidant effects. Example 8: Efficacy in ALS Humans [0258] The compounds of Formula (I) are administered to a human subject in a therapeutically effective amount as described herein.
Claims
WHAT IS CLAIMED IS: 1. A method of treating a neurodegenerative disease in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:
wherein R1 is (CO2)-, CO2(C1-C6 alkyl), or CO2H; R2 is CO2(C1-C6 alkyl), CO2H, or (CO2)-; R3 is independently selected at each occurrence from H, C(O)C1-C6 alkyl, or C1-C6 alkyl; X is a cation; and n is 0, 1, or 2.
2. The method of claim 1, wherein the compound of Formula (I) is formulated into lipid nanoparticles.
3. The method of claim 1 or claim 2, wherein the neurodegenerative disease is selected from the groups consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis.
4. The method of claim 3, wherein the neurodegenerative disease is amyotrophic lateral sclerosis.
5. The method of claim 3, wherein the neurodegenerative disease is multiple sclerosis.
6. The method of any one of claims 1 to 5, wherein the compound of Formula (I) is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof:
7. The method of any one of claims 1 to 5, wherein the compound of Formula (I) is a compound of Formula (III) or a pharmaceutically acceptable salt or solvate thereof: wherein
R1 is (CO2)-, CO2(C1-C6 alkyl), or CO2H; R2 is CO2(C1-C6 alkyl), CO2H, or (CO2)-; R3 is independently selected at each occurrence from H, C(O)C1-C6 alkyl, or C1-C6 alkyl; X is a cation; and n is 0, 1, or 2.
8. The method of any one of claims 1 to 7, wherein R1 is (CO2)-, CO2Me, or CO2H; R2 is CO2Me, CO2H, or (CO2)-; R3 is H; and X is Mg2+, Na+, K+, Ca2+, Aluminum, Arginine, choline, Diethanolamine, Ethanolamine, Lithium, Histidine, Lysine, Procaine, or Zinc.
9. The method of any one of claims 1 to 8, wherein R1 is (CO2)-; R2 is (CO2)-; R3 is H; and X is Mg2+; and n is 1.
10. The method of any one of claims 1 to 8, wherein R1 is CO2Me; R2 is CO2Me; R3 is H; and n is 0.
11. The method of any one of claims 1 to 8, wherein R1 is CO2H; R2 is CO2H; R3 is H; and n is 0.
14. The method of any one of claims 1 to 12, wherein said treating comprises delaying the progress of the neurodegenerative disease in said subject.
15. The method of any one of claims 1 to 14, wherein the compound of Formula (I) is administered orally, parenterally, sublingually, buccally, intravenously, or any combination thereof.
16. The method of any one of claims 1 to 15, wherein the compound of Formula (I) is administered orally.
17. The method of claim 15, wherein the compound of Formula (I) is administered as a granule, tablet, capsule, or oral film.
18. The method of any one of claims 1 to 15, wherein the compound of Formula (I) is administered intravenously.
19. The method of any one of claims 1 to 18, wherein the compound of Formula (I) is administered in a dosage from about 200 to 400 mg per day.
20. The method of any one of claims 1 to 19, wherein the compound of Formula (I) is administered once per day, twice per day, or three times per day.
21. The method of any one of claims 1 to 20 further comprising administering to said subject a secondary therapy, wherein the secondary therapy is administered simultaneously, concurrently, or sequentially with the compound of Formula (I).
22. A method of treating a fibrotic condition or disease in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:
wherein R1 is (CO2)-, CO2(C1-C6 alkyl), or CO2H; R2 is CO2(C1-C6 alkyl), CO2H, or (CO2)-; R3 is independently selected at each occurrence from H, C(O)C1-C6 alkyl, or C1-C6 alkyl; X is a cation; and n is 0, 1, or 2.
23. The method of claim 22, wherein the compound of Formula (I) is formulated into lipid nanoparticles.
24. The method of claim 22 or claim 23, wherein the compound of Formula (I) is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof:
25. The method of claim 22 or claim 23, wherein the compound of Formula (I) is a compound of Formula (III) or a pharmaceutically acceptable salt or solvate thereof:
wherein R1 is (CO2)-, CO2(C1-C6 alkyl), or CO2H; R2 is CO2(C1-C6 alkyl), CO2H, or (CO2)-; R3 is independently selected at each occurrence from H, C(O)C1-C6 alkyl, or C1-C6 alkyl; X is a cation; and n is 0, 1, or 2.
26. The method of any one of claims 22 to 25, wherein R1 is (CO2)-, CO2Me, or CO2H; R2 is CO2Me, CO2H, or (CO2)-; R3 is H; and X is Mg2+, Na+, K+, Ca2+, Aluminum, Arginine, choline, Diethanolamine, Ethanolamine, Lithium, Histidine, Lysine, Procaine, or Zinc.
27. The method of any one of claims 22 to 26, wherein R1 is (CO2)-; R2 is (CO2)-; R3 is H; and X is Mg2+; and n is 1.
28. The method of any one of claims 22 to 26, wherein R1 is CO2Me; R2 is CO2Me; R3 is H; and n is 0.
29. The method of any one of claims 22 to 26, wherein R1 is CO2H; R2 is CO2H; R3 is H; and n is 0.
31. The method of any one of claims 22 to 30, wherein said fibrotic condition or disease is selected from the group consisting of hepatic fibrosis, renal fibrosis, pulmonary fibrosis, interstitial fibrosis, systemic scleroderma, macular degeneration, pancreatic fibrosis, fibrosis of the spleen, cardiac fibrosis, mediastinal fibrosis, myelofibrosis, endomyocardial fibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, fibrotic complications of surgery, injection fibrosis, fibrotic skin conditions and combinations thereof.
32. The method of claim 31, wherein the fibrotic skin condition is selected from the group consisting of keloids, hypertrophic scars, scleroderma, nephrogenic fibrotic skin disease, mixed connective tissue disease, sclerosing mucoedema, scleredema disease, or eosinophilic fasciitis.
33. The method of claim 31, wherein the fibrotic skin condition is an autoimmune skin disorder selected from the group consisting of systemic lupus erythematosus (SLE), systemic sclerosis (scleroderma), pemphigus, vitiligo, dermatitis herpetiformis, psoriasis, or a combination thereof.
34. The method of claim 31, wherein the fibrotic condition or disease is pulmonary fibrosis.
35. The method of claim 31, wherein the fibrotic condition or disease is systemic scleroderma.
36. The method of any one of claims 22 to 35, further comprising administering at least one additional therapeutic agent selected from the group consisting of an anti-inflammatory agent, an analgesic agent, an anti-infective agent, or a combination thereof.
37. The method of claim 36, wherein the additional therapeutic agent is administered simultaneously, concurrently, or sequentially with the compound of Formula (I).
38. The method of any one of claims 22 to 37, wherein the compound of Formula (I) is administered topically.
39. The method of any one of claims 22 to 37, wherein the compound of Formula (I) is administered orally.
40. The method of any one of claims 22 to 37, wherein the compound of Formula (I) is administered intravenously.
41. The method of any one of claims 22 to 40, wherein the compound of Formula (I) is administered in a dosage from about 200 to 400 mg per day.
42. The method of any one of claims 22 to 41, wherein the compound of Formula (I) is formulated into a cream, gel, liquid, aerosol, hydrogel, dressing, granule, compressed tablet, pill, or capsule.
43. A method for reducing collagen production in cells, comprising contacting the cells with a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof: wherein
R1 is (CO2)-, CO2(C1-C6 alkyl), or CO2H; R2 is CO2(C1-C6 alkyl), CO2H, or (CO2)-; R3 is independently selected at each occurrence from H, C(O)C1-C6 alkyl, or C1-C6 alkyl; X is a cation; and n is 0, 1, or 2.
44. A pharmaceutical composition for the treatment of a neurodegenerative disease comprising a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof:
wherein R1 is (CO2)-, CO2(C1-C6 alkyl), or CO2H; R2 is CO2(C1-C6 alkyl), CO2H, or (CO2)-; R3 is independently selected at each occurrence from H, C(O)C1-C6 alkyl, or C1-C6 alkyl; X is a cation; and n is 0, 1, or 2.
45. The pharmaceutical composition of claim 44, wherein the compound of Formula (I) is in the form of lipid nanoparticles.
46. The pharmaceutical composition of claim 44 or claim 45, wherein the neurodegenerative disease is selected from the groups consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, or multiple sclerosis.
47. The pharmaceutical composition of claim 46, wherein the neurodegenerative disease is amyotrophic lateral sclerosis.
48. The pharmaceutical composition of claim 46, wherein the neurodegenerative disease is multiple sclerosis.
49. The pharmaceutical composition of any one of claims 44 to 48, wherein the compound of Formula (I) is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof: wherein
R1 is (CO2)-, CO2(C1-C6 alkyl), or CO2H; R2 is CO2(C1-C6 alkyl), CO2H, or (CO2)-; R3 is independently selected at each occurrence from H, C(O)C1-C6 alkyl, or C1-C6 alkyl; X is a cation; and n is 0, 1, or 2.
50. The pharmaceutical composition of any one of claims 44 to 48, wherein the compound of Formula (I) is a compound of Formula (III) or a pharmaceutically acceptable salt or solvate thereof:
wherein R1 is (CO2)-, CO2(C1-C6 alkyl), or CO2H;
R2 is CO2(C1-C6 alkyl), CO2H, or (CO2)-; R3 is independently selected at each occurrence from H, C(O)C1-C6 alkyl, or C1-C6 alkyl; X is a cation; and n is 0, 1, or 2.
51. The pharmaceutical composition of any one of claims 44 to 50, wherein R1 is (CO2)-, CO2Me, or CO2H; R2 is CO2Me, CO2H, or (CO2)-; R3 is H; and X is Mg2+, Na+, K+, Ca2+, Aluminum, Arginine, choline, Diethanolamine, Ethanolamine, Lithium, Histidine, Lysine, Procaine, or Zinc.
52. The pharmaceutical composition of any one of claims 44 to 51, wherein R1 is (CO2)-; R2 is (CO2)-; R3 is H; and X is Mg2+; and n is 1.
53. The pharmaceutical composition of any one of claims 44 to 51, wherein R1 is CO2Me; R2 is CO2Me; R3 is H; and n is 0.
54. The pharmaceutical composition of any one of claims 44 to 51, wherein R1 is CO2H; R2 is CO2H; R3 is H; and n is 0.
57 . The pharmaceutical composition of any one of claims 45 to 56, wherein the lipid nanoparticles have a polydispersity index of 0.25 or less.
58 . The pharmaceutical composition of any one of claims 45 to 57, wherein the lipid nanoparticles comprise a compound of Formula (I) ranging from 0.01% to 90%.
59 . The pharmaceutical composition of any one of claims 45 to 58, wherein the lipid nanoparticles comprise a lipid, an emulsifier, and a stabilizer.
60. The pharmaceutical composition of any one of claims 44 to 59, wherein the pharmaceutical composition is a solid selected from the group consisting of a powder, granule, compressed tablet, pill, capsule, oral thin film, and wafer.
61. The pharmaceutical composition of any one of claims 44 to 60, wherein the pharmaceutical composition is a liquid selected from the group consisting of an elixir, syrup, solution, emulsion, suspension, and sterile aqueous solution.
62. The pharmaceutical composition of any one of claims 44 to 61, further comprising a secondary therapy.
63. A pharmaceutical composition for the treatment of a fibrotic condition or disease comprising a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof:
wherein R1 is (CO2)-, CO2(C1-C6 alkyl), or CO2H; R2 is CO2(C1-C6 alkyl), CO2H, or (CO2)-; R3 is independently selected at each occurrence from H, C(O)C1-C6 alkyl, or C1-C6 alkyl; X is a cation; and n is 0, 1, or 2.
64. The pharmaceutical composition of claim 63, wherein the compound of Formula (I) is in the form of lipid nanoparticles.
65. The pharmaceutical composition of claim 63 or claim 64, wherein the fibrotic condition or disease is selected from the group consisting of hepatic fibrosis, renal fibrosis, pulmonary fibrosis, interstitial fibrosis, systemic scleroderma, macular degeneration, pancreatic fibrosis, fibrosis of the spleen, cardiac fibrosis, mediastinal fibrosis, myelofibrosis, endomyocardial fibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, fibrotic complications of surgery, injection fibrosis, fibrotic skin conditions and combinations thereof.
66. The pharmaceutical composition of claim 65, wherein the fibrotic skin condition is selected from the group consisting of keloids, hypertrophic scars, scleroderma, nephrogenic fibrotic skin disease, mixed connective tissue disease, sclerosing mucoedema, scleredema disease, or oreosinophilic fasciitis.
67. The pharmaceutical composition of claim 65, wherein the fibrotic skin condition is an autoimmune skin disorder selected from the group consisting of systemic lupus erythematosus (SLE), systemic sclerosis (scleroderma), pemphigus, vitiligo, dermatitis herpetiformis, psoriasis, or a combination thereof.
68. The pharmaceutical composition of claim 65, wherein the fibrotic condition or disease is pulmonary fibrosis.
69. The pharmaceutical composition of claim 65, wherein the fibrotic condition or disease is systemic scleroderma.
70. The pharmaceutical composition of any one of claims 63 to 69, wherein the compound of Formula (I) is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof:
wherein R1 is (CO2)-, CO2(C1-C6 alkyl), or CO2H; R2 is CO2(C1-C6 alkyl), CO2H, or (CO2)-; R3 is independently selected at each occurrence from H, C(O)C1-C6 alkyl, or C1-C6 alkyl; X is a cation; and n is 0, 1, or 2.
71. The pharmaceutical composition of any one of claims 63 to 69, wherein the compound of Formula (I) is a compound of Formula (III) or a pharmaceutically acceptable salt or solvate thereof:
wherein R1 is (CO2)-, CO2(C1-C6 alkyl), or CO2H; R2 is CO2(C1-C6 alkyl), CO2H, or (CO2)-; R3 is independently selected at each occurrence from H, C(O)C1-C6 alkyl, or C1-C6 alkyl; X is a cation; and n is 0, 1, or 2.
72. The pharmaceutical composition of any one of claims 63 to 71, wherein R1 is (CO2)-, CO2Me, or CO2H; R2 is CO2Me, CO2H, or (CO2)-; R3 is H; and X is Mg2+, Na+, K+, Ca2+, Aluminum, Arginine, choline, Diethanolamine, Ethanolamine, Lithium, Histidine, Lysine, Procaine, or Zinc.
73. The pharmaceutical composition of any one of claims 63 to 72, wherein R1 is (CO2)-;
R2 is (CO2)-; R3 is H; and X is Mg2+; and n is 1.
74. The pharmaceutical composition of any one of claims 63 to 72, wherein R1 is CO2Me; R2 is CO2Me; R3 is H; and n is 0.
75. The pharmaceutical composition of any one of claims 63 to 72, wherein R1 is CO2H; R2 is CO2H; R3 is H; and n is 0.
76. The pharmaceutical composition of claim 63 or claim 64, wherein the compound of Formula (I) is selected from the group consisting of
and
77. The pharmaceutical composition of any one of claims 63 to 76, wherein the pharmaceutical composition is selected from the group consisting of a cream, gel, liquid, aerosol, hydrogel, dressing, granule, compressed tablet, pill, and capsule. 78. The pharmaceutical composition of any one of claims 64 to 77, wherein the lipid nanoparticles have a mean diameter between 10 nm and 1000 nm. 79. The pharmaceutical composition of any one of claims 64 to 78, wherein the lipid nanoparticles have a polydispersity index of 0.25 or less. 80. The pharmaceutical composition of any one of claims 64 to 79, wherein the lipid nanoparticles comprise a compound of Formula (I) ranging from 0.01% to 90%. 81. The pharmaceutical composition of any one of claims 64 to 80, wherein the lipid nanoparticles comprise a lipid, an emulsifier, and a stabilizer. 82. The pharmaceutical composition of any one of claims 63 to 81, further comprising anti- inflammatory agent, an analgesic agent, an anti-infective agent, or a combination thereof.
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