METHODS OF USING AVERMECTIN COMPOSITIONS FOR THE TREATMENT OF SPASTICITY AND DOSING REGIMENS

FIELD

[0001] The present disclosure provides compositions and dosage forms of avermectins, and particularly of ivermectin. The compositions may be used for the treatment and prevention of spasticity.

BACKGROUND

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

[0003] Ivermectin, an avermectin family member, is a highly potent anti-parasitic agent. Ivermectin is a mixture of 5-(9-demethyl-22,23-dihydroavermectin Ala (also called 22,23- dihydroavermectin Bia) and 5-<9-demethyl-25-de(l-methylpropyl)-22,23-dihydro-25-(l- methylethyl)avermectin Ala (also called 22,23 -dihydroavermectin Bib). Ivermectin has been used historically as a broad-spectrum anti -parasitic medicinal product for human and veterinary use.

[0004] Ivermectin is commercially available for animal use as Cardomec (for felines), Eqvalane (for equines) and Ivomec (for bovines) by Merial; as Zimecterin (for equines) by Farnam Companies, Inc. The medicine is available in tablets and chewables for heartworm prevention, topical solution for ear mite treatment, and injectable solution, oral paste or solution for other parasites in veterinary use. Ivermectin is also available for human use for treating parasitic infestations. For example, Stromectol, containing 3 mg ivermectin/tablet and marketed by Merck & Co., is approved by the U.S. Food and Drug Administration to treat onchoceriasis (river blindness) and strongyloidiasis (non-disseminated intestinal threadworm). Ivermectin may exert its antiparasitic activity via activation of a chloride ion-gated glutamate channel present in the invertebrate nervous system. Binding to the chloride ion-gated glutamate channel may result in hyperpolarization of nerves and muscle fiber. Such hyperpolarization may lead to paralysis and death of the organism (parasite). The chloride ion-gated glutamate channels are specific for invertebrates and are not expressed in the mammalian hosts, allowing for a specific action of ivermectin to be directed at the parasites.

[0005] The currently used medications for spasticity may show significant side effects, such as behavioral changes, lethargy, insomnia, clinical depression, psychotic behavior, respiratory depression, coma and death, particularly when taken in overdoses or for long periods of time. Thus, there is an unmet need for development of alternative drugs and dosing regimens that can be used to treat or prevent spasticity while causing little or no adverse health risks.

SUMMARY

[0006] The present disclosure provides pharmaceutical compositions and dosage forms of avermectins, and particularly of ivermectin. The present disclosure also provides methods for the treatment of spasticity by administering to a patient in need thereof a composition comprising one or more avermectins, and particularly ivermectin. The compositions of the avermectins may be liquid or semi-solid at room temperature and comprise an avermectin, and particularly ivermectin, a first surfactant and a second surfactant. Also provided are dosing regimens for using the disclosed compositions and dosage forms for the treatment and prevention of spasticity. The methods, compositions and dosing regimens provided by this disclosure may address the need for avermectin formulations with improved pharmacokinetic properties, including, but not limited to bioavailability.

[0007] The disclosure provides a method of treating or preventing spasticity, the method comprising administering to a subject in need thereof a pharmaceutical composition comprising:

(i) about 1% to about 15% of a compound of Formula I:

or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, or isotopically labeled compound thereof; wherein each occurrence of X is independently selected from -CH2-, -NH-, -O-, -S-, -SO- and -SO2-;

Y is selected from -CH2-, -O-, -NH-, and -S-;

Z is selected from O and S; each occurrence of - is a single bond or a double bond; n is an integer 0-6; and each occurrence of R ¹ is independently selected from halogen, -R, -OR, -NO2, -NCS,

-CN, -CF ₃ , -OCF3, -NHR, -N(R) ₂ , -OC(O)R, -C(O)OR, -SR, -C(O)R, -C(O)C(O)R, -C(O)CH ₂ C(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), -CH2-OR, and -CH2-O-CH2-R; each occurrence of R ² is independently selected from independently selected from H, OH, O-Ci- ₄ alkyl, -OC(O)Ci- ₄ alkyl, -OC(O)NH ₂ , and -OC(O)NHCi- ₄ alkyl; each occurrence of R ³ is mono, di, or triglycoside, or OC(O)-(C3-Cs)alkenyl; each R is independently selected from H, -(Ci-Ci2)alkyl, -(C3-Cio)-cycloalkyl , (C3-C10)- cycloalkenyl , -[(C3-Cio)cycloalkyl]-(Ci-Ci2)alkyl, -[(C3-Cio)cycloalkenyl]-(Ci- Ci2)alkyl, -[(C3-Cio)cycloalkenyl]-(Ci-Ci2)alkyl, -[(C ₃ -Cio)cycloalkyl]-0-(Ci- Ci ₂ )alkyl, -[(C3-Cio)cycloalkenyl]-0-(Ci-Ci ₂ )alkyl, -(C ₆ -Cio)aryl, (C ₆ -Cio)aryl-(Ci- Ci ₂ )alkyl, -(C ₆ -Cio)aryl-0-(Ci-Ci2)alkyl, (C ₆ -Cio)aryl-N(R")-(Ci-Ci2)alkyl, 3- to 10- membered heterocyclyl, (3- to 10-membered heterocyclyl)-(Ci-Ci2)alkyl, (3- to 10- membered heterocyclyl)-O-(Ci-Ci2)alkyl, (3- to 10-membered heterocyclyl)-N(R')- (Ci-Ci2)alkyl, 5- to 10-membered heteroaryl, (5- to 10-membered heteroaryl)-(Ci- Ci2)-alkyl, (5- to 10-membered heteroaryl)-O-(Ci-Ci2)-alkyl and (5- to 10-membered heteroaryl)-N(R")-(Ci-Ci2)-alkyl; each heterocyclyl has 1-4 heteroatoms independently selected from N, NH, O, S, SO, and SO2, and heteroaryl has 1-4 heteroatoms independently selected from N, NH, O, and S; each occurrence of R is independently unsubstituted or is substituted with 1 to 5 R'; each occurrence of R' is halo, OH, oxo, -CH2OR", -CH2N(R")2, C(0)N(R")2, -C(O)OR", -NO2, -NCS, -CN, -CF ₃ , -OCF3 and -N(R") ₂ ; and each occurrence of R" is independently H, Ci-ealkyl, C2-ealkenyl, Cs-ecycloalkyl, Cs-ecycloalkenyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, and (Ce- Cio)-aryl;

(ii) about 20% to about 40% of a 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 acids are selected from Ce to C10 fatty acids; and

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

[0008] In some embodiments, the compound of Formula I is a compound of Formula II: or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate or isotopically labeled compound thereof, wherein n, R ¹ , R ² , and R ³ are each as defined in Formula I.

[0009] In some embodiments, the compound of Formula II is a compound of Formula III:

or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate or isotopically labeled compound thereof, wherein R ¹ , R ² , and R ³ are each as defined in Formula I.

[0010] In some embodiments, the compound of Formula III is a compound of Formula IV: or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate or isotopically labeled compound thereof, wherein each occurrence of R ¹ is independently selected from halogen, -R, -OR, -NO2, -NCS, -CN, -CF ₃ , -OCF3, -NHR, -N(R) ₂ , -OC(O)R, -C(O)OR, -C(O)N(R) ₂ , -OC(O)N(R) ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R) ₂ , -CH ₂ -OR, and -CH2-O-CH2-R; each occurrence of R ³ is mono, di, or triglycoside, or OC(O)-(C3-Cs) alkenyl; and

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

[0011] In some embodiments, the compound of Formula IV is a compound of Formula V:

or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate or isotopically labeled compound thereof, wherein each occurrence of R ¹ is independently selected from halogen, -R, -OR, -NO2, -NCS, -CN, -CF ₃ , -OCF3, -NHR, -N(R) ₂ , -OC(O)R, -C(O)OR, -C(O)N(R) ₂ , -OC(O)N(R) ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R) ₂ , -CH ₂ -OR, and -CH2-O-CH2-R; and R, R' and R" are each as defined in Formula I.

[0012] In embodiments, the pharmaceutical composition comprises about 1% to about 15% of a compound of any one of Formulas I- VII. In some embodiments, the pharmaceutical composition comprises about 1% to about 15% of one or more of a compound of Formulas I- VII. In some embodiments, the pharmaceutical composition comprises about 1% to about 15% of ivermectin comprising a compound of Formula VI (22,23 -dihydroavermectin Bia) and a compound of Formula VII (22,23 -dihydroavermectin Bib). In some embodiments, the pharmaceutical composition comprises ivermectin comprising at least about 70% of 22,23- dihydroavermectin Bia and less than about 30% of 22,23 -dihydroavermectin Bib. In some embodiments, the pharmaceutical composition comprises ivermectin comprising at least about 90% of 22,23 -dihydroavermectin Bia and less than about 10% of 22,23 -dihydroavermectin Bib.

[0013] In some embodiments, the pharmaceutical composition comprises about 3% to about 12% of a compound of any one of Formulas I- VII. In some embodiments, the pharmaceutical composition comprises about 5% to about 10% of a compound of any one of Formulas I- VII. In some embodiments, the pharmaceutical composition comprises about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, or about 12% of a compound of any one of Formulas I- VII.

[0014] In some embodiments, the pharmaceutical composition comprises about 3% to about 12% of one or more of a compound of Formulas I-VII. In some embodiments, the pharmaceutical composition comprises about 5% to about 10% of one or more of a of Formulas I- VII. In some embodiments, the pharmaceutical composition comprises about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, or about 12% of one or more of a of Formulas I- VII.

[0015] 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% 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% ivermectin comprising a compound of Formula VI and a compound of Formula VII. [0016] In embodiments, the pharmaceutical composition includes a first surfactant, wherein the fatty acids are selected from Cs to Cio 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 includes about 25% to about 30% of the first surfactant.

[0017] In embodiments, the pharmaceutical composition includes a second surfactant selected from polysorbate 80 (Tween 80), sorbitan monolaurate (Span 20), and combinations thereof. In some embodiments, the pharmaceutical composition includes about 15% to about 20% of the second surfactant. In some embodiments, the pharmaceutical composition includes about 30% to about 35% of the second surfactant. In some embodiments, the pharmaceutical composition includes about 60% to about 65% of the second surfactant.

[0018] In some embodiments, the pharmaceutical composition comprises about 5% to about 55% D-a-Tocopherol polyethylene glycol 1000 succinate (vitamin E TPGS); or about 30% to about 50% vitamin E TPGS. In an embodiment, the pharmaceutical composition is in a dosage form comprising a gelatin capsule.

[0019] In embodiments, the pharmaceutical composition comprises: (i) about 5% to about 10% ivermectin; (ii) about 25% to about 30% mono- and di- Cs to Cio fatty acid esters of glycerol; (iii) about 15% to about 30% of a polysorbate surfactant; and (iv) about 30% to about 50% vitamin E TPGS. [0020] In an embodiment, the pharmaceutical composition comprises: (i) about 8% ivermectin; (ii) about 27.6% mono- and di- Cs to Cio fatty acid esters of glycerol; (iii) about 32.2% polysorbate 80; and (iv) about 32.2% vitamin E TPGS.

[0021] In an 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.

[0022] In an embodiment, the pharmaceutical composition comprises: (i) about 8% ivermectin; (ii) about 27.6% mono- and di- Cs to Cio fatty acid esters of glycerol; (iii) about 18.4% polysorbate 80; and (iv) about 46% vitamin E TPGS.

[0023] In an 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.

[0024] In an embodiment, the pharmaceutical composition comprises: (i) about 8% ivermectin; (ii) about 27.6% mono- and di- Cs to Cio fatty acid esters of glycerol; and (iii) about 64.4% polysorbate 80.

[0025] In an embodiment, the pharmaceutical composition comprises: (i) about 8% ivermectin; (ii) about 27.6% Masester E8120; and (iii) about 64.4% polysorbate 80.

[0026] The disclosure provides a method of treating or preventing spasticity, the method comprising administering to a subject in need thereof a pharmaceutical composition disclosed herein. In some embodiments, the spasticity is secondary to multiple sclerosis, a spinal cord injury, a stroke, or a brain injury. In an embodiment, the spasticity is spinal spasticity. In an embodiment, the spasticity is not secondary to cerebral palsy. In an embodiment, the treatment reduces hyper-reflexia in the human subject. In an embodiment, the spasticity is secondary to a spinal cord injury, and the method further comprises beginning administering to the human subject a dose of the formulation after the spinal cord injury and before the spasticity develops. In an embodiment, the spasticity is secondary to multiple sclerosis, wherein the method further comprises beginning administering to the human subject a dose of the formulation after a diagnosis of the multiple sclerosis and before the spasticity develops. In an embodiment, the step of administering the formulation is effective to increase connexin 36 levels in spinal cord neuron. In an embodiment, the step of administering the formulation is effective to increase gap junctions in neurons in the spinal cord or increase electrical coupling between neurons in the spinal cord.

[0027] In an embodiment, the spasticity is associated with inflammation. [0028] In an embodiment, the method further comprises administering to the human subject another therapeutic agent. In some embodiments, the other therapeutic agent is baclofen, benzodiazepines, diazepam, clonazepam, dantrolene, or tizanidine.

[0029] In an embodiment, the subject is a mammal and particularly is a human.

[0030] The disclosure provides a method of treating spasticity, the method comprising administering about 10 mg to about 120 mg of a compound disclosed herein to the subject. In some embodiments, about 10 mg to about 80 mg of the compound is administered to the subject. In some embodiments, about 20 mg to about 40 mg of the compound is administered to the subject. In some embodiments, about 10 mg, about 20 mg, about 40 mg, about 60 mg, about 80 mg, or about 120 mg of the compound is administered to the subject. In embodiments, the pharmaceutical composition comprising a compound disclosed herein is administered once a day, every other day, or every three days. In an embodiment, the pharmaceutical composition comprising a compound disclosed herein is administered once a day. In some embodiments, the pharmaceutical composition is administered for at least 14 days. In some embodiments, the pharmaceutical composition is administered for about 14 days, for about 30 days, for about 60 days, for about 84 days, for about 90 days, or continuously. In an embodiment, the pharmaceutical composition is administered as a single dose on each day the pharmaceutical composition is administered. In an embodiment, the pharmaceutical composition is administered in the form of several divided doses on each day the pharmaceutical composition is administered.

BRIEF DESCRIPTION OF THE FIGURES

[0031] Fig. 1. Graph showing fiberoptic dispersion of ivermectin formulation prototypes in FaSSIF (IE - 7E).

[0032] Fig. 2. The mean concentration-time curve of ivermectin Bia in SD rat plasma after a single fasting intravenous injection with 2 mg/kg ivermectin API.

[0033] Fig. 3. The mean concentration-time curve of Ivermectin Bia in SD rat plasma after a single fasting oral administration with 2 mg/kg Stromectol.

[0034] Fig. 4. The mean concentration-time curve of ivermectin Bia in SD rat plasma after a single fasting oral administration with 2 mg/kg Ivomec.

[0035] Fig. 5. The mean concentration-time curve of ivermectin Bia in SD rat plasma after a single fasting oral administration with 2 mg/kg formulation 7E. [0036] Fig. 6. Schematic showing the study to evaluate modulation of pentylenetetrazol (PTZ)-induced seizures by a liquid solution of formulation 7E in rats.

[0037] Figs. 7A and 7B. Fig. 7A. Area under the curve values from the BOLD fMRI timeseries from selected brain regions. Data are presented 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 significances: (p < 0.05, p < 0.01, p < 0.001, p < 0.0001, Ordinary two-way ANOVA). Vehicle vs. Alprazolam in all; Vehicle vs. IVM (4 mg/kg + PTZ) in all except in HipAD and Pons. Alprazolam vs. IVM 2 mg/kg in CinCtx, MotCtx, RSCtx, SSCtx, ThalVM & mPFC. Fig. 7B. Area under the curve values from the BOLD fMRI timeseries from selected brain regions. Data are presented as mean + SEM, n=l l-12 per group. From left to right: (1) Vehicle + PTZ, (2) IVM liquid solution, 1 mg/kg + PTZ, (3) IVM liquid solution, 2 mg/kg + PTZ, Alprazolam (3 mg/kg) + PTZ. Statistical significances: were observed when comparing treatment groups (* p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001, Ordinary two-way ANOVA, Holm-Sidak's multiple comparisons test). 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 of the Accumbens Shell; Amygdala; CPu = Caudate Putamen; mPFC = medial prefrontal cortex; and ThalMD = mediodorsal nucleus of the thalamus.

[0038] Figs. 8A, 8B, 8C, 8D, 8E, 8F, and 8G illustrate the pharmacokinetic data (PK) obtained from the phase 1 clinical trial (single ascending dose (SAD) portion). Patients were administered the indicated dose of formulation 7E. Fig. 8G provides a summary of the data presented in Figs. 8A, 8B, 8C, 8D, 8E, and 8F.

[0039] Figs. 9A and 9B illustrate down-regulation of IL- 17 secretion in peripheral blood mononuclear cells (PBMCs) purified from healthy human subjects before and after (24 hours after the last dosing) oral administration of the indicated dose of formulation 7E. Fig. 9A. SAD cohort. Fig. 9B. Multiple ascending dose (MAD) cohort. Statistical significance: treatment effect vs placebo * p<0.05, ** p<0.01, *** p<0.001, **** p<0.0001 by Two-way RM ANOVA, Dunnett' s multiple comparisons test. DETAILED DESCRIPTION

[0040] The present disclosure provides pharmaceutical compositions and dosage forms of avermectins, and particularly of ivermectin. The compositions (also referred herein interchangeably as formulations) of the avermectins are liquid or semi-solid at room temperature and comprise an avermectin, and particularly ivermectin, a first surfactant and a second surfactant. The compositions may be used for the treatment and prevention of spasticity. Also provided are dosing regimens for using the disclosed compositions and dosage forms for the treatment and prevention of spasticity.

[0041] Avermectins and Ivermectin

[0042] Any of the avermectin compounds, which includes derivatives and analogs disclosed herein, may be used in the compositions and methods provided by this disclosure. Avermectins include a family of four closely related major components, Ala, A2a, Bia and B2a and four minor components Alb, A2b, Bib, B2b which are lower homologs of the corresponding major components. Eight different avermectins were isolated in four pairs of homologue compounds, with a major and minor component usually in ratios of about 80:20 to about 90: 10. Anthelmintics derived from the avermectins include ivermectin, selamectin, doramectin, eprinomectin, moxidectin, avermectin, and abamectin. The family members show anthelmintic and insecticidal/acaricidal activity in different degree of potencies.

[0043] Provided herein are compositions comprising about 1% to about 15% of an avermectin compound, wherein the avermectin compound may be a macrocyclic compound according to Formula I: or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, or isotopically labeled compound thereof; wherein: each occurrence of X is independently selected from -CH2-, -NH-, -O-, -S-, -SO- and -S0 ₂ -;

Y is selected from -CH2-, -O-, -NH-, and -S-;

Z is selected from O and S; each occurrence of == is a single bond or a double bond; n is an integer 0-6; and each occurrence of R ¹ is independently selected from halogen, -R, -OR, -NO2, -NCS, -CN, -CF ₃ , -OCF3, -NHR, -N(R) ₂ , -OC(O)R, -C(O)OR, -SR, -C(O)R, -C(O)C(O)R, -C(O)CH ₂ C(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), -CH2-OR, and -CH2-O-CH2-R; each occurrence of R ² is independently selected from independently selected from H, OH, O-Ci- ₄ alkyl, -OC(O)Ci- ₄ alkyl, -OC(O)NH ₂ , and -OC(O)NHCi- ₄ alkyl; each occurrence of R ³ is mono, di, or triglycoside, or OC(O)-(C3-Cs)alkenyl; each R is independently selected from H, -(Ci-Ci2)alkyl, -(C3-Cio)-cycloalkyl , (C3-C10)- cycloalkenyl , -[(C3-Cio)cycloalkyl]-(Ci-Ci2)alkyl, -[(C3-Cio)cycloalkenyl]-(Ci- Ci2)alkyl, -[(C3-Cio)cycloalkenyl]-(Ci-Ci2)alkyl, -[(C ₃ -Cio)cycloalkyl]-0-(Ci- Ci ₂ )alkyl, -[(C3-Cio)cycloalkenyl]-0-(Ci-Ci ₂ )alkyl, -(C ₆ -Cio)aryl, (C ₆ -Cio)aryl-(Ci- Ci ₂ )alkyl, -(C ₆ -Cio)aryl-0-(Ci-Ci2)alkyl, (C ₆ -Cio)aryl-N(R")-(Ci-Ci2)alkyl, 3- to 10- membered heterocyclyl, (3- to 10-membered heterocyclyl)-(Ci-Ci2)alkyl, (3- to 10- membered heterocyclyl)-O-(Ci-Ci2)alkyl, (3- to 10-membered heterocyclyl)-N(R')- (Ci-Ci2)alkyl, 5- to 10-membered heteroaryl, (5- to 10-membered heteroaryl)-(Ci-Ci2)- alkyl, (5- to 10-membered heteroaryl)-O-(Ci-Ci2)-alkyl and (5- to 10-membered heteroaryl)-N(R")-(Ci-Ci2)-alkyl; each heterocyclyl has 1-4 heteroatoms independently selected from N, NH, O, S, SO, and SO2, and heteroaryl has 1-4 heteroatoms independently selected from N, NH, O, and S; each occurrence of R is independently unsubstituted or is substituted with 1 to 5 R'; each occurrence of R' is halo, OH, oxo, -CH2OR", -CH2N(R")2, C(O)N(R")2, - C(O)OR", -NO2, NCS, CN, CF ₃ , OCF3 and -N(R") ₂ ; and each occurrence of R" is independently H, Ci-ealkyl, C2-ealkenyl, Cs-ecycloalkyl, C3- ecycloalkenyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, and (Ce- Cio)-aryl.

[0044] In some embodiments, the compound of Formula I is a compound of Formula II: or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate or isotopically labeled compound thereof, wherein n, R ¹ , R ² , and R ³ are each as defined in Formula I.

[0045] In some embodiments, the compound of Formula II is a compound of Formula III: or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate or isotopically labeled compound thereof, wherein R ¹ , R ² , and R ³ are each as defined in Formula I.

[0046] In some embodiments, the compound of Formula III is a compound of Formula IV:

or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate or isotopically labeled compound thereof, wherein: each occurrence of R ¹ is independently selected from halogen, -R, -OR, -NO2, -NCS, -CN, - CF ₃ , -OCF3, -NHR, -N(R) ₂ , -OC(O)R, -C(O)OR, -C(O)N(R) ₂ , -OC(O)N(R) ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R) ₂ , -CH ₂ -OR, and -CH ₂ -O-CH ₂ -R; each occurrence of R ³ is mono, di, or triglycoside, or OC(O)-(C3-Cs) alkenyl;

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

[0047] In some embodiments, the compound of Formula IV is a compound of Formula V: or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate or isotopically labeled compound thereof, wherein each occurrence of R ¹ is independently selected from halogen, -R, -OR, -NO ₂ , -NCS, -CN, -CF ₃ , -OCF3, -NHR, -N(R) ₂ , -OC(O)R, -C(O)OR, -C(O)N(R) ₂ , -OC(O)N(R) ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R) ₂ , -CH ₂ -OR, and -CH ₂ -O-CH ₂ -R:

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

[0048] In embodiments, the macrocyclic compound is an avermectin compound or derivative, a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N- oxide, or isotopically labeled compound thereof. In an embodiment, the macrocyclic compound is avermectin. In some embodiments, the macrocyclic compound is selected from the group consisting of ivermectin, selamectin, doramectin, eprinomectin, moxidectin, avermectin, and abamectin. In some embodiments, the macrocyclic compound is ivermectin or a derivative, a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N- oxide, or isotopically labeled compound thereof.

[0049] Provided herein is a composition 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 of a compound of any one of Formulas I- VII. In some embodiments, the composition comprises about 1% to about 15% ivermectin comprising 22,23- dihydroavermectin Bia (Formula VI) and 22,23 -dihydroavermectin Bib (Formula VII). In some embodiments, the composition comprises ivermectin comprising from at least about 70% to at least about 90% of a compound of Formula VI and from less than about 30% to less than about 10% of a compound of Formula VII:

Formula VI: 22,23 -Dihydroavermectin Bia, CAS No. 71827-03-7

Formula VII: 22,23 -Dihydroavermectin Bib, CAS No. 70209-81-3 [0050] In some embodiments, the composition comprises ivermectin comprising from at least about 70% to at least about 90% of a compound of Formula VI and from less than about 30% to less than about 10% of a compound of Formula VII. In some embodiments, ivermectin comprises at least about 70% of 22,23 -dihydroavermectin Bia and less than about 30% of 22,23 -dihydroavermectin Bib. In some embodiments, ivermectin comprises at least about 90% of 22, 23 -dihydroavermectin Bia and less than about 10% of 22,23 -dihydroavermectin Bib.

[0051] Derivatives of ivermectin, including abamectin and doramectin, and prodrugs of ivermectin, may have properties and uses similar to those of ivermectin. Abamectin and doramectin both have a double bond at positions C22-C23 in the structural formula of ivermectin. Additionally, in doramectin, position C25 is substituted at the side chain of a cyclohexyl ring.

Doramectin, CAS No. 117704-25-3 [0052] As used herein, “derivative” to a compound that retains the biological activity of the parent avermectin from which it is derived, or is a prodrug for the parent avermectin. Derivatives may include esters, amides, ethers or the like that are derived from the avermectin. [0053] As used herein, the term “alkyl” refers to a hydrocarbon chain that is a straight chain or a branched chain, containing the indicated number of carbon atoms. For example, Ci-6 indicates that the group has from 1 to 6 (inclusive) carbon atoms in it. In the absence of any numerical designation, “alkyl” is a chain (straight or branched) having 1 to 20 (inclusive) carbon atoms in it. The term “unsaturated alkyl” refers to a hydrocarbon having no unsaturated bonds (e.g., a carbon-carbon double bond or a carbon-carbon triple bond). The term “unsaturated alkyl” refers to a hydrocarbon having one or more unsaturated bonds (e.g., a carbon-carbon double bond or a carbon-carbon triple bond).

[0054] As used herein, the term “alkenyl” refers to a hydrocarbon chain that is a straight chain or branched chain having one or more carbon-carbon double bonds. The alkenyl moiety contains the indicated number of carbon atoms. For example, C2-6 indicates that the group has from 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.

[0055] The term “cycloalkyl” as employed herein includes saturated and partially unsaturated cyclic hydrocarbon groups. Unless indicated otherwise, a cycloalkyl has 3 to 12 carbons, or 3 to 8 carbons, or 3 to 6 carbons, wherein the cycloalkyl group additionally is optionally substituted. Some cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. [0056] As used herein, the term “aryl” refers to a 6 to 10 carbon monocyclic or bicyclic aromatic ring system wherein 0, 1, 2, 3, or 4 atoms of each ring are substituted by a substituent. Examples of aryl groups include phenyl, naphthyl and the like.

[0057] As used herein, the term “heterocyclyl group” or “heterocyclyl” refers to aromatic and non-aromatic ring compounds containing 3 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S. A heterocyclyl can be a cycloheteroalkyl, or a heteroaryl, or if polycyclic, any combination thereof. Heterocyclyl groups may comprise from 3 to about 20 ring members, whereas other such groups may comprise from 3 to about 15 ring members. A heterocyclyl group designated as a C2- heterocyclyl can be a 5-membered ring with two carbon atoms and three heteroatoms, a 6- membered ring with two carbon atoms and four heteroatoms, and so forth. Likewise, a C4- heterocyclyl can be a 5-membered ring with one heteroatom, a 6-membered ring with two heteroatoms, and so forth. The number of carbon atoms and the number of heteroatoms, when summed up, equal the total number of ring atoms. A heterocyclyl ring can also include one or more double bonds. A heteroaryl ring is an embodiment of a heterocyclyl group. In some embodiment, the “heterocyclyl” refers to a nonaromatic 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, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of O, N, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring are substituted by a substituent. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like.

[0058] 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, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of O, N, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2, 3, or 4 atoms of each ring are substituted by a substituent. Examples of heteroaryl groups include pyridyl, furyl or furanyl, imidazolyl, benzimidazolyl, pyrimidinyl, thiophenyl or thienyl, quinolinyl, indolyl, thiazolyl, and the like.

[0059] As used herein, the term “glycoside” refers to any material with a chemical structure comprising a glycosidic bond between a carbohydrate (sugar) molecule and another carbohydrate or a non-carbohydrate (non-sugar) moiety. A glycosidic bond or glycosidic linkage is a type of covalent bond that joins a carbohydrate (sugar) molecule, for example, via its hemiacetal or hemiketal group, to another molecule. The other molecule may or may not be a carbohydrate. The sugar moiety is generally known as the glycone part of a glycoside. The glycone can consist of a single sugar group (monosaccharide), two sugar groups (disaccharide) or several sugar groups (oligosaccharide).

[0060] As used herein, the term “substituent” refers to a group replacing a second atom or group such as a hydrogen atom on any molecule, compound or moiety. Suitable substituents include, without limitation, halo, hydroxy, mercapto, oxo, nitro, haloalkyl, alkyl, alkaryl, aryl, aralkyl, alkoxy, thioalkoxy, aryloxy, amino, alkoxycarbonyl, amido, carboxy, alkanesulfonyl, alkylcarbonyl, and cyano groups.

[0061] In embodiments, the avermectin used in the formulations and methods provided herein will be in the neutral form. However, when the avermectin comprises an ionizable group, the avermectin may be present as a pharmaceutically acceptable salt. As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are suitable for pharmaceutical use, such as, for example, for use in humans and animals. Pharmaceutically acceptable salts of amines, carboxylic acids, and other types of compounds, are well known in the art. For example, S. M. Berge, et al., describe pharmaceutically acceptable salts in detail in J Pharmaceutical Sciences, 66: 1-19 (1977), incorporated herein by reference. The salts can be prepared in situ during the final isolation and purification of the avermectin, or separately by reacting a free base or free acid function with a suitable reagent. For example, a free base function can be reacted with a suitable acid. Suitable pharmaceutically acceptable salts can, include metal salts such as alkali metal salts, e. g. sodium, potassium, and lithium salts; and alkaline earth metal salts, e. g. calcium or magnesium salts. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an 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, dodecyl sulfate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy- ethanesulfonate, 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 salts, and the like.

[0062] Avermectin Compositions

[0063] The compositions for use in the methods and dosages provided herein are liquid or semi-solid at room temperature and comprise an avermectin, and particularly ivermectin, a first surfactant and a second surfactant.

[0064] In embodiments, the composition comprises:

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

(ii) about 20% to about 40% of a first surfactant 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 acids are selected from Ce to Cio fatty acids; and

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

[0065] In some embodiments, the composition comprises about 3% to about 12% of a compound of any one of Formulas I- VII. In some embodiments, the composition comprises about 5% to about 10% of a compound of any one of Formulas I- VII. In some embodiments, the composition comprises about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, or about 12% of a compound of any one of Formulas I- VII.

[0066] In embodiments, the composition comprises:

(i) about 1% to about 15% of one or more of a compound of any one of Formulas I- VII;

(ii) about 20% to about 40% of a 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 acids are selected from Ce to Cio fatty acids; and

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

[0067] In some embodiments, the composition comprises about 3% to about 12% of one or more of a compound of Formulas I- VII. In some embodiments, the composition comprises about 5% to about 10% of one or more of a of Formulas I- VII. In some embodiments, the composition comprises about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, or about 12% of one or more of a of Formulas I-VII.

[0068] In embodiments, the composition comprises:

(i) about 1% to about 15% of ivermectin comprising a compound of Formula VI and a compound of Formula VII;

(ii) about 20% to about 40% of a 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 acids are selected from Ce to Cio fatty acids; and (iii) about 15% to about 70% of a second surfactant selected from one or more of a polysorbate surfactant and/or a fatty acid ester of sorbitan.

[0069] In some embodiments, the 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 composition comprises about 5% to about 10% 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 comprising a compound of Formula VI and a compound of Formula VII.

[0070] The composition provided herein comprises a first surfactant, which may be a mixture of surfactants, and comprise C>, to Cio fatty acid esters of glycerol, of 1,2-propylene glycol, and/or of polyethylene glycol. The Ce to Cio fatty acid(s) may be saturated or unsaturated, but is preferably saturated. More preferably, the fatty acid has from 8 to 10 carbons, and particularly may be 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.

[0071] The first surfactant may comprise mono-, di-, and/or tri- fatty acid esters of glycerol. The fatty acid ester of glycerol may be a mixture of mono- and di-esters of glycerol. The fatty acid component is one or more Ce to Cio fatty acid(s) and may be saturated or unsaturated, but is preferable saturated. More preferably, the fatty acid has from 8 to 10 carbons, and particularly may be caprate, caprylate and mixtures thereof. The fatty acid esters of glycerol are commercially available and include Capmul 808G EP/NF (glyceryl monocaprylate), Capmul MCM C8 EP/NF (glyceryl monocaprylate), Capmul MCM (glyceryl capryl ate/caprate), Masester E8120 (glycerol mono- and di- capryl ate/caprate).

[0072] Additionally, or alternatively, the first surfactant may comprise mono- and/or difatty acid esters of 1,2-propylene glycol. The fatty acid esters of propylene glycol may be a mixture of mono- and di-esters of propylene glycol, and preferably the fatty acid ester of propylene glycol may be a mono-ester of propylene glycol. The fatty acid component is one or more Ce to Cio fatty acid(s) and may be saturated or unsaturated but is preferable saturated. More preferably, the fatty acid has from 8 to 10 carbons, and particularly may be caprate, caprylate and mixtures thereof. The 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 mono- and di-caprylate). [0073] The first surfactant may additionally or alternatively comprise mono- and/or di- fatty acid esters of polyethylene glycol. The fatty acid ester of polyethylene glycol may be a mixture of mono- and di-esters of polyethylene glycol. The fatty acid component is one or more Ce to Cio fatty acid(s) and may be saturated or unsaturated but is preferable saturated. More preferably, the fatty acid has from 8 to 10 carbons, and particularly may be caprate, caprylate and mixtures thereof. The polyethylene glycol component may have an average molecular weight of from about 200 to about 800, or from about 300 to about 500. The fatty acid esters of propylene glycol are commercially available and include Labrasol ALF (small fraction of mono-, di- and triglycerides and mainly PEG-8 (MW 400) mono- and diesters of caprylic (Cs) and capric (Cio) acids).

[0074] The compositions provided herein also comprise a second surfactant, which may be a mixture of surfactants, and is selected from polysorbate surfactants, fatty acid esters of sorbitan, and mixtures thereof. The avermectin composition comprises 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 the second surfactant.

[0075] The second surfactant may comprise polysorbate surfactants. The polysorbate surfactants are polyethoxylated sorbitan esterified with fatty acids having the following general structure: in which R is the carbon chain of a medium to long chain fatty acid, and the sum of w, x, y, and z is the number of oxyethylene -(CH2CH2O)- groups found in the molecule. The fatty acid may be saturated or unsaturated. In embodiments, the fatty acid has from 12 to 18 carbons. In embodiments, 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. [0076] The second surfactant may additionally or alternatively comprise fatty acid esters of sorbitan (also known as Spans). The fatty acid component may be saturated or unsaturated. In embodiments, the fatty acid has from 12 to 18 carbons. The sorbitan ester may be mono-, di- or tri-esters of sorbitan, and particularly are mono-esters of sorbitan, such as sorbitan monolaurate. Sorbitan esters are commercially available and include Span 20 (sorbitan monolaurate), Span 40 (sorbitan monopalmitate), Span 60 (sorbitan monostearate), Span 65 (sorbitan tristearate) and Span 80 (sorbitan monooleate).

[0077] Optionally, the avermectin composition may additionally comprise vitamin E TPGS, also known as D-a-Tocopherol 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.

[0078] In embodiments, the pharmaceutical composition comprises: (i) about 5% to about 10% ivermectin; (ii) about 25% to about 30% mono- and di- Cs to Cio fatty acid esters of glycerol; (iii) about 15% to about 30% of a polysorbate surfactant; and (iv) about 30% to about 50% vitamin E TPGS.

[0079] In an embodiment, the pharmaceutical composition comprises: (i) about 8% ivermectin; (ii) about 27.6% mono- and di- Cs to Cio fatty acid esters of glycerol; (iii) about 32.2% polysorbate 80; and (iv) about 32.2% vitamin E TPGS.

[0080] In an 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.

[0081] In an embodiment, the pharmaceutical composition comprises: (i) about 8% ivermectin; (ii) about 27.6% mono- and di- Cs to Cio fatty acid esters of glycerol; (iii) about 18.4% polysorbate 80; and (iv) about 46% vitamin E TPGS.

[0082] In an 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.

[0083] In an embodiment, the pharmaceutical composition comprises: (i) about 8% ivermectin; (ii) about 27.6% mono- and di- Cs to Cio fatty acid esters of glycerol; and (iii) about 64.4% polysorbate 80.

[0084] In an embodiment, the pharmaceutical composition comprises: (i) about 8% ivermectin; (ii) about 27.6% Masester E8120; and (iii) about 64.4% polysorbate 80. [0085] The pharmaceutical composition may additionally comprise additional excipients such as additional surfactants, solvents, solubilizing agents, preservatives, anti-oxidants, bulking agents, dissolution enhancers, wetting agents, emulsifiers, suspending agents, antibacterial agents, pH buffering agents, sweeteners, flavoring agents, and combinations thereof.

[0086] Dosage Form

[0087] The disclosure provides a composition comprising the avermectin is a semi-solid or liquid-based when formulated as, including, but not limited to, an emulsion, suspension, solution, elixirs, or syrup in which the avermectin is dissolved and/or suspended.

[0088] The dosage form comprising the avermectin can take the form of solutions, suspensions, emulsion, aerosols, capsules, soft elastic or hard gelatin capsules, dermal patch, suspensions, and the like preferably in unit dosage forms suitable for simple administration of precise dosages. The composition may take the forms of liquid- or semi-solid filled capsules, sublingual spray, or nasal spray.

[0089] Capsule dosage forms may include soft capsules and hard capsules. Capsules may be used as an oral dosage form for the administration of many different types of active pharmaceuticals. The capsules may be filled with an active ingredient in the form of a liquid, or a powder suspended in liquid. Hard capsules can be made of unplasticized or low-plasticized gelatin and water to form a stiff capsule that can be filled with either powder or liquid. Soft capsules can be made of highly plasticized soft elastic gelatin and can contain a liquid or semisolid ingredient. These capsules are often referred to as “softgel” or “gelcap” capsules.

[0090] As used herein, the term “capsule” refers to any suitable capsular container or case adapted for oral ingestion, e.g., those adapted for use in conjunction with liquid fill compositions. The term “capsule” may include capsules having a shell composed of soft and/or hard materials, such as gelatin, starches, celluloses, cellulose derivatives (e.g., hydroxypropyl methyl cellulose), hydrocolloids, gums, carrageenans, or any other natural or synthetic material which can be used to encapsulate the liquid composition and be ingested by an animal. Optionally, the shell material can be gelatin and/or hydroxypropyl methyl cellulose. In an embodiment, the shell material is gelatin. The term “capsule” also includes a variety of capsule shapes and sizes. The instant disclosure does not limit the dosage form to a specific type or shape. Any commercially available capsule shells or shell materials can be used. [0091] In an embodiment, the dosage form of the instant disclosure is a soft capsule. In an embodiment, the dosage form of the instant disclosure is a coated liquid-filled soft capsule. The coated capsule can include a liquid fill encapsulated with a soft capsule shell. The exterior surface of the soft capsule shell can be coated with one or more layers of coating.

[0092] Suitable materials for encapsulating the liquid fill may include heat sealable polymers and gelatin. Examples of heat sealable polymers may include, but are not limited to, modified starches, cellulosic polymers, and carrageenans. In an embodiment, the material is gelatin. The gelatin can be natural gelatin, chemically modified gelatin, enzymatically modified gelatin, or combinations thereof.

[0093] The material that forms the capsule shell can further includes water. Water can be present in the original material mass before the capsules are made, in an amount sufficient to allow the processing of the material on the encapsulation machine. After the capsules are formed the majority of the moisture can be removed during the drying process.

[0094] The water can have a plasticizing effect on the material. In addition, a non-volatile plasticizer or blend of plasticizers can be added to the material which forms 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 glycerin, maltitol, sorbitan, sorbitol or similar low molecular weight polyhydric alcohols, and mixtures thereof. In embodiments, the ratio of plasticizer to material determines how hard or soft the shell can be.

[0095] The ratio of plasticizer to material in the shell may be sufficient to provide capsules that are not too hard, such that the capsules are brittle and crack if stressed during shipping and handling, and are not too soft, such that the capsules become deformed during shipping and handling. The non-volatile plasticizer can be present in the capsule shell from about 8% to 65% by total weight of the capsule shell, from about 10% to 35% by total weight of the capsule shell.

[0096] The material which forms the capsule shell can further contain extenders. The extender can be any extender which is compatible with the material. Examples of extenders may include natural or modified natural biopolymers and synthetic polymers. Natural biopolymers may include, for instance, cellulose, starch, starch derivatives, bacterial polysaccharides such as xanthan gum and gellan gum and vegetable gums such as guar gum, locust bean gum, gum tragacanth and gum Arabic and animal derived polymers such as chondroitin sulfate, hyaluronic acid, heparin, collagen and chitosan. An example of a modified natural biopolymer may be modified cellulose. Examples of synthetic polymers may include carbon chain polymers of the vinyl and acrylic types as well as heterochains of the polyoxide and polyamine types.

[0097] A coating can be applied on the exterior surface of the soft capsule shell. The coating can contain one or more layers. Any coating suitable for a soft capsule can be applied to the capsule. The coating can provide, for example, waterproofing and sealing, smoothing, polishing, enteric protection and/or delayed release properties to the liquid-filled capsule. The delayed release can be affected by, for example, temperature or pH. In an embodiment, the coating is an enteric coating.

[0098] The coating can be made by any standard coating ingredient 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 phyhalates, celluosics, vinyls, glycols, acrylics and carbohydrate polymers, polymers and co-polymers containing methacrylic acid and methacrylic acid alkyl esters, hydroxypropylmethyl cellulose (HPMC) and combinations thereof.

[0099] The coated capsule can further comprise a finishing coating. In an embodiment, the finishing layer is applied to the coated-capsule. Examples of substance suitable for use in a finishing coating may include, but are not limited to cellulosics, vinyls, glycols, acrylics and carbohydrate polymers and/or combinations thereof.

[0100] The liquid fill or semi-solid fill can be encapsulated with a soft capsule shell by any method known in the art. For example, a soft capsule can be made using a standard rotary die soft gelatin capsule machine as described in The Theory and Practice of Industrial Pharmacy, ed. Lachman, et al., 2nd Ed., Pt. II, 404-420, Lea & Febiger, 1976. Additional methods include using a plate process (see The Theory and Practice of Industrial Pharmacy, ed. Lachman, et al., 2nd Ed., Pt. II, 405, Lea & Febiger, 1976), as well as Globex type seamless capsule machines, which makes large microcapsules (see U.S. Pat. No. 5,254,294), non-standard rotary die machines, which uses extrusion technology to make gel ribbons (see U.S. Pat. Nos. 6,183,845 and 6,340,473), and other methods for making capsules which use high frequency, ultrasonic, or induction welding to seal the capsules (see U.S. Pat. No. 6,352,719). The above-listed U.S. patents and book are hereby incorporated by reference.

[0101] As used herein, the phrase “liquid hard-shell” refers to a hard capsule encapsulating a liquid or semi-solid formulation. Hard capsules can be single unit dosage forms and may comprise a cap and a body, which can be manufactured separately, and which can be supplied empty for filling with the liquid or semi-solid composition. In some embodiments, hard capsules are made from a polymer such as gelatin. An additional component can be water, which acts as a plasticizer. Another hard capsule may be manufactured from hydroxypropylmethyl cellulose (HPMC). Liquid-fill hard capsule can be filled on a filling machine, such as, for example, a high-speed filling machine.

[0102] In one example, disclosed herein is a method of prepare the filled hard capsule. Empty capsules are supplied to the filling machine in a prelocked condition, wherein the capsule body has a cap which is loosely attached thereto. A series of rings or protrusions are provided in the mating surfaces 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 are held together during storage but would enable the cap to be removed prior to filling of the capsule. Once the capsule has been filled, the cap can be replaced and be forced beyond the prelocked position into a fully locked position. Alternatively, other types of capsule filling machines can be used to accept separate supplies of capsule bodies and caps.

[0103] The capsules may be closed at high speed after filling with the formulated composition. During closure of the capsule, the cap is fitted over the body and the body is pushed up until it locks on the cap. The cap can be close fitting and can be approximately half the length of the body, so the cap can travel for a considerable distance down the capsule body before locking. This may have the effect of a piston in trapping and pressurizing the capsule. The excess gas can escape through the gap between the cap and the body, and vents may be provided in this region so as to facilitate the escape of excess pressure. Alternatively, the capsule may utilize a particularly tight locking mechanism rather than vents.

[0104] In an embodiment, the capsule is banded by applying a band of polymer solution around the junction between the cap and body. The polymer solution can be a solution of the same polymer as the capsule cap and/or body in a solvent therefor. Banding can provide a smooth capsule surface for coating, which may prevent movement between the cap and body of the capsule.

[0105] When preparing the filled capsule that is filled with the composition comprising an avermectin, it is preferred that the composition is in a liquid form at least during the encapsulation process. In an embodiment, the final capsule contains the composition in the liquid form. In an embodiment, the final capsule contains the composition is semi-solid form at room temperature. [0106] Method of Administration

[0107] The administration of the pharmaceutical composition comprising the avermectin can be carried out via oral, nasal, intraocular, intravenous, intramuscular, subcutaneous, transdermal, subdermal, sublingual or rectal route of administration.

[0108] In embodiments, the route of administration is oral, and the pharmaceutical composition is provided in the form of capsules, such as soft elastic or hard gelatin capsules.

[0109] In an embodiment, the route of administration is nasal. The composition can be a solution, an aerosol, a liquid suspension, or a liquid dispersion, in the form of a nasal spray, a nasal douche, an inhaler, a nasal drop, and/or a diffuser.

[0110] In embodiments, the route of administration is dermal including but not limited to topical, subcutaneous, subdermal, transdermal, intradermal or dermal patch.

[0111] Methods of Treatment and Prevention

[0112] Provided herein are methods of treating or preventing spasticity by administering to a subject in need thereof a therapeutically or a prophylactically effective amount of a composition disclosed herein.

[0113] A “therapeutically effective amount” of a composition comprising an (i) a compound of any one of Formulas I- VII, (ii) one or more of a compound of any one of Formulas I- VII, or (iii) ivermectin comprising a compound of Formula VI and a compound of Formula VII is an amount sufficient to confer a therapeutic benefit in a patient after administration for example to improve in the subject one or more symptoms of the disease. The “therapeutically effective amount” may result in a desired beneficial change of physiology in the subject or to cause an improvement in a clinically significant condition in the subject, for example, by delaying, reducing, minimizing or mitigating one or more symptoms associated with the disease or disorder. Generally, a therapeutically effective amount is also one in which any toxic or detrimental effects of a composition are outweighed by the therapeutically beneficial effects The effective amount may vary depending on the species, age, weight, sex, health of the subject and the nature or severity of the disease. Depending on the mode of administration, the effective amount may vary as well. In some cases, multiple doses of the composition are administered to achieve the effective amount for the therapeutic benefit intended. In some cases, the therapeutic amount may be used for treating refractory or resistant disorders, and in combination therapies. For example, the effective amount may be administered simultaneously, sequentially, and in the same or different dosage form as an adjunct therapy. [0114] As used herein, the terms “treating”, “treat”, “treatment” refer to reducing, relieving, ameliorating, or alleviating at least one of the symptoms of the disease or disorder. The term includes, for example, administering a formulation as provided herein prevent the onset of spasticity, to reduce or alleviate its severity, and/or to prevent its reoccurrence.

[0115] As used herein, the terms “prevent”, “prevention”, and the like refer to acting prior to overt disease or disorder onset, to prevent the disease or disorder from developing or to minimize the extent of the disease or disorder or slow its course of development.

[0116] A “prophylactically effective amount” of a composition comprising an (i) a compound of any one of Formulas I- VII, (ii) one or more of a compound of any one of Formulas I- VII, or (iii) ivermectin comprising a compound of Formula VI and a compound of Formula VII refers to an amount of a composition required to achieve a desired prophylactic result. In an embodiment, the prophylactically effective amount is less than the therapeutically effective amount, as a prophylactic dose is used in subjects prior to or at an earlier stage of disease.

[0117] A subject may be a mammal, including, but not limited to, a human or non- human mammal. The mammal may be a commercially farmed animal (such as a horse, a cow, a sheep or a pig), a laboratory 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 may be male or female. Individuals and patients are also subjects herein.

[0118] Spasticity

[0119] The disclosure provides a method of treating or preventing spasticity, including but not limited to spinal spasticity, by administering to a subject in need thereof a therapeutically or a prophylactically effective amount of (i) a compound of any one of Formulas I- VII, (ii) one or more of a compound of any one of Formulas I- VII, or (iii) ivermectin comprising a compound of Formula VI and a compound of Formula VII.

[0120] Spasticity is a disorder in which certain muscles are continuously contracted. Spasticity may produce uncontrollable, painful spasms of the legs or other extremities. Spasticity can also interfere with movement and speech. Untreated spasticity can lead to frozen or immobilized joints and pressure sores. It can prevent recovery of proper motor behavior after injury or disease. Further, spasticity may cause pain, fatigue and other problems. As such, spasticity can become a barrier to a person’s daily activities, walking, sitting, positioning and sleep. [0121] The degree of spasticity may vary from mild muscle stiffness to severe and uncontrollable muscle spasms. Spasticity can be very painful and, depending on the affected muscles, can result in an uncoordinated gait, stiff or deformed posture, and shortening of the range of limb movement. It can cause permanent muscle shortening and problems around the joints against which the two spastic muscles are supposed to move (contracture). It can be a permanent feature or brought on by a variety of factors such as fatigue, heat, or infection.

[0122] A major component of spasticity is exaggerated reflexes or hyper-refl exia. One measure to quantify hyper-reflexia is the electrical analogue of the classic tendon jerk reflex, referred to as the Hoffman or H-reflex. The H-reflex is a compound electromyographic (EMG) response elicited by the synaptic activation of motoneurons by muscle afferents following stimulation of muscle nerves.

[0123] Spasticity may occur in association with spinal cord injury; damage to the brain because of lack of oxygen, stroke, or head injury; amyotrophic lateral sclerosis (Lou Gehrig's disease); phenylketonuria; metabolic diseases such as adrenoleukodystrophy; cerebral palsy; Stiff-man Syndrome; and multiple sclerosis. In multiple sclerosis, it may affect the legs, although it can 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 those that collect sensory information back from them. Reflexive spasms which are generated by the spinal cord are not inhibited by the brain, as normal, and increased muscle tone results. The lesions responsible are usually in the cerebellum or the white matter tracts that connect it to the peripheral motor (efferent) and sensory (afferent) nerves.

[0124] Current drugs available for the management of spasticity include baclofen, which is a GABAB receptor agonist. Baclofen acts as an agonist to potentiate inhibition mediated by presynaptic GABAB receptors. The rationale for the use of baclofen for the treatment of spasticity was due to the assumption that excessive reflexes were induced in spinal cord injury by the elimination of presynaptic inhibition from nerve fibers descending from the brain, spinal cord injury has been thought to lesion these descending fibers, rendering the spinal cord hyperreactive. Baclofen is thought to restore some of that inhibition. However, baclofen taken orally unfortunately increases inhibition throughout the brain, leading to sleepiness and weakness. In order to avoid such unpleasant side effects (which reduce the ability of patients to concentrate), baclofen pumps were designed to inject the drug directly into the spinal fluid, usually in spinal cord injury victims and cerebral palsy patients. These pumps avoid the soporific effects of oral administration but are dangerous, have a limited lifetime (requiring repeated surgical implants) and are very expensive.

[0125] In an embodiment, the treatment reduces hyper-refl exia in the human subject. In an embodiment, a reduction in hyper-reflexia is used to evaluate the reduction of spasticity. As used herein, the term “reduce hyper-reflexia” refers to reducing the amplitude of the H-reflex measured at 1, 5, or 10 Hz as normalized to amplitude measured at 0.2 Hz stimulation. In other words, it refers to restoring low frequency-dependent depression of the H-reflex to closer to control levels. More preferably the H-reflex amplitude is reduced at 5 or 10 Hz, most preferably at 5 Hz.

[0126] In some embodiments, the formulations and methods disclosed herein are effective in reducing the degree of stiffness of spasticity.

[0127] The disclosure provides a method for treating or preventing spinal spasticity secondary to a disease including, but not limited to, spinal cord injury, stroke, brain injury, amyotrophic lateral sclerosis, phenylketonuria, adrenoleukodystrophy, cerebral palsy, Stiffman Syndrome, or multiple sclerosis.

[0128] In an embodiment, the spasticity is secondary to a spinal cord injury, and wherein the method further comprises beginning administering to the human subject a dose of the formulation after the spinal cord injury and before the spasticity develops.

[0129] In an embodiment, the spasticity is secondary to multiple sclerosis, wherein the method further comprises beginning administering to the human subject a dose of the formulation after a diagnosis of the multiple sclerosis and before the spasticity. In some embodiments, administering the formulation is effective to increase connexin 36 levels in spinal cord neuron, wherein administering the formulation is effective to increase gap junctions in neurons in the spinal cord or increase electrical coupling between neurons in the spinal cord. [0130] The subjects receiving a treatment described herein may experience as a result of the therapy a reduction of spasticity.

[0131] The level of Protein connexin36 (Cx36) can be used to evaluate the reduction of spasticity. Cx36 forms gap junctions between neurons, which are called electrical synapses, enabling adjacent neurons to communicate directly. Passive exercise, which also reduces spasticity, increases expression of the nerve gap junction protein connexin 36, which would increase gap junctions and increase electrical communication between neurons.

[0132] Another means of evaluating the effectiveness of a dose is by evaluating muscle tone. In spasticity there is a disruption in the normal behavior of the stretch reflex that causes muscles, particularly the flexors, to be extremely resistive to passive stretch, that is, to be high in tone. As a result, motor control is severely impaired, and stiffness or tightness of the muscles may interfere with gait, movement, and speech. Hence, assessing tone — the degree of resistance to stretch from an external source — is an important means by which one can evaluate the degree of spasticity that a patient has and the effectiveness of intervention.

[0133] Another accepted clinical measures of tone in spasticity is the Ashworth scale and the Modified Ashworth Scale. A clinician moves a patient's limbs about their joints and then assigns a grade to each limb corresponding to how much resistance the clinician feels.

[0134] Other means to evaluate the effectiveness of a dose include biomechanical studies, such as those performed by a pendulum test; electrophysiologic 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, Functional Independence Measure, and Fugl-Meyer Assessment of Sensorimotor Impairment (Fugl-Meyer scale).

[0135] In an embodiment, provided is a method of treating or preventing spinal spasticity by administering to a subject in need thereof a composition disclosed herein, the method further comprising administering to the human subject a second therapeutic agent. In some embodiments, the second agent is baclofen, benzodiazepines, diazepam, clonazepam, dantrolene, or tizanidine.

[0136] For certain disorders, spasticity can be associated with inflammation. Recent studies by the inventors have shown that ivermectin can be useful for the treatment of inflammation (see U.S. Provisional Application No. 63/322,255, filed March 22, 2022, entitled “Methods of Using Avermectin Compositions for the Treatment of Inflammatory Disorders and Dosing Regimens,” which is incorporated herein in its entirety). Accordingly, the disclosure provides a method to treating or preventing spasticity, wherein the spasticity is associated with inflammation.

[0137] Dosing Regimens

[0138] Provided herein are methods of treating or preventing spasticity by administering to a subject in need thereof a therapeutically or a prophylactically effective amount of a composition, the method comprising administering one of the compositions disclosed herein at a dose of about 10 mg to about 120 mg of (i) a compound of any one of Formulas I- VII, (ii) one or more of a compound of any one of Formulas I- VII, or (iii) ivermectin comprising a compound of Formula VI and a compound of Formula VII. In some embodiments, the method of treatment or prevention includes administering a composition disclosed herein at a dose of about 10 mg to about 80 mg of (i) a compound of any one of Formulas I- VII, (ii) one or more of a compound of any one of Formulas I- VII, or (iii) ivermectin comprising a compound of Formula VI and a compound of Formula VII. In some embodiments, the method of treatment or prevention includes administering a composition disclosed herein at a dose of about 10 mg to about 60 mg of (i) a compound of any one of Formulas I- VII, (ii) one or more of a compound 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 includes administering a composition disclosed herein at a dose of about 20 mg to about 40 mg of (i) a compound of any one of Formulas I- VII, (ii) one or more of a compound 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 includes administering a composition disclosed herein at a dose of about 1 mg, about 3 mg, about 5 mg, about 10 mg, about 20 mg, about 40 mg, about 60 mg, about 80 mg, or about 120 mg of (i) a compound of any one of Formulas I- VII, (ii) one or more of a compound of any one of Formulas I- VII, or (iii) ivermectin comprising a compound of Formula VI and a compound of Formula VII. In preferred embodiments, the composition comprises ivermectin comprising a compound of Formula VI and a compound of Formula VII.

[0139] The dosage regimens for the therapy may be adjusted to provide the optimum desired response (e.g., a therapeutic or prophylactic response). For example, a single dose may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased depending on the subject’s responsiveness to the therapy. In some embodiments, the composition is administered twice per day (BD), once per day (QD), once every other day, once every three days. In some embodiments, the dosage schedule is once a day, twice a day, every other day or once 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 schedule is daily, every other day, 2-4 times a week, 3-5 times a week, weekly, biweekly, monthly, or bimonthly for about 90 days, for about 6 months, for about 1 year or continuously. In an embodiment, the dosage schedule is once a day for about 14 days. In an embodiment, the dosage schedule is once a day for about 84 days. [0140] In an embodiment, the pharmaceutical composition comprises: (i) about 8% ivermectin; (ii) about 27.6% mono- and di- Cs to Cio fatty acid esters of glycerol; (iii) about 32.2% polysorbate 80; and (iv) about 32.2% vitamin E TPGS.

[0141] In an 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.

[0142] In an embodiment, the pharmaceutical composition comprises: (i) about 8% ivermectin; (ii) about 27.6% mono- and di- Cs to Cio fatty acid esters of glycerol; (iii) about 18.4% polysorbate 80; and (iv) about 46% vitamin E TPGS.

[0143] In an 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.

[0144] In an embodiment, the pharmaceutical composition comprises: (i) about 8% ivermectin; (ii) about 27.6% mono- and di- Cs to Cio fatty acid esters of glycerol; and (iii) about 64.4% polysorbate 80.

[0145] In an embodiment, the pharmaceutical composition comprises: (i) about 8% ivermectin; (ii) about 27.6% Masester E8120; and (iii) about 64.4% polysorbate 80.

[0146] In embodiments, the ivermectin comprises a compound of Formula VI (22,23- dihydroavermectin Bia) and a compound of Formula VII (22,23 -dihydroavermectin Bib). In some embodiments, ivermectin comprises at least about 70% of 22,23 -dihydroavermectin Bia and less than about 30% of 22,23 -dihydroavermectin Bib. In some embodiments, ivermectin comprises at least about 90% of 22,23 -dihydroavermectin Bia and less than about 10% of 22,23 -dihydroavermectin Bib.

[0147] In an 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 an 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 an 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 an 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.

[0148] In an 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 an 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 an 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 at a dose of about 10 mg daily and continuously. In an 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 at a dose of about 20 mg daily and continuously. In an 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 at a dose of about 40 mg daily and continuously. In an 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 at a dose of about 60 mg daily and continuously. In an 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 at a dose of about 80 mg daily and continuously. In an 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 at a dose of about 120 mg daily and continuously.

[0149] In an embodiment, the spasticity is associated with inflammation.

[0150] In embodiments, the method comprises administering to the subject a pharmaceutical composition disclosed herein, with one or more additional therapeutic agents, administered simultaneously, sequentially, and in the same or different dosage form as the composition comprising (i) a compound of any one of Formulas I- VII, (ii) one or more of a compound of any one of Formulas I- VII, or (iii) ivermectin comprising a compound of Formula VI and a compound of Formula VII. Examples of the one or more additional therapeutic agents include, but are not limited to, baclofen, benzodiazepines, diazepam, clonazepam, dantrolene, or tizanidine. EXAMPLES

[0151] Example 1 - Solubility Determination

[0152] The active pharmaceutical ingredient (API) used in the following examples, is ivermectin comprising greater than or equal to 90% of 22, 23 -dihydroavermectin Bia and less than 10% of 22,23 -dihydroavermectin Bib. The solubility assessments were performed by continually adding a known amount of the API into each individual excipient and letting the excipient reach solubility equilibrium via API saturation (visible solid observed). The experiments were conducted at ambient conditions (25 °C) and were left to mix on a stir plate at 500 RPM for at least 72 hours. Subsequently, samples were centrifuged and filtered via a 0.45 pm PVDF membrane filter (Millipore Durapore) and filtrate was assayed per United States Pharmacopeia (USP) ivermectin monograph. Quantitative composition of placebo vehicle and the corresponding ivermectin initial solubility results are reported in Table 1. Due to the melting point of Vitamin E TPGS (VE TPGS) at 38 °C, the solubility study in VE TPGS was conducted at 40 °C on a hot plate following same procedure as above.

Table 1. Ivermectin Solubility Determination at 25 °C [0153] Example 2 - Excipient Compatibility Study

[0154] An excipient compatibility study was initiated with selected excipients ranging from oils to surfactants based on equilibrium solubility results (Table 2). The study was designed to provide an ivermectin solution at approximately 5% in selected excipients as in Table 2 with the exception of excipients that the equilibrium solubility are below 5%, namely fractionated coconut oil and oleic acid at approximately 1%. After solutions were prepared using a handheld homogenizer (Model IKAT10 Ultra-Turrax), each excipient sample was aliquoted in amber vials, approximately 10% water was added in each excipient aliquot, and bench scale gel stripe OET-004037 was also made and added in a separate set of aliquot samples at approximately 1 : 1 w/w.

[0155] All samples were stored at 40 °C/75 % relative humidity (RH) condition (Model: Lunaire environmental chamber) and tested by developmental reversed phase HPLC method for Assay/Related Substances at T = 0, 2 weeks, and 1 month. Results are summarized in Table 3 and Table 4.

[0156] Oily vehicles including Maisine CC, fractionated coconut oil, and oleic acid had good chemical compatibility with the API, among which Maisine CC has the highest equilibrium solubility, therefore Maisine CC was chosen to be studied further as an oily vehicle. Tween 80, Labrasol ALF and Vitamin E TPGS categorized as surfactant were compared and Vitamin E TPGS showed the best chemical compatibility with the API with minimum increase in impurities over time, followed by Tween 80 having less stability over time. Both Vitamin E TPGS and Tween 80 were selected as emulsifiers to be used in formulation development. Due to the high solubility in Masester E8120, Masester E8120 was selected for further evaluation for formulation development as solubilizer and emulsifer. PEG 400, as a co-solvent was not considered for further formulation development, due to its poor chemical compatibility.

Table 2. Excipients list for Compatibility Study and Actual API w/w%

Table 3. Summary of Excipient Compatibility Study (Assay) Table 4. Results Summary for Compatibility Study of Excipient Samples (Total impurities).

% adjusted area = Total Impurities % excluding API impurities %

[0157] Example 3 - Fiber Optic Dispersion Study

[0158] Fiberoptic Dispersion in fasted state simulated intestinal fluid (FaSSIF) and FaSSIF- V2 were performed using a Distec dissolution system 2500 and PIONfiber optic dissolution system to collect real-time dissolution data and data processing. With a target of 20 mg/capsule and based on the compatibility studies, a range of formulations (Table 5) were designed for dispersibility evaluations. FaSSIF medium was chosen to mimic intestinal environment after ivermectin is ingested orally. Dispersion analysis was conducted firstly in 500 mL Fasted State Simulated Intestinal Fluid (pH~6.5) at 50 rpm paddle speed (USP <711> Apparatus II) for screening various excipient combinations and compositions for approximately 6 hours. Results were plotted as a graph shown in Fig. 1. [0159] FaSSIF-V2 was used later to confirm dispersibility of formulations 7E and 9E as they have shown higher dispersibility than other formulation evaluated from the first round of the dispersion study.

[0160] Kinetic solubility in FaSSIF and FaSSIF-V2 for both 7E and 9E reached 80% release at T = 30 minutes suggesting an immediate release profile. No drug precipitation was observed indicating good dispersibility of both formulations and ability to maintain solubilization of API with low risk of API precipitation once ingested into GI tract. Data processing using Aupro.

Table 5. Quantitative Compositions of Formulations in Dispersion Study

[0161] Example 4 - Analysis of Prototype Formulations

[0162] 7E and 9E were selected as prototype formulations following the kinetic solubility study where both formulations showed good dispersibility in simulated intestinal fluids. A 12- month informal stability study was conducted to challenge these two formulations at 40 °C/75%RH in a Lunaire environmental chamber and with the addition of 5% water and gel stripes (OET-004037) in separate vials to mimic softgel water migration and the impact of gel on formulation in softgel dosage form, respectively. The formulation control samples (without water and gel stripes) were stored in 8 oz amber Boston round bottles to mimic preliminary intended packaging for first in human clinical study (SAD/MAD study). All other samples were stored in amber glass vials. The Assay/RS results are summarized in Table 6 and Table 7, analyzed by a developmental HPLC method.

[0163] There was no precipitation nor phase separation observed at T = 0 to 1 month at 40 °C/75% RH in all sample vials. There was light slurry observed in the T = 3-month water added sample in 7E which indicates minor API precipitation with 5% water addition possibly due to polymorphism change of API. However, water added samples is a simulation and not a true representation of water migration in softgels. The minor precipitation in this sample is inconclusive and deemed to be minor in terms of formulation stability.

Table 6. Results Summary for Informal Stability Study of Prototype Formulations (Assay)

Table 7. Results Summary for Informal Stability Study of Prototype Formulations (Related

Substances)

[0164] Example 5 - Freeze-Thaw Study

[0165] Prototype formulations 7E and 9E were challenged in a freeze-thaw study for physical and chemical stability from -15°C to 40°C in a ClimaCell environmental test chamber for a 7-day period of time, 24-hour cycle. There was no precipitation nor phase separation observed from two samples vials at day 7. Chemical stability (Assay) is summarized in Table 8. It can be concluded that both formulations are stable under extreme temperature fluctuation stress. Table 8. Results Summary for Freeze-thaw Study of Prototype Formulations (Assay)

[0166] Example 6 - Pharmacokinetic Profiles of Ivermectin Bia in Sprague Dawley Rats Following IV and Oral Administration

[0167] Thirty-six male Sprague Dawley rats were randomly assigned into four groups, with nine male rats in each group. All animals in all groups are fasted overnight prior to the experimental date.

[0168] Rats in Group 1 were administered ivermectin API solubilized in DMSO, solutol, and saline (n=9) administered intravenously (IV). Rats in Group 2 were administered 2 mg/kg Stromectol crushed and solubilized in water (n=9) via oral gavage. Stromectol is formulated by the manufacturer as a tablet comprising 3 mg ivermectin comprising at least 90% 22,23- dihydroavermectin Bia and less than 10% 22,23 -dihydroavermectin Bib. Rats in Group 3 were administered 2 mg/kg Ivomec in water (n=9) via oral gavage. Ivomec is formulated by the manufacturer as a 1% ivermectin solution. Rats in Group 4 were administered 2 mg/kg prototype formulations 7E (“7E”) in water (n=9) via oral gavage.

[0169] Blood samples were collected from 6 of 9 animals per group at 0.5, 1, 2, 3, 4, 6, 8, 24, 72, 120, 168 hours post-dose. The collected plasma samples were analyzed for the concentration of Ivermectin Bia by a validated LC-MS/MS method. Pharmacokinetic parameters were calculated by the concentration data of Ivermectin Bia in plasma samples using non-compartment model of Phoenix WinNonlin 7.0 software.

[0170] The remaining 3 of 9 animals per group were sacrificed 4 hours after study product administration. Blood samples were collected via jugular vein or other suitable vein. Brains were removed, rinsed with saline, dried with filter paper and weighed immediately. The brain samples were homogenized and the samples were analyzed for the concentration of Ivermectin Bia by a LC-MS/MS method per FDA’s guidelines. The brain samples and plasma sample ratios were calculated for the BBB penetration percentages.

[0171] Results

[0172] The main pharmacokinetic parameters of Ivermectin Bia in SD rat plasma after single administration of Ivermectin API, Stromectol, Ivomec, and 7E are summarized in Table 9 and Figs. 2-5. Table 9. Main Pharmacokinetic Parameters of Ivermectin Bia in SD Rat Plasma After Single Intravenous Administration of Ivermectin (API) or Oral Administration of Stromectol, Ivomec, and 7E (Mean ± SD). Dose level: 2 mg/kg. Fating status: Fasting. Sex: Male, n = 6.

[0173] Group 1 : After a single IV injection of 2 mg/kg Ivermectin API in male SD rats with fasting, the AUC(o-t) of Ivermecin Bia in plasma was 8259.31 ± 1032.95 hr*ng/ml, the T1/2 were 14.82 ± 0.72 hr.

[0174] Group 2: After a single PO administration of 2 mg/kg Stromectol in male SD rats with fasting, the AUC(o-t) of Ivermecin Bia in plasma was 4220.94 ± 1594.22 hr*ng/ml, the T1/2 were 12.85 ± 2.16 hr.

[0175] Group 3: After a single PO administration of 2 mg/kg Ivomec in male SD rats with fasting, the AUC(o-t) of Ivermecin Bia in plasma was 3396.36 ± 353.94 hr*ng/ml, the Ti/2were 18.49 ± 1.89 hr.

[0176] Group 4: After a single PO administration of 2 mg/kg 7E in male SD rats with fasting, the AUC(o-t) of Ivermecin Bia in plasma was 4677.49 ± 920.69 hr*ng/ml, the T 1/2 were 17.15 ± 13.14 hr.

[0177] The ratio between the concentration of Ivermectin B la in brain and the concentration of Ivermectin Bia in the plasma were calculated and summarized in Table 10.

Table 10. Ratio of Ivermectin Bia in SD Rat Plasma and Brain After Single Intravenous Administration of Ivermectin (API) or Oral Administration of Stromectol, Ivomec, and 7E (Mean ± SD). Dose level: 2 mg/kg. Fating status: Fasting. Sex: Male, n = 3.

[0178] Group 1 : After a single IV injection of 2 mg/kg Ivermectin API in male SD rats with fasting, the ratio between the concentration of Ivermectin Bla in the brain and the concentration of Ivermectin Bia in the plasma was 0.171±0.010.

[0179] Group 2: After a single PO administration of 2 mg/kg Stromectol in male SD rat with fasting, the ratio between the concentration of Ivermectin Bia in the brain and the concentration of Ivermectin Bia in the plasma was 0.046±0.006.

[0180] Group 3: After a single PO administration of 2 mg/kg Ivomec in male SD rats with fasting, the ratio between the concentration of Ivermectin Bla in the brain and the concentration of Ivermectin Bia in the plasma was 0.033±0.008.

[0181] Group 4: After a single PO administration of 2 mg/kg 7E in male SD rats with fasting, the ratio between the concentration of Ivermectin Bla in the brain and the concentration of Ivermectin Bia in the plasma was 0.043±0.005.

[0182] Conclusion

[0183] After a single fasting oral administration of 2 mg/kg Stromectol and 7E there was no significant difference in Cmax (Stromectol vs 7E 1 : 1.10) or AUCo-t (Stromectol vs 7E 1 : 1.11).

[0184] Example 7 - Modulation of Pentylenetetrazol (PTZ)-Induced Seizures by Liquid Solution of Formulation 7E in Rats

[0185] Functional MRI (fMRI) was performed using a high-field preclinical MRI system in anesthetized male Wistar rats in order to determine the modulation of pentylenetetrazol (PTZ)- induced ictal brain activity by chronic treatment with test compound (TC). In a first experiment, animals were treated with 2 mg/kg or 4 mg/kg dosages of the ivermectin liquid solution having formulation 7E. Vehicle and 3 mg/kg Alprazolam served as controls (see, Table 11) Seizures were induced with PTZ in each experimental group. A schematic of the study design can be seen in Fig- 6 Various physiological parameters were also measured throughout the experiment including body weight, CO2 levels, blood pH, and heart rate. In a second experiment, 1 mg/kg or 2 mg/kg dosages of the ivermectin liquid solution having formulation 7E were administered. Vehicle and 3 mg/kg Alprazolam served as controls (see, Table 12).

Table 11. Groups for Modulation of PTZ-Induced Seizures (Experiment 1)

Table 12. Groups for Modulation of PTZ-Induced Seizures (Experiment 2)

[0186] Results

[0187] Area under the curve was calculated for each brain region and treatment as shown in Fig. 7A (experiment 1) and Fig. 7B (experiment 2). In the first experiment, in each brain area, a decrease in (PTZ)-induced ictal brain activity was seen with both 2 mg/kg and 4 mg/kg dosages of the ivermectin liquid solution having formulation 7E, as compared to the control (vehicle). Similar results were observed for the second experiment.

[0188] Conclusion

[0189] Physiological parameters measured with arterial blood sampling and pulse oximetry indicated good cardiovascular and respiratory stability of the subjects throughout the functional imaging experiments. The positive control compounds Alprazolam and Diazepam effectively cancelled PTZ-induced brain activity with high statistical significance in all tested brain regions.

[0190] Both 2 mg/kg and 4 mg/kg doses of the liquid solution of formulation 7E demonstrated significant modulation of the PTZ-induced BOLD signal change in several brain areas (Striatum, Hippocampus, VTA, cortical areas) with dose-dependent manner, shortening or attenuating the activity duration. The higher IVM dose 4 mg/kg induced significant modulation in all studied brain regions attenuating the PTZ-response.

[0191] Example 8 - Patient Dosed Phase 1 Study

[0192] To evaluate safety, tolerability, PK, and high-fat food effects on formulation 7E, a Phase 1 double-blind, placebo-controlled, randomized (3: 1), dose-finding study was performed in healthy subjects and its effects on quality of life was assessed. A single ascending dose (SAD) portion of the study was followed by a multiple ascending dose (MAD) cohorts at 10, 20, 40, 80 and 120 mg of formulation 7E once a day for 14 days. The study population were healthy individuals over 18-65 years of age.

[0193] SAD portion of the study

[0194] Participants were admitted to the clinical research center the day before dosing for a baseline assessment, including an eligibility review, physical exam, neurological exam, laboratory evaluations, an EKG, and pupillometry. Subjects followed a fasting dose protocol and were given a single dose administration of the study product followed by serial PK, vital signs, and safety assessments including pupillometry and neurological exams over 120 hours. Additionally, PK sample collection occurred at the following time points: pre-dose (within 2 hours prior to dosing) and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48, 72, and 120 hours post-dose). Each subsequent SAD cohort (see, Table 13) begun 72 hours after the last subject in the previous cohort was dosed, as long as fewer than 2 of the participants in that cohort experienced a dose limiting toxicity (DLT), as ivermectin toxicity manifests within 24 hours of dosing. Participants in the 40 mg cohort of the SAD portion of the study were not discharged on day 6 and instead continued onto a fed sub-study, with the fed dose administered 10 days after the fasted dose in conjunction with a high-fat meal. Evaluations following the fed dose were identical to those after the fasted SAD doses and continued through 120 hours.

[0195] Two vials of whole blood samples for PD measurements were collected pre-dose and 24 hours after the single dose for exploratory biomarker research.

[0196] The results of the PK analysis for the SAD portion of the study are shown in Fig. 8 and Table 14.

[0197] MAD portion of the study (14-Day study, one dose per day)

[0198] Each MAD cohort 10 mg - 80 mg (see, Table 13) begun dosing the day after the SAD cohort at the dose above had completed dosing and had been monitored for 72 hours, provided stopping criteria were not met in the SAD study or in a lower dose MAD cohort. If stopping criteria were not yet met, the 120 mg MAD cohort begun after the last subject in the 80 mg cohort had been dosed through day 5, as steady state was estimated to occur around 4 days.

[0199] Volunteers underwent screening and baseline assessments as described above for the SAD portion of the study. Subjects followed a fasting dose protocol on days 1, 2, and 14, and were given a single daily administration of the study product for 14 days. After dosing on days 1, 7 and 14, vital signs and safety assessments including pupillometry and neurological exams were performed. These and additional safety assessments were also performed on day 19. PK sample collection occurred at the following time points after Day 1 and Day 14 dosing: predose (within 2 hour prior to dosing) and at 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 pre-dose on days 5, 7, 8, 9, 10, 12, and 14. If two participants in a cohort experienced a DLT, that cohort was stopped as were any overlapping cohorts at a higher dose.

[0200] Two vials of whole blood samples for PD measurements were collected pre-dose and on Day 15 (24 hours after a subject’s last dose of study drug in the MAD study) for exploratory biomarker research. Table 13. Phase I Dose Cohorts

*Formulation 7E gelcap 40 mg (or MTD, whichever is lower) (n=the 8 from the 40 mg or MTD SAD cohort)

Table 14. PK Data for Phase I SAD Portion

[0201] Peripheral blood mononuclear cells (PBMCs) were purified from the human subjects from the SAD and MAD cohortos before and after (24 hours after the last dosing) oral administration of the drug at doses 10, 20, 40, 80, 120 or placebo. The PBMCs were stimulated for 48 h using immobilized monoclonal antibodies (mAbs) against CD3 and CD28 (anti- CD3/28). The supernatants were analyzed for IL-17 by ELISA.

[0202] As shown in Fig. 9, oral administration of formulation 7E by healthy subjects down- regulates the ability of T cells to secrete IL-17 in response to T cell receptor stimulation ex vivo. The inhibitory effect of EQU-001 on IL- 17 secretion was robust and dose-dependent.

[0203] Example 9 - Patient Dosed Phase 2 Study (Daily, 12 Weeks) (Prophetic Example)

[0204] To evaluate preliminary efficacy in terms of overall seizure reduction, seizure reduction by seizure type (focal, generalized, and unknown), reduction of generalized tonic- clonic seizures and focal to generalized tonic-clonic seizures, seizure freedom over time, tolerability, and impacts suicidality of formulation 7E, a double-blind, placebo-controlled, randomized (4: 1), a Phase II safety and dose-finding study of adjunctive composition 7E is performed. The population are subjects ages 18 years to 70 years who have been diagnosed with epilepsy according to International League Against Epilepsy (ILAE) Classification of the Epilepsies 2017 criteria (ILAE 2017) and who are uncontrolled on one to four concomitant antiepileptic drugs (AEDs) at optimal stable dosages for >4 weeks prior to screening and throughout the treatment period.

[0205] Cohorts (see, Table 15) are dosed sequentially beginning with Dose Cohort 1. This study initially randomizes a total of 10 subjects into the first dosing cohort (10 mg daily, 4: 1 active to placebo) for 12 weeks. Safety data is reviewed after 14 days to determine whether the next cohort can be opened. Dosing continues through a continuous reassessment method (CRM) with oversight of the Safety Review Committee (SRC) after each cohort until 10 subjects have completed 14 days of dosing at 60 mg QD, or until a total of 10 subjects have received the same active dose for 14 days and this dose is identified as the MTD. In each dosing cohort, subjects with no DLTs during the initial 14 days of treatment continue with dosing through 12 weeks, as long as they do not experience a DLT, otherwise meet withdrawal criteria, or decide to withdraw from treatment.

[0206] Evaluations of PK parameters together with safety, efficacy, and concomitant antiepileptic drugs (AED) are made after 2, 4, 8, and 12 weeks of treatment by an unblinded study statistician and provided to a sponsor-designated study physician for review. This review will be performed separately from the review for dose escalation, which is based on DLT development.

Table 15. Phase II Dose Cohorts, Estimated