Liquid formulations of ivermectin compositions and use in gelatin dosage forms

Abstract

Disclosed herein are formulations and dosage forms of abamectin drugs, and in particular ivermectin. The disclosed compositions can be used in methods for treating and preventing various neurological and other conditions in a human.

Description

Technical Field

[0001] The present disclosure provides compositions and dosage forms of avermectins, and in particular ivermectin. The compositions can be used for the treatment and prevention of various neurological disorders and other disorders. Background Art

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

[0003] Ivermectin, a member of the avermectin family, is a highly effective antiparasitic agent. Ivermectin is a mixture of 5-O-desmethyl-22,23-dihydroavermectin A1a (also known as 22,23-dihydroavermectin B1a) and 5-O-desmethyl-25-des(1-methylpropyl)-22,23-dihydro-25-(1-methylethyl)avermectin A1a (also known as 22,23-dihydroavermectin B1b). Ivermectin has historically been used as a broad-spectrum antiparasitic drug for human and veterinary use.

[0004] Ivermectin is commercially available from Merial as Cardomec (for felines), Eqvalane (for equines), and Ivomec (for bovines); and from Famam Companies, Inc. as Zimecterin (for equines) for animal use. In veterinary use, the drug is available in tablets and chewable tablets for heartworm prevention, topical solutions for ear mite treatment, and injectable solutions, oral pastes, or solutions for other parasites. Ivermectin is also available for human use for the treatment of parasitic infestations. For example, Stromectol, which contains 3 mg of ivermectin per tablet and is sold by Merck & Co., is approved by the US Food and Drug Administration for the treatment of onchocerciasis (river blindness) and strongyloidiasis (non-disseminated intestinal threadworm). Ivermectin can exert its antiparasitic activity via the activation of chloride-gated glutamate channels present in the nervous system of invertebrates. Binding to chloride-gated glutamate channels can lead to hyperpolarization of nerve and muscle fibers. Such hyperpolarization can lead to paralysis and death of the organism (parasite). Chloride-gated glutamate channels are specific to invertebrates and are not expressed in mammalian hosts, allowing ivermectin to exert a specific effect against parasites.

[0005] Currently used drugs for neurological disorders characterized by epilepsy or movement disorders exhibit significant side effects, such as behavioral changes, drowsiness, insomnia, clinical depression, psychotic behavior, respiratory depression, coma and death, especially when taken in excessive doses or for long periods of time. Therefore, there is an urgent need to develop alternative drugs that can be used to treat or prevent such neurological disorders and other disorders, which drugs cause little or no adverse health risks. Summary of the invention

[0006] The present disclosure provides a pharmaceutical composition, comprising:

[0007] (i) about 1% to about 15% ivermectin, wherein the ivermectin comprises a compound of Formula VI (22,23-dihydroavermectin B1a) and a compound of Formula VII (22,23-dihydroavermectin B1b);

[0008] (ii) from about 20% to about 40% of a first surfactant, the first surfactant comprising one or more of:

[0009] (a) mono-, di- and / or tri-fatty acid esters of glycerol;

[0010] (b) mono- and / or di-fatty acid esters of 1,2-propylene glycol; and

[0011] (c) mono- and / or di-fatty acid esters of polyethylene glycol, wherein the fatty acid is selected from C 6 To C 10 fatty acids; and

[0012] (iii) from about 15% to about 70% of a second surfactant selected from one or more polysorbate surfactants and / or fatty acid esters of sorbitan.

[0013] In some embodiments, the pharmaceutical composition comprises ivermectin comprising 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 comprising at least about 90% 22,23-dihydroavermectin B1a and less than about 10% 22,23-dihydroavermectin B1b.

[0014] In embodiments, the pharmaceutical composition comprises about 3% to about 12% of a compound of any one of formula I-VII. In some embodiments, the pharmaceutical composition comprises about 5% to about 10% of a compound of any one of formula 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 formula I-VII.

[0015] In some embodiments, the pharmaceutical composition comprises about 3% to about 12% of one or more compounds of Formula I-VII. In some embodiments, the pharmaceutical composition comprises about 5% to about 10% of one or more Formula 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 Formula I-VII.

[0016] In some embodiments, the pharmaceutical composition comprises about 3% to about 12% of ivermectin comprising a compound of Formula VI and a compound of Formula VII. In some embodiments, the pharmaceutical composition comprises about 5% to about 10% of ivermectin comprising a compound of Formula VI and a 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% of ivermectin comprising a compound of Formula VI and a compound of Formula VII.

[0017] In an embodiment, the pharmaceutical composition comprises a first surfactant wherein the fatty acid is selected from C 8 To C 10 Fatty acids. In some embodiments, the first surfactant comprises 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.

[0018] 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.

[0019] In some embodiments, the pharmaceutical composition comprises about 5% to about 55% D-alpha-tocopheryl 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.

[0020] In an embodiment, the pharmaceutical composition comprises: (i) about 5% to about 10% ivermectin; (ii) about 25% to about 30% mono- and di-C glycerol; 8 To C 10 fatty acid ester; (iii) from about 15% to about 30% of a polysorbate surfactant; and (iv) from about 30% to about 50% Vitamin E TPGS.

[0021] In one embodiment, the pharmaceutical composition comprises: (i) about 8% ivermectin; (ii) about 27.6% mono- and di-C glycerol; 8 To C 10 fatty acid esters; (iii) about 32.2% polysorbate 80; and (iv) about 32.2% Vitamin E TPGS.

[0022] 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.

[0023] In one embodiment, the pharmaceutical composition comprises: (i) about 8% ivermectin; (ii) about 27.6% mono- and di-C glycerol;8 To C 10 fatty acid esters; (iii) about 18.4% polysorbate 80; and (iv) about 46% Vitamin E TPGS.

[0024] 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.

[0025] In one embodiment, the pharmaceutical composition comprises: (i) about 8% ivermectin; (ii) about 27.6% mono- and di-C glycerol; 8 To C 10 fatty acid esters; and (iii) about 64.4% polysorbate 80.

[0026] 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

[0027] Figure 1 . Graph showing fiber dispersion of prototype ivermectin formulations in FaSSIF (1E-7E).

[0028] Figure 2 .The average concentration-time curve of ivermectin B1a in the plasma of SD rats after a single fasting intravenous injection of 2 mg / kg ivermectin API.

[0029] Figure 3 Mean concentration-time curve of ivermectin B1a in plasma of SD rats after single oral administration of 2 mg / kg Stromectol on an empty stomach.

[0030] Figure 4 Mean concentration-time curve of ivermectin B1a in plasma of SD rats after single oral administration of 2 mg / kg Ivomec on an empty stomach.

[0031] Figure 5 Mean concentration-time curve of ivermectin B1a in plasma of SD rats after single oral administration of 2 mg / kg formulation 7E on an empty stomach.

[0032] Figure 6 . Schematic diagram showing a study evaluating the modulation of pentylenetetrazol (PTZ)-induced seizures in rats by a liquid solution of Formulation 7E.

[0033] Figure 7.Area under the curve values ​​for BOLD fMRI time series from selected brain regions. Data are expressed as mean + SEM, n = 12 per group. From left to right: (1) Vehicle + PTZ, (2) IVM liquid solution, 2 mg / kg + PTZ, (3) IVM liquid 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 = Cortex Cingulate; MotCtx = Motor Cortex; RSCtx = Retrosplenial Cortex; SSCtx = Somatosensory Cortex; TAssocCtx = Temporal Association Cortex; HipAD = Hippocampus Antero Dorsal; Pons; ThalDL = Dorsolateral Thalamus; ThalVM = Ventromedial Thalamus; VTA = Ventral Tegmental Area; nAcbSh = Nucleus Accumbens Shell; Amygdala; CPu = Caudate Putamen; and mPFC = medial prefrontal cortex. DETAILED DESCRIPTION

[0034] The present disclosure provides pharmaceutical compositions and dosage forms of avermectins, and in particular ivermectin. The compositions of avermectins (also interchangeably referred to herein as preparations) are liquid or semisolid at room temperature and comprise avermectin (and in particular ivermectin), a first surfactant and a second surfactant. The compositions can be used to treat and prevent neurological disorders and other disorders.

[0035] Avermectins and ivermectin

[0036] Any avermectin compound (including derivatives and analogs disclosed herein) can be used in the compositions and methods provided by the present disclosure. Avermectins include a family of four closely related major components A1a, A2a, B1a and B2a, and four minor components A1b, A2b, B1b, B2b, which are lower homologs of the corresponding major components. Eight different avermectins were isolated from four pairs of homologous compounds, wherein the ratio of the major component to the minor component is generally 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 / miticidal activity with varying degrees of efficacy.

[0037] Provided herein are compositions comprising from about 1% to about 15% of an avermectin compound, wherein the avermectin compound may be according to Formula I:

[0038]

[0039] A macrocyclic compound or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate or isotope-labeled compound thereof; wherein:

[0040] Each occurrence of X is independently selected from -CH 2 -, -NH-, -O-, -S-, -SO- and -SO 2 -;

[0041] Y is selected from -CH 2 -, -O-, -NH-, and -S-;

[0042] Z is selected from O and S;

[0043] Each occurrence is either a single bond or a double bond;

[0044] n is an integer from 0 to 6; and

[0045] R 1 Each occurrence is independently selected from halogen, -R, -OR, -NO 2 、-NCS、-CN、-CF 3 、-OCF 3 、-NHR、-N(R) 2 , -OC(O)R, -C(O)OR, -SR, -C(O)R, -C(O)C(O)R, -C(O)CH 2C(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)R, -C(=NOR)R, -OP(O)(OR) 2 、-P(O)(R) 2 、-P(O)(OR) 2 、-P(O)(H)(OR)、-CH 2 -OR and -CH 2 -O-CH 2 -R;

[0046] R 2 Each occurrence is independently selected from H, OH, OC 1-4 Alkyl, -OC(O)C 1-4 Alkyl, -OC(O)NH 2 and -OC(O)NHC 1-4 alkyl;

[0047] R 3 Each occurrence is a mono-, di-, or tri-glycoside, or OC(O)-(C 3 -C 5 )alkenyl;

[0048] Each R is independently selected from H, -(C 1 -C 12 )alkyl, -(C 3 -C 10 )-cycloalkyl, (C 3 -C 10 )-cycloalkenyl, -[(C 3 -C 10 )cycloalkyl]-(C 1 -C 12 )alkyl, -[(C 3 -C 10 )cycloalkenyl]-(C 1 -C 12 )alkyl, -[(C 3 -C 10 )cycloalkenyl]-(C1 -C 12 )alkyl, -[(C 3 -C 10 )cycloalkyl]-O-(C 1 -C 12 )alkyl, -[(C 3 -C 10 )cycloalkenyl]-O-(C 1 -C 12 )alkyl, -(C 6 -C 10 ) aryl, (C 6 -C 10 )Aryl-(C 1 -C 12 )alkyl, -(C 6 -C 10 )Aryl-O-(C 1 -C 12 ) alkyl, (C 6 -C 10 )aryl-N(R")-(C 1 -C 12 )alkyl, 3- to 10-membered heterocyclic group, (3- to 10-membered heterocyclic group)-(C 1 -C 12 )alkyl, (3 to 10 membered heterocyclic)-O-(C 1 -C 12 )alkyl, (3 to 10 membered heterocyclyl)-N(R")-(C 1 -C 12 )alkyl, 5- to 10-membered heteroaryl, (5- to 10-membered heteroaryl)-(C 1 -C 12 )-alkyl, (5- to 10-membered heteroaryl)-O-(C 1 -C 12 )-alkyl and (5- to 10-membered heteroaryl)-N(R")-(C 1 -C 12 )-alkyl;

[0049] Each heterocyclic group has 1 to 4 atoms independently selected from N, NH, O, S, SO and SO 2 heteroatoms, and

[0050] The heteroaryl group has 1-4 heteroatoms independently selected from N, NH, O and S;

[0051] Each occurrence of R is independently unsubstituted or substituted with 1 to 5 R';

[0052] R' is halo, OH, oxo, -CH 2 OR”, -CH2N(R”) 2、C(O)N(R”) 2 、-C(O)OR”、-NO 2 、NCS、CN、CF 3 、OCF 3 and-N(R") 2 ;and

[0053] Each time "R" appears, it is independently H, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, and (C 6 -C 10 )-aryl.

[0054] In some embodiments, the compound of Formula I is Formula II:

[0055]

[0056] or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate or isotope-labeled compound thereof, wherein n, R 1 , R 2 and R 3 Each is as defined in Formula I.

[0057] In some embodiments, the compound of Formula II is Formula III:

[0058]

[0059] or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate or isotope-labeled compound thereof, wherein R 1 , R 2 and R 3 Each is as defined in Formula I.

[0060] In some embodiments, the compound of formula III is formula IV:

[0061]

[0062] A compound or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate or isotope-labeled compound thereof, wherein:

[0063] R 1 Each occurrence is independently selected from halogen, -R, -OR, -NO 2 、-NCS、-CN、-CF 3 、-OCF 3 、-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 、-CH 2 -OR and -CH 2 -O-CH 2 -R;

[0064] R 3 Each occurrence is a mono-, di-, or tri-glycoside, or OC(O)-(C 3 -C 5 )alkenyl;

[0065] R, R' and R" are each as defined in Formula I.

[0066] In some embodiments, the compound of Formula IV is of Formula V:

[0067]

[0068] or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate or isotope-labeled compound thereof, wherein

[0069] R 1 Each occurrence is independently selected from halogen, -R, -OR, -NO 2 、-NCS、-CN、-CF 3 、-OCF 3 、-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 、-CH 2 -OR and -CH 2 -O-CH 2 -R:

[0070] R, R' and R" are each as defined in Formula I.

[0071] In an embodiment, the macrocyclic compound is an avermectin compound or a derivative thereof, a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or isotope-labeled compound. In one embodiment, the macrocyclic compound is avermectin. In some embodiments, the macrocyclic compound is selected from the group consisting of ivermectin, selamectin, doramectin, erinostatin, moxidectin, avermectin, and abatin. In some embodiments, the macrocyclic compound is ivermectin or a derivative thereof, a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or isotope-labeled compound.

[0072] Provided herein are compositions comprising about 1% to about 15% of a compound of any one of formulas I-VII. In some embodiments, the composition comprises about 1% to about 15% of one or more compounds of any one of formulas I-VII. In some embodiments, the composition comprises about 1% to about 15% of ivermectin, comprising 22,23-dihydroavermectin B1a (Formula VI) and 22,23-dihydroavermectin B1b (Formula VII). In some embodiments, the composition comprises ivermectin, comprising 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:

[0073]

[0074] Formula VI: 22,23-dihydroavermectin B1a, CAS No. 71827-03-7

[0075]

[0076] Formula VII: 22,23-dihydroavermectin B1b, CAS No. 70209-81-3

[0077] In some embodiments, the composition comprises ivermectin comprising 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. In some embodiments, the ivermectin comprises at least about 70% of 22,23-dihydroavermectin B1a and less than about 30% of 22,23-dihydroavermectin B1b. In some embodiments, the ivermectin comprises at least about 90% of 22,23-dihydroavermectin B1a and less than about 10% of 22,23-dihydroavermectin B1b.

[0078] Derivatives of ivermectin (including abatin and doramectin) and prodrugs of ivermectin may have properties and uses similar to ivermectin. Abatin and doramectin both have double bonds at positions C22-C23 in the ivermectin structural formula. In addition, in doramectin, position C25 at the side chain of the cyclohexyl ring is substituted.

[0079]

[0080] Abatin, CAS No. 71751-41-2

[0081]

[0082] Doramectin, CAS No. 117704-25-3

[0083] As used herein, "derivative" refers to a compound that retains the biological activity of the parent avermectin from which it is derived, or is a prodrug of the parent avermectin. Derivatives may include esters, amides, ethers, etc. derived from avermectin.

[0084] As used herein, the term "alkyl" refers to a straight or branched hydrocarbon chain containing the specified number of carbon atoms. 1-6 Indicates that there are 1 to 6 (inclusive) carbon atoms in the group. In the absence of any numerical designation, "alkyl" is a chain (straight or branched) having 1 to 20 (inclusive) carbon atoms therein. The term "unsaturated alkyl" refers to a hydrocarbon that does not have an unsaturated bond (e.g., a carbon-carbon double bond or a carbon-carbon triple bond). The term "unsaturated alkyl" refers to a hydrocarbon that has one or more unsaturated bonds (e.g., a carbon-carbon double bond or a carbon-carbon triple bond).

[0085] As used herein, the term "alkenyl" refers to a straight or branched hydrocarbon chain having one or more carbon-carbon double bonds. The alkenyl moiety contains the specified number of carbon atoms. For example, C 2-6 Indicates that the group has 2 to 6 (inclusive) carbon atoms in it. In the absence of any numerical designation, "alkenyl" is a chain (straight or branched) having 2 to 20 (inclusive) carbon atoms in it.

[0086] As used herein, the term "cycloalkyl" includes saturated and partially unsaturated cyclic hydrocarbon groups. Unless otherwise indicated, cycloalkyl has 3 to 12 carbons, or 3 to 8 carbons, or 3 to 6 carbons, wherein the cycloalkyl group is optionally substituted in addition. Some cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl and cyclooctyl.

[0087] As used herein, the term "aryl" refers to a monocyclic or bicyclic aromatic ring system of 6 to 10 carbons, wherein 0, 1, 2, 3 or 4 atoms of each ring are substituted with substituents. Examples of aryl groups include phenyl, naphthyl, etc.

[0088] As used herein, the term "heterocyclyl group" or "heterocyclyl" refers to aromatic and non-aromatic ring compounds containing 3 or more ring members, one or more of which are heteroatoms such as, but not limited to, N, O, and S. The heterocyclyl group may be a cycloheteroalkyl or heteroaryl group, or if polycyclic, any combination thereof. The heterocyclyl group may contain 3 to about 20 ring members, while other such groups may contain 3 to about 15 ring members. Designated as C 2 The heterocyclyl group of -heterocyclyl can be a 5-membered ring having two carbon atoms and three heteroatoms, a 6-membered ring having two carbon atoms and four heteroatoms, etc. 4 -Heterocyclyl can be a 5-membered ring with one heteroatom, a 6-membered ring with two heteroatoms, etc. The number of carbon atoms and the number of heteroatoms add up to the total number of ring atoms. The heterocyclyl ring may also contain one or more double bonds. Heteroaryl ring is an 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 system, if it is a monocyclic ring, there are 1-3 heteroatoms, if it is a bicyclic ring, there are 1-6 heteroatoms, or if it is a tricyclic ring, there are 1-9 heteroatoms, the heteroatoms are selected from O, N or S (for example, if it is a monocyclic, bicyclic or tricyclic ring, there are carbon atoms and 1-3, 1-6 or 1-9 O, N or S heteroatoms, respectively), wherein 0, 1, 2 or 3 atoms of each ring are substituted by substituents. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, etc.

[0089] 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 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, the heteroatoms being selected from O, N or S (e.g., having carbon atoms and 1-3, 1-6 or 1-9 O, N or S heteroatoms, respectively, if monocyclic, bicyclic or tricyclic), wherein 0, 1, 2, 3 or 4 atoms of each ring are substituted by substituents. Examples of heteroaryl groups include pyridyl, furyl / furanyl, imidazolyl, benzimidazolyl, pyrimidinyl, thiophenyl / thienyl, quinolinyl, indolyl, thiazolyl, and the like.

[0090] As used herein, the term "glycoside" refers to any material having a chemical structure comprising a glycosidic bond between a carbohydrate (sugar) molecule and another carbohydrate or non-carbohydrate (non-sugar) moiety. Glycosidic bonds or glycosidic linkages are a class of covalent bonds that join a carbohydrate (sugar) molecule, for example, to another molecule via its hemiacetal or hemiketal group. The other molecule may or may not be a carbohydrate. The sugar moiety is generally referred to as the glycosyl moiety of a glycoside. The glycosyl group may be composed of a single sugar group (monosaccharide), two sugar groups (disaccharides) or several sugar groups (oligosaccharides).

[0091] As used herein, the term "substituent" refers to a group that replaces a second atom or group (such as a hydrogen atom) on any molecule, compound or moiety. Suitable substituents include, but are not limited to, halo, hydroxyl, sulfhydryl, oxo, nitro, haloalkyl, alkyl, alkaryl, aryl, aralkyl, alkoxy, thioalkoxy, aryloxy, amino, alkoxycarbonyl, amide, carboxyl, alkylsulfonyl, alkylcarbonyl and cyano groups.

[0092] In embodiments, the avermectin used in the formulations and methods provided herein will be in neutral form. However, when avermectin contains an ionizable group, avermectin may exist as a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable salt" refers to those salts suitable for pharmaceutical use, such as, for example, for humans and animals. Pharmaceutically acceptable salts of amines, carboxylic acids and other types of compounds are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J Pharmaceutical Sciences, 66: 1-19 (1977), which is incorporated herein by reference. The salt may be prepared in situ during the final separation and purification of avermectin, or may be prepared separately by reacting a free base or free acid function with a suitable reagent. For example, a free base function may react with a suitable acid. Suitable pharmaceutically acceptable salts may include metal salts, such as alkali metal salts, such as sodium salts, potassium salts and lithium salts; and alkaline earth metal salts, such as calcium salts or magnesium salts. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of the amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hernisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, 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, valerate, and the like.

[0093] Avermectin Composition

[0094] The compositions used in the methods and doses provided herein are liquid or semisolid at room temperature and comprise an avermectin (and particularly ivermectin), a first surfactant, and a second surfactant.

[0095] In an embodiment, the composition comprises:

[0096] (i) from about 1% to about 15% of a compound of any one of Formulas I-VII;

[0097] (ii) from about 20% to about 40% of a first surfactant, the first surfactant comprising one or more of:

[0098] (a) mono-, di- and / or tri-fatty acid esters of glycerol;

[0099] (b) mono- and / or di-fatty acid esters of 1,2-propylene glycol; and

[0100] (c) Mono- and / or di-fatty acid esters of polyethylene glycol

[0101] The fatty acid is selected from C 6 To C 10 fatty acids; and

[0102] (iii) from about 15% to about 70% of a second surfactant selected from one or more polysorbate surfactants and / or fatty acid esters of sorbitan.

[0103] In some embodiments, the composition comprises about 3% to about 12% of a compound of any one of formula I-VII. In some embodiments, the composition comprises about 5% to about 10% of a compound of any one of formula 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 formula I-VII.

[0104] In an embodiment, the composition comprises:

[0105] (i) from about 1% to about 15% of one or more compounds of any of Formulas I-VII;

[0106] (ii) from about 20% to about 40% of a first surfactant, the first surfactant comprising one or more of:

[0107] (a) mono-, di- and / or tri-fatty acid esters of glycerol;

[0108] (b) mono- and / or di-fatty acid esters of 1,2-propylene glycol; and

[0109] (c) mono- and / or di-fatty acid esters of polyethylene glycol;

[0110] The fatty acid is selected from C 6 To C 10 fatty acids; and

[0111] (iii) from about 15% to about 70% of a second surfactant selected from one or more polysorbate surfactants and / or fatty acid esters of sorbitan.

[0112] In some embodiments, the composition comprises about 3% to about 12% of one or more compounds of formula I-VII. In some embodiments, the composition comprises about 5% to about 10% of one or more formula 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 formula I-VII.

[0113] In an embodiment, the composition comprises:

[0114] (i) about 1% to about 15% ivermectin, wherein the ivermectin comprises a compound of Formula VI and a compound of Formula VII;

[0115] (ii) from about 20% to about 40% of a first surfactant, the first surfactant comprising one or more of:

[0116] (a) mono-, di- and / or tri-fatty acid esters of glycerol;

[0117] (b) mono- and / or di-fatty acid esters of 1,2-propylene glycol; and

[0118] (c) mono- and / or di-fatty acid esters of polyethylene glycol;

[0119] The fatty acid is selected from C 6 To C 10 fatty acids; and

[0120] (iii) from about 15% to about 70% of a second surfactant selected from one or more polysorbate surfactants and / or fatty acid esters of sorbitan.

[0121] In some embodiments, the composition comprises about 3% to about 12% ivermectin, the ivermectin comprising a compound of formula VI and a compound of formula VII. In some embodiments, the composition comprises about 5% to about 10% ivermectin, the ivermectin comprising a compound of formula VI and a 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, the ivermectin comprising a compound of formula VI and a compound of formula VII.

[0122] The compositions provided herein include a first surfactant, which may be a mixture of surfactants, and a C content of glycerol, 1,2-propylene glycol and / or polyethylene glycol. 6 To C 10 Fatty acid esters. 6 To 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. The avermectin composition comprises about 20% to about 40% of the first surfactant, or about 25% to about 30% of the first surfactant.

[0123] The first surfactant may comprise a mono-, di- and / or tri-fatty acid ester of glycerol. The fatty acid ester of glycerol may be a mixture of a mono- and di-ester of glycerol. The fatty acid component is one or more C 6 To C 10 Fatty acids, and may be saturated or unsaturated, but are preferably saturated. More preferably, the fatty acids have 8 to 10 carbons, and may be caprate, caprylate, and mixtures thereof in particular. Fatty acid esters of glycerol are commercially available and include Capmul 808G EP / NF (glycerol monocaprylate), Capmul MCM C8 EP / NF (glycerol monocaprylate), Capmul MCM (glycerol caprylate / caprate), Masester E8120 (glycerol mono- and dicaprylate / caprate).

[0124] 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 a mono- and di-ester of propylene glycol, and preferably the fatty acid ester of propylene glycol may be a mono-ester of propylene glycol. The fatty acid component is one or more C 6 To C 10 Fatty acids, and may be saturated or unsaturated, but are preferably saturated. More preferably, the fatty acids have 8 to 10 carbons, and may be, in particular, caprate, caprylate, and mixtures thereof. Fatty acid esters of propylene glycol are commercially available, and include Capmul PG-8 (propylene glycol monocaprylate), Capryol 90 (propylene glycol monocaprylate), Capryol PGMC (propylene glycol monocaprylate and dicaprylate).

[0125] 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 a mono- and di-ester of polyethylene glycol. The fatty acid component is one or more C 6 To C 10The fatty acid may be saturated or unsaturated, but preferably saturated. More preferably, the fatty acid has 8 to 10 carbons, and may be, in particular, caprylate, caprylate, and mixtures thereof. 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 and include Labrasol ALF (a small portion of monoglycerides, diglycerides, and triglycerides, and primarily caprylic acid (C 8 ) and decanoic acid (C 10 ) of PEG-8 (MW 400) monoester and diester).

[0126] Compositions provided herein also include a second surfactant, which 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 a second surfactant, about 15% to about 40% of a second surfactant, or about 15% to about 20% of a second surfactant.

[0127] The second surfactant may include a polysorbate surfactant. A polysorbate surfactant is a polyethoxylated sorbitan esterified with a fatty acid and has the following general structure:

[0128]

[0129] 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 total number of oxyethylene groups -(CH 2 CH 2 O)-groups. The fatty acid may be saturated or unsaturated. In an embodiment, the fatty acid has 12 to 18 carbons. In an embodiment, the number of oxyethylene groups (i.e., w+x+y+z) is about 20. Polysorbate surfactants are commercially available and include polysorbate 80 (polyoxyethylene 20 sorbitan monooleate) such as Tween 80, Montanox 80, Alkest TW 80; polysorbate 60 (polyoxyethylene 20 sorbitan monostearate) such as Tween 60; polysorbate 40 (polyoxyethylene 20 sorbitan monopalmitate) such as Tween 40; and polysorbate 20 (polyoxyethylene 20 sorbitan monolaurate) such as Tween 20 and Alkest TW 20.

[0130] The second surfactant may additionally or alternatively comprise a fatty acid ester of sorbitan (also referred to as Span). The fatty acid component may be saturated or unsaturated. In an embodiment, the fatty acid has 12 to 18 carbons. The sorbitan ester may be a monoester, diester or triester of sorbitan, and in particular a monoester of sorbitan, such as sorbitan monolaurate. Sorbitol 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).

[0131] Optionally, the avermectin composition may additionally comprise Vitamin E TPGS, also known as D-α-tocopheryl polyethylene glycol 1000 succinate. The composition may comprise from about 5% to about 55% Vitamin E TPGS, or from about 30% to about 50% Vitamin E TPGS.

[0132] In an embodiment, the pharmaceutical composition comprises: (i) about 5% to about 10% ivermectin; (ii) about 25% to about 30% mono- and di-C glycerol; 8 To C 10 fatty acid ester; (iii) from about 15% to about 30% of a polysorbate surfactant; and (iv) from about 30% to about 50% Vitamin E TPGS.

[0133] In one embodiment, the pharmaceutical composition comprises: (i) about 8% ivermectin; (ii) about 27.6% mono- and di-C glycerol; 8 To C 10 fatty acid esters; (iii) about 32.2% polysorbate 80; and (iv) about 32.2% Vitamin E TPGS.

[0134] 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.

[0135] In one embodiment, the pharmaceutical composition comprises: (i) about 8% ivermectin; (ii) about 27.6% mono- and di-C glycerol; 8 To C 10 fatty acid esters; (iii) about 18.4% polysorbate 80; and (iv) about 46% Vitamin E TPGS.

[0136] 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.

[0137] In one embodiment, the pharmaceutical composition comprises: (i) about 8% ivermectin; (ii) about 27.6% mono- and di-C glycerol; 8 To C 10 fatty acid esters; and (iii) about 64.4% polysorbate 80.

[0138] In one embodiment, the pharmaceutical composition comprises: (i) about 8% ivermectin; (ii) about 27.6% Masester E8120; and (iii) about 64.4% polysorbate 80.

[0139] The pharmaceutical composition may additionally comprise additional excipients, such as additional surfactants, solvents, solubilizers, preservatives, antioxidants, fillers, solubility enhancers, wetting agents, emulsifiers, suspending agents, antibacterial agents, pH buffers, sweeteners, flavoring agents, and combinations thereof.

[0140] Dosage form

[0141] The present disclosure provides a composition comprising avermectin, which is semi-solid or liquid-based when formulated into, including but not limited to, an emulsion, suspension, solution, elixir or syrup in which the avermectin is dissolved and / or suspended.

[0142] The dosage form containing avermectin can be in the form of solution, suspension, emulsion, aerosol, capsule, soft elastic or hard gelatin capsule, skin patch, suspension, etc., preferably in a unit dosage form suitable for simple administration of accurate doses. The composition can be in the form of liquid or semisolid filled capsules, sublingual sprays or nasal sprays.

[0143] Capsule dosage forms may include soft capsules and hard capsules. Capsules can be used as oral dosage forms for the administration of a variety of different types of active drugs. Capsules can be filled with active ingredients in liquid form or in powder form suspended in a liquid. Hard capsules can be prepared from unplasticized or low-plasticized gelatin and water to form hard capsules that can be filled with powder or liquid. Soft capsules can be prepared from highly plasticized soft elastic gelatin and can contain liquid or semisolid ingredients. These capsules are commonly referred to as "soft capsules" or "gelatin capsules."

[0144] As used herein, the term "capsule" refers to any suitable capsule container or box suitable for oral intake, for example, those capsule containers or boxes suitable for use in combination with liquid-filled compositions. The term "capsule" may include a capsule having a shell composed of soft and / or hard materials, such as gelatin, starch, cellulose, cellulose derivatives (e.g., hydroxypropyl methylcellulose), hydrocolloids, gums, carrageenan, or any other natural or synthetic materials that can be used to encapsulate liquid compositions and be ingested by animals. Optionally, the shell material can be gelatin and / or hydroxypropyl methylcellulose. In one embodiment, the shell material is gelatin. The term "capsule" also includes various capsule shapes and sizes. The present disclosure does not limit dosage forms to specific types or shapes. Any commercially available capsule shell or shell material can be used.

[0145] 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 may include a liquid fill encapsulated with a soft capsule shell. The outer surface of the soft capsule shell may be coated with one or more layers of coating.

[0146] Suitable materials for encapsulating liquid fillers can include heat-sealable polymers and gelatin. Examples of heat-sealable polymers can include, but are not limited to, modified starches, cellulose polymers, and carrageenan. In one embodiment, the material is gelatin. Gelatin can be natural gelatin, chemically modified gelatin, enzyme-modified gelatin, or a combination thereof.

[0147] The material forming the capsule shell may further contain water. Before preparing the capsule, water may be present in the raw material mass in an amount sufficient to allow the material to be processed on the encapsulating machine. After the capsule is formed, most of the water may be removed during the drying process.

[0148] Water can have a plasticizing effect on the material. In addition, a non-volatile plasticizer or a plasticizer mixture can be added to the material forming the capsule shell. The non-volatile plasticizer can be any plasticizer compatible with the material of the capsule shell. For example, the non-volatile plasticizer can be glycerol, maltitol, sorbitan, sorbitol or similar low molecular weight polyols and mixtures thereof. In an embodiment, the ratio of plasticizer to material determines the hardness or softness of the shell.

[0149] The ratio of plasticizer to material in the shell can be sufficient to provide a capsule that is not too hard, so that the capsule becomes brittle and breaks if stressed during shipping and handling, and is not too soft, so that the capsule deforms during shipping and handling. The non-volatile plasticizer can be present in the capsule shell at about 8% to 65% of the total weight of the capsule shell, at about 10% to 35% of the total weight of the capsule shell.

[0150] The material forming the capsule shell may further contain an extender. The extender may be any extender compatible with the material. The example of an extender may include natural or modified natural biopolymers and synthetic polymers. Natural biopolymers may include, for example, cellulose, starch, starch derivatives, bacterial polysaccharides (such as xanthan gum and gellan gum) and plant gums (such as guar gum, locust bean gum, tragacanth gum and gum arabic) and polymers of animal origin (such as chondroitin sulfate, hyaluronic acid, heparin, collagen and chitosan). The example of modified natural biopolymers may be modified cellulose. The example of synthetic polymers may include carbon chain polymers of vinyl and acrylic acid types and heterochains of polyoxide and polyamine types.

[0151] A coating can be applied on the outer surface of the soft capsule shell. The coating can contain one or more layers. Any coating suitable for soft capsules can be applied to the capsule. The coating can provide liquid filled capsules with characteristics such as waterproofing and sealing, smoothness, polishing, enteric protection and / or delayed release. Delayed release can be affected by, for example, temperature or pH. In one embodiment, the coating is an enteric coating.

[0152] The coating may be prepared by any standard coating ingredients known to those skilled in the art. Coating ingredients may include, but are not limited to, fats, fatty acids, waxes, shellac, ammoniated shellac, cellulose acetate phthalate, cellulose, vinyls, ethylene glycol, acrylics, and carbohydrate polymers, polymers and copolymers containing methacrylic acid and alkyl methacrylates, hydroxypropyl methylcellulose (HPMC), and combinations thereof.

[0153] The coated capsule may further comprise a finishing coating. In one embodiment, a finishing layer is applied to the coated capsule. Examples of materials suitable for the finishing coating may include, but are not limited to, cellulose, vinyl resins, ethylene glycol, acrylic resins, and carbohydrate polymers and / or combinations thereof.

[0154] Liquid filler or semisolid filler can be encapsulated with soft capsule shell by any method known in the art.For example, standard rotary mold soft gelatin capsule machine can be used to prepare soft capsule, such as The Theory and Practice of Industrial Pharmacy, edited by Lachman, et al., 2nd edition, Part II, 404-420, Lea and Febiger, described in 1976. Additional methods include using flat plate process (see The Theory and Practice of Industrial Pharmacy, edited by Lachman, et al., 2nd edition, Part II, 405, Lea and Febiger, 1976), and manufacturing Globex seamless capsule machine (see U.S. Patent number 5,254,294) for large microcapsules, non-standard rotary mold machine (see U.S. Patent number 6,183,845 and 6,340,473) for manufacturing gel band using extrusion technology, and other methods (see U.S. Patent number 6,352,719) for manufacturing capsules using high frequency, ultrasonic or induction welding to seal capsules. The U.S. Patents and books listed above are hereby incorporated by reference.

[0155] As used herein, the phrase "liquid hard shell" refers to a hard capsule that encapsulates a liquid or semisolid formulation. The hard capsule can be a single unit dosage form, and can include a cap and a body, which can be manufactured separately, and it can be supplied in an empty form for filling a liquid or semisolid composition. In some embodiments, the hard capsule is prepared by a polymer such as gelatin. An additional component can be water, which acts as a plasticizer. Another hard capsule can be manufactured by hydroxypropyl methylcellulose (HPMC). Liquid-filled hard capsules can be filled on a filling machine, such as a high-speed filling machine.

[0156] In one example, a method for preparing a filled hard capsule is disclosed herein. Empty capsules are supplied to a filling machine under pre-locking conditions, wherein the capsule body has a cap loosely attached thereto. A series of rings or protrusions are provided in the mating surface of the cap or body. These rings are configured to enable the cap to be loosely attached to the body so that the cap and body remain together during storage, but before filling of the capsule, the cap can be removed. Once the capsule is filled, the cap can be replaced and forced beyond the pre-locking position into a fully locked position. Alternatively, other types of capsule filling machines can also be used to accept separate supplies of capsule bodies and caps.

[0157] The capsule can be closed at high speed after being filled with the formulated composition. During the closing of the capsule, the cap is put over the body and the body is pushed up until it locks on the cap. The cap can fit tightly and can be about half the length of the body, so the cap can travel a considerable distance down the capsule body before locking. This can have the effect of the piston capturing and pressurizing the capsule. Excess gas can escape through the gap between the cap and the body, and a vent can be provided in this area to facilitate the escape of excess pressure. Alternatively, the capsule can utilize a particularly tight locking mechanism instead of a vent.

[0158] In one embodiment, the capsule is banded by applying a batch of polymer solution around the junction between the cap and the body. The polymer solution can be a solution of the same polymer as the capsule cap and / or body in its solvent. Banding can provide a smooth capsule surface for coating, which can prevent movement between the cap and body of the capsule.

[0159] When preparing a filled capsule filled with a composition comprising avermectin, it is preferred that the composition is in liquid form at least during the encapsulation process. In one embodiment, the final capsule contains a composition in liquid form. In one embodiment, the final capsule contains a composition that is in semi-solid form at room temperature.

[0160] Application method

[0161] Administration of the pharmaceutical composition comprising avermectin may be carried out via oral, nasal, intraocular, intravenous, intramuscular, subcutaneous, transdermal, subdermal, sublingual or rectal administration routes.

[0162] In an embodiment, the route of administration is oral, and the pharmaceutical composition is provided in the form of a capsule, such as a soft elastic capsule or a hard gelatin capsule.

[0163] In one embodiment, the route of administration is nasal. The composition may be a solution, an aerosol, a liquid suspension or a liquid dispersion in the form of a nasal spray, a nasal rinser, an inhaler, nasal drops and / or a diffuser.

[0164] In an embodiment, the route of administration is skin, including but not limited to topical, subcutaneous, subdermal, transdermal, intradermal, or skin patch.

[0165] Treatment and prevention methods

[0166] Provided herein are methods of treating or preventing a neurological disorder or other disorder by administering to a subject in need thereof a therapeutically or prophylactically effective amount of a composition disclosed herein.

[0167] A "therapeutically effective amount" of a composition comprising (i) a compound of any one of formulas I-VII, (ii) one or more compounds of any one of formulas I-VII, or (iii) an ivermectin comprising a compound of formula VI and a compound of formula VII is an amount sufficient to confer a therapeutic benefit to a patient after administration, such as improving one or more disease symptoms of a subject. A "therapeutically effective amount" may produce a desired beneficial change in the subject's physiology, or cause an improvement in the subject's clinically significant condition, such as by delaying, reducing, minimizing, or alleviating one or more symptoms associated with a disease or condition. In general, a therapeutically effective amount is also an amount in which the therapeutically beneficial effects outweigh any toxic or deleterious effects of the composition. The effective amount may vary according to the species, age, weight, sex, health, and nature or severity of the disease of the subject. Depending on the mode of administration, the effective amount may also vary. In some cases, multiple doses of the composition are administered to achieve an effective amount of the expected therapeutic benefit. In some cases, the therapeutic amount may be used to treat refractory or drug-resistant conditions, as well as for combination therapy. For example, the effective amount may be administered simultaneously, sequentially, and in the same or different dosage forms with adjuvant therapy.

[0168] As used herein, the terms "treating", "treat", and "treatment" refer to reducing, alleviating, ameliorating, or alleviating at least one symptom of a disease or disorder. The terms include, for example, administering a formulation as provided herein to prevent the onset of spasms, to reduce or lessen their severity, and / or to prevent their recurrence.

[0169] As used herein, the terms "prevent," "prevention," and the like refer to acting before the onset of a manifest disease or condition to prevent the disease or condition from developing or to minimize the extent of the disease or condition, or to slow its progression.

[0170] A "prophylactically effective amount" of a composition comprising (i) a compound of any one of Formulas I-VII, (ii) one or more compounds of any one of Formulas I-VII, or (iii) ivermectin comprising a compound of Formula VI and a compound of Formula VII refers to the amount of the composition required to achieve the desired preventive result. In one embodiment, the prophylactic effective amount is less than the therapeutically effective amount because the prophylactic dose is used for subjects before or at an early stage of the disease.

[0171] The subject can be a mammal, including but not limited to a human or non-human mammal. The mammal can be a commercially raised animal (such as a horse, a cow, a sheep or a pig), an experimental animal (such as a mouse or a rat) or a pet (such as a cat, a dog, a rabbit or a guinea pig). The subject is preferably a human. The subject can be male or female. Individuals and patients are also subjects herein.

[0172] Neurological disorders

[0173] The present disclosure provides a method of treating or preventing a nervous system 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 compounds of any one of Formulas I-VII, or (iii) ivermectin comprising a compound of Formula VI and a compound of Formula VII.

[0174] Ivermectin has been shown to bind to human purinergic P2X4 receptors, γ-aminobutyric acid A (GABA A ) receptors, glycine receptors (GlyR) and neuronal α-7-nicotinic receptors; the EC50 of each of the above interactions is about 0.25μM, 0.92μM, 1.2μM and 30μM, respectively. These channels play a vital role in epilepsy. Therefore, ivermectin can be used as an anticonvulsant. The anticonvulsant effect of ivermectin can be achieved through the collective action of any combination of interactions with the above four receptors.

[0175] Ivermectin is likely to be mostly lipophilic, which is advantageous for use in the central nervous system because lipophilic agents can easily cross the blood-brain barrier (BBB). The blood-brain barrier may be an obstacle for many therapeutic drugs 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 serve as a substrate for P-glycoprotein. Specifically, multidrug resistance protein 1 (MDR1), also known as P-glycoprotein or ATP-binding cassette subfamily B member 1 (ABCB1), is an efflux transport system that selectively transports substrates from the interstitial fluid (ISF) to the blood. P-glycoprotein can limit the entry of materials from the blood into the brain parenchyma. P-glycoprotein, an ATP-dependent drug transporter, can be found in the apical membrane of various epithelial cell types in the body, including the hemocoelom of brain capillary endothelial cells. Brain capillary endothelial cells can form the blood-brain barrier. Since P-glycoprotein can actively transport many hydrophobic amphiphilic drugs out of cells, it can be responsible for pumping hydrophobic drugs out of the brain by actively transporting these drugs back into the blood. Therefore, after crossing the BBB, ivermectin can be pumped out of brain cells and returned to the blood. Therefore, provided herein are compositions that meet the need for formulations with improved pharmacokinetic properties, including but not limited to bioavailability.

[0176] Thus, in one aspect, the present disclosure provides a method for treating or preventing a neurological condition characterized by an epileptic disorder, including but not limited to epilepsy, treatment-resistant epilepsy, Gravet syndrome, Lenox Gastaut syndrome, spinal cord injury, childhood absence 5 (ECA5), epileptic encephalopathy (EE), early infantile epileptic encephalopathy 43 (EIEE43), Angelman syndrome, brain injury, stroke, addictive behavior, subarachnoid hemorrhage, anoxic encephalopathy, infectious or metabolic encephalopathy, hemorrhagic, embolic / atherosclerotic cerebrovascular accident and other epilepsy indications.

[0177] On the other hand, the present disclosure provides a method for treating or preventing epilepsy. In some embodiments, epilepsy is refractory or treatment-resistant epilepsy. In embodiments, this method includes administering a composition comprising (i) a compound of any one of formulas I-VII, (ii) one or more compounds of any one of formulas I-VII, or (iii) an ivermectin containing a compound of formula VI and a compound of formula VII, and one or more adjunctive therapies including up to four anti-epileptic drugs (AEDs), wherein the one or more adjunctive therapies are administered simultaneously, sequentially, and in the same or different dosage forms with a therapeutically effective amount or a preventively effective amount of one or more compositions, wherein the one or more compositions comprise one or more avermectins, and in particular ivermectin or ivermectin derivatives. AEDs may include drugs such as lorazepam, cenobamate, brivaracetam, striripentol, acetazolamide, phenytoin, sodium valproate, buccal midazolam, and valproate. midazolam, felbarnate, clobazam, permpanel, tiagabine, rufinamide, levetiracetam, larnotrigine, pregabalin, primidone, gabapentin, nitrazepam, phenobarbital, clonazepam, vigabatrin, carbamazepine, topiramate, oxcarbazepine, rectal diazepam, lacosamide, ethosuximide, eslicarbazepine acetate, and / or zonisamide. Non-drug anti-epileptic therapies may also be administered concurrently, including implantable devices such as vagus nerve stimulators, responsive neurostimulators, and deep brain stimulators.

[0178] In another aspect, the present disclosure provides a method for treating or preventing a neurological disorder associated with muscle movement disorders, including but not limited to multiple sclerosis, essential tremor, various forms of spasticity (including spasticity associated with spinal cord injury, spasticity associated with other diseases (including parasitic paresis), spasticity associated with cerebral palsy), incontinence following spinal cord injury, dystonia, lateral sclerosis, myotonic dystrophy, congenital (genetic) muscular dystrophy (e.g., Duchenne's and Becker's), Rett syndrome, Prader-Willi syndrome, and any orphan motor neuron disease.

[0179] In one aspect, the present disclosure provides a method for treating or preventing a neurological disorder caused by GABAergic dysfunction, including but not limited to Alzheimer's, Parkinson's disease, schizophrenia, autism, autism spectrum disorder, global developmental delay, decreased fine and gross motor control, or attention deficit hyperactivity disorder (ADHD).

[0180] In one aspect, the present disclosure provides a method for treating or preventing a neurological disorder caused by glycinergic dysfunction, including but not limited to stiff person syndrome or startle disease.

[0181] In one aspect, the present disclosure provides a method of 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 a central nervous system abscess.

[0182] In one aspect, the present disclosure provides a method of treating or preventing a neurological disorder resulting from injury.

[0183] Spinal spasm

[0184] In one aspect, the present disclosure provides a method of treating or preventing spinal spasm 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 compounds of any one of Formulas I-VII, or (iii) ivermectin comprising a compound of Formula VI and a compound of Formula VII.

[0185] Spasticity is a condition in which certain muscles contract continuously. Spasticity may produce uncontrollable painful spasms of the legs or other limbs. Spasticity may also interfere with movement and speech. Untreated spasticity can lead to frozen or immobile joints and pressure sores. Spasticity may prevent the return of normal motor activity after an injury or illness. In addition, spasticity may cause pain, fatigue, and other problems. As a result, spasticity may prevent a person from doing daily activities, walking, sitting, maintaining posture, and sleeping.

[0186] The degree of spasticity can vary from mild muscle stiffness to severe and uncontrollable muscle cramps. Spasticity can be very painful and, depending on the muscles affected, can cause an uncoordinated gait, a stiff or deformed posture, and a reduced range of motion in the limbs. Spasticity can cause permanent muscle shortening and problems (contractures) around the joints where the two spastic muscles are supposed to move. Spasticity can be a permanent feature or be brought on by various factors such as fatigue, heat, or infection.

[0187] The main component of spasticity is excessive reflexes or hyperreflexia. One measure to quantify hyperreflexia is the electrical analog of the classic tendon reflex, called the Hoffman or H-reflex. The H-reflex is a compound electromyographic (EMG) response caused by synaptic activation of muscle afferents to motor neurons following muscle nerve stimulation.

[0188] Spasticity may be associated with spinal cord injury; brain damage due to lack of oxygen, stroke, or head injury; amyotrophic lateral sclerosis (Lou Gehrig's disease); phenylketonuria; metabolic diseases such as adrenoleukodystrophy; cerebral palsy; stiff-person syndrome, and multiple sclerosis. In multiple sclerosis, spasticity may affect the legs, although it may affect almost any muscle pair in the body. In multiple sclerosis, spasticity is usually caused by damage to the nerves (neurons) that control muscles or receive sensory information from muscles. Reflex spasms generated by the spinal cord are not inhibited by the brain as they normally are, resulting in increased muscle tone. The lesions that cause the symptoms usually occur in the cerebellum or in the white matter tracts that connect the cerebellum to peripheral motor (efferent) and sensory (afferent) nerves.

[0189] Current medications available for the management of spasticity include baclofen, a GABA B Baclofen acts as an agonist to enhance the activity of presynaptic GABA BReceptor-mediated inhibition. The rationale for using baclofen to treat spasticity is based on the hypothesis that elimination of presynaptic inhibition from descending nerve fibers from the brain induces hyperreflexia in spinal cord injuries. Spinal cord injuries are thought to damage these descending fibers, making the spinal cord overreactive. Baclofen is thought to restore some inhibition. However, oral baclofen unfortunately increases inhibition throughout the brain, leading to drowsiness and weakness. To avoid such unpleasant side effects (which reduce the patient's ability to concentrate), baclofen pumps are designed to inject the drug directly into the cerebrospinal fluid, typically in spinal cord injury victims and cerebral palsy patients. These pumps avoid the hypnotic effects of oral administration, but are dangerous, have a limited lifespan (requiring repeated surgical implants), and are very expensive.

[0190] In one embodiment, the treatment reduces hyperreflexia in a human subject. In one embodiment, the reduction in hyperreflexia is used to evaluate the reduction in spasticity. As used herein, the term "reducing hyperreflexia" refers to reducing the amplitude of the H reflex measured at 1, 5 or 10 Hz and normalizing it to the amplitude measured at 0.2 Hz stimulation. In other words, "reducing hyperreflexia" refers to restoring the low-frequency dependent inhibition of the H reflex to a level closer to control. More preferably, the H reflex amplitude is reduced at 5 or 10 Hz, most preferably at 5 Hz.

[0191] In some embodiments, the formulations and methods disclosed herein are effective in reducing the stiffness of a spasticity.

[0192] In one aspect, the present disclosure provides a method for treating or preventing spinal spasm secondary to a disease including, but not limited to, spinal cord injury, stroke, brain injury, amyotrophic lateral sclerosis, phenylketonuria, adrenoleukodystrophy, cerebral palsy, stiff-person syndrome, or multiple sclerosis.

[0193] In one embodiment, the spasticity is secondary to spinal cord injury, and wherein the method further comprises administering to the human subject a dose of the formulation beginning after the spinal cord injury and before the development of spasticity.

[0194] In one embodiment, the spasticity is secondary to multiple sclerosis, wherein the method further comprises administering to the human subject a dose of the formulation starting after diagnosis of multiple sclerosis and before the onset of spasticity. In one embodiment, administration of the formulation is effective to increase connexin 36 levels in spinal neurons, wherein administration of the formulation is effective to increase gap junctions in spinal neurons or increase electrical coupling between spinal neurons.

[0195] A subject receiving a treatment described herein may experience a reduction in spasticity as a result of the therapy.

[0196] Levels of the protein connexin 36 (Cx36) can be used to assess reduction in spasticity. Cx36 forms gap junctions between neurons, which are called electrical synapses, allowing adjacent neurons to communicate directly. Passive exercise can also reduce spasticity by increasing the expression of the gap junction protein connexin 36, which increases gap junctions and increases electrical communication between neurons.

[0197] Another means of evaluating the effectiveness of a dose is by assessing muscle tone. In spasticity, the normal behavior of the stretch reflex is disturbed, which causes the muscles (particularly the flexors) to be extremely resistant to passive stretching, i.e., the tone becomes high. As a result, motor control is severely impaired, and stiffness or tightness of the muscles may interfere with gait, movement, and speech. Therefore, assessing tone (i.e., the degree of resistance to stretching from an external source) is an important means by which the degree of spasticity in a patient and the effectiveness of an intervention can be assessed.

[0198] Another well-recognized clinical measure of spastic tension is the Ashworth Scale and the Modified Ashworth Scale. The clinician moves the patient's limbs around the joints and then assigns a grade to each limb corresponding to the amount of resistance felt by the clinician.

[0199] Other means of evaluating the effectiveness of a dose include biomechanical studies, such as those performed by the pendulum test; electrophysiological studies, such as by electromyography (such as dynamic multichannel electromyography with gait studies) or Hoffman reflex studies (measuring deep tendon reflexes); and functional measurements, such as those given by the Barthel Index, the Functional Independence Measure, and the Fugl-Meyer Sensorimotor Dysfunction Assessment (Fugl-Meyer Scale).

[0200] In one embodiment, a method of treating or preventing spinal spasm by administering a composition disclosed herein to a subject in need thereof is provided, the method further comprising administering a second therapeutic agent to the human subject. In some embodiments, the second agent is baclofen, benzodiazepines, diazepam, clonazepam, dantrolene, or tizanidine.

[0201] pain

[0202] In one aspect, the present disclosure provides a method of treating or preventing pain by administering to a subject in need thereof a therapeutically effective amount or a prophylactically effective amount of (i) a compound of any one of Formulas I-VII, (ii) one or more compounds of any one of Formulas I-VII, or (iii) ivermectin comprising a compound of Formula VI and a compound of Formula VII.

[0203] In some embodiments, the pain is pain associated with a disease including, but not limited to, post-traumatic stress disorder (PTSD), gastroesophageal reflex 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 tumor), Parkinson's disease, or Alzheimer's disease. Other non-limiting examples of neurological diseases or disorders that can be treated or prevented by the compositions and methods herein include: avolition, agraphia, alcoholism, alexia, 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 damage, brain injury, brain tumor, Canavan disease, Capgras delusion, delusion), carpal tunnel syndrome, causalgia, central pain syndrome, central pontine myelinolysis, centronuclear myopathy, head disease, cerebral aneurysm, cerebral arteriosclerosis, brain atrophy, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral gigantism, cerebral palsy, cerebral vasculitis, cervical spinal stenosis, Charcot-Marie-Tooth disease, cerebellar tonsillar herniation, chorea, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic pain, Coffin-Lowry syndrome, coma, complex regional pain syndrome, compressive neuropathy, congenital facial diplegia, corticobasal degeneration, cranial arteritis, craniosynostosis, Creutzfeldt-Jakob disease disease), cumulative trauma disorder, Cushing's syndrome, cyclothymic inclusion disease (CIBD), cytomegalovirus infection, Dandy-Walker syndrome, Dawson disease, De Morsier's syndrome, Dejerine-Klumpke palsy, Dejerine-Sottas diseasedisease), delayed sleep phase syndrome, dementia, dermatomyositis, developmental coordination disorder, diabetic neuropathy, diffuse sclerosis, diplopia, Down syndrome, Dravet syndrome, Duchenne muscular dystrophy, dysarthria, dysautonomia, dyscalculia, dysgraphia, dyspraxia, dyslexia, dystonia, empty sella syndrome, encephalitis, encephalocele, encephalic trigeminal angiomatosis, fecal incontinence, enuresis, epilepsy, female epilepsy-mental disability, Erb's palsy, erythromelalgia, exploding head syndrome, Fabry's disease, Fahr's syndrome, syncope, familial spastic palsy, febrile seizures, Fisher syndrome, Friedreich's ataxia, fibromyalgia, Foville's syndrome, fetal alcohol syndrome, fragile X syndrome, fragile X-associated tremor / ataxia syndrome (FXTAS), Gaucher's disease, generalized epilepsy with febrile seizures, Gerstmann's syndrome, giant cell arteritis, giant cell inclusion disease, globoid cell leukodystrophy, gray matter heterotopia, Guillain-Barré syndrome, generalized anxiety disorder, HTLV-1-associated myelopathy, Hallervorden-Spatz disease, head injury, headache, hemifacial spasm, hereditary spastic paraplegia, polyneuritis, herpes zoster oticus, herpes zoster, Hirayama syndrome, Hirschsprung disease, Holmes-Adie syndrome syndrome), holoprosencephaly, Huntington's disease, hydrocephalus, hydrocephalus, hypercortisolism, hypoxia, immune-mediated encephalomyelitis, inclusion body myositis, incontinence pigmenti, infantile Refsum disease, infantile spasms, inflammatory myopathy, intracranial cysts, intracranial hypertension, isoventricular 15, Joubert syndrome, Karak syndrome, Kearns-Sayre syndrome, Kinsbourne syndrome, Kleine-Levin syndrome, Klippel-Feil syndromesyndrome, Krabbe disease, Lafora disease, Lambert-Eaton myasthenic syndrome, Landau-Kleffner syndrome, Wallenberg syndrome, learning disabilities, Leigh's disease, Lennox-Gastaut syndrome, Lesch-Nyhan syndrome, leukodystrophy, leukoencephalopathy with effacement of white matter, Lewybody dementia, anencephaly, locked-in syndrome, lumbar disc disease, lumbar spinal stenosis, Lyme disease—neurological sequelae, Machado-Joseph disease (spinocerebellar ataxia type 3), megalencephaly, macroscopy, Mal dementia debarquement), megalencephalic leukoencephalopathy with subcortical cysts, megalencephaly, Melkersson-Rosenthal syndrome, Menieres disease, meningitis, Menkes disease, metachromatic leukodystrophy, microcephaly, microsight, migraine, Miller Fisher syndrome, mini-stroke (transient ischemic attack), misophonia, mitochondrial myopathy, Mobius syndrome, monosomic muscular atrophy, motor skill impairment, moyamoya disease, mucopolysaccharidosis, multi-infarct dementia, multifocal motor neuropathy, multiple sclerosis, multiple system atrophy, muscular dystrophy, myalgic encephalomyelitis, myasthenia gravis, diffuse myelin fragmentation sclerosis, infantile myoclonic encephalopathy, myoclonus, myopathy, myotubular myopathy, myotonia congenita, narcolepsy, neuro-Behcet's disease ( disease), neurofibromatosis, neuroleptic malignant syndrome, neurologic manifestations of AIDS, neurologic sequelae of lupus, neuromyotonia, neuronal ceroid lipofuscinosis, neuronal migration disorder, neuropathy, neurosis, Niemann-Pick disease, non-24-hour sleep-wake disorder, nonverbal learning disorder, O'Sullivan-McLeod syndrome, occipital neuralgia, latent spinal dysraphism sequence, Ohtahara syndrome, olivopontocerebellar atrophy, opsoclonus-myoclonus syndrome, optic neuritis, postural hypotension, otosclerosis, overuse syndrome, visual hallucinations, paresthesias, Parkinson's disease, paramyotonia congenita, paraneoplastic disorders, paroxysmal aggression, Parry-Romberg syndrome, PANDAS, Pelizaeus-Merzbacher disease), periodic paralysis, peripheral neuropathy, pervasive developmental disorder, photopic sneeze reflex, phytanic acid storage disease, Pick's disease, pinched nerve, pituitary tumor, PMG, polyneuropathy, poliomyelitis, polymicrogyria, polymyositis, foramina, postpoliomyelitis 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, quadrantanopia, quadriplegia, rabies, radiculopathy, Ramsay Hunt syndrome type I, Ramsay Hunt syndrome type II, Ramsay Hunt syndrome type III, Rasmussen encephalitis encephalitis, reflex vascular dystrophy, Refsum disease, REM sleep behavior disorder, repetitive stress injury, restless legs syndrome, retroviral myelopathy, Rett syndrome, Reye's syndrome, rhythmic movement dyscrasia, Romberg syndrome, Saint Vitus dance, Sandhoff disease, Schilder's disease, schizencephaly, sensory processing disorder, septo-optic dysplasia, shaken baby syndrome, Shingles, Shy-Drager syndromesyndrome), Sjögren's syndrome syndrome, sleep apnea, sleeping sickness, sneezing, Sotos syndrome, spasticity, spina bifida, spinal cord injury, spinal cord tumor, spinal muscular atrophy, spinal and bulbar muscular atrophy, spinocerebellar ataxia, split-brain, Steele-Richardson-Olszewski syndrome, stiff-person syndrome, stroke, Sturge-Weber syndrome, stuttering, subacute sclerosing panencephalitis, subcortical arteriosclerotic encephalopathy, superficial siderosis, Sydenham's chorea, syncope, synesthesia, syringomyelia, tarsal tunnel syndrome, tardive dyskinesia, tardive mental disorder, Tarlov cyst, Tay-Sachs disease, temporal arteritis, temporal lobe epilepsy, tetanus, tethered cord syndrome, Thomson disease disease, thoracic outlet syndrome, spastic tics, Todd's paralysis, Tourette 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-Lindaudisease (VHL), Viliuisk Encephalomyelitis (VE), Wallenberg's syndrome, West syndrome, whiplash, Williams syndrome, Wilson's disease, or Zellweger syndrome.

[0204] On the other hand, the present disclosure provides a method for treating or preventing pain in a subject. "Pain" refers to the uncomfortable feeling and / or unpleasant perception of the subject's body. The sensation of pain can range from mild and occasional to severe and continuous. Pain can be divided into 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 by or is associated with a disease (e.g., cancer, arthritis, diabetes). In other cases, pain is caused by injury (e.g., sports injury, trauma). Non-limiting examples of pain that can be treated or prevented using the compositions and methods herein include: neuropathic pain, including peripheral neuropathy, diabetic neuropathy, postherpetic 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, pain associated with Parkinson's disease, epilepsy, osteoarthritis pain, rheumatoid arthritis pain, visceral pain, and pain associated with vitamin deficiency; and nociceptive pain, including pain associated with central nervous system trauma, strains / sprains, and burns; myocardial infarction, acute pancreatitis, postoperative pain, post-traumatic pain, renal colic, pain associated with cancer, pain associated with fibromyalgia, pain associated with carpal tunnel syndrome, and back pain.

[0205] Illustrative examples of pain that can be treated or prevented with 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), dental pain, headache, migraine, carpal tunnel syndrome, fibromyalgia, neuritis, sciatica, pelvic allergy, pelvic pain, postherpetic neuralgia, postoperative pain, post-stroke pain, and menstrual pain.

[0206] Pain can be classified as acute or chronic. As used herein, the term "acute pain" refers to pain that starts suddenly and is usually severe in nature. Acute pain can be mild and last only a few moments, or acute pain can be severe and last for weeks or months. In most cases, acute pain does not last more than three months, and the pain disappears when the underlying cause of the pain is treated or cured. However, unrelieved acute pain may lead to chronic pain. As used herein, the term "chronic pain" refers to persistent or recurrent pain that lasts longer than the normal course of an acute disease or injury or lasts more than three to six months and has an adverse effect on the health of the individual. In one embodiment, the term "chronic pain" refers to pain that persists when it should not last. Chronic pain can be nociceptive pain or neuropathic pain.

[0207] In some embodiments, the formulations and methods are effective in reducing acute pain. In some embodiments, the formulations and methods are effective in reducing chronic pain.

[0208] Clinical pain occurs when discomfort and abnormal sensitivity are present among a patient's symptoms. Individuals may experience a variety of pain symptoms. Such symptoms may include: 1) spontaneous pain, which may be dull, burning, or stabbing; 2) exaggerated pain responses to noxious stimuli (hyperalgesia); and 3) pain produced by normally harmless stimuli. Pain can also be divided into many different subtypes, including nociceptive pain, inflammatory pain, and neuropathic pain, depending on the different pathophysiologies.

[0209] In some embodiments, the formulations and methods are effective in reducing nociceptive pain. In some embodiments, the formulations and methods are effective in reducing inflammatory pain. In some embodiments, the compositions and methods are effective in reducing neuropathic pain.

[0210] Nociceptive pain is induced by tissue damage or strong stimulation that may cause damage. The non-limiting examples of pain include pain from central nervous system trauma, strain / sprain, burns, myocardial infarction and acute pancreatitis, postoperative pain (pain after any type of surgical operation), post-traumatic pain, renal colic, cancer pain and back pain. Cancer pain can be chronic pain, such as tumor-related pain (such as bone pain, headache, facial pain or visceral pain) or pain related to cancer therapy (such as post-chemotherapy syndrome, chronic postoperative pain syndrome or radiotherapy syndrome (post radiation syndrome)). Cancer pain may also occur in response to chemotherapy, immunotherapy, hormone therapy or radiotherapy. Back pain may be due to disc herniation or rupture, or the abnormality of lumbar facet joints, sacroiliac joints, paraspinal muscles or posterior longitudinal ligament.

[0211] Neuropathic pain may be pain initiated or caused by a primary lesion or dysfunction of the nervous system. Causes of neuropathic pain include, for example, peripheral neuropathy, diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, back pain, cancerous neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel syndrome, central post-stroke pain, and pain associated with chronic alcoholism, hypothyroidism, uremia, multiple sclerosis, spinal cord injury, Parkinson's disease, epilepsy, and vitamin deficiency.

[0212] Neuropathic pain may be associated with a pain disorder, the term pain disorder refers to a disease, condition or disorder associated with or caused by pain. Illustrative examples of pain disorders include arthritis, allodynia, classic trigeminal neuralgia, trigeminal neuralgia, somatoform disorders, hypoesthesia, hypoalgesia, neuralgia, neuritis, neurogenic pain, analgesia, painful anesthesia, causalgia, sciatica pain disorder, degenerative joint disorder, fibromyalgia, visceral disease, chronic pain disorder, migraine / headache, chronic fatigue syndrome, complex regional pain syndrome, neurodystrophy, plantar fasciitis, or pain associated with cancer.

[0213] The inflammatory process is a complex series of biochemical and cellular events that are activated in response to tissue damage or the presence of foreign substances, which leads to swelling and pain. Arthritis pain is a common type of inflammatory pain.

[0214] Other types of pain that can be treated or prevented with the formulations and methods may include, but are not limited to, pain caused by musculoskeletal disorders, including myalgia, fibromyalgia, spondylitis, seronegative (non-rheumatoid) arthropathy, non-articular rheumatism, muscular dystrophy, 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; headaches, such as migraine (including migraine with aura and migraine without aura), cluster headaches, tension-type mixed headaches, and headaches associated with vascular disorders; and maxillofacial pain, including toothache, earache, burning mouth syndrome, and temporomandibular myofascial pain.

[0215] Various pain scales can be used to determine the effective amount of the composition and method for reducing the amount of pain experienced by a human subject. Patient self-report can be used to assess whether pain is reduced; see, e.g., Katz and Melzack (1999) Surg. Clin. North Am. 79: 231. Alternatively, an observational pain scale can be used. The LANSS pain scale can be used to assess whether pain is reduced; see, e.g., Bennett (2001) Pain 92: 147. A visual analog pain scale can be used; see, e.g., Schmader (2002) Clin. J. Pain 18: 350. A Likert pain scale can be used; e.g., where 0 is no pain, 5 is moderate pain, and 10 is the worst possible pain. Children's self-report pain scales include, e.g., the Facial Pain Scale; the Wong-Baker FACES pain rating scale; and the Color Analog Scale. Adult self-report pain scales include, e.g., the Visual Analog Scale; the Verbal Numeric Rating Scale; the Verbal Description Scale; and the Brief Pain Scale.Pain measurement scales include, for example, the Alder Hey Triage Pain Score (Stewart et al. (2004) Arch. Dis. Child. 89:625); Behavioral Pain Rating Scale (Payen et al. (2001) Critical Care Medicine 29:2258); Brief Pain Inventory (Cleeland and Ryan (1994) Ann. Acad. Med. Singapore 23:129); Nonverbal Pain Index Checklist (Feldt (2000) Pain Manag. Nurs. 1:13); Critical Care Pain Observation Tool (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 Pain Questionnaire). 27:1783); Pain Index (Hardy et al. (1952) Pain Sensations and Reactions Baltimore: The Williams & Wilkins Co.); Faces Pain Scale-Revised (Hicks et al. (2001) Pain 93:173); Face Leg Movement Crying Comfort Scale; McGill Pain Questionnaire (Melzack (1975) Pain 1:277); Descriptor Difference Scale (Gracely and Kwilosz (1988) Pain 35:279); 11-point value box (Jensen et al. (1989) Clin. J. Pain 5:153); Numerical Rating Scale (Hartrick et al. (2003) Pain Pract. 3:310); Wong-Baker FACES pain rating scale; and visual analog scale (Huskisson (1982) J. Rheumatol. 9:768).

[0216] Dosage regimen

[0217] Provided herein is a method for treating or preventing a neurological disorder or other disorder (including but not limited to treating drug-resistant epilepsy) by administering a therapeutically or prophylactically effective amount of a composition to a subject in need thereof, the method comprising administering one of the compositions disclosed herein at a dose of about 10 mg to about 120 mg, the composition comprising (i) a compound of any one of formulas I-VII, (ii) one or more compounds of any one of formulas I-VII, or (iii) 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 10 mg to about 80 mg, the composition comprising (i) a compound of any one of formulas I-VII, (ii) one or more compounds of any one of formulas I-VII, or (iii) ivermectin comprising a compound of formula VI and a compound of formula VII. In some embodiments, the treatment or prevention method comprises administering a composition disclosed herein comprising (i) a compound of any one of Formulas I-VII, (ii) one or more compounds of any one of Formulas I-VII, or (iii) ivermectin comprising a compound of Formula VI and a compound of Formula VII at a dose of about 10 mg to about 60 mg. In some embodiments, the treatment or prevention method comprises administering a composition disclosed herein comprising (i) a compound of any one of Formulas I-VII, (ii) one or more compounds of any one of Formulas I-VII, or (iii) ivermectin comprising a compound of Formula VI and a compound of Formula VII at a dose of about 20 mg to about 40 mg. In some embodiments, the method of treatment or prevention comprises administering a composition disclosed herein comprising (i) a compound of any one of Formulas I-VII, (ii) one or more compounds of any one of Formulas I-VII, or (iii) ivermectin comprising a compound of Formula VI and a compound of Formula VII 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. In a preferred embodiment, the composition comprises ivermectin comprising a compound of Formula VI and a compound of Formula VII.

[0218] The dosage regimen of the therapy can be adjusted to provide the best desired response (e.g., therapeutic or preventive response). For example, a single dose can be administered, several divided doses can be administered over a period of time, or the dosage can be proportionally reduced or increased according to the responsiveness of the subject to the therapy. In some embodiments, the composition is administered twice a day (BD), once a day (QD), once every other day, and once every three days. In some embodiments, the dosage regimen is once a day, twice a day, every other day, or every three days, for about 14 days, for about 30 days, for about 60 days, for about 84 days, for about 90 days, or continuously. In some embodiments, the dosage regimen is daily, every other day, 2-4 times a week, 3-5 times a week, weekly, every two weeks, monthly, or every two months, for about 90 days, for about 6 months, for about 1 year, or continuously. In one embodiment, the dosage regimen is once a day for about 14 days. In one embodiment, the dosage regimen is once a day for about 84 days.

[0219] In an embodiment, the pharmaceutical composition comprises: (i) about 8% ivermectin; (ii) about 27.6% mono- and di-C glycerol; 8 To C 10 fatty acid esters; (iii) about 32.2% polysorbate 80; and (iv) about 32.2% Vitamin E TPGS.

[0220] 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.

[0221] In one embodiment, the pharmaceutical composition comprises: (i) about 8% ivermectin; (ii) about 27.6% mono- and di-C glycerol; 8 To C 10 fatty acid esters; (iii) about 18.4% polysorbate 80; and (iv) about 46% Vitamin E TPGS.

[0222] 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.

[0223] In one embodiment, the pharmaceutical composition comprises: (i) about 8% ivermectin; (ii) about 27.6% mono- and di-C glycerol; 8 To C 10 fatty acid esters; and (iii) about 64.4% polysorbate 80.

[0224] In one embodiment, the pharmaceutical composition comprises: (i) about 8% ivermectin; (ii) about 27.6% Masester E8120; and (iii) about 64.4% polysorbate 80.

[0225] 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.

[0226] 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 and continuously at a dose of about 10 mg to 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 daily and continuously at a dose of about 10 mg to 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 daily and continuously 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 daily and continuously at a dose of about 20 mg to 40 mg.

[0227] 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 daily and continuously. 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 and continuously 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 daily and continuously 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 daily and continuously 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 daily and continuously 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 daily and continuously 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 daily and continuously at a dose of about 120 mg.

[0228] In one embodiment, the neurological disorder is epilepsy. In some embodiments, the epilepsy is refractory or treatment-resistant epilepsy.

[0229] In an embodiment, the method comprises administering to a subject a pharmaceutical composition disclosed herein, and one or more adjunctive therapies comprising up to four additional anti-epileptic drugs (AEDs), wherein the one or more adjunctive therapies are administered simultaneously, sequentially, and in the same or different dosage forms as a composition comprising (i) a compound of any one of Formulas I-VII, (ii) one or more compounds of any one of Formulas I-VII, or (iii) ivermectin comprising a compound of Formula VI and a compound of Formula VII. AEDs may include drugs such as lorazepam, cinobate, brivaracetam, stappentol, acetazolamide, phenytoin, sodium valproate, sublingual midazolam, filbatate, clobazam, perampanel, tiagabine, rufinamide, levetiracetam, lanotriazine, pregabalin, primidone, gabapentin, nitrazepam, phenobarbital, clonazepam, vigabatrin, carbamazepine, topiramate, oxcarbazepine, rectal diazepam, lacosamide, ethosuximide, eslicarbazepine acetate, and / or zonisamide. Non-drug anti-epileptic therapies may also be administered simultaneously, including implantable devices such as vagus nerve stimulators, responsive neurostimulators, and deep brain stimulators.

[0230] Example

[0231] Example 1 - Solubility Determination

[0232] The active pharmaceutical ingredient (API) used in the following examples is ivermectin, which contains more than or equal to 90% of 22,23-dihydroavermectin B1a and less than 10% of 22,23-dihydroavermectin B1b. Solubility assessment is performed by continuously adding a known amount of API to each individual excipient and allowing the excipient to reach solubility equilibrium (visible solids are observed) via API saturation. The experiment was carried out under ambient conditions (25°C) and mixed at 500RPM on a stirring plate for at least 72 hours. Subsequently, the sample was centrifuged and filtered through a 0.45μm PVDF membrane filter (Millipore Durapore), and the filtrate was determined according to the United States Pharmacopoeia (USP) ivermectin monograph. 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, solubility studies of VE TPGS were performed on a hot plate at 40°C following the same procedure as above.

[0233] Table 1. Determination of ivermectin solubility at 25°C

[0234]

[0235]

[0236] Example 2 - Excipient Compatibility Study

[0237] Based on the equilibrium solubility results, excipient compatibility studies were initiated with selected excipients ranging from oils to surfactants (Table 2). The studies were designed to provide approximately 5% ivermectin solutions in selected excipients as shown in Table 2, except for excipients with equilibrium solubility below 5%, i.e., approximately 1% fractionated coconut oil and oleic acid. After preparing the solutions using a handheld homogenizer (Model IKAT10 Ultra-Turrax), each excipient sample was aliquoted into amber vials, approximately 10% water was added to each excipient aliquot, and a laboratory scale gel strip OET-004037 was made and added to a separate set of aliquots at approximately 1:1 weight / weight.

[0238] All samples were stored at 40°C / 75% RH (Model: Lunaire Environmental Chamber) and assayed / tested for related substances by the developed reverse phase HPLC method at T=0, 2 weeks and 1 month. The results are summarized in Tables 3 and 4.

[0239] Oily vehicles including Maisine CC, fractionated coconut oil, and oleic acid had good chemical compatibility with the API, with Maisine CC having the highest equilibrium solubility, so Maisine CC was selected as the oily vehicle for further study. Tween 80, Labrasol ALF, and Vitamin E TPGS, which are classified as surfactants, were compared, and Vitamin E TPGS showed the best chemical compatibility with the API 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 for use in formulation development. Due to its high solubility in Masester E8120, Masester E8120 was selected as a solubilizer and emulsifier for further evaluation for formulation development. Due to its poor chemical compatibility, PEG 400 was not considered for further formulation development as a co-solvent.

[0240] Table 2. List of excipients used for compatibility studies and actual API wt / wt%

[0241]

[0242] Table 3. Summary of excipient compatibility studies (assays)

[0243]

[0244]

[0245] Table 4. Summary of results of excipient sample compatibility study (total impurities). %Adjusted Area = Total Impurities % (excluding API impurities %)

[0246]

[0247]

[0248] Example 3 - Fiber Dispersion Study

[0249] Distec Dissolution System 2500 and PION Fiber Optic Dissolution System were used for fiber dispersion in fasting state simulated intestinal fluid (FaSSIF) and FaSSIF-V2 to collect real-time dissolution data and perform data processing. With 20 mg / capsule as the target and based on compatibility studies, a series of formulations (Table 5) were designed for dispersibility evaluation. FaSSIF medium was selected to simulate the intestinal environment after oral ingestion of ivermectin. First, 500 mL of fasting state simulated intestinal fluid (pH about 6.5) was paddled at 50 rpm (USP <711> Apparatus II) was used for the dispersion analysis to screen various excipient combinations and compositions for approximately 6 hours. The results were plotted in a graph showing Figure 1 .

[0250] FaSSIF-V2 was subsequently used to confirm the dispersibility of Formulations 7E and 9E, as they exhibited higher dispersibility than the other formulations evaluated in the first round of dispersion studies.

[0251] The kinetic solubility of 7E and 9E in both FaSSIF and FaSSIF-V2 reached 80% release at T = 30 minutes, indicating an immediate release profile. No drug precipitation was observed, indicating that both formulations have good dispersibility and the ability to maintain the solubility of the API, and once ingested into the gastrointestinal tract, the risk of API precipitation is low. Data processing was performed using Aupro.

[0252] Table 5. Quantitative composition of formulations in dispersibility studies

[0253]

[0254]

[0255] Example 4 - Analysis of Prototype Formulations

[0256] Based on kinetic solubility studies, 7E and 9E were selected as prototype formulations, both of which showed good dispersibility in simulated intestinal fluid. A 12-month informal stability study was conducted to challenge the two formulations at 40°C / 75%RH in a Lunaire environmental chamber, and 5% water and gel strips (OET-004037) were added in separate vials to simulate the migration of soft capsule water and the effect of gel on the soft capsule dosage form formulation, respectively. The formulation control samples (without water and gel strips) were stored in 8-ounce amber Boston round bottles to simulate the preliminary expected packaging of the first human clinical study (SAD / MAD study). All other samples were stored in amber glass vials. The assay / RS results are summarized in Tables 6 and 7 and analyzed by developing an HPLC method.

[0257] No precipitation or phase separation was observed in any sample vial at 40°C / 75% RH from T=0 to 1 month. In 7E, a light slurry was observed in the water-added sample at T=3 months, indicating a small amount of API precipitation after the addition of 5% water, possibly due to polymorphic changes in the API. However, the water-added sample is a simulation and not a true representation of water migration in the softgel. The small amount of precipitation in this sample is inconclusive and is considered minor in terms of formulation stability.

[0258] Table 6. Summary of Results of Informal Stability Studies of Prototype Formulations (Assays)

[0259]

[0260] Table 7. Summary of Results of Informal Stability Studies of Prototype Formulations (Related Substances)

[0261]

[0262] Example 5 - Freeze-thaw studies

[0263] The physical and chemical stability of prototype formulations 7E and 9E was studied by freeze-thaw in a ClimaCell environmental test chamber from -15°C to 40°C, over a 7-day period, with 24-hour cycles. No precipitation or phase separation was observed from either sample vial at day 7. The chemical stability (assays) are summarized in Table 8. It can be concluded that both formulations are stable under extreme temperature fluctuation stress.

[0264] Table 8. Summary of results of freeze-thaw studies of prototype formulations (assays)

[0265]

[0266] Example 6 - Pharmacokinetics of Ivermectin B1a in Sprague Dawley Rats after IV and Oral Administration condition

[0267] Thirty-six male Sprague Dawley rats were randomly divided into 4 groups of 9 male rats each. All animals in all groups were fasted overnight before the experimental date.

[0268] The ivermectin API dissolved in DMSO, solutol and saline was administered intravenously (IV) to the first group of rats (n=9). The 2nd group of rats was administered 2 mg / kg Stromectol (n=9) crushed and dissolved in water via oral gavage. Stromectol was formulated by the manufacturer as a tablet containing 3 mg of ivermectin, which contained at least 90% 22,23-dihydroavermectin B1a and less than 10% 22,23-dihydroavermectin B1b. The 3rd group of rats was administered 2 mg / kg Ivomec in water via oral gavage (n=9). Ivomec was formulated as a 1% ivermectin solution by the manufacturer. The 4th group of rats was administered 2 mg / kg prototype formulation 7E ("7E") (n=9) in water via oral gavage.

[0269] Blood samples were collected from 6 of the 9 animals in each group at 0.5, 1, 2, 3, 4, 6, 8, 24, 72, 120, and 168 hours after dosing. The concentration of ivermectin B1a in the collected plasma samples was analyzed by a validated LC-MS / MS method. The pharmacokinetic parameters were calculated using the non-compartmental model of PhoenixWinNonlin7.0 software using the concentration data of ivermectin B1a in plasma samples.

[0270] The remaining 3 of the 9 animals in each group were sacrificed 4 hours after the study product was administered. Blood samples were collected via the jugular vein or other suitable vein. The brain was removed, rinsed with saline, dried with filter paper and weighed immediately. The brain samples were homogenized and analyzed for ivermectin B1a concentration by LC-MS / MS method in accordance with FDA guidelines. The ratio of brain samples and plasma samples was calculated for BBB penetration percentage.

[0271] result

[0272] The main pharmacokinetic parameters of ivermectin B1a in SD rat plasma after single administration of ivermectin API, Stromectol, Ivomec and 7E are summarized in Tables 9 and Figure 2-5 .

[0273] Table 9. Main pharmacokinetic parameters of ivermectin B1a in plasma of SD rats after single intravenous administration of ivermectin (API) or oral administration of Stromectol, Ivomec and 7E (mean ± SD). Dose level: 2 mg / kg. Fasting state: fasting. Gender: male. n=6.

[0274]

[0275] Group 1: AUC of ivermectin B1a in plasma after a single IV injection of 2 mg / kg ivermectin API in male SD rats on an empty stomach (0-t) 8259.31±1032.95 hours*ng / ml, T 1 / 2 It is 14.82±0.72 hours.

[0276] Group 2: AUC of ivermectin B1a in plasma after a single PO administration of 2 mg / kg Stromectol to fasting male SD rats (0-t) 4220.94±1594.22 hours*ng / ml, T 1 / 2 It is 12.85±2.16 hours.

[0277] Group 3: AUC of ivermectin B1a in plasma after a single PO administration of 2 mg / kg Ivomec to male SD rats on an empty stomach (0-t) 3396.36±353.94 hours*ng / ml, T 1 / 2 It is 18.49±1.89 hours.

[0278] Group 4: AUC of ivermectin B1a in plasma after a single PO administration of 2 mg / kg 7E to male SD rats on an empty stomach (0-t) 4677.49±920.69 hours*ng / ml, T 1 / 2 It is 17.15±13.14 hours.

[0279] The ratios of ivermectin B1a concentrations in brain to plasma were calculated and summarized in Table 10.

[0280] Table 10. Ratios of ivermectin B1a in plasma and brain of SD rats after single intravenous administration of ivermectin (API) or oral administration of Stromectol, Ivomec and 7E (mean ± SD). Dose level: 2 mg / kg. Fasting state: fasting. Gender: male. n=3.

[0281]

[0282] Group 1: After a single IV injection of 2 mg / kg ivermectin API on an empty stomach in male SD rats, the ratio between the ivermectin B1a concentration in the brain and the ivermectin B1a concentration in the plasma was 0.171±0.010.

[0283] Group 2: After a single PO administration of 2 mg / kg Stromectol to male SD rats on an empty stomach, the ratio between the ivermectin B1a concentration in the brain and in the plasma was 0.046 ± 0.006.

[0284] Group 3: After a single PO administration of 2 mg / kg Ivomec to male SD rats on an empty stomach, the ratio between the ivermectin B1a concentration in the brain and in the plasma was 0.033 ± 0.008.

[0285] Group 4: After a single PO administration of 2 mg / kg 7E to male SD rats on an empty stomach, the ratio between the ivermectin B1a concentration in the brain and in the plasma was 0.043 ± 0.005.

[0286] in conclusion

[0287] After a single oral administration of 2 mg / kg Stromectol and 7E on an empty stomach, C max (Stromectol relative to 7E 1:1.10) or AUC 0-t (Stromectol vs. 7E 1:1.11) There was no significant difference.

[0288] Example 7 - Modulation of PTZ-induced epilepsy by a liquid solution of Formulation 7E in rats

[0289] Functional MRI (fMRI) was performed on anesthetized male Wistar rats using a high-field preclinical MRI system to determine the modulation of pentylenetetrazol (PTZ)-induced paroxysmal brain activity by chronic treatment with a test compound (TC). Animals treated with vehicle and 3 mg / kg alprazolam served as controls. A schematic diagram of the study design can be found in Figure 6 TC was a liquid solution of Formulation 7E at 2 mg / kg or 4 mg / kg. Various physiological parameters were also measured throughout the experiment, including body weight, CO 2 levels, blood pH, and heart rate.

[0290] result

[0291] The area under the curve was calculated for each brain region and treatment, as Figure 7 In each brain region, significant reductions in (PTZ)-induced paroxysmal brain activity were seen with both 2 mg / kg and 4 mg / kg doses of ivermectin liquid solution with Formulation 7E compared to control (vehicle).

[0292] in conclusion

[0293] Physiological parameters measured with arterial blood sampling and pulse oximetry indicated good cardiovascular and respiratory stability of the subjects throughout the functional imaging experiment. The positive control compound (alprazolam, 3 mg / kg) effectively abolished PTZ-induced brain activity with high statistical significance in all brain regions tested.

[0294] Both doses of the liquid solution of Formulation 7E showed significant modulation of PTZ-induced BOLD signal changes in several brain regions (striatum, hippocampus, VTA, cortical areas) in a dose-dependent manner, shortening or attenuating activity duration. The higher IVM dose of 4 mg / kg induced significant modulation in all brain regions studied, thereby attenuating PTZ responses.

[0295] Example 8 - Phase 1 Study of Patient Dosing

[0296] To evaluate the safety, tolerability, PK and high-fat food effects of Formulation 7E, a Phase 1 double-blind, placebo-controlled, randomized (3:1) dose-finding study was conducted in healthy subjects and its effects on quality of life were evaluated. The single ascending dose (SAD) portion of the study was followed by a multiple ascending dose (MAD) cohort of 10, 20, 40, 80 and 120 mg of Formulation 7E once daily for 14 days. The study population was healthy individuals aged 18 to 65 years.

[0297] SAD portion of the study

[0298] Participants were sent to the clinical research center for baseline assessments, including eligibility review, physical examination, neurological examination, laboratory assessment, EKG and pupil measurement one day before dosing. Subjects followed the fasting dose regimen and received a single dose of the study product, followed by continuous PK, vital signs and safety assessments within 120 hours, including pupil measurement and neurological examinations. In addition, PK sample collection occurred at the following time points: pre-dose (within 2 hours before dosing) and 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48, 72 and 120 hours after dosing). Each subsequent SAD cohort (see Table 11) was started 72 hours after the last subject of the previous cohort was administered, as long as less than 2 participants in this cohort experienced dose-limiting toxicity (DLT) because ivermectin toxicity appeared within 24 hours after administration. Participants in the 40mg cohort of the SAD part of the study were not discharged on Day 6, but continued to the feeding sub-study, administering the feeding dose with a high-fat meal 10 days after the fasting dose. Assessments after the fed dose were identical to those after the fasted SAD dose and continued for 120 hours.

[0299] Two vials of whole blood samples for PD measurements were collected pre-dose and 24 hours after a single dose for exploratory biomarker studies.

[0300] MAD portion of the study (14-day study, one dose per day)

[0301] Each MAD cohort (10mg-80mg) (see Table 11) will start dosing the day after the SAD cohort completes dosing at the above doses and has been monitored for 72 hours, provided that the SAD study or the lower dose MAD cohort has not met the stopping criteria. If the stopping criteria have not been met, the 120mg MAD cohort will start after the last subject in the 80mg cohort has been dosed to Day 5, as it is estimated that steady state will occur around 4 days.

[0302] Volunteers received screening and baseline assessments for the SAD portion of the study as described above. Subjects followed the fasting dose regimen on days 1, 2, and 14, and were administered a single study product daily for 14 days. After dosing on days 1, 7, and 14, vital signs and safety assessments were performed, including pupillometry and neurological examinations. These and additional safety assessments were also performed on day 19. PK sample collection occurred at the following time points after dosing on days 1 and 14: pre-dose (within 2 hours before dosing) and 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48, 72, and 120 hours (pre-dose) after the initial day 1 dose. Blood for PK was also drawn on days 5, 7, 8, 9, 10, 12, and 14 before dosing. If two participants in a cohort experienced DLT, this cohort and any higher dose overlapping cohorts were stopped.

[0303] Two vials of whole blood samples for PD measurements were collected pre-dose and on Day 15 (24 hours after the last dose of study drug for subjects in the MAD study) for exploratory biomarker studies.

[0304] Table 11. Phase I dose cohorts

[0305]

[0306]

[0307] *Formulation 7E Gelatin Capsules 40 mg (or MTD, whichever is lower) (n=8 from 40 mg or MTD SAD cohort)

[0308] Example 9 - Phase 2 Study of Patient Dosing (Daily, 12 Weeks)

[0309] A double-blind, placebo-controlled, randomized (4:1) Phase II safety and dose-finding study of adjunctive composition 7E was conducted to evaluate the preliminary efficacy of formulation 7E in terms of overall seizure reduction, seizure reduction by seizure type (focal, generalized, and unknown), reduction in generalized tonic-clonic seizures and focal to generalized tonic-clonic seizures, seizure-free rate over time, tolerability, and effect on suicidality. The population was subjects aged 18 to 70 years who were diagnosed with epilepsy according to the International League Against Epilepsy (ILAE) 2017 Classification of Epilepsy Criteria (ILAE 2017) and were uncontrolled on one to four concomitant best stable doses of antiepileptic drugs (AEDs) for ≥4 weeks prior to screening and throughout the treatment period.

[0310] The cohorts (see Table 12) were dosed sequentially starting with dose cohort 1. This study initially randomized a total of 10 subjects into the first dosing cohort (10 mg daily, 4:1 active agent to placebo) for 12 weeks. Safety data was reviewed after 14 days to determine whether the next cohort could be opened. After each cohort, under the supervision of the Safety Review Committee (SRC), dosing continued through the continuous reassessment method (CRM) until 10 subjects completed 14 days of dosing at 60 mg QD, or until a total of 10 subjects received the same active dose for 14 days and this dose was identified as MTD. In each dosing cohort, subjects who did not have DLT during the initial 14 days of treatment will continue to be dosed for 12 weeks as long as they do not experience DLT, otherwise meet exit criteria, or decide to withdraw from treatment.

[0311] After 2, 4, 8, and 12 weeks of treatment, PK parameters as well as safety, efficacy, and concomitant antiepileptic drugs (AEDs) will be evaluated by an unblinded study statistician and provided to the sponsor-designated study physician for review. This review will be conducted separately from the dose escalation review based on DLT development.

[0312] Table 12. Estimated Phase II dose cohorts

[0313]

Claims

1. A pharmaceutical composition, comprising: (i) about 1% to about 15% ivermectin comprising a compound of Formula VI and a compound of Formula VII: (ii) from about 20% to about 40% of a first surfactant, the first surfactant comprising one or more of: (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, wherein the fatty acid is selected from C6 to C 10 fatty acids; and (iii) from about 15% to about 70% of a second surfactant selected from one or more polysorbate surfactants and / or fatty acid esters of sorbitan.

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

5. The pharmaceutical composition of any one of claims 1 to 4, wherein the fatty acid of the first surfactant is selected from C8 to C 10 fatty acid.

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

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

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

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

13. 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. The pharmaceutical composition of any one of claims 1 to 4, comprising: (i) about 5% to about 10% ivermectin; (ii) about 25% to about 30% mono- and di-C8 to C6 glycerol; 10 fatty acid ester; (iii) from about 15% to about 30% of a polysorbate surfactant; and (iv) from about 30% to about 50% Vitamin E TPGS.

15. The pharmaceutical composition of any one of claims 1 to 4, comprising: (i) about 8% ivermectin; (ii) about 27.6% mono- and di-C8 to C6 glycerol; 10 fatty acid esters; (iii) about 32.2% polysorbate 80; and (iv) about 32.2% Vitamin E TPGS.

16. 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. The pharmaceutical composition of any one of claims 1 to 4, comprising: (i) about 8% ivermectin; (ii) about 27.6% mono- and di-C8 to C6 glycerol; 10 fatty acid esters; (iii) about 18.4% polysorbate 80; and (iv) about 46% Vitamin E TPGS.

18. 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 in a gelatin capsule.

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