Liquid Formulations of Ivermectin Compositions and Use in Gelatin Dosage Forms

Abstract

Formulations and dosage forms of avermectins, particularly ivermectin, are disclosed. The compositions of the disclosure can be used in methods for the treatment and prevention of a variety of neurological and other disorders in humans.

Description

[Technical field]

[0001] The present disclosure provides compositions and dosage forms of avermectins, particularly ivermectin, that can be used to treat and prevent a variety of neurological and other disorders. [Background technology]

[0002] Avermectins are a family of 16-membered macrocyclic lactone derivatives with potent anthelmintic and insecticidal properties and are used as active agents for the treatment and prevention of infections by parasites and other parasitic infections. The avermectins are a series of macrolides, each of which is substituted at the 13-position with a 4-(α-L-oleandrosyl)-α-L-oleandrosyl group. The avermectins are produced in cultures of the bacterium Streptomyces avermitilis or by synthetic or semisynthetic means. Members of the avermectin family bind selectively and with high affinity to glutamate-gated chloride ion channels present in invertebrate nerve and muscle cells. This increases the permeability of the cell membrane to chloride ions, hyperpolarizing the nerve or muscle cells and resulting in paralysis and death of the parasite. All avermectin family compounds show a similar spectrum of activity at different levels of potency.

[0003] Ivermectin, a member of the avermectin family, is a highly potent antiparasitic agent. Ivermectin is a mixture of 5-O-demethyl-22,23-dihydroavermectin A1a (also called 22,23-dihydroavermectin B1a) and 5-O-demethyl-25-de(1-methylpropyl)-22,23-dihydro-25-(1-methylethyl)avermectin A1a (also called 22,23-dihydroavermectin B1b). Ivermectin has been used as a broad-spectrum antiparasitic drug for humans and animals.

[0004] Ivermectin is commercially available for veterinary use as Cardomec (for cats), Equivaran (for horses), and Ivomec (for cattle) from Merial, and as Zimecterin (for horses) from Famam Companies, Inc. The drug is available in tablets and chewables for heartworm prevention, topical solutions for ear mite treatment, and injectables, oral pastes, or solutions for other parasites for veterinary use. Ivermectin is also available for human use to treat parasitic infections. For example, Stromectol (containing 3 mg ivermectin, marketed by Merck & Co.) is approved by the U.S. Food and Drug Administration for the treatment of onchocerciasis (river blindness) and strongyloidiasis (non-disseminated intestinal nematodes). Ivermectin may exert its antiparasitic activity through activation of chloride-gated glutamate channels present in the invertebrate nervous system. Binding to chloride ion-gated glutamate channels results in hyperpolarization of nerve and muscle fibers. Such hyperpolarization can result in paralysis and death of the organism (parasite). Chloride ion-gated glutamate channels are specific to invertebrates and are not expressed in mammalian hosts, allowing ivermectin to act specifically against parasites.

[0005] Medications currently used for neurological disorders characterized by seizures or movement disorders exhibit significant side effects (e.g., behavioral changes, lethargy, insomnia, clinical depression, psychotic behavior, respiratory depression, coma, and death), especially when taken in excessive doses or over long periods of time. Thus, there is an unmet need for the development of alternative drugs that can be used to treat or prevent such neurological and other disorders, with little or no adverse health risks. Summary of the Invention

[0006] The present disclosure provides a pharmaceutical composition comprising: (i) about 1% to about 15% ivermectin, including the compound of formula VI (22,23-dihydroavermectin B1a) and the compound of formula VII (22,23-dihydroavermectin B1b); (ii) about 20% to about 40% of a first surfactant that includes one or more of the following: (a) mono-, di-, and / or tri-fatty acid esters of glycerol; (b) mono- and / or di-fatty acid esters of 1,2-propylene glycol; and (c) Mono- and / or di-fatty acid esters of polyethylene glycol (fatty acids are C6 to C 10 selected from fatty acids); (iii) about 15% to about 70% of a second surfactant selected from one or more of a polysorbate surfactant and / or a fatty acid ester of sorbitan.

[0007] In some embodiments, the pharmaceutical composition comprises ivermectin that comprises at least about 70% 22,23-dihydroavermectin B1a and less than about 30% 22,23-dihydroavermectin B1b.In some embodiments, the pharmaceutical composition comprises ivermectin that comprises at least about 90% 22,23-dihydroavermectin B1a and less than about 10% 22,23-dihydroavermectin B1b.

[0008] In various embodiments, the pharmaceutical composition comprises about 3% to about 12% of a compound of any one of Formulas I-VII. In some embodiments, the pharmaceutical composition comprises about 5% to about 10% of a compound of any one of Formulas I-VII. In some embodiments, the pharmaceutical composition comprises about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, or about 12% of a compound of any one of Formulas I-VII.

[0009] In some embodiments, the pharmaceutical composition comprises about 3% to about 12% of one or more of the compounds of Formulae I-VII. In some embodiments, the pharmaceutical composition comprises about 5% to about 10% of one or more of Formulae I-VII. In some embodiments, the pharmaceutical composition comprises about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, or about 12% of one or more of Formulae I-VII.

[0010] In some embodiments, the pharmaceutical composition comprises about 3% to about 12% ivermectin, including the compound of formula VI and the compound of formula VII. In some embodiments, the pharmaceutical composition comprises about 5% to about 10% ivermectin, including the compound of formula VI and the compound of formula VII. In some embodiments, the pharmaceutical composition comprises about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, or about 12% ivermectin, including the compound of formula VI and the compound of formula VII.

[0011] In various embodiments, the pharmaceutical composition comprises a first surfactant, the fatty acid being C8-C 10 In some embodiments, the first surfactant is selected from mono- and di-fatty acid esters of glycerol. In some embodiments, the first surfactant is selected from Masester M8120, Capryol 90, Labrasol ALF, and combinations thereof. In some embodiments, the pharmaceutical composition comprises about 25% to about 30% of the first surfactant.

[0012] In embodiments, the pharmaceutical composition comprises a second surfactant selected from polysorbate 80 (Tween 80), sorbitan monolaurate (Span 20), and combinations thereof. In some embodiments, the pharmaceutical composition comprises about 15% to about 20% of the second surfactant. In some embodiments, the pharmaceutical composition comprises about 30% to about 35% of the second surfactant. In some embodiments, the pharmaceutical composition comprises about 60% to about 65% of the second surfactant.

[0013] In some embodiments, the pharmaceutical composition comprises about 5% to about 55% D-α-tocopherol polyethylene glycol 1000 succinate (vitamin E TPGS), or about 30% to about 50% Vitamin E TPGS. In one embodiment, the pharmaceutical composition is in a dosage form comprising a gelatin capsule.

[0014] In various embodiments, the pharmaceutical composition comprises: (i) about 5% to about 10% ivermectin; and (ii) about 25% to about 30% mono- and di-C8-C glycerol. 10 (iii) about 15% to about 30% of a polysorbate surfactant; and (iv) about 30% to about 50% of Vitamin E TPGS.

[0015] In one embodiment, the pharmaceutical composition comprises: (i) about 8% ivermectin; and (ii) about 27.6% mono- and di-C8-C glycerol. 10 (iii) about 32.2% polysorbate 80; and (iv) about 32.2% vitamin E TPGS.

[0016] In one embodiment, the pharmaceutical composition comprises: (i) about 8% ivermectin; (ii) about 27.6% Masester E8120; (iii) about 32.2% polysorbate 80; and (iv) about 32.2% Vitamin E TPGS.

[0017] In one embodiment, the pharmaceutical composition comprises: (i) about 8% ivermectin; and (ii) about 27.6% mono- and di-C8-C glycerol. 10 (iii) about 18.4% polysorbate 80; and (iv) about 46% vitamin E TPGS.

[0018] In one embodiment, the pharmaceutical composition comprises: (i) about 8% ivermectin; (ii) about 27.6% Masester E8120; (iii) about 18.4% polysorbate 80; and (iv) about 46% Vitamin E TPGS.

[0019] In one embodiment, the pharmaceutical composition comprises: (i) about 8% ivermectin; and (ii) about 27.6% mono- and di-C8-C glycerol. 10 fatty acid esters; and (iii) about 64.4% polysorbate 80.

[0020] In one embodiment, the pharmaceutical composition comprises: (i) about 8% ivermectin; (ii) about 27.6% Masester E8120; and (iii) about 64.4% polysorbate 80. [Brief description of the drawings]

[0021] [Figure 1] Graphs (1E–7E) showing fiber optic dispersion of ivermectin formulation prototypes in FaSSIF. [Diagram 2] Mean concentration-time curves of ivermectin B1a in SD rat plasma after a single intravenous injection of 2 mg / kg ivermectin drug substance under fasting conditions. [Diagram 3] Mean concentration-time curves of ivermectin B1a in SD rat plasma after a single oral dose of 2 mg / kg Stromectol in the fasted state. [Figure 4] Mean concentration-time curves of ivermectin B1a in SD rat plasma after a single oral dose of 2 mg / kg Ivomec in the fasted state. [Diagram 5] Mean concentration-time curves of ivermectin B1a in SD rat plasma after a single oral dose of 2 mg / kg formulation 7E in the fasted state. [Figure 6] FIG. 2 is a schematic diagram showing a rat study to evaluate modulation of pentylenetetrazole (PTZ)-induced seizures by a solution of Formulation 7E. [Figure 7]Area under the curve values ​​obtained from BOLD fMRI time series of selected brain regions. Data are presented as mean + SEM, n = 12 per group. From left to right: (1) Vehicle + PTZ, (2) IVM solution, 2 mg / kg + PTZ, (3) IVM solution, 4 mg / kg + PTZ, alprazolam (3 mg / kg) + PTZ. Statistical significance: (p<0.05, p<0.01, p<0.001, p<0.0001, ordinary two-way ANOVA). Vehicle vs alprazolam (all); Vehicle vs IVM (4 mg / kg + PTZ) (all except HipAD and pons); Alprazolam vs IVM 2 mg / kg (CinCtx, MotCtx, RSCtx, SSCtx, ThaIVM, and mPFC). CC=corpus callosum; CinCtx=cingulate cortex; MotCtx=motor cortex; RSCtx=retrosplenial cortex; SSCtx=somatosensory cortex; TAssocCtx=temporal association cortex; HipAD=dorsal hippocampus; pons; ThalDL=dorsolateral thalamus; ThalVM=medial thalamus; VTA=ventral tegmental area; nAcbSh=nucleus accumbens shell; amygdala; CPu=caudate putamen; and mPFC=medial prefrontal cortex. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] The present disclosure provides pharmaceutical compositions and dosage forms of avermectins, particularly ivermectins. The avermectin compositions (also interchangeably referred to herein as formulations) are liquid or semi-solid at room temperature and include avermectins, particularly ivermectins, a first surfactant, and a second surfactant. The compositions can be used for the treatment and prevention of neurological and other disorders.

[0023] Avermectin and Ivermectin

[0024] Any of the avermectin compounds disclosed herein (including derivatives and analogs) can be used in the compositions and methods provided by this disclosure. The avermectins comprise a family consisting of four closely related major components A1a, A2a, B1a, and B2a, and four minor components A1b, A2b, B1b, and B2b, which are sub-homologs of the corresponding major components. Eight different avermectins have been isolated from the four pairs of homologous compounds (the ratio of major and minor components is usually about 80:20 to about 90:10). Anthelmintics derived from avermectins include ivermectin, selamectin, doramectin, eprinomectin, moxidectin, avermectin, and abamectin. The family members exhibit anthelmintic and insecticidal / acaricidal activity at different degrees of efficacy.

[0025] Provided herein are compositions comprising about 1% to about 15% of an avermectin compound, the avermectin compound being a macrocyclic compound according to Formula I: [ka] or a pharma- ceutically acceptable salt, stereoisomer, polymorph, solvate, or isotopically labeled compound thereof, wherein: Each occurrence of X is independently -CH2-, -NH-, -O-, -S-, -SO-, and -SO2, Y is selected from -CH2-, -O-, -NH-, and -S-; Z is selected from O and S; [ka] each occurrence of is a single bond or a double bond, n is an integer from 0 to 6, R 1 Each occurrence of is independently a halogen, -R, -OR, -NO2, -NCS, -CN, -CF3, -OCF3, -NHR, -N(R)2, -OC(O)R, -C(O)OR, -SR, -C(O)R, -C(O)C(O)R, -C(O)CH2C(O)R, -C(S)R, - C(S)OR, -C(O)C(O)OR, -C(O)C(O)N(R)2, -C(O)N(R)2, -OC(O)N(R)2, -C(S)N(R)2, -N(R)C(O)OR, -N(R)C( O)R, -N(R)C(S)R, -N(R)C(O)N(R)2, -N(R)C(S)N(R)2, -N(COR)COR, -N(OR)R, -C(=NH)N(R)2, -C(O)N(OR) selected from R, -C(=NOR)R, -OP(O)(OR)2, -P(O)(R)2, -P(O)(OR)2, -P(O)(H)(OR), -CH2-OR, and -CH2-O-CH2-R, R 2 Each occurrence of is independently H, OH, OC 1-4 Alkyl, -OC(O)C 1-4 Alkyl, -OC(O)NH2, and -OC(O)NHC 1-4 alkyl, R 3 each occurrence of is a mono-, di-, or triglycoside, or O-C(O)-(C-C) alkenyl; Each R is independently H, -(C 12 ) alkyl, -(C3-C 10 )-Cycloalkyl, (C3-C 10 )-cycloalkenyl, -[(C3-C 10 )Cycloalkyl]-(C1-C 12 ) alkyl, -[(C3-C 10 )Cycloalkenyl]-(C1-C 12 ) alkyl, -[(C3-C 10 )Cycloalkenyl]-(C1-C 12 ) alkyl, -[(C3-C 10 )Cycloalkyl]-O-(C1-C 12 ) alkyl, -[(C3-C 10 )cycloalkenyl]-O-(C1-C 12 ) alkyl, -(C6-C 10 )Aryl, (C6-C 10 )Aryl-(C1-C12 ) alkyl, -(C6-C 10 )Aryl-O-(C1-C 12 )Alkyl, (C6-C 10 )Aryl-N(R'')-(C1-C 12 ) alkyl, 3-10 membered heterocyclyl, (3-10 membered heterocyclyl)-(C1-C 12 ) alkyl, (3-10 membered heterocyclyl)-O-(C1-C 12 ) alkyl, (3-10 membered heterocyclyl)-N(R'')-(C1-C 12 ) alkyl, 5-10 membered heteroaryl, (5-10 membered heteroaryl)-(C1-C 12 )-alkyl, (5-10 membered heteroaryl)-O-(C1-C 12 )-alkyl, and (5-10 membered heteroaryl)-N(R'')-(C1-C 12 )-alkyl; each heterocyclyl has 1 to 4 heteroatoms independently selected from N, NH, O, S, SO, and SO2; Heteroaryl has 1 to 4 heteroatoms independently selected from N, NH, O, and S; each occurrence of R is independently unsubstituted or substituted with 1 to 5 R'; each occurrence of R' is halo, OH, oxo, -CH2OR'', -CH2N(R'')2, C(O)N(R'')2, -C(O)OR'', -NO2, NCS, CN, CF3, OCF3, and -N(R'')2; Each occurrence of R″ is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 3-6 membered heterocyclyl, 5-10 membered heteroaryl, and (C6-C 10 )-aryl.

[0026] In some embodiments, the compound of formula I is a compound of formula II: [ka] or a pharma- ceutically acceptable salt, stereoisomer, polymorph, solvate, or isotopically labeled compound thereof, wherein n, R 1 , R 2 , and R 3 are each as defined in Formula I.

[0027] In some embodiments, the compound of formula II is a compound of formula III: [ka] or a pharma- ceutically acceptable salt, stereoisomer, polymorph, solvate, or isotopically labeled compound thereof, wherein R 1 , R 2 , and R 3 are each as defined in Formula I.

[0028] In some embodiments, the compound of formula III is a compound of formula IV: [ka] or a pharma- ceutically acceptable salt, stereoisomer, polymorph, solvate, or isotopically labeled compound thereof, wherein R 1 each occurrence is independently selected from halogen, -R, -OR, -NO2, -NCS, -CN, -CF3, -OCF3, -NHR, -N(R)2, -OC(O)R, -C(O)OR, -C(O)N(R)2, -OC(O)N(R)2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R)2, -CH2-OR, and -CH2-O-CH2-R; R 3 each occurrence of is a mono-, di-, or triglycoside, or O-C(O)-(C-C) alkenyl; R, R′, and R″ are each as defined in Formula I.

[0029] In some embodiments, the compound of formula IV is a compound of formula V: [ka] or a pharma- ceutically acceptable salt, stereoisomer, polymorph, solvate, or isotopically labeled compound thereof, wherein R 1 Each occurrence of is independently selected from halogen, -R, -OR, -NO2, -NCS, -CN, -CF3, -OCF3, -NHR, -N(R)2, -OC(O)R, -C(O)OR, -C(O)N(R)2, -OC(O)N(R)2, selected from -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R), -CH-OR, and -CH-O-CH-R; R, R′, and R″ are each as defined in Formula I.

[0030] In embodiments, the macrocyclic compound is an avermectin compound, or a derivative, a pharma- ceutically acceptable salt, an ester, a stereoisomer, a polymorph, a solvate, an N-oxide, or an isotopically labeled compound thereof. In one embodiment, the macrocyclic compound is an avermectin. In some embodiments, the macrocyclic compound is selected from the group consisting of ivermectin, selamectin, doramectin, eprinomectin, moxidectin, avermectin, and abamectin. In some embodiments, the macrocyclic compound is an ivermectin, or a derivative, a pharma- ceutically acceptable salt, an ester, a stereoisomer, a polymorph, a solvate, an N-oxide, or an isotopically labeled compound thereof.

[0031] Provided herein are compositions comprising about 1% to about 15% of a compound of any one of formulas I-VII. In some embodiments, the compositions comprise about 1% to about 15% of one or more of a compound of any one of formulas I-VII. In some embodiments, the compositions comprise about 1% to about 15% of ivermectin, including 22,23-dihydroavermectin B1a (formula VI) and 22,23-dihydroavermectin B1b (formula VII). In some embodiments, the compositions comprise ivermectin, including at least about 70% to at least about 90% of a compound of formula VI and less than about 30% to less than about 10% of a compound of formula VII. [ka] [ka]

[0032] In some embodiments, the composition comprises ivermectin comprising at least about 70% to at least about 90% of the compound of formula VI and less than about 30% to less than about 10% of the compound of formula VII. In some embodiments, the ivermectin comprises at least about 70% 22,23-dihydroavermectin B1a and less than about 30% 22,23-dihydroavermectin B1b. In some embodiments, the ivermectin comprises at least about 90% 22,23-dihydroavermectin B1a and less than about 10% 22,23-dihydroavermectin B1b.

[0033] Derivatives of ivermectin (including abamectin and doramectin), as well as prodrugs of ivermectin, may have similar properties and uses as ivermectin. Both abamectin and doramectin have a double bond at position C22-C23 of the ivermectin structural formula. Furthermore, in the case of doramectin, position C25 is substituted with a side chain of a cyclohexyl ring. [ka]

[0034] As used herein, "derivative" refers to a compound that retains the biological activity of the parent avermectin from which it is derived, or a compound that is a prodrug of the parent avermectin. Derivatives can include esters, amides, ethers, etc., derived from avermectins.

[0035] As used herein, the term "alkyl" refers to a hydrocarbon chain that is a straight or branched chain containing the indicated number of carbon atoms. For example, C 1-6indicates that the group has 1 to 6 carbon atoms in it (inclusive). If no numerical value is specified, the "alkyl" is a chain (straight or branched) having 1 to 20 carbon atoms in it (inclusive). The term "unsaturated alkyl" refers to a hydrocarbon that has no unsaturated bonds (e.g., carbon-carbon double bonds or carbon-carbon triple bonds). The term "unsaturated alkyl" refers to a hydrocarbon that has one or more unsaturated bonds (e.g., carbon-carbon double bonds or carbon-carbon triple bonds).

[0036] As used herein, the term "alkenyl" refers to a hydrocarbon chain that is a straight or branched chain having one or more carbon-carbon double bonds. The alkenyl moiety contains the indicated number of carbon atoms. For example, C 2-6 indicates that the group has 2 to 6 (inclusive) carbon atoms in it. If no numerical value is specified, "alkenyl" is a chain (straight or branched) having 2 to 20 (inclusive) carbon atoms in it.

[0037] The term "cycloalkyl" as used herein includes saturated and partially unsaturated cyclic hydrocarbon groups. Unless otherwise specified, cycloalkyl has 3 to 12 carbons, or 3 to 8 carbons, or 3 to 6 carbons, and cycloalkyl groups are further optionally substituted. Some cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

[0038] As used herein, the term "aryl" refers to a monocyclic or bicyclic aromatic ring system of 6 to 10 carbons in which 0, 1, 2, 3, or 4 atoms of each ring are substituted by substituents. Examples of aryl groups include phenyl, naphthyl, and the like.

[0039] As used herein, the term "heterocyclyl group" or "heterocyclyl" refers to aromatic and non-aromatic ring compounds containing three or more ring members, one or more of which are heteroatoms (such as, but not limited to, N, O, and S). Heterocyclyl can be cycloheteroalkyl, heteroaryl, or any combination thereof if polycyclic. Heterocyclyl groups can contain from 3 to about 20 ring members, while other such groups can contain from 3 to about 15 ring members. A heterocyclyl group referred to as C2-heterocyclyl can be a 5-membered ring having 2 carbon atoms and 3 heteroatoms, a 6-membered ring having 2 carbon atoms and 4 heteroatoms, etc. Similarly, a C4-heterocyclyl can be a 5-membered ring having 1 heteroatom, a 6-membered ring having 2 heteroatoms, etc. The number of carbon atoms and the number of heteroatoms add up to the total number of ring atoms. A heterocyclyl ring may contain one or more double bonds. A heteroaryl ring is one embodiment of a heterocyclyl group. In some embodiments, "heterocyclyl" refers to a non-aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 (for monocyclic), 1-6 (for bicyclic), or 1-9 (for tricyclic) heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3 (for monocyclic), 1-6 (for bicyclic), or 1-9 heteroatoms (for tricyclic)), with 0, 1, 2, or 3 atoms of each ring being substituted by substituents. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like.

[0040] As used herein, the term "heteroaryl" refers to an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 (for monocyclic), 1-6 (for bicyclic), or 1-9 (for tricyclic) heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3 (for monocyclic), 1-6 (for bicyclic), or 1-9 heteroatoms (for tricyclic)), with 0, 1, 2, 3, or 4 atoms of each ring being substituted by substituents. Examples of heteroaryl groups include pyridyl, furyl or furanyl, imidazolyl, benzimidazolyl, pyrimidinyl, thiophenyl or thienyl, quinolinyl, indolyl, thiazolyl, and the like.

[0041] As used herein, the term "glycoside" refers to any substance having a chemical structure that includes a glycosidic bond between a carbohydrate (sugar) molecule and another carbohydrate or non-carbohydrate (non-sugar) moiety. A glycosidic bond or linkage is a type of covalent bond that links a carbohydrate (sugar) molecule to another molecule, for example, via a hemiacetal or hemiketal group. The other molecule may or may not be a carbohydrate. The sugar portion is commonly known as the glycone portion of the glycoside. A glycone can consist of a single sugar group (monosaccharide), two sugar groups (disaccharide), or multiple sugar groups (oligosaccharide).

[0042] As used herein, the term "substituent" refers to a group (e.g., a hydrogen atom on any molecule, compound, or moiety) that replaces a second atom or group. Suitable substituents include, but are not limited to, halo, hydroxy, mercapto, oxo, nitro, haloalkyl, alkyl, alkaryl, aryl, aralkyl, alkoxy, thioalkoxy, aryloxy, amino, alkoxycarbonyl, amido, carboxy, alkanesulfonyl, alkylcarbonyl, and cyano groups.

[0043] In various embodiments, the avermectins used in the formulations and methods provided herein are considered to be in neutral form. However, if the avermectins contain ionizable groups, they may exist as pharmaceutically acceptable salts. As used herein, the term "pharmaceutically acceptable salts" refers to salts that are suitable for pharmaceutical use (e.g., human and animal use). Pharmaceutically acceptable salts of amines, carboxylic acids, and other types of compounds are well known in the art. For example, SM Berge et al. provide a detailed description of pharmaceutically acceptable salts in J Pharmaceutical Sciences, 66:1-19 (1977), which is incorporated herein by reference. Salts can be prepared in situ during the final isolation and purification of avermectins, or prepared separately by reacting the free base or free acid functions with a suitable reagent. For example, the free base function can be reacted with a suitable acid. Suitable pharmaceutically acceptable salts can include metal salts, such as alkali metal salts (e.g., sodium, potassium, and lithium salts), and alkaline earth metal salts (e.g., calcium or magnesium salts). Examples of pharma- ceutically acceptable non-toxic acid addition salts include salts of amino groups formed with inorganic acids (e.g., hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, and perchloric acids), or organic acids (e.g., acetic, oxalic, maleic, tartaric, citric, succinic, or malonic acids), or by using other methods used in the art, such as ion exchange.Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hernisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanoate, and the like. Examples of the salts include toluenesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.

[0044] Avermectin Compositions

[0045] The compositions for use in the methods and dosages provided herein are liquid or semi-solid at room temperature and comprise an avermectin, particularly ivermectin, a first surfactant, and a second surfactant.

[0046] In various embodiments, the composition comprises: (i) about 1% to about 15% of a compound of any one of Formulas I-VII; (ii) about 20% to about 40% of a first surfactant that includes one or more of the following: (a) mono-, di-, and / or tri-fatty acid esters of glycerol; (b) mono- and / or di-fatty acid esters of 1,2-propylene glycol; and (c) Mono- and / or di-fatty acid esters of polyethylene glycol (Fatty acids are C6 to C 10 fatty acids) (iii) about 15% to about 70% of a second surfactant selected from one or more of a polysorbate surfactant and / or a fatty acid ester of sorbitan.

[0047] In some embodiments, the composition comprises about 3% to about 12% of a compound of any one of Formulas I-VII. In some embodiments, the composition comprises about 5% to about 10% of a compound of any one of Formulas I-VII. In some embodiments, the composition comprises about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, or about 12% of a compound of any one of Formulas I-VII.

[0048] In various embodiments, the composition comprises: (i) about 1% to about 15% of one or more compounds of any one of Formulas I-VII; (ii) about 20% to about 40% of a first surfactant that includes one or more of the following: (a) mono-, di-, and / or tri-fatty acid esters of glycerol; (b) mono- and / or di-fatty acid esters of 1,2-propylene glycol; and (c) mono- and / or di-fatty acid esters of polyethylene glycol; (Fatty acids are C6 to C 10 fatty acids) (iii) about 15% to about 70% of a second surfactant selected from one or more of a polysorbate surfactant and / or a fatty acid ester of sorbitan.

[0049] In some embodiments, the composition comprises about 3% to about 12% of one or more of the compounds of formulae I-VII. In some embodiments, the composition comprises about 5% to about 10% of one or more of formulae I-VII. In some embodiments, the composition comprises about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, or about 12% of one or more of formulae I-VII.

[0050] In various embodiments, the composition comprises: (i) about 1% to about 15% ivermectin comprising a compound of formula VI and a compound of formula VII; (ii) about 20% to about 40% of a first surfactant that includes one or more of the following: (a) mono-, di-, and / or tri-fatty acid esters of glycerol; (b) mono- and / or di-fatty acid esters of 1,2-propylene glycol; and (c) mono- and / or di-fatty acid esters of polyethylene glycol; (Fatty acids are C6 to C 10 fatty acids) (iii) about 15% to about 70% of a second surfactant selected from one or more of a polysorbate surfactant and / or a fatty acid ester of sorbitan.

[0051] In some embodiments, the composition comprises about 3% to about 12% ivermectin, including the compound of formula VI and the compound of formula VII. In some embodiments, the composition comprises about 5% to about 10% ivermectin, including the compound of formula VI and the compound of formula VII. In some embodiments, the composition comprises about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, or about 12% ivermectin, including the compound of formula VI and the compound of formula VII.

[0052] The compositions provided herein include a first surfactant. The first surfactant can be a mixture of surfactants and can include glycerol, 1,2-propylene glycol, and / or polyethylene glycol C6-C 10 Contains fatty acid esters. C6~C 10 The fatty acid(s) may be saturated or unsaturated, but are preferably saturated. More preferably, the fatty acid has 8 to 10 carbons, and may be, in particular, caprate, caprylate, and mixtures thereof. The avermectin composition comprises about 20% to about 40% of the first surfactant, or about 25% to about 30% of the first surfactant.

[0053] The first surfactant may comprise mono-, di-, and / or tri-fatty acid esters of glycerol. The fatty acid esters of glycerol may be a mixture of mono- and di-esters of glycerol. The fatty acid component may comprise one or more C6-C 10 The fatty acid may be saturated or unsaturated, but is preferably saturated. More preferably, the fatty acid has 8-10 carbons, and may be, in particular, caprate, caprylate, and mixtures thereof. Fatty acid esters of glycerin are commercially available, including Capmul 808G EP / NF (glyceryl monocaprylate), Capmul MCM C8 EP / NF (glyceryl monocaprylate), Capmul MCM (caprylic / capric glyceryl), Masester E8120 (mono- and di-caprylic / capric glyceryl).

[0054] Additionally or alternatively, the first surfactant may comprise a mono- and / or di-fatty acid ester of 1,2-propylene glycol. The fatty acid ester of propylene glycol may be a mixture of mono- and di-esters of propylene glycol, and preferably, the fatty acid ester of propylene glycol may be a monoester of propylene glycol. The fatty acid component may comprise one or more C6-C 10 The fatty acid may be saturated or unsaturated, but is preferably saturated. More preferably, the fatty acid has 8 to 10 carbons, and may be, in particular, caprate, caprylate, and mixtures thereof. Fatty acid esters of propylene glycol are commercially available, including Capmul PG-8 (propylene glycol monocaprylate), Capryol 90 (propylene glycol monocaprylate), and Capryol PGMC (propylene glycol mono- and dicaprylate).

[0055] The first surfactant may additionally or alternatively comprise a mono- and / or di-fatty acid ester of polyethylene glycol. The fatty acid ester of polyethylene glycol may be a mixture of mono- and di-esters of polyethylene glycol. The fatty acid component may be one or more C6-C 10 The fatty acids may be saturated or unsaturated, but are preferably saturated. More preferably, the fatty acids have 8 to 10 carbons, and may be caprates, caprylates, and mixtures thereof, among others. The polyethylene glycol component may have an average molecular weight of about 200 to about 800, or about 300 to about 500. Fatty acid esters of propylene glycol are commercially available, including Labrasol ALF (mono-, di-, and small fractions of triglycerides, as well as primarily caprylic (C8) and capric (C9) acids. 10 ) PEG-8 (MW 400) mono- and diesters.

[0056] The compositions provided herein can also include a second surfactant. The second surfactant can be a mixture of surfactants and is selected from polysorbate surfactants, fatty acid esters of sorbitan, and mixtures thereof. The avermectin composition includes about 15% to about 70% of the second surfactant, about 15% to about 40% of the second surfactant, or about 15% to about 20% of the second surfactant.

[0057] The second surfactant may comprise a polysorbate surfactant, which is a polyethoxylated sorbitan esterified with fatty acids having the following general structure: [ka] where R is the carbon chain of a medium to long chain fatty acid, and the sum of w, x, y, and z is the number of oxyethylene -(CH2CHO)- groups present in the molecule. The fatty alcohol may be saturated or unsaturated. In embodiments, the fatty acid has 12 to 18 carbons. The number of oxyethylene groups (i.e., w+x+y+z) is about 20 in embodiments. Polysorbate surfactants are commercially available and include polysorbate 80 (polyoxyethylene 20 sorbitan monooleate) (e.g., Tween 80, Montanox 80, Alkest TW 80), polysorbate 60 (polyoxyethylene 20 sorbitan monostearate) (e.g., Tween 60), polysorbate 40 (polyoxyethylene 20 sorbitan monopalmitate) (e.g., Tween 40), and polysorbate 20 (polyoxyethylene 20 sorbitan monolaurate) (e.g., Tween 20 and Alkest TW 20).

[0058] The second surfactant may additionally or alternatively include fatty acid esters of sorbitan (also known as Span). The fatty acid moieties may be saturated or unsaturated. In embodiments, the fatty acids have 12-18 carbons. The sorbitan esters may be mono-, di-, or tri-esters of sorbitan, particularly mono-esters of sorbitan (e.g., sorbitan monolaurate). Sorbitan esters are commercially available and include Span 20 (sorbitan monolaurate), Span 40 (sorbitan monopalmitate), Span 60 (sorbitan monostearate), Span 65 (sorbitan tristearate), and Span 80 (sorbitan monooleate).

[0059] Optionally, the avermectin compositions may further comprise Vitamin E TPGS (also known as D-α-tocopherol polyethylene glycol 1000 succinate). The compositions can comprise from about 5% to about 55% Vitamin E TPGS, or from about 30% to about 50% Vitamin E TPGS.

[0060] In various embodiments, the pharmaceutical composition comprises: (i) about 5% to about 10% ivermectin; and (ii) about 25% to about 30% mono- and di-C8-C glycerol. 10 (iii) about 15% to about 30% of a polysorbate surfactant; and (iv) about 30% to about 50% of Vitamin E TPGS.

[0061] In one embodiment, the pharmaceutical composition comprises: (i) about 8% ivermectin; and (ii) about 27.6% mono- and di-C8-C glycerol. 10 (iii) about 32.2% polysorbate 80; and (iv) about 32.2% vitamin E TPGS.

[0062] In one embodiment, the pharmaceutical composition comprises: (i) about 8% ivermectin; (ii) about 27.6% Masester E8120; (iii) about 32.2% polysorbate 80; and (iv) about 32.2% Vitamin E TPGS.

[0063] In one embodiment, the pharmaceutical composition comprises: (i) about 8% ivermectin; and (ii) about 27.6% mono- and di-C8-C glycerol. 10 (iii) about 18.4% polysorbate 80; and (iv) about 46% vitamin E TPGS.

[0064] In one embodiment, the pharmaceutical composition comprises: (i) about 8% ivermectin; (ii) about 27.6% Masester E8120; (iii) about 18.4% polysorbate 80; and (iv) about 46% Vitamin E TPGS.

[0065] In one embodiment, the pharmaceutical composition comprises: (i) about 8% ivermectin; and (ii) about 27.6% mono- and di-C8-C glycerol. 10 fatty acid esters; and (iii) about 64.4% polysorbate 80.

[0066] In one embodiment, the pharmaceutical composition comprises: (i) about 8% ivermectin; (ii) about 27.6% Masester E8120; and (iii) about 64.4% polysorbate 80.

[0067] The pharmaceutical compositions may further comprise additional excipients (e.g., additional surfactants, solvents, solubilizing agents, preservatives, antioxidants, bulking agents, solubility enhancers, wetting agents, emulsifying agents, suspending agents, antibacterial agents, pH buffering agents, sweetening agents, flavoring agents, and combinations thereof).

[0068] Dosage form

[0069] The present disclosure provides compositions containing avermectins in a semi-solid or liquid base when formulated as emulsions, suspensions, solutions, elixirs, or syrups in which the avermectins are dissolved and / or suspended.

[0070] Dosage forms containing avermectins can take the form of solutions, suspensions, emulsions, aerosols, capsules, soft elastic or hard gelatin capsules, skin patches, suspensions, etc., preferably in unit dosage forms suitable for convenient administration of precise dosages. The compositions can take the form of liquid or semisolid filled capsules, sublingual sprays, or nasal sprays.

[0071] Capsule dosage forms may include soft capsules and hard capsules. Capsules can be used as oral dosage forms for administration of many different types of active pharmaceuticals. Capsules can be filled with active ingredients in the form of liquid or powder suspended in liquid. Hard capsules can be made from non-plasticized or low-plasticized gelatin and water to form a hard capsule that can be filled with powder or liquid. Soft capsules are made from highly plasticized soft elastic gelatin and can contain liquid or semi-solid ingredients. These capsules are often referred to as "soft gel" or "gel cap" capsules.

[0072] As used herein, the term "capsule" refers to any suitable capsule container or case adapted for oral ingestion (e.g., adapted for use with a liquid fill composition). The term "capsule" may include capsules having a shell composed of soft and / or hard materials (e.g., gelatin, starch, cellulose, cellulose derivatives (e.g., hydroxypropyl methylcellulose), hydrocolloids, gums, carrageenan, or any other natural or synthetic material that can be used to encapsulate and ingest a liquid composition by an animal). Optionally, the shell material can be gelatin and / or hydroxypropyl methylcellulose. In one embodiment, the shell material is gelatin. The term "capsule" also includes capsules of various shapes and sizes. The present disclosure does not limit the dosage form to a particular type or shape. Any commercially available capsule shell or shell material can be used.

[0073] In one embodiment, the dosage form of the present disclosure is a soft capsule. In one embodiment, the dosage form of the present disclosure is a coated liquid-filled soft capsule. The coated capsule can include a liquid fill encapsulated by a soft capsule shell. The exterior surface of the soft capsule can be coated with one or more coating layers.

[0074] Suitable materials for encapsulating liquid filling include heat-sealable polymers and gelatin. Examples of heat-sealable polymers include, but are not limited to, modified starch, cellulosic polymers, and carrageenan. In one embodiment, the material is gelatin. The gelatin can be natural gelatin, chemically modified gelatin, enzyme modified gelatin, or a combination thereof.

[0075] The material forming the capsule shell can further include water. The water can be present in the original mass of material prior to making the capsules in an amount sufficient to allow processing of the material in the encapsulation equipment. After the capsules are formed, most of the moisture can be removed during a drying process.

[0076] Water may have a plasticizing effect on the material. Additionally, a non-volatile plasticizer or blend of plasticizers may be added to the material forming the capsule shell. The non-volatile plasticizer may be any plasticizer that is compatible with the material of the capsule shell. For example, the non-volatile plasticizer may be glycerin, maltitol, sorbitan, sorbitol, or similar low molecular weight polyhydric alcohols, and mixtures thereof. In embodiments, the ratio of plasticizer to material determines the hardness or softness of the shell.

[0077] The ratio of plasticizer to material in the shell may be sufficient to provide a capsule that is not too hard so that it becomes brittle and cracks when subjected to stress during shipping and handling, and not too soft so that it deforms during shipping and handling. The non-volatile plasticizer may be present in the capsule shell at about 8% to 65% of the total weight of the capsule shell, and about 10% to 35% of the total weight of the capsule shell.

[0078] The material forming the capsule shell may further include a bulking agent. The bulking agent may be any bulking agent compatible with the material. Examples of bulking agents may include natural or modified natural biopolymers and synthetic polymers. Natural biopolymers may include, for example, cellulose, starch, starch derivatives, bacterial polysaccharides (e.g., xanthan gum and gellan gum), vegetable gums (e.g., guar gum, locust bean gum, tragacanth gum, and gum arabic), animal-derived polymers (e.g., chondroitin sulfate, hyaluronic acid, heparin, collagen, and chitosan). An example of a modified natural biopolymer may be modified cellulose. Examples of synthetic polymers may include carbon chain polymers of vinyl and acrylic types, and hetero chains of polyoxide and polyamine types.

[0079] A coating may be applied to the outer surface of the soft capsule. The coating may include one or more layers. Any coating suitable for soft capsules may be applied. The coating may provide, for example, waterproof and sealing, lubricity, polishing, enteric protection, and / or delayed release properties to the liquid-filled capsule. The delayed release may be affected, for example, by temperature or pH. In one embodiment, the coating is an enteric coating.

[0080] Coating can be accomplished with any standard coating ingredients known to those skilled in the art, including, but not limited to, fats, fatty acids, waxes, shellac, ammoniated shellac, cellulose acetate phyhalates, celluosics, vinyl, glycol, acrylic, and carbohydrate polymers, polymers and copolymers containing methacrylic acid and methacrylic acid alkyl esters, hydroxypropyl methylcellulose (HPMC), and combinations thereof.

[0081] The coated capsule may further include a finish coating. In one embodiment, a finish layer is applied to the coated capsule. Examples of materials suitable for use in the finish coating may include, but are not limited to, cellulose, vinyl, glycol, acrylic, and carbohydrate polymers, and / or combinations thereof.

[0082] The liquid or semi-solid fill can be encapsulated in a soft capsule shell by any method known in the art. For example, soft capsules can be made using a standard rotary die soft gelatin capsule machine as described in The Theory and Practice of Industrial Pharmacy, ed. Lachman, et al., 2nd Ed., Pt. II, 404-420, Lea & Febiger, 1976. Further methods include the use of plate processes (Theory and Practice of Industrial Pharmacy, ed. Lachman, et al., 2nd Ed., Pt. II, 405, Lea & Febiger, 1976), as well as Globex-type seamless capsule machines (see U.S. Pat. No. 5,254,294) that make large microcapsules, non-standard rotary die machines that use extrusion techniques to make gel ribbons (see U.S. Pat. Nos. 6,183,845 and 6,340,473), and other capsule making methods that use high frequency, ultrasonic, or induction welding to seal the capsules (see U.S. Pat. No. 6,352,719). The U.S. patents and books cited above are incorporated herein by reference.

[0083] As used herein, the expression "liquid hard shell" refers to a hard capsule that encapsulates a liquid or semi-solid formulation. A hard capsule can be a single unit dosage form and can include a cap and a body, which can be manufactured separately and can be supplied empty to be filled with a liquid or semi-solid composition. In some embodiments, the hard capsule is made from a polymer such as gelatin. An additional component can be water, which acts as a plasticizer. Another hard capsule can be made from hydroxypropylmethylcellulose (HPMC). Liquid-filled hard capsules can be filled with a filling machine (e.g., a high-speed filling machine).

[0084] In one example, disclosed herein is a method for preparing filled hard capsules. Empty capsules are fed into a filling machine in a pre-locked state, with the capsule body having a loosely attached cap. A series of rings or protrusions are provided on the mating surface of the cap or body. These rings allow the cap to be loosely attached to the body, thus holding the cap and body together during storage, and allow the cap to be removed before filling the capsule. Once the capsule is filled, the cap can be pushed back past the pre-lock position to a fully locked position. Alternatively, other types of capsule filling machines may be used to accept separate feeds of capsule bodies and caps.

[0085] The capsule can be closed at high speed after being filled with the formulated composition. When closing the capsule, the cap is fitted to the body and the body is pushed up until it is locked by the cap. The cap can be a tight fit and can be approximately half the length of the body. Thus, the cap moves a significant distance against the capsule body before locking. This can have a piston effect in trapping and pressurizing the capsule. Excess air can escape through the gap between the cap and the body. A vent may be provided in this area to facilitate the escape of excess pressure. Alternatively, the capsule may utilize a particularly tight locking mechanism rather than a vent.

[0086] In one embodiment, the capsule is banded by applying a band of polymer solution around the junction between the cap and body. The polymer solution can be a solution of the same polymer as the capsule cap and / or body dissolved in a solvent. Banding provides a smooth capsule surface for coating, which can prevent migration between the capsule cap and body.

[0087] When preparing a filled capsule filled with a composition containing avermectin, it is preferred that the composition is in liquid form at least during the encapsulation process.In one embodiment, the final capsule contains the composition in liquid form.In one embodiment, the final capsule contains the composition in semi-solid form at room temperature.

[0088] Method of administration

[0089] Administration of pharmaceutical compositions containing avermectins can be by oral, nasal, intraocular, intravenous, intramuscular, subcutaneous, transdermal, subdermal, sublingual, or rectal routes of administration.

[0090] In embodiments, the route of administration is oral and the pharmaceutical composition is provided in the form of a capsule (eg, a soft elastic or hard gelatin capsule).

[0091] In one embodiment, the route of administration is intranasal. The composition may be a solution, aerosol, liquid suspension, or liquid dispersion, and takes the form of a nasal spray, nasal wash, inhaler, nasal drops, and / or diffuser.

[0092] In embodiments, the route of administration is transdermal, including but not limited to topical, subcutaneous, dermal, transdermal, intradermal, or transdermal patch.

[0093] Treatment and prevention methods

[0094] Provided herein are methods for treating or preventing neurological or other disorders by administering to a subject in need thereof a therapeutically or prophylactically effective amount of a composition disclosed herein.

[0095] A "therapeutically effective amount" of an ivermectin-containing composition comprising (i) any one of the compounds of formulas I-VII, (ii) one or more of the compounds of formulas I-VII, or (iii) a compound of formula VI and a compound of formula VII is an amount sufficient to provide a therapeutic benefit to a patient after administration (e.g., improve one or more symptoms of a disease in a subject). A "therapeutically effective amount" can result in a desired beneficial physiological change in a subject, for example, by delaying, reducing, minimizing, or alleviating one or more symptoms associated with a disease or disorder, or cause an improvement in a clinically problematic condition in a subject. Generally, a therapeutically effective amount is also an amount in which any toxic or adverse effects of the composition are outweighed by the therapeutically beneficial effects. The effective amount may vary depending on the species, age, weight, sex, health status, and nature or severity of the disease of the subject. The effective amount may also vary depending on the mode of administration. In some cases, multiple doses of the composition are administered to achieve an effective amount for the intended therapeutic effect. In some cases, a therapeutic amount can be used for the treatment of refractory or resistant disorders and combination therapy. For example, the effective amount may be administered simultaneously, sequentially, in the same or different dosage form as the adjunct therapeutic agent.

[0096] As used herein, the terms "treating," "treat," and "treatment" refer to reducing, alleviating, ameliorating, or relieving at least one of the symptoms of a disease or disorder. The terms include, for example, administering a formulation provided herein to prevent the onset of spasticity, reduce or reduce its severity, and / or prevent its recurrence.

[0097] As used herein, the terms "prevent", "prevention" and the like refer to acting before the onset of an overt disease or disorder to prevent the disease or disorder from occurring or to minimize the extent of the disease or disorder or to slow the course of its development.

[0098] A "prophylactically effective amount" of a composition comprising ivermectin, including (i) any one of the compounds of formulas I-VII, (ii) one or more of any one of the compounds of formulas I-VII, or (iii) a compound of formula VI and a compound of formula VII, refers to the amount of the composition necessary to achieve the desired prophylactic result. In one embodiment, the prophylactically effective amount is less than the therapeutically effective amount, since a prophylactic dose is used in subjects prior to or at an early stage of disease.

[0099] The subject may be a mammal, including, but not limited to, a human or a non-human mammal. The mammal may be a commercial livestock animal (e.g., a horse, a cow, a sheep, or a pig), a laboratory animal (e.g., a mouse or a rat), or a pet (e.g., a cat, a dog, a rabbit, or a guinea pig). The subject is preferably a human. The subject may be male or female. Individuals and patients are also subjects herein.

[0100] Neuropathy

[0101] The present disclosure provides methods for treating or preventing a neurological disorder by administering to a subject in need thereof a therapeutically or prophylactically effective amount of (i) a compound of any one of Formulas I-VII, (ii) one or more of the compounds of any one of Formulas I-VII, or (iii) an ivermectin compound, including a compound of Formula VI and a compound of Formula VII.

[0102] Ivermectin activates the purinergic P2X4 receptor, γ-aminobutyric acid A (GABA A) receptor, glycine receptor (GlyR) and neuronal alpha-7-nicotinic receptor, with EC50 of each of the above interactions being approximately 0.25 μM, 0.92 μM, 1.2 μM and 30 μM, respectively. These channels play an important role in epilepsy. Therefore, ivermectin can be used as an anticonvulsant. The anticonvulsant action of ivermectin can be achieved by the combined effect from any combination of interactions with these four receptors mentioned above.

[0103] Ivermectin is primarily lipophilic, which may be advantageous for use in the central nervous system, since lipophilic drugs can easily cross the blood-brain barrier (BBB). The blood-brain barrier can be an obstacle for many therapeutic agents to enter the brain. However, ivermectin may have a limited half-life in the brain after crossing the BBB. The reason may be that ivermectin can be a substrate for P-glycoprotein. Specifically, multidrug resistance protein 1 (MDR1), also called P-glycoprotein or ATP-binding cassette subfamily B member 1 (ABCB1), is an efflux transport system that selectively transports substrates from interstitial fluid (ISF) to blood. P-glycoprotein can limit the entry of substances from blood to brain parenchyma. P-glycoprotein, an ATP-dependent drug transport protein, can be found in the apical membrane of multiple epithelial cell types in the body, including the blood luminal membrane of brain capillary endothelial cells. Brain capillary endothelial cells can constitute the blood-brain barrier. P-glycoprotein can dynamically transport a wide variety of hydrophobic amphipathic drugs out of cells, and thus may play a role in pumping hydrophobic drugs out of the brain by implementing dynamic reverse transport of these drugs back into the blood. Thus, ivermectin may be pumped out of brain cells and back into the blood after crossing the BBB. Thus, compositions are provided herein that address the need for formulations with improved pharmacokinetic properties, including but not limited to bioavailability.

[0104] Thus, in one aspect, the disclosure provides a method for treating or preventing a neurological disorder characterized by a seizure disorder, including, but not limited to, epilepsy, childhood absence 5 (ECA5), Gravet syndrome, Lennox-Gastaut syndrome, spinal cord injury, epileptic encephalopathy (EE), early infantile epileptic encephalopathy 43 (EIEE43), Angelman syndrome, brain injury, stroke, addictive behaviors, subarachnoid hemorrhage, anoxic encephalopathy, infectious or metabolic encephalopathy, hemorrhagic, embolic / atherosclerotic cerebrovascular disease, and other seizure indications.

[0105] In another aspect, the disclosure provides a method for treating or preventing epilepsy. In some embodiments, the epilepsy is refractory or treatment-resistant epilepsy. In various embodiments, the method comprises administering a composition comprising ivermectin, including (i) any one of the compounds of formulas I-VII, (ii) one or more of any one of the compounds of formulas I-VII, or (iii) a compound of formula VI and a compound of formula VII, together with one or more adjunctive therapeutic agents, including up to four antiepileptic drugs (AEDs), which are administered simultaneously, sequentially, and in the same or different dosage forms with a composition(s) comprising a therapeutically or prophylactically effective amount of one or more avermectins, particularly ivermectin or ivermectin derivatives. AEDs can include drugs such as lorazepam, cenobamate, brivaracetam, strilipentol, acetazolamide, phenytoin, sodium valproate, buccal midazolam, fervalnate, clobazam, perumpanel, tiagabine, rufinamide, levetiracetam, larnotrigine, pregabalin, primidone, gabapentin, nitrazepam, phenobarbital, clonazepam, vigabatrin, carbamazepine, topiramate, oxcarbazepine, rectal diazepam, lacosamide, ethosuximide, eslicarbazepine acetate, and / or zonisamide. Non-pharmaceutical anti-epileptic therapies can also be administered simultaneously, including implantable devices (e.g., vagus nerve stimulators, responsive neurostimulators, deep brain stimulators).

[0106] In another aspect, the disclosure provides a method for treating or preventing neurological disorders associated with muscle movement disorders (including, but not limited to, multiple sclerosis, essential tremor, multiple forms of spasticity (including spasticity associated with spinal cord injury), spasticity associated with other diseases (including parasitic paresis), spasticity associated with cerebral palsy, urinary incontinence after spinal cord injury, dystonia, lateral sclerosis, myotonic dystrophy, congenital (genetic) muscular dystrophies such as Duchenne and Becker, Rett syndrome, Prader-Willi syndrome, and any rare motor neuron disease).

[0107] In one aspect, the disclosure provides a method for treating or preventing a neurological disorder caused by GABAergic dysfunction (including, but not limited to, Alzheimer's disease, Parkinson's disease, schizophrenia, autism, autism spectrum disorder, global developmental delay, reduced fine and gross motor control, or attention deficit hyperactivity disorder (ADHD)).

[0108] In one embodiment, the disclosure provides a method for treating or preventing neurological disorders caused by glycinergic dysfunction (including but not limited to, stiff-body syndrome or startle disease).

[0109] In one embodiment, the present disclosure provides a method for treating or preventing a neurological disorder caused by an infection (including but not limited to meningitis, meningoencephalitis, encephalitis, mycobacterial infection, Zika infection, cerebral malaria, or an abscess in the central nervous system).

[0110] In one embodiment, the disclosure provides a method for treating or preventing neurological disorders caused by injury.

[0111] Spastic spinal cord paralysis

[0112] In one aspect, the disclosure provides a method for treating or preventing spastic spinal cord paralysis by administering to a subject in need thereof a therapeutically or prophylactically effective amount of (i) a compound of any one of Formulas I-VII, (ii) one or more of the compounds of any one of Formulas I-VII, or (iii) an ivermectin compound, including a compound of Formula VI and a compound of Formula VII.

[0113] Spasticity is a disorder in which certain muscles contract continuously. Spasticity can result in uncontrollable, painful spasms of the legs or other limbs. Spasticity can also interfere with movement and speech. If untreated, spasticity can result in joint stiffness or immobility and bedsores. It can also prevent proper motor behavior from returning after injury or disease. In addition, spasticity can cause pain, fatigue, and other problems. Thus, spasticity can be an obstacle to a person's daily activities, walking, sitting, positioning, and sleeping.

[0114] The degree of spasticity can vary from mild muscle stiffness to severe uncontrollable muscle spasms. Spasticity can be very painful and, depending on the affected muscles, can result in uncoordinated walking, stiff or deformed posture, and shortened range of motion of the limbs. Spasticity can cause permanent muscle shortening and problems around the joints where the two spastic muscles are supposed to move (contractures). Spasticity can be a permanent feature or can be brought on by various factors such as fatigue, fever, or infection.

[0115] A major component of spasticity is hyperreflexia or hyperreflexia. One measure to quantify hyperreflexia is the electrical analog of the classical tendon twitch reflex (called the Hoffman or H-reflex). The H-reflex is a compound electromyographic (EMG) response elicited by synaptic activation of motor neurons by muscle afferents after stimulation of the muscle nerve.

[0116] Spasticity may occur in association with spinal cord injury, brain damage from lack of oxygen, stroke, or head trauma, amyotrophic lateral sclerosis (Lou Gehrig's disease), phenylketonuria, metabolic disorders (e.g., adrenoleukodystrophy), cerebral palsy, stiff-body syndrome, and multiple sclerosis. In multiple sclerosis, the lower limbs may be affected, but almost any muscle in the body may be affected. In multiple sclerosis, spasticity is usually caused by damage to the nerves (neurons) that control the muscles or the nerves that collect sensory information returning from the muscles. Reflex spasms generated by the spinal cord are not inhibited by the brain as they normally would be, resulting in increased muscle tone. The causative lesion is usually found in the cerebellum or in the white matter tracts that connect the cerebellum to peripheral motor and sensory nerves (afferent nerves).

[0117] Currently, the drugs available for the management of spasticity are GABA B Baclofen is a presynaptic GABA receptor agonist. B It acts as an agonist that enhances the inhibition mediated by the receptors. The rationale for using baclofen to treat spasticity is based on the assumption that in spinal cord injury, the exaggerated reflex is induced by the removal of presynaptic inhibition from nerve fibers emanating from the brain. The spinal cord is thought to damage these emanating fibers, making the spinal cord hyperresponsive. Baclofen is thought to restore some of that inhibition. However, when baclofen is taken orally, it unfortunately increases inhibition throughout the brain, resulting in drowsiness and weakness. To avoid this unpleasant side effect (decreased patient concentration), baclofen pumps have been designed to inject the drug directly into the cerebrospinal fluid, usually in spinal cord injury victims and cerebral palsy patients. Although these pumps avoid the hypnotic effects of oral administration, they are risky, have a limited useful life (requiring repeated surgical implantation), and are very expensive.

[0118] In one embodiment, the treatment reduces hyperreflexia in human subjects. In one embodiment, the reduction of hyperreflexia is used to evaluate the reduction of spasticity. As used herein, the term "reducing hyperreflexia" refers to reducing the amplitude of H-reflex measured at 1, 5 or 10 Hz, normalized to the amplitude measured at 0.2 Hz stimulation. In other words, it refers to restoring the low frequency-dependent depression of H-reflex to near control level. More preferably, H-reflex amplitude is reduced at 5 or 10 Hz, most preferably at 5 Hz.

[0119] In some embodiments, the formulations and methods disclosed herein may be effective in reducing the degree of spasticity stiffness.

[0120] In one embodiment, the disclosure provides a method for treating or preventing spastic spinal cord paralysis secondary to a disease, including but not limited to, spinal cord injury, stroke, brain injury, amyotrophic lateral sclerosis, phenylketonuria, adrenoleukodystrophy, cerebral palsy, rigidity syndrome, or multiple sclerosis.

[0121] In one embodiment, the spasticity is secondary to a spinal cord injury, and the method further comprises administering to the human subject a dose of the formulation beginning after the spinal cord injury and prior to the onset of spasticity.

[0122] In one embodiment, the spasticity is secondary to multiple sclerosis, and the method further comprises initiating administration of a dose of the formulation to the human subject after a diagnosis of multiple sclerosis and prior to spasticity. In one embodiment, administration of the formulation is effective to increase connexin 36 levels in spinal neurons, and administration of the formulation is effective to increase gap junctions in spinal neurons or increase electrical coupling between spinal neurons.

[0123] Subjects undergoing the treatments described herein may experience a reduction in spasticity as a result of the therapy.

[0124] Levels of the protein connexin 36 (Cx36) can be used to assess the reduction in spasticity. Cx36 forms gap junctions between neurons, called electrical synapses, that allow adjacent neurons to communicate directly. Passive exercise (which also reduces spasticity) increases the expression of the neural gap junction protein connexin 36, which increases gap junctions and increases electrical communication between neurons.

[0125] Another way to evaluate the effectiveness of dosage is by evaluating muscle tone.In spasticity, the normal behavior of stretch reflex is disrupted, which makes muscles, especially flexor muscles, extremely resistant to passive stretching, i.e., high tone.As a result, motor control is severely impaired, and muscle stiffness or tension can interfere with walking, movement, and speech.Therefore, evaluation of tone (the degree of resistance to stretching from external sources) is an important means by which the degree of spasticity that a patient has and the effectiveness of intervention can be evaluated.

[0126] Another accepted clinical measure of tone in spasticity is the Ashworth and Modified Ashworth scales: the clinician moves the patient's limbs around the joints and then assigns a grade to each limb depending on the degree of resistance felt by the clinician.

[0127] Other means of assessing the efficacy of a dose include biomechanical testing such as pendulum testing (e.g., performed by pendulum testing), electrophysiological testing such as electromyography (e.g., dynamic multichannel electromyography and gait testing) or Hoffman reflex testing (measurement of deep tendon reflexes), functional measurements (e.g., Barthel Index, Functional Independence Scale, and Fugl-Meyer Assessment of Sensorimotor Impairment (Fugl-Meyer Scale)).

[0128] In one embodiment, a method is provided for treating or preventing spastic spinal cord paralysis by administering a composition disclosed herein to a subject in need thereof, the method further comprising administering a second therapeutic agent to the human subject. In some embodiments, the second agent is baclofen, benzodiazepine, diazepam, clonazepam, dantrolene, or tizanidine.

[0129] pain

[0130] In one aspect, the disclosure provides a method of treating or preventing pain by administering to a subject in need thereof a therapeutically or prophylactically effective amount of (i) a compound of any one of Formulas I-VII, (ii) one or more of the compounds of any one of Formulas I-VII, or (iii) an ivermectin compound comprising a compound of Formula VI and a compound of Formula VII.

[0131] In some embodiments, the pain is pain associated with a disease including, but not limited to, post-traumatic stress disorder (PTSD), gastroesophageal reflux disease (GERD), addiction (e.g., alcohol, drugs), anxiety, depression, memory loss, dementia, sleep apnea, stroke, urinary incontinence, narcolepsy, essential tremor, movement disorders, atrial fibrillation, cancer (e.g., brain tumors), Parkinson's disease, or Alzheimer's disease. Other non-limiting examples of neurological diseases or disorders that may be treated or prevented by the compositions and methods herein include apraxia, agraphia, alcoholism, dyslexia, aneurysm, amaurosis fugax, amnesia, amyotrophic lateral sclerosis (ALS), Angelman syndrome, aphasia, apraxia, arachnoiditis, Arnold-Chiari malformation, Asperger syndrome, ataxia, ataxia-telangiectasia, attention deficit hyperactivity disorder, auditory processing disorder, autism spectrum, bipolar disorder, Bell's palsy, brachial plexus injury, brain injury, brain tumor, Canavan disease, Capgras delusion, carpal tunnel syndrome, causalgia, central pain syndrome, central pontine myelinolysis, centronuclear myopathy, head injury, cerebral aneurysm, cerebral arteriosclerosis, brain atrophy, autosomal dominant with subcortical infarction and leukoencephalopathy. CADASIL, cerebral gigantism, cerebral palsy, cerebral vasculitis, cervical spinal canal stenosis, Charcot-Marie-Tooth disease, Chiari malformation, chorea, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic pain, Coffin-Lowry syndrome, coma, complex regional pain syndrome, compressive neuropathy, congenital bilateral facial nerve palsy, corticobasal degeneration, cranial arteritis, cranial suture premature fusion, Creutzfeldt-Jakob disease, cumulative trauma disorder, Cushing's syndrome, cyclothymic disorder, cytomegalovirus infection, Dandy-Walker syndrome, Dawson's disease, De Morcier syndrome, Dejerine-Klumpke palsy, Dejerine-Sottas disease, delayed sleep phase syndrome, dementia, Dermatomyositis, Developmental Coordination Disorder, Diabetic Neuropathy, Diffuse Sclerosis, Diplopia, Down's Syndrome, Dravet Syndrome, Duchenne Muscular Dystrophy, Dysarthria, Autonomic Neuropathy, Dyscalculia, Dysgraphia, Dyskinesia, Dyslexia, Dystonia, Empty Sella Syndrome, Encephalitis, Encephalocele, Cerebral Trigeminal Angiomatosis, Encopresis, Enuresis, Epilepsy, Epilepsy with Intellectual Disability in Women, Erb's Palsy, Pure Red Cell Aplasia, Exploding Head Syndrome, Fabry's Disease, Fahr's Syndrome, Syncope, Familial Spastic Paraparesis, Febrile Convulsions, Fisher's Syndrome, Friedreich's Ataxia, Fibromyalgia, Foville's Syndrome, Fetal Alcohol Syndrome group, fragile X syndrome, fragile X-associated tremor / ataxia syndrome (FXTAS), Gaucher disease, generalized epilepsy with febrile seizures, Gerstmann syndrome, giant cell arteritis, giant cell inclusion disease, globoid cell leukodystrophy, heterotopic gray matter, Guillain-Barré syndrome, generalized anxiety disorder, HTLV-1-associated myelopathy, Hallervorden-Spatz disease, head trauma, headache, hemifacial spasm, hereditary spastic paraplegia, hereditary polyneuropathic ataxia, herpes zoster oticus, herpes zoster, Hirayama syndrome, Hirschsprung disease, Holmes-Adie syndrome, holoprosencephaly, Huntington's disease, hydranencephaly, hydrocephalus, hypercortisolism, hypoxia, Immune-mediated encephalomyelitis, inclusion body myositis, incontinentia pigmenti, infantile Refsum disease, infantile spasms, inflammatory myopathy, intracranial cysts, intracranial hypertension, isodicentric 15, Joubert syndrome, Karak syndrome, Kearns-Sayre syndrome, Kinsbourne syndrome, Kleine-Lewin syndrome, Klippel-Feil syndrome, Krabbe disease, Lafora disease, Lambert-Eaton myasthenic syndrome, Landau-Kleffner syndrome, lateral medullary (Wallenberg) syndrome, learning disabilities, Leigh disease, Lennox-Gastaut syndrome, Lesch-Nyhan syndrome, white matter dysplasia leukoencephalopathy with disappearance of white matter, dementia with Lewy bodies, lissencephaly, locked-in syndrome, lumbar discopathy, lumbar spinal canal stenosis, Lyme disease (neurological sequelae), Machado-Joseph disease (spinocerebellar ataxia type 3), macrocephaly, macropsia, disembarkation disease, megalencephaly with subcortical cysts, megalencephaly, Melkersson-Rosenthal syndrome, Meniere's disease, meningitis, Menkes disease, metachromatic leukodystrophy, microcephaly, micropsia, migraine, Miller-Fisher syndrome, mini-infarction (transient ischemic attack), misophonia, mitochondrial myopathy, Moebius syndrome, monolimbic muscular atrophy, luck Motor disability, Moyamoya disease, Mucopolysaccharidosis, Multi-infarct dementia, Multifocal motor neuropathy, Multiple sclerosis, Multiple system atrophy, Muscular dystrophy, Myalgic encephalomyelitis, Myasthenia gravis, Myelin destructive diffuse sclerosis, Myoclonic encephalopathy of childhood, Myoclonus, Myopathy, Myotubular myopathy, Congenital myotonia, Narcolepsy, Neuro-Behçet's disease, Neurofibromatosis, Neuroleptic malignant syndrome, Neurological symptoms of AIDS, Neurological sequelae of lupus, Neuromyotonia, Neuronal ceroid lipofuscinosis, Neuronal migration disorder, Neuropathy, Neurosis, Niemann-Pick disease, Non-24-hour sleep awareness Awakening disorder, non-verbal learning disorder, O'Sullivan-McLeod syndrome, occipital neuralgia, spina bifida occult, Ohtahara syndrome, olivopontocerebellar atrophy, opsoclonus-myoclonus syndrome, optic neuritis, orthostatic hypotension, otosclerosis, overuse syndrome, recurrent vision, paresthesia, Parkinson's disease, congenital paramyotonia, paraneoplastic disease, paroxysmal symptoms, Parry-Romberg syndrome, PANDAS, Pelizaeus-Merzbach disease, periodic paralysis, peripheral neuropathy, pervasive developmental disorder, photophotic sneeze reflex, phytanic acid storage disease, Pick's disease, nerve compression, pituitary tumor, PMG,Polyneuropathy, polio, polymicrogyria, polymyositis, brain cyst, post-polio syndrome, postherpetic neuralgia (PHN), postural hypotension, Prader-Willi syndrome, primary lateral sclerosis, prion disease, progressive hemifacial atrophy, progressive multifocal leukoencephalopathy, progressive supranuclear palsy, prosopagnosia, pseudotumor cerebri, quadriplegia, rabies, radiculopathy, Ramsay Hunt syndrome type I, Ramsay Hunt syndrome type II, Ramsay Hunt syndrome type III, Rasmussen encephalitis, reflex neurovascular dystrophy, Refsum's disease, REM sleep behavior disorder, repetitive stress injury, restless legs syndrome, retrovirus-associated myelopathy, Rett syndrome, Reye's syndrome, rhythmic movement disorder, Romberg syndrome, Saint Vitus chorea, Sandhoff disease, Schilder's disease, schizencephaly, sensory processing disorder, septo-optic dysplasia, shaken baby syndrome, shingles, Shy-Drager syndrome, Sjogren's syndrome, sleep apnea, sleeping sickness, gastric sneeze, Sotos syndrome, spasticity, spina bifida, spinal cord injury, spinal tumor, spinal muscular atrophy, spinal-bulbar muscular atrophy, spinocerebellar degeneration, split encephalopathy, Steele-Richardson-Olszewski syndrome, stiff-body syndrome, stroke, Sturge-Weber syndrome, stuttering, subacute sclerosing panencephalitis, subcortical arteriosclerotic encephalopathy, superficial siderosis, Sydenham's chorea, syncope, synesthesia, syringomyelia, tarsal tunnel syndrome, retardation onset dyskinesia, tardive functional psychosis, Tarlov cyst, Tay-Sachs disease, temporal arteritis, temporal lobe epilepsy, tetanus, tethered spinal cord syndrome, Thomsen's disease, thoracic outlet syndrome, trigeminal neuralgia, Todd's palsy, Tourette's syndrome, toxic encephalopathy, transient ischemic attack, transmissible spongiform encephalopathy, transverse myelitis, traumatic brain injury, tremor, trichotillomania, trigeminal neuralgia, tropical spastic paraplegia, trypanosomiasis, tuberous sclerosis, Unverricht-Lundborg disease, von Hippel-Lindau disease (VHL), Viliuisk encephalomyelitis (VE), Wallenberg syndrome, West syndrome, whiplash injury, Williams syndrome, Wilson's disease, or Zellweger syndrome.

[0132] In another aspect, the present disclosure provides a method for treating or preventing pain in a subject. "Pain" refers to discomfort and / or unpleasant sensations in the body of a subject. Pain sensations can range from mild and occasional to severe and constant. Pain can be classified as acute pain or chronic pain. Pain can be nociceptive pain (i.e., pain caused by tissue damage), neuropathic pain, or psychogenic pain. In some cases, pain is caused or associated with disease (e.g., cancer, arthritis, diabetes). In other cases, pain is caused by injury (e.g., sports injury, trauma). Non-limiting examples of pain amenable to treatment or prevention with the compositions and methods herein include neuropathic pain (including peripheral neuropathy, diabetic neuropathy, post-herpetic neuralgia, trigeminal neuralgia, back pain, neuropathy associated with cancer, neuropathy associated with HIV / AIDS, phantom limb pain, carpal tunnel syndrome, central post-stroke pain), pain associated with chronic alcoholism, hypothyroidism, uremia, pain associated with multiple sclerosis, pain associated with spinal cord injury, Parkinson's disease, pain associated with epilepsy, pain associated with osteoarthritis, pain associated with rheumatoid arthritis, visceral pain, pain associated with vitamin deficiency, and nociceptive pain (including pain associated with central nervous system trauma, strain / sprain, and burn), myocardial infarction, acute pancreatitis, post-operative pain, post-traumatic pain, renal colic, pain associated with cancer, pain associated with fibromyalgia, pain associated with carpal tunnel syndrome, and back pain.

[0133] Illustrative examples of pain amenable to treatment or prevention by the formulations and methods include, but are not limited to, acute pain, chronic pain, neuropathic pain, nociceptive pain, allodynia, inflammatory pain, inflammatory hyperalgesia, neuropathy, neuralgia, diabetic neuropathy, human immunodeficiency virus-associated neuropathy, nerve injury, rheumatoid arthritis pain, osteoarthritis pain, burns, back pain, eye pain, visceral pain, cancer pain (e.g., bone cancer pain), toothache, headache, migraine, carpal tunnel syndrome, fibromyalgia, neuritis, sciatica, pelvic hypersensitivity, pelvic pain, post-herpetic neuralgia, post-operative pain, post-stroke pain, and menstrual pain.

[0134] Pain can be classified as acute or chronic. As used herein, the term "acute pain" refers to pain that begins suddenly and is usually intense in quality. Acute pain may be mild and last only a short time, or it may be severe and last for weeks or months. In most cases, acute pain does not last more than three months and disappears once the underlying cause of the pain is treated or cured. However, if acute pain is not relieved, it can lead to chronic pain. As used herein, the term "chronic pain" refers to ongoing or recurrent pain that lasts beyond the normal course of an acute illness or injury, or that lasts for more than three to six months and adversely affects the health of an individual. In one embodiment, the term "chronic pain" refers to pain that continues when it should not. Chronic pain can be nociceptive pain or neuropathic pain.

[0135] In some embodiments, the formulations and methods may be effective in reducing acute pain, hi some embodiments, the formulations and methods may be effective in reducing chronic pain.

[0136] Clinical pain exists when a patient's symptoms include discomfort and abnormal sensitivity as characteristics. Individuals may present with a variety of pain symptoms. These symptoms may include: 1) spontaneous pain, which may be dull, burning, or stabbing; 2) an exaggerated pain response to noxious stimuli (hyperalgesia); and 3) pain caused by stimuli that are normally innocuous. Pain can also be classified into several different subtypes according to differences in pathophysiology, including nociceptive pain, inflammatory pain, and neuropathic pain.

[0137] In some embodiments, the compositions and methods may be effective in reducing nociceptive pain, in some embodiments, the compositions and methods may be effective in reducing inflammatory pain, in some embodiments, the compositions and methods may be effective in reducing neuropathic pain.

[0138] Nociceptive pain is induced by tissue injury or by strong stimuli that may cause injury. Non-limiting examples of pain include central nervous system trauma, muscle strain / sprain, burn, myocardial infarction, and acute pancreatitis, postoperative pain (pain after any type of surgical procedure), posttraumatic pain, renal colic, cancer pain, and back pain. Cancer pain can be tumor-related pain (e.g., bone pain, headache, facial pain, or visceral pain), or chronic pain such as pain associated with cancer therapy (e.g., post-chemotherapy syndrome, chronic postoperative pain syndrome, or post-radiotherapy syndrome). Cancer pain can also occur in response to chemotherapy, immunotherapy, hormonal therapy, or radiation therapy. Back pain can be due to herniated or ruptured intervertebral disc, or abnormality of lumbar facet joints, sacroiliac joints, paraspinal muscles, or posterior longitudinal ligament.

[0139] Neuropathic pain can be pain initiated or caused by a primary lesion or dysfunction in the nervous system. The etiology of neuropathic pain includes, for example, peripheral neuropathy, diabetic neuropathy, post-herpetic neuralgia, trigeminal neuralgia, back pain, cancer neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel syndrome, central post-stroke pain, pain associated with chronic alcoholism, hypothyroidism, uremia, multiple sclerosis, spinal cord injury, Parkinson's disease, epilepsy, and vitamin deficiency.

[0140] Neuropathic pain may be associated with a pain disorder (a term referring to a disease, disorder, or condition associated with or caused by pain). Illustrative examples of pain disorders include arthritis, allodynia, classic trigeminal neuralgia, trigeminal neuralgia, somatoform disorder, hypoesthesia, hyperalgesia, neuralgia, neuritis, neurogenic pain, analgesia, anesthesia painful, causalgia, sciatic pain disorder, degenerative joint disorders, fibromyalgia, visceral disease, chronic pain disorders, migraine / headache, chronic fatigue syndrome, complex regional pain syndrome, neurodystrophy, plantar fasciitis, or pain associated with cancer.

[0141] The inflammatory process is a complex series of biochemical and cellular events that are activated in response to tissue injury or the presence of foreign substances, resulting in swelling and pain. Joint pain is a common form of inflammatory pain.

[0142] Other types of pain amenable to treatment or prevention by the formulations and methods include, but are not limited to, pain resulting from musculoskeletal disorders (including myalgia, fibromyalgia, spondylitis, seronegative (non-rheumatic) arthropathy, non-rheumatoid arthritis, dystrophinopathy, glycogenolysis, polymyositis, and pyomyositis), cardiac and vascular pain (including pain caused by angina, myocardial infarction, mitral stenosis, pericarditis, Raynaud's phenomenon, scleroderma, and skeletal muscle ischemia), headache (e.g., migraine (including migraine with aura and migraine without aura), cluster headache, mixed tension-type headache, and headache associated with vascular disorders), and orofacial pain (including toothache, earache, burning mouth syndrome, and jaw myofascial pain).

[0143] The effective amount and method of the composition for reducing the amount of pain experienced by a human subject can be determined using various pain scales. Patient self-report can be used to assess whether pain has been reduced. See, for example, Katz and Melzack (1999) Surg. Clin. North Am. 79:231. Alternatively, observational pain scales can be used. The LANSS pain scale can be used to assess whether pain has been reduced. See, for example, Bennett (2001) Pain 92:147. Visual analog pain scales can be used. See, for example, Schmader (2002) Clin. J. Pain 18:350. Likert pain scales can be used (e.g., 0 is no pain, 5 is moderate pain, 10 is the worst pain imaginable). Self-report pain scales for children include the Faces Pain Scale (FPS), Wong-Baker FACES Pain Rating Scale, and Colored Analog Scale (CAS). Self-report pain assessment scales for adults include the Visual Analog Scale (VAS), the Verbal Numerical Rating Scale (VNRS), the Verbal Descriptor Scale (VDS), and the Brief Pain Inventory (BPI). Examples of pain measurement scales include the Alder Hey Triage Pain Score (Stewart et al. Dis. Child. 89:625), Behavioral Pain Scale (BPS) (Payen et al. (2001) Critical Care Medicine 29:2258), Brief Pain Inventory (BPI) (Cleeland and Ryan (1994) Ann. Acad. Med. Singapore 23:129), Checklist of Nonverbal Pain Indicators (CNPI) (Feldt (2000) Pain Manag. Nurse. 1:13), and Critical-Care Pain Observation Tool (CPOT) (Gelinas et al. (2006) Am. J. Crit.Care 15:420), COMFORT scale (Ambuel et al. (1992) J. Pediatric Psychol. 17:95), Dallas Pain Questionnaire (Ozguler et al. (2002) Spine 27:1783), DPI (Dolorimeter Pain Index) (Hardy et al. (1952) Pain Sensations and Reactions Baltimore: The Williams & Wilkins Co.), FPS-R (Faces Pain Scale-Revised) (Hicks et al. (2001) Pain 93:173), FLACC scale (Face Legs Activity Cry Consolability Scale), McGill Pain Questionnaire (Melzack (1975) Pain 1:277), Descriptor Differential Scale (Gracely and Kwilosz (1988) Pain 35:279), Numerical 11 point Box (Jensen et al. (1989) Clin. J. Pain 5:153), NRS (Numeric Rating Scale) (Hartrick et al. (2003) Pain Pract. 3:310), Wong-Baker FACES Pain Rating Scale, and VAS (Visual Analog Scale) (Huskisson (1982) J. Rheumatol. 9:768) are mentioned.

[0144] Administration regimen

[0145] Provided herein are methods of treating or preventing neurological and other disorders, including but not limited to treatment-resistant epilepsy, by administering a therapeutically or prophylactically effective amount of a composition to a subject in need thereof, the methods comprising administering one of the compositions disclosed herein at a dose of about 10 mg to about 120 mg of (i) any one of the compounds of formulas I-VII, (ii) one or more of the compounds of formulas I-VII, or (iii) an ivermectin comprising a compound of formula VI and a compound of formula VII. In some embodiments, the methods of treatment or prevention comprise administering a composition disclosed herein at a dose of about 10 mg to about 80 mg of (i) any one of the compounds of formulas I-VII, (ii) one or more of the compounds of formulas I-VII, or (iii) an ivermectin comprising a compound of formula VI and a compound of formula VII. In some embodiments, the method of treatment or prevention includes administering a composition disclosed herein at a dose of about 10 mg to about 60 mg of (i) a compound of any one of formulas I-VII, (ii) one or more of the compounds of any one of formulas I-VII, or (iii) an ivermectin comprising a compound of formula VI and a compound of formula VII. In some embodiments, the method of treatment or prevention includes administering a composition disclosed herein at a dose of about 20 mg to about 40 mg of (i) a compound of any one of formulas I-VII, (ii) one or more of the compounds of any one of formulas I-VII, or (iii) an ivermectin comprising a compound of formula VI and a compound of formula VII. In some embodiments, the method of treatment or prevention comprises administering a composition disclosed herein at a dose of about 1 mg, about 3 mg, about 5 mg, about 10 mg, about 20 mg, about 40 mg, about 60 mg, about 80 mg, or about 120 mg of (i) a compound of any one of formulas I-VII, (ii) one or more of a compound of any one of formulas I-VII, or (iii) an ivermectin comprising a compound of formula VI and a compound of formula VII. In a preferred embodiment, the composition comprises an ivermectin comprising a compound of formula VI and a compound of formula VII.

[0146] The dosing regimen for therapy can be adjusted to provide the optimum desired response (e.g., therapeutic or prophylactic response). For example, a single dose may be administered, or several divided doses may be administered over time, and the dose may be proportionally reduced or increased depending on the subject's responsiveness to therapy. In some embodiments, the composition is administered twice a day (BD), once a day (QD), once every other day, or once every three days. In some embodiments, the dosing schedule is once a day, twice a day, every other day, or once every three days for about 14 days, about 30 days, about 60 days, about 84 days, about 90 days, or continuously. In some embodiments, the dosing schedule is daily, every other day, 2-4 times a week, 3-5 times a week, weekly, biweekly, monthly, or bimonthly for about 90 days, about 6 months, about 1 year, or continuously. In one embodiment, the dosing schedule is once a day for about 14 days. In one embodiment, the dosing schedule is once daily for about 84 days.

[0147] In various embodiments, the pharmaceutical composition comprises: (i) about 8% ivermectin; and (ii) about 27.6% mono- and di-C8-C glycerol. 10 (iii) about 32.2% polysorbate 80; and (iv) about 32.2% vitamin E TPGS.

[0148] In one embodiment, the pharmaceutical composition comprises: (i) about 8% ivermectin; (ii) about 27.6% Masester E8120; (iii) about 32.2% polysorbate 80; and (iv) about 32.2% Vitamin E TPGS.

[0149] In one embodiment, the pharmaceutical composition comprises: (i) about 8% ivermectin; and (ii) about 27.6% mono- and di-C8-C glycerol. 10 (iii) about 18.4% polysorbate 80; and (iv) about 46% vitamin E TPGS.

[0150] In one embodiment, the pharmaceutical composition comprises: (i) about 8% ivermectin; (ii) about 27.6% Masester E8120; (iii) about 18.4% polysorbate 80; and (iv) about 46% Vitamin E TPGS.

[0151] In one embodiment, the pharmaceutical composition comprises: (i) about 8% ivermectin; and (ii) about 27.6% mono- and di-C8-C glycerol. 10 fatty acid esters; and (iii) about 64.4% polysorbate 80.

[0152] In one embodiment, the pharmaceutical composition comprises: (i) about 8% ivermectin; (ii) about 27.6% Masester E8120; and (iii) about 64.4% polysorbate 80.

[0153] In embodiments, ivermectin comprises a compound of formula VI (22,23-dihydroavermectin B1a) and a compound of formula VII (22,23-dihydroavermectin B1b). In some embodiments, ivermectin comprises at least about 70% 22,23-dihydroavermectin B1a and less than about 30% 22,23-dihydroavermectin B1b. In some embodiments, ivermectin comprises at least about 90% 22,23-dihydroavermectin B1a and less than about 10% 22,23-dihydroavermectin B1b.

[0154] In one embodiment, a pharmaceutical composition comprising (i) about 8% ivermectin, (ii) about 27.6% Masester E8120, (iii) about 32.2% polysorbate 80, and (iv) about 32.2% vitamin E TPGS is administered continuously every day at a dose of about 10 mg to about 120 mg. In one embodiment, a pharmaceutical composition comprising (i) about 8% ivermectin, (ii) about 27.6% Masester E8120, (iii) about 32.2% polysorbate 80, and (iv) about 32.2% vitamin E TPGS is administered continuously every day at a dose of about 10 mg to about 80 mg. In one embodiment, a pharmaceutical composition comprising (i) about 8% ivermectin, (ii) about 27.6% Masester E8120, (iii) about 32.2% polysorbate 80, and (iv) about 32.2% vitamin E TPGS is administered continuously daily at a dose of about 10 mg to 60 mg. In one embodiment, a pharmaceutical composition comprising (i) about 8% ivermectin, (ii) about 27.6% Masester E8120, (iii) about 32.2% polysorbate 80, and (iv) about 32.2% vitamin E TPGS is administered continuously daily at a dose of about 20 mg to 40 mg.

[0155] In one embodiment, a pharmaceutical composition comprising (i) about 8% ivermectin, (ii) about 27.6% Masester E8120, (iii) about 32.2% polysorbate 80, and (iv) about 32.2% vitamin E TPGS is administered daily. In one embodiment, a pharmaceutical composition comprising (i) about 8% ivermectin, (ii) about 27.6% Masester E8120, (iii) about 32.2% polysorbate 80, and (iv) about 32.2% vitamin E TPGS is administered continuously daily. In one embodiment, a pharmaceutical composition comprising (i) about 8% ivermectin, (ii) about 27.6% Masester E8120, (iii) about 32.2% polysorbate 80, and (iv) about 32.2% vitamin E TPGS is administered continuously daily at a dose of about 10 mg. In one embodiment, a pharmaceutical composition comprising (i) about 8% ivermectin, (ii) about 27.6% Masester E8120, (iii) about 32.2% polysorbate 80, and (iv) about 32.2% vitamin E TPGS is administered continuously daily at a dose of about 20 mg. In one embodiment, a pharmaceutical composition comprising (i) about 8% ivermectin, (ii) about 27.6% Masester E8120, (iii) about 32.2% polysorbate 80, and (iv) about 32.2% vitamin E TPGS is administered continuously daily at a dose of about 40 mg. In one embodiment, a pharmaceutical composition comprising (i) about 8% ivermectin, (ii) about 27.6% Masester E8120, (iii) about 32.2% polysorbate 80, and (iv) about 32.2% vitamin E TPGS is administered continuously daily at a dose of about 60 mg. In one embodiment, a pharmaceutical composition comprising (i) about 8% ivermectin, (ii) about 27.6% Masester E8120, (iii) about 32.2% polysorbate 80, and (iv) about 32.2% Vitamin E TPGS is administered continuously daily at a dose of about 80 mg.In one embodiment, a pharmaceutical composition comprising (i) about 8% ivermectin, (ii) about 27.6% Masester E8120, (iii) about 32.2% polysorbate 80, and (iv) about 32.2% Vitamin E TPGS is administered continuously daily at a dose of about 120 mg.

[0156] In one embodiment, the neurological disorder is epilepsy. In some embodiments, the epilepsy is intractable or treatment-resistant epilepsy.

[0157] In embodiments, the method comprises administering to a subject a pharmaceutical composition disclosed herein with one or more adjunctive therapeutic agents, including up to four additional antiepileptic drugs (AEDs), administered simultaneously, sequentially, and in the same or different dosage forms with (i) a compound of any one of Formulas I-VII, (ii) one or more of any one of Formulas I-VII, or (iii) a composition comprising ivermectin, including a compound of Formula VI and a compound of Formula VII. AEDs can include drugs such as lorazepam, cenobamate, brivaracetam, strilipentol, acetazolamide, phenytoin, sodium valproate, buccal midazolam, fervalnate, clobazam, perumpanel, tiagabine, rufinamide, levetiracetam, larnotrigine, pregabalin, primidone, gabapentin, nitrazepam, phenobarbital, clonazepam, vigabatrin, carbamazepine, topiramate, oxcarbazepine, rectal diazepam, lacosamide, ethosuximide, eslicarbazepine acetate, and / or zonisamide. Non-pharmaceutical anti-epileptic therapies can also be administered simultaneously, including implantable devices (e.g., vagus nerve stimulators, responsive neurostimulators, deep brain stimulators). EXAMPLES

[0158] Example 1: Determination of Solubility

[0159] The active pharmaceutical ingredient (API) used in the following examples is ivermectin containing ≥90% 22,23-dihydroavermectin B1a and <10% 22,23-dihydroavermectin B1b. Solubility evaluation was performed by continuously adding known amounts of the API to each individual excipient and allowing the excipients to reach dissolution equilibrium upon saturation of the API (visible solids observed). Experiments were performed at ambient conditions (25°C) and mixed at 500 rpm on a stir plate for at least 72 hours. Samples were subsequently centrifuged and filtered through 0.45 μm PVDF membrane filters (Millipore Durapore) and the filtrates were assayed according to the Ivermectin monograph of the United States Pharmacopeia (USP). The quantitative composition of the placebo vehicle and the corresponding Ivermectin initial solubility results are reported in Table 1. Since the melting point of Vitamin E TPGS (VE TPGS) is 38°C, the solubility test of VE TPGS was carried out on a hot plate at 40°C following the same procedure as above.

[0160] [Table 1]

[0161] Example 2: Excipient compatibility testing

[0162] Based on the equilibrium solubility results, compatibility studies with selected excipients ranging from oils to surfactants were initiated (Table 2). The studies were designed to obtain approximately 5% ivermectin solutions in the selected excipients as per Table 2 (except for excipients with equilibrium solubility less than 5%, i.e., fractionated coconut oil and oleic acid at approximately 1%). After preparing the solutions using a handheld homogenizer (IKAT10 Ultra-Turrax model), each excipient sample was dispensed into amber vials and approximately 10% water was added to each excipient aliquot; bench scale gel stripe OET-004037 was also prepared and added to a separate set of aliquot samples at approximately 1:1 w / w.

[0163] All samples were stored at 40°C / 75% relative humidity (RH) conditions (Model: Lunaire environmental chamber) and tested by developmental reversed-phase HPLC method for assay / related substances at T=0, 2 weeks, and 1 month. The results are summarized in Tables 3 and 4.

[0164] The oil vehicles containing Maisine CC, fractionated coconut oil, and oleic acid showed good chemical compatibility with the drug substance. Among them, Maisine CC had the highest equilibrium solubility, so Maisine CC was selected for further testing as an oil vehicle. Comparing Tween 80, Labrasol ALF, and Vitamin E TPGS, which were classified as surfactants, Vitamin E TPGS showed the highest chemical compatibility with the drug substance and the least increase in impurities over time, followed by Tween 80, which had poor stability over time. Both Vitamin E TPGS and Tween 80 were selected as emulsifiers to be used in formulation development. Due to its high solubility, Masester E8120 was selected for further evaluation as a solubilizer and emulsifier in formulation development. PEG 400 as a co-solvent was not considered in further formulation development due to its insufficient chemical compatibility.

[0165] [Table 2]

[0166] [Table 3]

[0167] [Table 4]

[0168] Example 3: Optical Fiber Dispersion Test

[0169] Fiber optic dispersion in fasted-state simulated intestinal fluid (FaSSIF) and FaSSIF-V2 was performed using a Distec dissolution system 2500 and a PION fiber optic dissolution system to collect real-time dissolution data and data processing. Based on suitability testing, a series of formulations (Table 5) were designed for dispersibility evaluation, with a target of 20 mg / capsule. The FaSSIF medium was selected to mimic the intestinal environment after oral ingestion of ivermectin. The capsules were first dispersed in 500 mL of fasted-state simulated intestinal fluid (pH approx. 6.5) at a paddle speed of 50 rpm (USP <711> Analysis of variance was performed for approximately 6 hours to screen various excipient combinations and compositions in a 350-mL PBS Apparatus II, and the results are plotted in the graph shown in Figure 1.

[0170] FaSSIF-V2 was later used to confirm the dispersibility of formulations 7E and 9E, as they showed higher dispersibility than the other formulations evaluated in the first round of dispersibility testing.

[0171] The kinetic solubility of both 7E and 9E in FaSSIF and FaSSIF-V2 reached 80% release at T = 30 min, suggesting an immediate release profile. No drug precipitation was observed, indicating that both formulations had good dispersibility and could maintain drug substance solubilization when ingested into the gastrointestinal tract, with a low risk of drug substance precipitation. Data processing using Aupro.

[0172] [Table 5-1] [Table 5-2]

[0173] Example 4: Analysis of prototype formulations

[0174] 7E and 9E were selected as prototype formulations and then subjected to kinetic solubility studies, which showed that both formulations had good dispersibility in simulated intestinal fluid. A 12-month informal stability study was conducted in which these two formulations were subjected to a Lunaire environmental chamber at 40°C / 75% RH, and 5% water and gel stripes (OET-004037) were added to separate vials to mimic the softgel moisture migration and the effect of gel on the formulation in a softgel dosage form, respectively. Formulation control samples (without water and gel stripes) were stored in 8 oz amber Boston round bottles to mimic the initial preliminary intended packaging in human clinical trials (SAD / MAD studies). All other samples were stored in amber glass vials. The assay / RS results are summarized in Tables 6 and 7 (analysis by advanced HPLC method).

[0175] No precipitation or phase separation was observed in any sample vial at 40°C / 75% RH, T=0-1 month. A small amount of slurry was observed in the water-added sample at T=3 months in 7E. This indicates slight drug substance precipitation with 5% water addition, possibly due to polymorphic changes in the drug substance. However, the water-added sample is a simulation and does not represent true softgel water migration. The slight precipitation in this sample is not conclusive and is considered minor from the perspective of formulation stability.

[0176] [Table 6]

[0177] [Table 7]

[0178] Example 5: Freeze-thaw test

[0179] Prototype formulations 7E and 9E were subjected to freeze-thaw testing for physical and chemical stability at -15°C to 40°C in a 24-hour cycle for 7 days in a ClimaCell environmental test chamber. No precipitation or phase separation was observed from the two sample vials on the 7th day. The chemical stability (assay) is summarized in Table 8. It can be concluded that both formulations are stable under extreme temperature fluctuation stress.

[0180] [Table 8]

[0181] Example 6: Pharmacokinetic profile of ivermectin B1a after intravenous and oral administration in Sprague-Dawley rats

[0182] Thirty-six male Sprague-Dawley rats were randomly assigned to four groups, with nine male rats in each group. All animals in the groups were fasted overnight prior to the experimental day.

[0183] Group 1 rats were administered intravenously ivermectin drug substance dissolved in DMSO, Solutol, and saline (n=9). Group 2 rats were administered 2 mg / kg Stromectol by gavage, crushed and dissolved in water (n=9). Stromectol is formulated by the manufacturer as a tablet containing 3 mg ivermectin with at least 90% 22,23-dihydroavermectin B1a and less than 10% 22,23-dihydroavermectin B1b. Group 3 rats were administered 2 mg / kg Ivomec by gavage in water (n=9). Ivomec is formulated by the manufacturer as a 1% ivermectin solution. Group 4 rats were administered 2 mg / kg prototype formulation 7E ("7E") by gavage in water (n=9).

[0184] Blood samples were collected from 6 of 9 animals in each group at 0.5, 1, 2, 3, 4, 6, 8, 24, 72, 120, and 168 hours after dosing. The collected plasma samples were analyzed for ivermectin B1a concentrations using a validated LC-MS / MS method. Pharmacokinetic parameters were calculated from the ivermectin B1a concentration data in the plasma samples using a noncompartmental model in Phoenix WinNonlin 7.0 software.

[0185] The remaining three of nine rats in each group were sacrificed 4 hours after administration of the test drug. Blood samples were collected from the jugular vein or other suitable vein. The brains were removed, rinsed with saline, dried on filter paper, and immediately weighed. The brain samples were homogenized and analyzed for ivermectin B1a concentration by LC-MS / MS method according to FDA guidelines. The ratio of brain samples and plasma samples was calculated to obtain the BBB penetration percentage.

[0186] result

[0187] The main pharmacokinetic parameters of ivermectin B1a in SD rat plasma after single doses of ivermectin drug substance, Stromectol, Ivomec, and 7E are summarized in Table 9 and Figures 2 to 5.

[0188] [Table 9]

[0189] Group 1: AUC of ivermectin B1a in plasma after a single intravenous injection of 2 mg / kg ivermectin drug substance in fasted male SD rats. (0-t) is 8259.31±1032.95hr*ng / ml, T 1 / 2 was 14.82±0.72hr.

[0190] Group 2: AUC of ivermectin B1a in plasma after a single oral dose of 2 mg / kg Stromectol in fasted male SD rats. (0-t) was 4220.94±1594.22hr*ng / ml, T 1 / 2was 12.85±2.16hr.

[0191] Group 3: AUC of Ivomec B1a in plasma after a single oral dose of 2 mg / kg Ivomec in fasted male SD rats. (0-t) 3396.36±353.94hr*ng / ml, T 1 / 2 was 18.49±1.89hr.

[0192] Group 4: AUC of ivermectin B1a in plasma after a single oral dose of 2 mg / kg 7E in fasted male SD rats (0-t) was 4677.49±920.69hr*ng / ml, T 1 / 2 was 17.15±13.14hr.

[0193] The ratio of ivermectin B1a concentrations in the brain to those in the plasma was calculated and is summarized in Table 10.

[0194] [Table 10]

[0195] Group 1: After a single intravenous injection of 2 mg / kg ivermectin drug substance in fasted male SD rats, the ratio of ivermectin B1a concentration in the brain to that in the plasma was 0.171 ± 0.010.

[0196] Group 2: After a single oral dose of 2 mg / kg Stromectol was administered to fasted male SD rats, the ratio of ivermectin B1a concentration in the brain to that in the plasma was 0.046 ± 0.006.

[0197] Group 3: After a single oral dose of 2 mg / kg Ivomec was administered to fasted male SD rats, the ratio of ivermectin B1a concentration in the brain to that in the plasma was 0.033 ± 0.008.

[0198] Group 4: After a single oral dose of 2 mg / kg 7E was administered to fasted male SD rats, the ratio of ivermectin B1a concentration in the brain to that in the plasma was 0.043 ± 0.005.

[0199] conclusion

[0200] After a single oral administration of 2 mg / kg of Stromectol and 7E under fasting conditions, max (Stromectol vs 7E 1:1.10) and AUC 0-t No significant difference was observed (Stromectol vs 7E 1:1.11).

[0201]

[0202] Example 7: Modulation of pentylenetetrazole (PTZ)-induced seizures in rats by solutions of formulation 7E To quantify the modulation of pentylenetetrazole (PTZ)-induced seizure brain activity by chronic administration of test compound (TC), functional MRI (fMRI) was performed in anesthetized male Wistar rats using a high-field preclinical MRI system. Vehicle and 3 mg / kg alprazolam-treated animals served as controls. A schematic diagram of the study design is shown in Figure 6. TC was either 2 mg / kg or 4 mg / kg of formulation 7E solution. Various physiological parameters were also measured throughout the experiment, including body weight, CO2 concentration, blood pH, and heart rate.

[0203] result

[0204] The area under the curve for each brain region and treatment was calculated, as shown in Figure 7. In each brain region, both the 2 mg / kg and 4 mg / kg doses of ivermectin solution with formulation 7E showed a significant reduction in (PTZ)-induced seizure brain activity compared to the control (vehicle).

[0205] conclusion

[0206] Physiological parameters measured by arterial blood sampling and pulse oximetry indicated that subjects had good cardiovascular and respiratory stability throughout the functional imaging experiments.A positive control compound (alprazolam, 3 mg / kg) effectively canceled PTZ-induced brain activity in all brain regions tested, with high statistical significance.

[0207] Both doses of formulation 7E solution significantly modulated PTZ-induced BOLD signal changes and shortened or attenuated activity duration in several brain regions (striatum, hippocampus, VTA, cortical regions) in a dose-dependent manner. The higher dose of IVM 4 mg / kg induced significant modulation and attenuated PTZ responses in all tested brain regions.

[0208] Example 8: Phase 1 Patient Administration Study

[0209] A phase 1, double-blind, placebo-controlled, randomized (3:1), dose-ranging study was conducted in healthy subjects to evaluate the safety, tolerability, PK, and high-fat meal effects of formulation 7E and its impact on quality of life. The single ascending dose (SAD) portion of the study was followed by multiple ascending dose (MAD) cohorts receiving 10, 20, 40, 80, and 120 mg of the 7E formulation once daily for 14 days. The study population was healthy individuals aged 18-65 years.

[0210] SAD portion of the exam

[0211] Participants were admitted to the Clinical Trials Center the day before dosing for baseline evaluations. The baseline evaluations included eligibility screening, physical examination, neurological examination, laboratory tests, EKG, and pupillometry. Subjects received a single dose of study drug according to a fasting dosing protocol, followed by continuous PK, vital signs, and safety assessments over 120 hours, including pupillometry and neurological examination. In addition, PK samples were collected at the following time points: pre-dose (within 2 hours prior to dosing), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48, 72, and 120 hours post-dose. Because ivermectin toxicity occurs within 24 hours of dosing, each subsequent SAD cohort (see Table 11) was initiated 72 hours after dosing the last subject in the previous cohort, as long as fewer than two participants experienced dose-limiting toxicity (DLT) within that cohort. Participants in the 40 mg cohort of the SAD portion of the study were not discharged on day 6, but instead continued in the fed substudy, in which fed dosing was combined with a high-fat meal 10 days after fasted dosing. Assessments after fed dosing were the same as those after fasted SAD dosing and continued through 120 hours.

[0212] For exploratory biomarker studies, two vials of whole blood samples for PD measurements were collected pre-dose and 24 hours after a single dose.

[0213] MAD portion of the study (14-day study, once-daily dosing)

[0214] Each MAD cohort, 10 mg to 80 mg (see Table 11), was started the day after the SAD cohort at that dose completed dosing and was monitored for 72 hours, provided that the discontinuation criteria had not been met in the SAD study or in the lower dose MAD cohort. If the discontinuation criteria were still not met, the last subject in the 80 mg cohort was dosed through day 5 before starting the 120 mg MAD cohort (as steady state was estimated to occur in around 4 days).

[0215] Volunteers underwent screening and baseline assessments as described above for the SAD portion of the study. Subjects received study drug once daily for 14 days following a fasting dosing protocol on days 1, 2, and 14. Safety assessments including vital signs and pupillometry and neurological examinations were performed after dosing on days 1, 7, and 14. These and additional safety assessments were also performed on day 19. PK samples were collected post-dose on days 1 and 14, pre-dose (within 2 hours pre-dose), and 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48, 72, and 120 hours (pre-dose) after the first day 1 dose. Blood for PK was also collected pre-dose on days 5, 7, 8, 9, 10, 12, and 14. If two participants within a cohort experienced a DLT, that cohort was discontinued and any overlapping cohorts at higher doses were also discontinued.

[0216] For exploratory biomarker studies, two vials of whole blood samples for PD measurements were collected pre-dose and on day 15 (24 hours after the subject's last dose of study drug in the MAD study).

[0217] [Table 11]

[0218] Example 9: Phase 2 Patient Administration Study (Daily, 12 Weeks)

[0219] A double-blind, placebo-controlled, randomized (4:1) Phase II safety and dose-finding study of adjunctive composition 7E will be conducted to evaluate the preliminary efficacy of formulation 7E in reducing overall seizures, reducing seizures by seizure type (focal, generalized, and unknown), reducing generalized tonic-clonic and focal-generalized tonic-clonic seizures, seizure freedom over time, tolerability, and impact on suicidality. The population will include subjects aged 18-70 years with a diagnosis of epilepsy according to the International League Against Epilepsy (ILAE) Classification of Epilepsy 2017 criteria (ILAE 2017) and uncontrolled on optimally stable doses of 1-4 concomitant antiepileptic drugs (AEDs) for at least 4 weeks prior to screening and throughout the treatment period.

[0220] Cohorts (see Table 12) will be dosed sequentially starting with dosing cohort 1. The study will initially randomize a total of 10 subjects to the first dosing cohort (10 mg daily, 4:1 active:placebo) for 12 weeks. After 14 days, safety data will be reviewed to determine whether the next cohort can be initiated. After each cohort, dosing will continue with a continuous reassessment procedure (CRM) under the oversight of a safety review committee (SRC) until 10 subjects have completed 14 days of dosing at 60 mg once daily or until a total of 10 subjects have been administered the same active dose for 14 days and this dose has been identified as the MTD. In each dosing cohort, subjects without DLTs during the first 14 days of treatment will continue treatment for up to 12 weeks unless they experience a DLT, meet discontinuation criteria, or decide to withdraw from treatment.

[0221] PK parameters, as well as safety, efficacy, and concomitant antiepileptic drug (AED) assessments will be performed by an unblinded study statistician at 2, 4, 8, and 12 weeks of treatment and provided for review by sponsor-designated investigators. This review will be performed separately from any dose escalation studies based on DLT development.

[0222] [Table 12]

Claims

1. 1. A pharmaceutical composition comprising: (i) about 1% to about 15% ivermectin, including a compound of formula VI and a compound of formula VII; 【Chemistry 1】 (ii) about 20% to about 40% of a first surfactant comprising one or more of the following: (a) mono-, di-, and / or tri-fatty acid esters of glycerol; (b) mono- and / or di-fatty acid esters of 1,2-propylene glycol; and (c) mono- and / or di-fatty acid esters of polyethylene glycol, the fatty acids being C ６ ~C １０ fatty acids); (iii) about 15% to about 70% of a second surfactant selected from one or more of a polysorbate surfactant and / or a fatty acid ester of sorbitan.

2. 2. The pharmaceutical composition of claim 1, wherein the ivermectin comprises at least about 70% of the compound of formula VI and less than about 30% of the compound of formula VII.

3. 3. The pharmaceutical composition of claim 2, wherein the ivermectin comprises at least about 90% of the compound of formula VI and less than about 10% of the compound of formula VII.

4. 10. The pharmaceutical composition of any one of the preceding claims, wherein the pharmaceutical composition comprises from about 3% to about 12% ivermectin.

5. The fatty acid of the first surfactant is ８ ~C １０ The pharmaceutical composition according to any one of claims 1 to 4, wherein the fatty acid is selected from the group consisting of phenylalanine, ...

6. 6. The pharmaceutical composition of claim 5, wherein the first surfactant comprises mono- and di-fatty acid esters of glycerol.

7. 7. The pharmaceutical composition of any one of claims 1 to 6, wherein the first surfactant is selected from Masester M8120, Capryol 90, Labrasol ALF, and combinations thereof.

8. 8. The pharmaceutical composition of any one of claims 1 to 7, wherein the second surfactant is selected from polysorbate 80 (Tween 80), sorbitan monolaurate (Span 20), and combinations thereof.

9. The pharmaceutical composition of any one of claims 1 to 8, comprising about 25% to about 30% of the first surfactant.

10. 10. The pharmaceutical composition of any one of claims 1 to 9, comprising about 15% to about 20% of said second surfactant.

11. The pharmaceutical composition of any one of claims 1 to 10, comprising about 30% to about 35% of said second surfactant.

12. 10. The pharmaceutical composition of any one of claims 1 to 9, comprising about 60% to about 65% of said second surfactant.

13. 12. The pharmaceutical composition of any one of claims 1 to 11, further comprising about 5% to about 55% Vitamin E TPGS, or about 30% to about 50% Vitamin E TPGS.

14. (i) about 5% to about 10% ivermectin, and (ii) about 25% to about 30% mono- and di-C of glycerol. ８ ~C １０ 5. The pharmaceutical composition of claim 1, comprising: a fatty acid ester; (iii) about 15% to about 30% of a polysorbate surfactant; and (iv) about 30% to about 50% of Vitamin E TPGS.

15. (i) about 8% ivermectin, and (ii) about 27.6% mono- and di-C glycerol. ８ ~C １０ 5. The pharmaceutical composition of claim 1, comprising: a fatty acid ester; (iii) about 32.2% polysorbate 80; and (iv) about 32.2% Vitamin E TPGS.

16. 5. The pharmaceutical composition of any one of claims 1 to 4, comprising: (i) about 8% ivermectin; (ii) about 27.6% Masester E8120; (iii) about 32.2% Polysorbate 80; and (iv) about 32.2% Vitamin E TPGS.

17. (i) about 8% ivermectin, and (ii) about 27.6% mono- and di-C glycerol. ８ ~C １０ 5. The pharmaceutical composition of claim 1, comprising: a fatty acid ester; (iii) about 18.4% polysorbate 80; and (iv) about 46% Vitamin E TPGS.

18. 5. The pharmaceutical composition of any one of claims 1 to 4, comprising: (i) about 8% ivermectin; (ii) about 27.6% Masester E8120; (iii) about 18.4% Polysorbate 80; and (iv) about 46% Vitamin E TPGS.

19. A pharmaceutical dosage form comprising the composition of any one of claims 1 to 18 within a gelatin capsule.

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