WO2022271537A1

WO2022271537A1 - Compositions and methods relating to injectable microemulsions

Info

Publication number: WO2022271537A1
Application number: PCT/US2022/033924
Authority: WO
Inventors: Samir Mitragotri; Jayoung Kim
Original assignee: President And Fellows Of Harvard College
Priority date: 2021-06-25
Filing date: 2022-06-17
Publication date: 2022-12-29

Abstract

The technology described herein is directed to compositions and methods for the administration of injectable emulsions.

Description

COMPOSITIONS AND METHODS RELATING TO INJECTABLE MICROEMULSIONS

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. filed 63/214,979 filed June 25, 2021, the contents of which are incorporated herein by reference in their entirety.

TECHNICAL FIELD

[0002] The technology described herein relates to drug delivery, e.g., subcutaneous delivery.

BACKGROUND

[0003] Many drugs suitable for subcutaneous or intraperitoneal delivery require frequent dosing. The injectable nature of such drug formulations typically precludes the use of sustained release drug formulations. This bolus dosing, coupled with short systemic half-lives leads to the need for repeated dosing, in some cases, multiple times per day. For example, apomorphine (a treatment for Parkinson’s disease) has a short systemic half-life which necessitates 3 injections per day. Such a frequent dosing regimen imposes a significant compliance challenge, especially given the nature of the disease.

SUMMARY

[0004] Described herein is a first of its kind deep eutectic-based formulation that slows the release of drugs after subcutaneous injection and extends pharmacokinetics to drastically reduce the total number and frequency of injections. In an exemplary embodiment, the formulation comprises a homogeneous mixture of a deep eutectic solvent (e.g., choline-geranate), a co-solvent n-methyl- pyrrolidone, a stabilizer polyethylene glycol, and water, which spontaneously emulsifies into a microemulsion upon injection in the subcutaneous space, thereby entrapping the active agents and significantly slowing its release. In vivo pharmacokinetics confirmed extended sustained release and improvement over a clinical comparator. In vivo pharmacokinetics, supported by a pharmacokinetic simulation, demonstrate that the deep eutectic formulation reported here allows maintenance of the therapeutic drug concentration in plasma in humans with a reduced-frequency dosing regimen.

[0005] In one aspect of any of the embodiments, described herein is a composition comprising an ionic liquid and n-methyl-pyrrolidone. In some embodiments of any of the aspects, the composition further comprises at least one active agent. In some embodiments of any of the aspects, the composition further comprises polyethylene glycol. In some embodiments of any of the aspects, the composition comprises the ionic liquid, n-methyl-pyrrolidone and polyethylene glycol. In some embodiments of any of the aspects, the composition comprises the ionic liquid, n-methyl-pyrrolidone; polyethylene glycol; and at least one active agent.

[0006] In some embodiments of any of the aspects, the ionic liquid is 1-90% v/v with a cation: anion ratio such that there is more anion than cation. In some embodiments of any of the aspects, the ionic liquid has a cation: anion ratio in which there is at least twice as much anion as cation. In some embodiments of any of the aspects, the ionic liquid has a cation: anion ratio in which there is at least four times as much anion as cation. In some embodiments of any of the aspects, the ionic liquid is 1- 90% v/v with a catiomanion ratio of 1:2. In some embodiments of any of the aspects, the ionic liquid is 1-55% v/v. In some embodiments of any of the aspects, the ionic liquid is 5-20% v/v. In some embodiments of any of the aspects, the ionic liquid is 10% v/v. In some embodiments of any of the aspects, the ionic liquid has an anion with a LogP of 1.0 or greater. In some embodiments of any of the aspects, the ionic liquid has an anion with a LogP of 2.0 or greater. In some embodiments of any of the aspects, the ionic liquid has an anion with a LogP of 3.0 or greater. In some embodiments of any of the aspects, the anion of the ionic liquid is geranate or geranic acid. In some embodiments of any of the aspects, the ionic liquid has an cation comprising a quaternary ammonium. In some embodiments of any of the aspects, the cation is choline or one of C1-C7. In some embodiments of any of the aspects, the ionic liquid is CAGE.

[0007] In some embodiments of any of the aspects, the n-methyl-pyrrolidone is present at least about 35% v/v. In some embodiments of any of the aspects, the n-methyl-pyrrolidone is present at less than 45% v/v. In some embodiments of any of the aspects, the n-methyl-pyrrolidone is present at 1-45% v/v.

[0008] In some embodiments of any of the aspects, the n-methyl-pyrrolidone is present at least about 35% v/v, and the CAGE is 1-90% v/v CAGE at a ratio of choline: geranate such that there is more geranate than choline present. In some embodiments of any of the aspects, the n-methyl-pyrrolidone is present at least about 35% v/v, and the CAGE is 10% CAGE 1 :2. In some embodiments of any of the aspects, the n-methyl-pyrrolidone is present at about 42.7% v/v, and the CAGE is 10% CAGE 1:2. [0009] In some embodiments of any of the aspects, the polyethylene glycol is PEG 3350 present at about 10 to about 50 mg/mL. In some embodiments of any of the aspects, the polyethylene glycol is PEG 3350 present at about 28.8 mg/mL.

[0010] In some embodiments of any of the aspects, the active agent is present at 20 mg/mL or greater. In some embodiments of any of the aspects, the active agent is present at 30 mg/mL or greater. In some embodiments of any of the aspects, the active agent is present at 40 mg/mL or greater. In some embodiments of any of the aspects, the active agent is present at 50 mg/mL or greater. In some embodiments of any of the aspects, the active agent is apomorphine. In some embodiments of any of the aspects, the apomorphine is at a concentration of 30 mg/mL.

[0011] In some embodiments of any of the aspects, the composition further comprises sodium metabisulfite. In some embodiments of any of the aspects, the sodium metabisulfite is present at about 1% w/v. In some embodiments of any of the aspects, the sodium metabisulfite is present at about 0.3% w/v. In some embodiments of any of the aspects, the sodium metabisulfite is present at about 3 mg/mL. [0012] In some embodiments of any of the aspects, the composition is formulated for subcutaneous administration. [0013] In one aspect of any of the embodiments, described herein is a method of treating a disease in a subject in need thereof, the method comprising subcutaneously administering a therapeutically effective dose of a composition wherein the active agent is therapeutic for the disease. In one aspect of any of the embodiments, described herein is a composition as described herein, wherein the active agent is therapeutic for a disease, for use in a method of treating that disease in a subject in need thereof, the method comprising subcutaneously administering a therapeutically effective dose of the composition. [0014] In one aspect of any of the embodiments, described herein is a method of treating Parkinson’s Disease in a subject in need thereof, the method comprising subcutaneously administering a therapeutically effective dose of a composition wherein the active agent comprises apomorphine. In one aspect of any of the embodiments, described herein is a composition as described herein, wherein the active agent is apomorphine, for use in a method of treating Parkinson’s Disease in a subject in need thereof, the method comprising subcutaneously administering a therapeutically effective dose of the composition. [0015] In some embodiments of any of the aspects, the administration is daily or no more frequent than daily. In some embodiments of any of the aspects, the administration is every other day or no more frequent than every other day. [0016] In some embodiments of any of the aspects, the dosing regime comprises a 60 mg apomorphine dose on Day 1, a 30 mg apomorphine dose on Day 3, and an 18 mg apomorphine dose every 48 hours thereafter for the duration of treatment. BRIEF DESCRIPTION OF THE DRAWINGS [0017] Fig. 1 depicts a schematic diagram of SEAPORT principle. APO, PEG3350, and sodium metabisulfite are solubilized in a CAGE_1:2/NMP/water (10:42.7:47.3% v/v) mixture in SEAPORT, and then upon subcutaneous injection, water-miscible NMP diffuses away quickly and the remaining CAGE_1:2 emulsifies with APO to form a depot, allowing sustained release of the drug. [0018] Figs. 2A-2C demonstrate the solubility and stability of APO in SEAPORT. Fig. 2A) Photograph image of SEAPORT formulation, Fig. 2B) APO concentration in SEAPORT immediately following formulation detected by LC-MS (n=3), and Fig. 2C) long-term stability determined by apomorphine concentration using LC-MS on days 1, 2, 4, and 7 after incubation at 4^oC (n=3). [0019] Figs. 3A-3E demonstrate the ex vivo diffusion of APO. Fig. 3A) Schematic illustration of ex vivo apparatus for APO release study from harvested rat skin, Fig. 3B) % release of APO into saline from harvested rat skin subcutaneously injected with 50 ^L rApokyn, SEAPORT, and SEAPORT w/o CAGE_1:2, as determined by LC-MS (n=5), Fig. 3C) photograph images of 36% w/v agarose gel prepared in 20 mL glass scintillation vial (white arrows: hollow channel at the center of agarose gel), Fig. 3D) photograph image of opaque, emulsified SEAPORT after incubation in the agarose gel, and Fig. 3E) % of APO remaining at the center of agarose gel after incubation at 37^oC for specified time- point, determined by LC-MS (n=3), [0020] Figs. 4A-4D demonstrate the self-emulsification of SEAPORT. Fig. 4A) Hydrodynamic diameter of the SEAPORT formulation pre- and post-incubation in 36% w/v agarose gel in water determined by dynamic light scattering (n=3, formulation replicates, inlet: zoomed in on SEAPORT), Fig. 4B) cryo-TEM image of SEAPORT formulation before and following 20 min incubation in agarose gel (scale bar: top = 50 nm, bottom = 1 µm), Fig. 4C) ATR-FTIR spectra of SEAPORT, SEAPORT w/o APO, SEAPORT w/o CAGE_1:2, APO in NMP, NMP alone, and CAGE_1:2, and Fig. 4D) diffusion coefficients of APO in rApokyn and SEAPORT 20 min post-incubation in 36% w/v agarose gel, as determined by DOSY NMR (n=3). [0021] Figs. 5A-5E demonstrate pharmacokinetics and toxicity in rats. Fig. 5A) Pharmacokinetics of APO in male Wistar rats subcutaneously injected with rApokyn (2.5 mg APO/kg), SEAPORT (7.5 mg APO/kg), and SEAPORT w/o CAGE_1:2 (7.5 mg APO/kg) (n=4 / group, mean ± sem), detected with triple-quadrupole LC-MS/MS, Fig. 5B) AUC, Fig. 5C) C_max, Fig. 5D) duration of plasma [APO] above 10% C_max, and Fig. 5E) representative images of H&E-stained skin sections at the site of injection, collected on day 1 and 7 post-injection (scale bar = 1 mm). [0022] Figs. 6A-6C demonstrate modeling and simulation of pharmacokinetics from repeated dosing of SEAPORT. Fig. 6A) Compartmental model diagram used to generate pharmacokinetics model, Fig. 6B) simulation of SEAPORT pharmacokinetics in human over a 10-day period from two initial injections of 60 mg and 30 mg APO 48 hours apart (2 and 1 mL SEAPORT, respectively), followed by injections of 18 mg APO (0.6 mL SEAPORT) every 48 hours thereafter, and Fig. 6C) time spent between MTC and MEC during the time window between 96 and 720 hours (day 3 and 30) post initial injection (SEAPORT: 18 mg APO dose every 48 hours, rApokyn: 10 mg APO dose every 8 hours). [0023] Figs.7A-7E depict CAGE_1:2 and SEAPORT characterization. Fig.7A) Ternary phase diagram of CAGE_1:2/NMP/water mixture, excluding NMP concentrations greater than 45% v/v (inlet: photograph images of CAGE_1:2/water mixture at 100:0, 5:95, 10:90, 20:80, and 30:70 v/v ratios, showing emulsified opaque product at or below 10% v/v CAGE_1:2), Fig.7B) apomorphine concentration via LC-MS on days 1, 2, 4, and 7 after incubation at 25^oC and 37^oC (n=3), Fig.7C) photograph images of SEAPORT, SEAPORT w/o SMB, SEAPORT w/o APO formulations freshly prepared or incubated at 4^oC, 25^oC, and 37^oC for 1, 3, 5, and 7 days, where oxidation of APO is presented as discoloration of the formulation into dark blue color, and indirect detection of APO oxidation via colorimetric assay through absorbance at 600 nm in Fig.8C) SEAPORT w/o SMB formulation, Fig.7D) compared to SEAPORT formulations (n=3). [0024] Figs.8A-8D demonstrate the ex vivo diffusion of APO. Fig 8A) Cumulative amount of APO released into saline from rat skin subcutaneously injected with 50 ^L rApokyn, SEAPORT, and SEAPORT w/o CAGE_1:2, as determined by LC-MS (n=5), Fig 8B) photograph images of rat skin injected with SEAPORT and SEAPORT w/o CAGE_1:2 and incubated for 10 min, 24 hour, and 48 hour at 37^oC (white arrow: oxidized APO accumulated at the boundary of rat skin), Fig 8C) 5 cm x 10 cm rat skin harvested from euthanized male Wistar rats, and Fig 8D) bleb resulting from injection of 50 ^L formulation containing trypan blue for visualization. [0025] Figs.9A-9F depict the characterization of self-emulsified SEAPORT. Fig.9A) Ratio of peak heights at 1675 cm^-1 and 1645 cm^-1 in the time-course FTIR spectra of SEAPORT and SEAPORT w/o CAGE_1:2 following incubation in 36% w/v agarose gel (dotted line: ratio in neat CAGE_1:2), DOSY NMR spectra of Fig.9B) rApokyn and Fig.9C) SEAPORT formulations 20 min post-incubation in agarose gel, Fig.9D) rApokyn and Fig.9E) SEAPORT formulations prepared fresh, and Figure 9F) diffusion coefficients of APO in fresh rApokyn and SEAPORT formulations, as determined by DOSY NMR (n=3). [0026] Figs.10A-10C depict pharmacokinetics modeling. Fig.10A) simulation of rApokyn pharmacokinetics in human over a 10-day period from serial injections of 10 mg APO 8 hours apart (1 mL rApokyn), Fig.10B) time spent below MEC and Fig.10C) above MTC during the time window between 96 and 720 hours (day 3 and 30) post initial injection (SEAPORT: 18 mg APO dose every 48 hours, rApokyn: 10 mg APO dose every 8 hours). DETAILED DESCRIPTION [0027] The compositions described herein offer highly advantageous drug delivery characteristics. Ex vivo, the compositions are in a liquid form that provides good solubility for active agents. Upon subcutaneous injection, the compositions take the form of an emulsion, providing a sustained release kinetics for the active agent. Thus, the compositions described herein provide injectable compositions that provide emulsions in vivo. [0028] As used herein, the term "emulsion" refers to a heterogeneous system comprising at least two or more substantially immiscible liquids, wherein one liquid is dispersed in another liquid in the form of droplets. By way of example only, emulsions can be biphasic systems comprising two immiscible liquid phases intimately mixed and dispersed with each other. Examples of an emulsion include, but are not limited to, water-in-oil emulsions, oil-in-water emulsion, water-in-water, water-in-oil-in-water emulsions, and oil-in-water-in-oil emulsions. In some embodiments of any of the aspects, the continuous phase of the emulsion is water. In some embodiments of any of the aspects, the emulsion is a microemulsion, e.g., comprising droplets of a 1 to 1,000 µm diameter. [0029] Accordingly, provided herein are compositions comprising an ionic liquid (e.g., the ionic liquid choline:geranate) and one or more of n-methyl-pyrrolidone; polyethylene glycol; and sodium metabisulfite. In some embodiments of any of the aspects, the composition comprises an ionic liquid (e.g., the ionic liquid choline:geranate); n-methyl-pyrrolidone; and at least one of: polyethylene glycol and sodium metabisulfite. In some embodiments of any of the aspects, the composition comprises an ionic liquid (e.g., the ionic liquid choline :geranate); polyethylene glycol; and at least one of: n- methyl-pyrrolidone and sodium metabisulfite. In some embodiments of any of the aspects, the composition comprises an ionic liquid (e.g., the ionic liquid choline :geranate); n-methyl-pyrrolidone; and polyethylene glycol. In some embodiments of any of the aspects, the composition comprises an ionic liquid (e.g., the ionic liquid choline :geranate); n-methyl-pyrrolidone; polyethylene glycol and sodium metabisulfite. In some embodiments of any of the aspects, the composition further comprises at least one active agent.

[0030] In one aspect of any of the embodiments, described herein is a composition comprising: a. a 1-90% v/v IL; an IL having a cation: anion ratio such that there is more anion than cation present; or a 1-90% v/v IL having a catiomanion ratio such that there is more anion than cation present; and b. N-methyl-pyrrolidone.

In one aspect of any of the embodiments, described herein is a composition comprising: a. a 1-90% v/v IL; an IL having a cation: anion ratio such that there is more anion than cation present; or a 1-90% v/v IL having a catiomanion ratio such that there is more anion than cation present; b. N-methyl-pyrrolidone; and c. polyethylene glycol.

In one aspect of any of the embodiments, described herein is a composition comprising: a. a 1-90% v/v IL; an IL having a cation: anion ratio such that there is more anion than cation present; or a 1-90% v/v IL having a catiomanion ratio such that there is more anion than cation present; b. N-methyl-pyrrolidone; c. polyethylene glycol; and d. sodium metabisulfite.

[0031] In one aspect of any of the embodiments, described herein is a composition comprising: a. a 1-90% v/v IL; an IL having a cation: anion ratio such that there is more anion than cation present; or a 1-90% v/v IL having a catiomanion ratio such that there is more anion than cation present; b. N-methyl-pyrrolidone; and c. At least one active agent.

In one aspect of any of the embodiments, described herein is a composition comprising: a. a 1-90% v/v IL; an IL having a cation: anion ratio such that there is more anion than cation present; or a 1-90% v/v IL having a catiomanion ratio such that there is more anion than cation present; b. N-methyl-pyrrolidone; c. polyethylene glycol; and d. At least one active agent.

In one aspect of any of the embodiments, described herein is a composition comprising: a. a 1-90% v/v IL; an IL having a cation: anion ratio such that there is more anion than cation present; or a 1-90% v/v IL having a catiomanion ratio such that there is more anion than cation present; b. N-methyl-pyrrolidone; c. polyethylene glycol; d. sodium metabisulfite; and e. At least one active agent.

[0032] In one aspect of any of the embodiments, described herein is a composition comprising: a. 1-90% v/v CAGE; CAGE at a ratio of choline :geranate such that there is more geranate than choline present; or 1-90% v/v CAGE at a ratio of choline :geranate such that there is more geranate than choline present; and b. N-methyl-pyrrolidone.

In one aspect of any of the embodiments, described herein is a composition comprising: a. 1-90% v/v CAGE; CAGE at a ratio of choline: geranate such that there is more geranate than choline present; or 1-90% v/v CAGE at a ratio of choline :geranate such that there is more geranate than choline present; b. N-methyl-pyrrolidone; and c. polyethylene glycol.

In one aspect of any of the embodiments, described herein is a composition comprising: a. 1-90% v/v CAGE; CAGE at a ratio of choline: geranate such that there is more geranate than choline present; or 1-90% v/v CAGE at a ratio of choline :geranate such that there is more geranate than choline present; and b. N-methyl-pyrrolidone; c. polyethylene glycol; and d. sodium metabisulfite.

[0033] In one aspect of any of the embodiments, described herein is a composition comprising: a. 1-90% v/v CAGE; CAGE at a ratio of choline: geranate such that there is more geranate than choline present; or 1-90% v/v CAGE at a ratio of choline :geranate such that there is more geranate than choline present; b. N-methyl-pyrrolidone; and c. At least one active agent.

In one aspect of any of the embodiments, described herein is a composition comprising: a. 1-90% v/v CAGE; CAGE at a ratio of choline :geranate such that there is more geranate than choline present; or 1-90% v/v CAGE at a ratio of choline :geranate such that there is more geranate than choline present; b. N-methyl-pyrrolidone; c. polyethylene glycol; and d. At least one active agent.

In one aspect of any of the embodiments, described herein is a composition comprising: a. 1-90% v/v CAGE; CAGE at a ratio of choline: geranate such that there is more geranate than choline present; or 1-90% v/v CAGE at a ratio of choline :geranate such that there is more geranate than choline present; b. N-methyl-pyrrolidone; c. polyethylene glycol; d. sodium metabisulfite; and e. At least one active agent.

[0034] In some embodiments of any of the aspects, the composition comprises at least one antioxidant.

[0035] In some embodiments of any of the aspects, the composition further comprises at least one of: choline bicarbonate; methionine; ascorbic acid; sodium metabisulfite; and DMSO.

[0036] In some embodiments of any of the aspects, the composition further comprises at least: a. methionine; ascorbic acid; and sodium metabisulfite; or b. ascorbic acid and sodium metabisulfite.

In some embodiments of any of the aspects, the composition further comprises choline bicarbonate and: a. methionine; ascorbic acid; and sodium metabisulfite; or b. ascorbic acid and sodium metabisulfite.

In some embodiments of any of the aspects, the composition further comprises choline bicarbonate, DMSO, and: a. methionine; ascorbic acid; and sodium metabisulfite; or b. ascorbic acid and sodium metabisulfite.

In some embodiments of any of the aspects, the composition further comprises choline bicarbonate; methionine; ascorbic acid; sodium metabisulfite; and DMSO.

[0037] The term "ionic liquids (ILs)" as used herein refers to organic salts or mixtures of organic salts which are in liquid state at room temperature. This class of solvents has been shown to be useful in a variety of fields, including in industrial processing, catalysis, pharmaceuticals, and electrochemistry. The ionic liquids contain at least one anionic and at least one cationic component. Ionic liquids can comprise an additional hydrogen bond donor (i.e. any molecule that can provide an -OH or an - NH group), examples include but are not limited to alcohols, fatty acids, and amines. The at least one anionic and at least one cationic component may be present in any molar ratio. Exemplary molar ratios (cation: anion) include but are not limited to 1 : 1, 1:2, 2: 1, 1 :3, 3: 1, 2:3, 3:2, and ranges between these ratios. For further discussion of ionic liquids, see, e.g., Hough, et ah , "The third evolution of ionic liquids: active pharmaceutical ingredients", New Journal of Chemistry, 31 : 1429 (2007) and Xu, et al., "Ionic Liquids: Ion Mobilities, Glass Temperatures, and Fragilities", Journal of Physical Chemistry B, 107(25): 6170-6178 (2003); each of which is incorporated by reference herein in its entirety. In some embodiments of any of the aspects, the ionic liquid or solvent exists as a liquid below 100 °C. In some embodiments of any of the aspects, the ionic liquid or solvent exists as a liquid at room temperature.

[0038] ILs for use in the compositions and methods described herein can be hydrophobic to promote phase-separation from water following the diffusion of NMP out of the composition. Hydrophobicity be increased or be provided by a long chain anion, and/or an IL with low polarity.

[0039] Hydrophobicity may be assessed by analysis of logP. “LogP” refers to the logarithm of P (Partition Coefficient). P is a measure of how well a substance partitions between a lipid (oil) and water. P itself is a constant. It is defined as the ratio of concentration of compound in aqueous phase to the concentration of compound in an immiscible solvent, as the neutral molecule.

Partition Coefficient, P=[Organic]/[Aqueous] where [ ]=concentration

Log P=logio (Partition Coefficient)=logio P

In practice, the LogP value will vary according to the conditions under which it is measured and the choice of partitioning solvent. A LogP value of 1 means that the concentration of the compound is ten times greater in the organic phase than in the aqueous phase. The increase in a logP value of 1 indicates a ten fold increase in the concentration of the compound in the organic phase as compared to the aqueous phase.

[0040] In some embodiments of any of the aspects, the anion of an IL described herein is has a LogP of at least 1.0, e.g., 1.0 or greater. In some embodiments of any of the aspects, the anion of an IL described herein is has a LogP of at least 2.0, e.g., 2.0 or greater. In some embodiments of any of the aspects, the anion of an IL described herein is has a LogP of at least 2.5 e.g., 2.5 or greater. In some embodiments of any of the aspects, the anion of an IL described herein is has a LogP of at least 2.75, e.g., 2.75 or greater. In some embodiments of any of the aspects, the anion of an IL described herein is has a LogP of at least about 1.0, e.g., about 1.0 or greater. In some embodiments of any of the aspects, the anion of an IL described herein is has a LogP of at least about 2.0, e.g., about 2.0 or greater. In some embodiments of any of the aspects, the anion of an IL described herein is has a LogP of at least about 2.5 e.g., about 2.5 or greater. In some embodiments of any of the aspects, the anion of an IL described herein is has a LogP of at least about 2.75, e.g., about 2.75 or greater.

[0041] The LogP values for anions are known in the art and/or can be calculated by one of skill in the art. For example, PubChem and SpiderChem provide these values for various anions and chemical manufacturers typically provide them as part of the catalog listings for their products. LogP values for exemplary anions are provided in Table 1 herein.

[0042] When the number of carbons in a chain is referred to herein, it is contemplated that the entire number of carbons in the chain (including branches) is referred to. In the case of a straight chain, this is the same as the carbon chain length. In the case of a branched chain, “chain length” refers to the longest carbon chain branch of the branched chain.

[0043] In some embodiments of any of the aspects, the anion comprises a carbon chain of at least 6 carbons. In some embodiments of any of the aspects, the anion comprises a carbon chain of at least 7 carbons. In some embodiments of any of the aspects, the anion comprises a carbon chain of at least 8 carbons. In some embodiments of any of the aspects, the anion comprises a carbon chain of at least 9 carbons. In some embodiments of any of the aspects, the anion comprises a carbon chain of at least 10 carbons. In some embodiments of any of the aspects, the anion comprises a carbon chain of at least 11 carbons.

[0044] In some embodiments of any of the aspects, the anion comprises a carboxylic acid. In some embodiments, the anion comprises one carboxylic acid group.

[0045] In some embodiments of any of the aspects, the carboxylic acid comprises a carbon chain of at least 6 carbons. In some embodiments of any of the aspects, the carboxylic acid comprises a carbon chain of at least 7 carbons. In some embodiments of any of the aspects, the carboxylic acid comprises a carbon chain of at least 8 carbons. In some embodiments of any of the aspects, the carboxylic acid comprises a carbon chain of at least 9 carbons. In some embodiments of any of the aspects, the carboxylic acid comprises a carbon chain of at least 10 carbons. In some embodiments of any of the aspects, the carboxylic acid comprises a carbon chain of at least 11 carbons.

[0046] In some embodiments of any of the aspects, the anion is an alkane. In some embodiments of any of the aspects, the anion is an alkene. In some embodiments of any of the aspects, the anion comprises a single carboxyl group. In some embodiments of any of the aspects, the carbon chain of the carboxylic acid comprises one or more substituent groups. In some embodiments of any of the aspects, the carbon chain backbone of the carboxylic acid comprises one or more substituent groups, wherein each substituent group comprises at least one carbon atom. In some embodiments of any of the aspects, the carbon chain backbone of the carboxylic acid comprises one or more substituent groups, wherein at least one substituent group comprises a methyl group. In some embodiments of any of the aspects, the carbon chain backbone of the carboxylic acid comprises two substituent groups, wherein each substituent group comprises at least one carbon atom. In some embodiments of any of the aspects, the carbon chain backbone of the carboxylic acid comprises two substituent groups, wherein one substituent group comprises a methyl group. In some embodiments of any of the aspects, the carbon chain backbone of the carboxylic acid comprises two substituent groups, wherein each substituent group comprises a methyl group.

[0047] In some embodiments of any of the aspects, the anion is an unsubstituted alkane. In some embodiments of any of the aspects, the anion is an unsubstituted alkene. In some embodiments of any of the aspects, the carbon chain backbone of the carboxylic acid comprises one or more substituent groups. In some embodiments of any of the aspects, the carbon chain of the carboxylic acid comprises one or more substituent groups, wherein each substituent group comprises at least one carbon atom. In some embodiments of any of the aspects, the carbon chain of the carboxylic acid comprises one or more substituent groups, wherein each substituent group is alkyl, aryl, heteroalkayl, heteroaryl, alkane, or alkene. In some embodiments of any of the aspects, the carbon chain of the carboxylic acid comprises one or more substituent groups, wherein each substituent group is unsubstituted alkyl, unsubstituted aryl, unsubstituted heteroalkayl, unsubstituted heteroaryl, unsubstituted alkane, or unsubstituted alkene.

[0048] In some embodiments of any of the aspects, the carboxylic acid comprises a carbon backbone chain having 8 carbons, is optionally a mono-alkene, and optionally has two substituents. In some embodiments of any of the aspects, at least one of the substituents is a methyl group. In some embodiments of any of the aspects, both of the substituents is a methyl group.

[0049] The term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include mono-, di- and multivalent radicals, having the number of carbon atoms designated (i.e., Ci-Cio means one to ten carbons). An alkyl is an uncyclized chain. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, (cyclohexyl)methyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An “alkenyl” is an unsaturated alkyl group is one having one or more double bonds bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl), and the higher homologs and isomers.

[0050] The term “aryl” means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently. A fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring. The term “heteroaryl” refers to aryl groups (or rings) that contain at least one heteroatom such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quatemized. Thus, the term “heteroaryl” includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring). A 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. Likewise, a 6,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. And a 6,5 -fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Exemplary aryl and heteroaryl groups include, but are not limited to, phenyl, 4- nitrophenyl, 1 -naphthyl, 2-naphthyl, biphenyl, 4-biphenyl, pyrrole, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, pyrazole, 3-pyrazolyl, imidazole, imidazolyl, 2-imidazolyl, 4-imidazolyl, benzimidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, thiazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, pyridine, 2- pyridyl, naphthyridinyl, 3-pyridyl, 4-pyridyl, benzophenonepyridyl, pyridazinyl, pyrazinyl, 2- pyrimidyl, 4-pyrimidyl, pyrimidinyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, indolyl, 5-indolyl, quinoline, quinolinyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, 6- quinolyl, fiiran, furyl or furanyl, thiophene, thiophenyl or thienyl, diphenylether, diphenylamine, and the like.

[0051] The term “optionally substituted” means that the specified group or moiety is unsubstituted or is substituted with one or more (typically 1, 2, 3, 4, 5 or 6 substituents) independently selected from the group of substituents listed below in the definition for “substituents” or otherwise specified. The term “substituents” refers to a group “substituted” on a substituted group at any atom of the substituted group. Suitable substituents include, without limitation, halogen, hydroxy, caboxy, oxo, nitro, haloalkyl, alkyl, alkenyl, alkynyl, alkaryl, aryl, heteroaryl, cyclyl, heterocyclyl, aralkyl, alkoxy, aryloxy, amino, acylamino, alkylcarbanoyl, arylcarbanoyl, aminoalkyl, alkoxycarbonyl, carboxy, hydroxyalkyl, alkanesulfonyl, arenesulfonyl, alkanesulfonamido, arenesulfonamido, aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano or ureido. In some cases, two substituents, together with the carbons to which they are attached to can form a ring.

[0052] In some embodiments of any of the aspects, the carboxylic acid is selected from the group consisting of: octanoic acid; 2-octenoic acid; 3-octenoic acid; 4-octenoic acid; 5-octenoic acid; 6- octenoic acid; 7-octenoic acid; 2,2-dimethyloctanoic acid; 2,3-dimethyloctanoic acid; 2,4- dimethyloctanoic acid; 2,5-dimethyloctanoic acid; 2,6-dimethyloctanoic acid; 2,7-dimethyloctanoic acid; 3,3-dimethyloctanoic acid; 3,4-dimethyloctanoic acid; 3,5-dimethyloctanoic acid; 3,6- dimethyloctanoic acid; 3,7-dimethyloctanoic acid; 4,4-dimethyloctanoic acid; 4,5-dimethyloctanoic acid; 4,6-dimethyloctanoic acid; 4,7-dimethyloctanoic acid; 5,5-dimethyloctanoic acid; 5,6- dimethyloctanoic acid; 5,7-dimethyloctanoic acid; 6,6-dimethyloctanoic acid; 6,7-dimethyloctanoic acid; 7,7-dimethyloctanoic acid; 2,3-dimethyl-2-octenoic acid; 2,4-dimethyl-2-octenoic acid; 2,5- dimethyl-2-octenoic acid; 2,6-dimethyl-2-octenoic acid; 2,7-dimethyl-2-octenoic acid; 3,4-dimethyl-

2-octenoic acid; 3,5-dimethyl-2-octenoic acid; 3,6-dimethyl-2-octenoic acid; 3, 7-dimethyl -2 -octenoic acid; 4,4-dimethyl-2-octenoic acid; 4,5-dimethyl-2-octenoic acid; 4,6-dimethyl-2-octenoic acid; 4,7- dimethyl-2-octenoic acid; 5,5-dimethyl-2-octenoic acid; 5,6-dimethyl-2-octenoic acid; 5,7-dimethyl-

2-octenoic acid; 6, 6-dimethyl-2 -octenoic acid; 6,7-dimethyl-2-octenoic acid, 7, 7-dimethyl-2 -octenoic acid;2,2-dimethyl-3 -octenoic acid; 2,3-dimethyl-3-octenoic acid; 2, 4-dimethyl-3 -octenoic acid; 2,5- dimethy 1-3 -octenoic acid; 2, 6-dimethyl-3 -octenoic acid; 2,7-dimethyl-3-octenoic acid; 3,4-dimethyl-

3-octenoic acid; 3, 5 -dimethyl-3 -octenoic acid; 3,6-dimethyl-3-octenoic acid; 3, 7 -dimethyl-3 -octenoic acid; 4,5 -dimethyl-3 -octenoic acid; 4, 6-dimethyl-3 -octenoic acid; 4, 7 -dimethyl-3 -octenoic acid; 5,5- dimethy 1-3 -octenoic acid; 5, 6-dimethyl-3 -octenoic acid; 5,7-dimethyl-3-octenoic acid; 6,6-dimethyl-

3-octenoic acid; 6, 7 -dimethyl-3 -octenoic acid; 7,7-dimethyl-3-octenoic acid; 2,2-dimethyl-4-octenoic acid; 2,3-dimethyl-4-octenoic acid; 2,4-dimethyl-4-octenoic acid; 2,5-dimethyl-4-octenoic acid; 2,6- dimethyl-4-octenoic acid; 2,7-dimethyl-4-octenoic acid; 3,3-dimethyl-4-octenoic acid; 3,4-dimethyl-

4-octenoic acid; 3, 5 -dimethyl -4-octenoic acid; 3,6-dimethyl-4-octenoic acid; 3, 7-dimethyl -4-octenoic acid; 4,5-dimethyl-4-octenoic acid; 4,6-dimethyl-4-octenoic acid; 4,7-dimethyl-4-octenoic acid; 5,6- dimethyl-4-octenoic acid; 5,7-dimethyl-4-octenoic acid; 6,6-dimethyl-4-octenoic acid; 6,7-dimethyl-

4-octenoic acid; 7, 7-dimethyl -4-octenoic acid; 2, 2-dimethyl-5 -octenoic acid; 2,3 -dimethyl-5 -octenoic acid; 2, 4-dimethyl-5 -octenoic acid; 2,5 -dimethyl-5 -octenoic acid; 2, 6-dimethyl-5 -octenoic acid; 2,7- dimethy 1-5 -octenoic acid; 3, 3 -dimethyl-5 -octenoic acid; 3, 4-dimethyl-5 -octenoic acid; 3, 5 -dimethyl -

5-octenoic acid; 3, 6-dimethyl-5 -octenoic acid; 3,7-dimethyl-5-octenoic acid; 4, 4-dimethyl-5 -octenoic acid; 4,5 -dimethyl-5 -octenoic acid; 4, 6-dimethyl-5 -octenoic acid; 4, 7 -dimethyl-5 -octenoic acid; 5,6- dimethy 1-5 -octenoic acid; 5, 7-dimethyl-5 -octenoic acid; 6,7-dimethyl-5-octenoic acid; 7,7-dimethyl-

5-octenoic acid; 2,2-dimethyl-6-octenoic acid; 2,3-dimethyl-6-octenoic acid; 2,4-dimethyl-6-octenoic acid; 2,5-dimethyl-6-octenoic acid; 2,6-dimethyl-6-octenoic acid; 2,7-dimethyl-6-octenoic acid; 3,3- dimethyl-6-octenoic acid; 3,4-dimethyl-6-octenoic acid; 3,5-dimethyl-6-octenoic acid; 3,6-dimethyl-

6-octenoic acid; 3,7-dimethyl-6-octenoic acid (citranellic acid); 4,4-dimethyl-6-octenoic acid; 4,5- dimethyl-6-octenoic acid; 4,6-dimethyl-6-octenoic acid; 4,7-dimethyl-6-octenoic acid; 5,5-dimethyl-

6-octenoic acid; 5,6-dimethyl-6-octenoic acid; 5,7-dimethyl-6-octenoic acid; 6,7-dimethyl-6-octenoic acid; 2,2-dimethyl-7-octenoic acid; 2,3-dimethyl-7-octenoic acid; 2,4-dimethyl-7-octenoic acid; 2,5- dimethyl-7-octenoic acid; 2,6-dimethyl-7-octenoic acid; 2,7-dimethyl-7-octenoic acid; 4,4-dimethyl-

7-octenoic acid; 3,4-dimethyl-7-octenoic acid; 3,5-dimethyl-7-octenoic acid; 3,6-dimethyl-7-octenoic acid; 3,7-dimethyl-7-octenoic acid; 4,4-dimethyl-7-octenoic acid; 4,5-dimethyl-7-octenoic acid; 4,6- dimethyl-7-octenoic acid; 4,7-dimethyl-7-octenoic acid; 5,5-dimethyl-7-octenoic acid; 5,6-dimethyl-

7-octenoic acid; 5,7-dimethyl-7-octenoic acid; 6,6-dimethyl-7-octenoic acid; 6,7-dimethyl-7-octenoic acid; and isomers thereof. In some embodiments of any of the aspects, the carboxylic acid is selected from the group consisting of: octanoic acid; 2-octenoic acid; 3 -octenoic acid; 4-octenoic acid; 5- octenoic acid; 6-octenoic acid; 7-octenoic acid; 2,2-dimethyloctanoic acid; 2,4-dimethyloctanoic acid; 2,5-dimethyloctanoic acid; 2,6-dimethyloctanoic acid; 2,7-dimethyloctanoic acid; 3,3- dimethyloctanoic acid; 3,5-dimethyloctanoic acid; 3,6-dimethyloctanoic acid; 3,7-dimethyloctanoic acid; 4,4-dimethyloctanoic acid; 4,5-dimethyloctanoic acid; 4,6-dimethyloctanoic acid; 5,5- dimethyloctanoic acid; 5,6-dimethyloctanoic acid; 5,7-dimethyloctanoic acid; 6,6-dimethyloctanoic acid; 7,7-dimethyloctanoic acid; 3, 7-dimethyl-2 -octenoic acid; 3,7-dimethyl-3-octenoic acid; 3,7- dimethyl-4-octenoic acid; 2,7-dimethyl-6-octenoic acid; 3,7-dimethyl-6-octenoic acid (citranellic acid); 2,2-dimethyl-7-octenoic acid; 2,3-dimethyl-7-octenoic acid; and isomers thereof. In some embodiments of any of the aspects, octenoic acid as used herein (for example in Table 1) refers to trans-2-octcnoic acid.

[0053] In some embodiments of any of the aspects, the carboxylic acid comprises a carbon backbone chain having 8 carbons and is optionally a mono-alkene. In some embodiments of any of the aspects, the carbon backbone chain of the carboxylic acid is not substituted.

[0054] Exemplary, non-limiting anions are provided in Table 1 below.

Table 1

[0055] In some embodiments of any of the aspects, the anion is selected from Table 1. In some embodiments of any of the aspects, the anion is selected from Group 1 of Table 1. In some embodiments of any of the aspects, the anion is selected from Group 2 of Table 1. In some embodiments of any of the aspects, the anion is selected from Group 3 of Table 1. In some embodiments of any of the aspects, the anion is selected from Group 4 of Table 1. In some embodiments of any of the aspects, the anion is selected from Group 5 of Table 1. In some embodiments of any of the aspects, the anion is selected from Group 6 of Table 1. In some embodiments of any of the aspects, the anion is selected from Groups 3-6 of Table 1.

[0056] Choline and derivatives thereof are shown to be particularly well suited as IL cations for the types of anions described herein. Accordingly, the cation of an IL described herein can be a cation comprising a quaternary ammonium. A quaternary ammonium is a positively charged polyatomic ion of the structure NR₄ ⁺, each R independently being an alkyl group or an aryl group.

[0057] The general term “quaternary ammonium” relates to any compound that can be regarded as derived from ammonium hydroxide or an ammonium salt by replacement of all four hydrogen atoms of the NR₄ ⁺ ion by organic groups. For example, the quaternary ammonium has the structure of NR₄ ⁺, where each R is independently selected from hydroxyl, optionally substituted C₁-C₁₀alkyl, optionally substituted C₂-C₁₀alkenyl, optionally substituted C₂-C₁₀alkynyl, optionally substituted aryl, or optionally substituted heteroaryl.

[0058] In some embodiments of any of the aspects, the cation has a molar mass equal to or greater than choline, e.g., a molar mass equal to or greater than 104.1708 g/mol. In some embodiments of any of the aspects, the cation has a molar mass greater than choline, e.g., a molar mass equal greater than 104.1708 g/mol.

[0059] In some embodiments of any of the aspects, each R group of the quaternary ammoniun independently comprises an alkyl, alkane, alkene, or aryl. In some embodiments of any of the aspects, each R group of the quaternary ammonium independently comprises an alkyl, alkane, or alkene. In some embodiments of any of the aspects, each R group of the quaternary ammoniun independently comprises an alkane or alkene. In some embodiments of any of the aspects, each R group of the quaternary ammonium independently comprises a carbon chain of no more than 10 carbon atoms in length, e.g., no more than 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, or 30 carbon atoms in length. In some embodiments of any of the aspects, each R group of the quaternary ammonium independently comprises a carbon chain of no more than 12 carbon atoms in length. In some embodiments of any of the aspects, each R group of the quaternary ammonium independently comprises a carbon chain of no more than 15 carbon atoms in length. In some embodiments of any of the aspects, each R group of the quaternary ammonium independently comprises a carbon chain of no more than 20 carbon atoms in length.

[0060] In some embodiments of any of the aspects, each R group of the quaternary ammonium independently comprises a carbon chain of no more than 10 carbon atoms, e.g., no more than 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, or 30 carbon atoms. In some embodiments of any of the aspects, each R group of the quaternary ammonium independently comprises a carbon chain of no more than 12 carbon atoms. In some embodiments of any of the aspects, each R group of the quaternary ammonium independently comprises a carbon chain of no more than 15 carbon atoms. In some embodiments of any of the aspects, each R group of the quaternary ammonium independently comprises a carbon chain of no more than 20 carbon atoms.

[0061] In some embodiments of any of the aspects, each R group of the quaternary ammonium independently comprises an alkyl group of no more than 10 carbon atoms, e.g., no more than 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, or 30 carbon atoms. In some embodiments of any of the aspects, each R group of the quaternary ammonium independently comprises an alkyl group of no more than 12 carbon atoms. In some embodiments of any of the aspects, each R group of the quaternary ammonium independently comprises an alkyl group of no more than 15 carbon atoms. In some embodiments of any of the aspects, each R group of the quaternary ammonium independently comprises an alkyl group of no more than 20 carbon atoms.

[0062] In some embodiments of any of the aspects, each R group of the quaternary ammonium independently comprises an alkane, alkene, aryl, heteroaryl, alkyl, or heteroalkyl. In some embodiments of any of the aspects, each R group of the quaternary ammonium independently comprises an unsubstituted alkane, unsubstituted alkene, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkyl, or unsubstituted heteroalkyl. In some embodiments of any of the aspects, each R group of the quaternary ammonium independently an unsubstituted alkane. In some embodiments of any of the aspects, each R group of the quaternary ammonium independently an unsubstituted alkene. In some embodiments of any of the aspects, each R group of the quaternary ammonium independently comprises one or more substituent groups.

[0063] In some embodiments of any of the aspects, at least one R group of the quaternary ammonium comprises a hydroxy group. In some embodiments of any of the aspects, one R group of the quaternary ammonium comprises a hydroxy group. In some embodiments of any of the aspects, only one R group of the quaternary ammonium comprises a hydroxy group. [0064] Exemplary, non-limiting cations can include choline and any of the cations designated C1-C7 which are defined by structure below.

[0065] Further non-limiting examples of cations include the following: 1 -(hydroxymethyl)- 1 -methylpyrrolidin- 1 -ium 1 -(2-hydroxy ethyl) - 1 -methylpyrrolidin- 1 -ium 1 -ethyl- 1 -(3 -hydroxypropyl)pyrrolidin- 1 -ium 1 -(3-hydroxypropyl)- 1 -methylpyrrolidin- 1 -ium 1 -(4-hydroxybutyl)- 1 -methylpyrrolidin- 1 -ium 1 -ethyl- 1 -(4-hydroxybutyl)pyrrolidin- 1 -ium 1 -(4-hydroxybutyl)- 1 -propylpyrrolidin- 1 -ium 1 -(5-hydroxypentyl)- 1 -propylpyrrolidin- 1 -ium 1 -ethyl- 1 -(5-hydroxypentyl)pyrrolidin- 1 -ium 1 -(5 -hydroxypentyl)- 1 -methylpyrrolidin- 1 -ium 1 -(hydroxymethyl)- 1 -methylpiperidin- 1 -ium 1 -(2-hydroxy ethyl) - 1 -methylpiperidin- 1 -ium 1 -ethyl- 1 -(2-hydroxy ethyl)piperidin- 1 -ium -ethyl- 1 -(3 -hydroxypropyl)piperidin- 1 -ium -(3-hydroxypropyl)- 1 -propylpiperidin- 1 -ium -(3-hydroxypropyl)- 1 -methylpiperidin- 1 -ium -(4-hydroxybutyl)- 1 -methylpiperidin- 1 -ium -ethyl- 1 -(4-hydroxybutyl)piperidin- 1 -ium -(4-hydroxybutyl)- 1 -propylpiperidin- 1 -ium -butyl- 1 -(5 -hydroxypentyl)piperidin- 1 -ium -(5-hydroxypentyl)- 1 -propylpiperidin- 1 -ium -ethyl- 1 -(5 -hydroxypentyl)piperidin- 1 -ium -(5-hydroxypentyl)- 1 -methylpiperidin- 1 -ium -ethyl- 1 -methyl- lH-imidazol-3 -ium -methyl-3 -propyl- lH-imidazol-3 -ium -butyl- 1 -methyl- lH-imidazol-3 -ium -methyl-3 -pentyl- lH-imidazol-3 -ium .2-dimethyl-3-pentyl-lH-imidazol-3-ium -butyl- 1 ,2-dimethyl- lH-imidazol-3 -ium .2-dimethyl-3 -propyl- lH-imidazol-3 -ium -(hydroxymethyl)- 1 ,2-dimethyl- lH-imidazol-3 -ium -(2-hydroxyethyl)-l,2-dimethyl-lH-imidazol-3-ium -(3-hydroxypropyl)-l,2-dimethyl-lH-imidazol-3-ium -(4-hydroxybutyl)-l,2-dimethyl-lH-imidazol-3-ium -(5-hydroxypentyl)-l,2-dimethyl-lH-imidazol-3-ium -(5-hydroxypentyl)- 1 -methyl- lH-imidazol-3 -ium -(4-hydroxybutyl)- 1 -methyl- lH-imidazol-3 -ium -(3 -hydroxypropyl)- 1 -methyl- lH-imidazol-3 -ium -(2-hydroxy ethyl) - 1 -methyl- 1 H-imidazol-3 -ium -(hydroxymethyl)- 1 ,2,4,5 -tetramethyl- lH-imidazol-3 -ium-(2-hydroxyethyl)-l,2,4,5-tetramethyl-lH-imidazol-3-ium-(3-hydroxypropyl)-l,2,4,5-tetramethyl-lH-imidazol-3-ium -(4-hydroxybutyl)- 1 ,2,4,5 -tetramethyl- lH-imidazol-3 -ium-(5-hydroxypentyl)-l,2,4,5-tetramethyl-lH-imidazol-3-ium -(5-hydroxypentyl)pyridin- 1 -ium -(4-hydroxybutyl)pyridin- 1 -ium -(3-hydroxypropyl)pyridin- 1 -ium -(2-hydroxyethyl)pyridin- 1 -ium -(hydroxymethyl)pyridin- 1 -ium 1-hydroxypyridin-1-ium (hydroxymethyl)trimethylphosphonium triethyl(hydroxymethyl)phosphonium triethyl(2-hydroxyethyl)phosphonium (2-hydroxyethyl)tripropylphosphonium (3-hydroxypropyl)tripropylphosphonium tributyl(3-hydroxypropyl)phosphonium (3-hydroxypropyl)tripentylphosphonium (4-hydroxybutyl)tripentylphosphonium (5-hydroxypentyl)tripentylphosphonium [0066] In some embodiments of any of the aspects, the cation is choline, C1, C6, and/or C7. In some embodiments of any of the aspects, the cation is C1, C6, and/or C7. [0067] In some embodiments of any of the aspects, the cation is selected from C1, C6, and/or C7 and the anion is geranic acid. In some embodiments of any of the aspects, the cation is C1 and the anion is geranic acid. In some embodiments of any of the aspects, the cation is C6 and the anion is geranic acid. In some embodiments of any of the aspects, the cation is C7 and the anion is geranic acid. [0068] Non-limiting examples of ionic liquids comprise CAGE, [C₆MIM]Cl, [C₄MIM][PF₆], [C_4- ₈MIM][PF₆], [C_2-10MIM][NTf2], [C_2-10MIM][CF₃SO₃], [N_111C2OH][NO₃], ammonium anions with long (didecyldimethylammonium anion) and short [ethyl(2-hydroxyethyl)dimethylammonium] alkyl chains combined with [NTf₂] and [NO₃] anions, [C_4-8MIM][PF₆], [poly(3-butyl-1vinylimidazolium) L-prolinate], [C₂MIM][BF₄], [C₂MIM][CH₃SO₃], and [C₂MIM][CF₃SO₃], N-dodecyldabco bromide, N-methyl-N-decylmorpholinium bromide, choline combined with carboxylic acids, and the like. Further non-limiting examples include the ionic liquids described in Agatemor et al. Bioengineering and Translational Medicine 3:7-25 (2018), the contents of which are incorporated by reference herein in their entirety. [0069] In some embodiments of any of the aspects, the IL is choline:geranate (CAGE). CAGE is an ionic liquid comprising the cation choline (see, e.g., Formula II) and the anion geranate or geranic acid (see, e.g., Formula III and IV). Preparation of CAGE can be, e.g., as described in International Patent Publication WO2015/066647; which is incorporated by reference herein in its entirety, or as described in the examples herein.

[0070] In some embodiments of any of the aspects, the anion of CAGE comprises geranate and/or geranic acid. In some embodiments of any of the aspects, the anion comprises geranate. In some embodiments of any of the aspects, the anion comprises geranic acid.

[0071] In some embodiments of any of the aspects, the IL (e.g., CAGE) has a ratio of catiomanion of about 1: 1. In some embodiments of any of the aspects, the IL (e.g., CAGE) has a ratio of catiomanion of 1 : 1. In some embodiments of any of the aspects, the IL (e.g., CAGE) has a ratio of catiomanion of about 1 :2 or a ratio with more relative anion. In some embodiments of any of the aspects, the IL (e.g., CAGE) has a ratio of catiomanion of 1:2 or a ratio with more relative anion. In some embodiments of any of the aspects, the IL (e.g., CAGE) has a ratio of catiomanion of about 1 :3 or a ratio with more relative anion. In some embodiments of any of the aspects, the IL (e.g., CAGE) has a ratio of catiomanion of 1:3 or a ratio with more relative anion. In some embodiments of any of the aspects, the IL (e.g., CAGE) has a ratio of catiomanion of about 1:4 or a ratio with more relative anion. In some embodiments of any of the aspects, the IL (e.g., CAGE) has a ratio of catiomanion of 1 :4 or a ratio with more relative anion. In some embodiments of any of the aspects, the IL (e.g., CAGE) has a ratio of catiomanion of about 1:1 to about 1:5. In some embodiments of any of the aspects, the IL (e.g., CAGE) has a ratio of catiomanion of 1 : 1 to 1 :5. In some embodiments of any of the aspects, the IL (e.g., CAGE) has a ratio of catiomanion of about 1:2 to about 1:4. In some embodiments of any of the aspects, the IL (e.g., CAGE) has a ratio of catiomanion of 1:2 to 1:4.

[0072] In some embodiments of any of the aspects, the IL (e.g., CAGE) has a ratio of catiomanion of about 1: 1 to about 1:3. In some embodiments of any of the aspects, the IL (e.g., CAGE) has a ratio of cation:anion of 1: 1 to 1:3. In some embodiments of any of the aspects, the IL (e.g., CAGE) has a ratio of catiomanion of about 1:2. In some embodiments of any of the aspects, the IL (e.g., CAGE) has a ratio of cation: anion of 1:2.

[0073] In some embodiments of any of the aspects, the IL (e.g., CAGE) has a ratio of catiomanion of about 1:3 to about 1:5. In some embodiments of any of the aspects, the IL (e.g., CAGE) has a ratio of catiomanion of 1:3 to 1:5. In some embodiments of any of the aspects, the IL (e.g., CAGE) has a ratio of catiomanion of about 1:4. In some embodiments of any of the aspects, the IL (e.g., CAGE) has a ratio of cation: anion of 1:4.

[0074] In some embodiments of any of the aspects, the IL (e.g., CAGE) has a ratio of catiomanion of from about 10: 1 to about 1 : 10. In some embodiments of any of the aspects, the IL (e.g., CAGE) has a ratio of cation: anion of from 10: 1 to 1:10.

[0075] In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of about 1% v/v to 90% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least about 1% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least 1% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least about 5% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least 5% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least about 10% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least 10% v/v.

[0076] In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least about 15% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least 15% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least about 20% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least 20% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least about 25% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least 25% v/v.

[0077] In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least 0.1% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least 1%. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least about 5%. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least 5%. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least about 10% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least 10% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least about 15% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least 15% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least about 20% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least 20% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least about 25% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least 25% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least about 30% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least 30% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least about 35% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least 35% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least about 40% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least 40% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least about 45% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least 45% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least about 50% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least 50% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least about 55% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least 55% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least about 60% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least 60% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least about 65% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least 65% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least about 70% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least 70% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least about 75% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least 75% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least about 80% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least 80% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least about 90% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least 90% v/v.

[0078] In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at about 10% to about 15% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at about 15% to about 20% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at about 20% to about 25% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at about 25% to about 30% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at about 30% to about 35% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at about 35% to about 40% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at about 40% to about 45% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at about 45% to about 50% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at about 50% to about 55% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at about 55% to about 60% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at about 60% to about 65% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at about 65% to about 70% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of from about 10% v/v to about 60 % v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of from about 10% v/v to about 50 % v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of from about 10% v/v to about 45 % v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of from about 10% v/v to about 40 % v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of from about 30% v/v to about 60 % v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of from about 40% v/v to about 70 % v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of from about 40% v/v to about 50 % v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at about 70% to about 80% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at about 80% to about 90% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of from about 50% v/v to about 70 % v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of from about 60% v/v to about 70 % v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of about 67% to about 81% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at about 1% to about 5% v/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at about 5% to about 10%.In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least about 0.01% w/v, e.g., at least about 0.01%, at least about 0.05%, at least about 0.1%, at least about 0.2%, at least about 0.3% w/v, at least about 0.4% w/v, at least about 0.5% w/v, at least about 1% w/v or greater. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least 0.01% w/v, e.g., at least 0.01%, at least 0.05%, at least 0.1%, at least 0.2%, at least 0.3% w/v, at least 0.4% w/v, at least 0.5% w/v, at least 1% w/v or greater. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of from about 0.01% w/v to about 1% w/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of from 0.01% w/v to 1% w/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of from about 0.05% w/v to about 0.5% w/v. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of from 0.05% w/v to 0.5% w/v.

[0079] In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least about 0.1 % w/w. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least 0.1 % w/w. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least about 25% w/w. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of at least 25% w/w. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of from about 5% w/w to about 75% w/w. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of from 5% w/w to 75% w/w. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of from about 10 % w/w to about 70 % w/w. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of from 10 % w/w to 70 % w/w. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of from about 30 % w/w to about 50 % w/w. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of from 30 % w/w to 40 % w/w. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of from about 30 % w/w to about 50 % w/w. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of from about 30 % w/w to about 45 % w/w. In some embodiments of any of the aspects, the IL (e.g., CAGE) is at a concentration of from 30 % w/w to 40 % w/w.

[0080] In some embodiments of any of the aspects, the % w/w concentration of the IL (e.g., CAGE) is % w/w concentration in water, saline, or a physiologically compatible buffer. In some embodiments of any of the aspects, the % w/v concentration of the IL (e.g., CAGE) is % w/v concentration in water, saline, or a physiologically compatible buffer. In some embodiments of any of the aspects, the % v/v concentration of the IL (e.g., CAGE) is % v/v concentration in water, saline, or a physiologically compatible buffer.

[0081] In some embodiments of any of the aspects, the IL (e.g., CAGE) is 100% by w/w, v/v, or w/v. [0082] In some embodiments of any of the aspects, the IL (e.g., CAGE) concentration in the composition or formulation is about 0.1 mM to 20 mM. In some embodiments of any of the aspects, the IL (e.g., CAGE) concentration in the composition or formulation is 0.5 mM to 20 mM, 0.5 mM to 18 mM, 0.5 mM to 16 mM, 0.5 mM to 14 mM, 0.5 mM to 12 mM, 0.5 mM to 10 mM, 0.5 mM to 8 mM, 1 mM to 20 mM, 1 mM to 18 mM, 1 mM to 16 mM, 1 mM to 14 mM, ImM to 12 mM, 1 mM to 10 mM, 1 mM to 8 mM, 2 mM to 20 mM, 2 mM to 18 mM, 2 mM to 16 mM, 2 mM to 14 mM, 2 mM to 12 mM, 2 mM to 10 mM, 2 mM to 8 mM, 4 mM to 20 mM, 4 mM to 18 mM, 4 mM to 16 mM, 4 mM to 14 mM, 4 mM to 12 mM, 4 mM to 10 mM, 4 mM to 8 mM, 6 mM to 20 mM, 6 mM to 18 mM, 6 mM to 14 mM, 6 mM to 12 mM, 6 mM to 10 mM, 6 mM to 8 mM, 8 mM to 20 mM, 8 mM to 18 mM, 8 mM to 16 mM, 8 mM to 14 mM, 8 mM to 12 mM, 8 mM to 10 mM, 10 mM to 20 mM, 10 mM to 18 mM, 10 mM to 16 mM, 10 mM to 14 mM, 10 mM to 12 mM, 12 mM to 20 mM, 12 mM to 18 mM, 12 mM to 16 mM, 12 mM to 14 mM, 14 mM to 20 mM, 14 mM to 18 mM, 14 mM to 16 mM, 16 mM to 20 mM, 16 mM to 18 mM, or 18 mM to 20 mM. In some embodiments of any of the aspects, the IL (e.g., CAGE) concentration in the composition or formulation is about ImM, about 2 mM, about 3mM, about 4mM, about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, about 10 mM, about 11 mM, about 12 mM, about 13 mM, about 14 mM, about 15 mM, about 16 mM, about 17 mM, about 18 mM, about 19 mM or about 20 mM. In some embodiments of any of the aspects, the IL (e.g., CAGE) concentration in the composition or formulation is ImM, 2 mM, 3mM, 4mM, 5 mM, 6 mM, 7 mM, 8 mM, 9 mM, 10 mM, 11 mM, 12 mM, 13 mM, 14 mM, 15 mM, 16 mM, 17 mM, 18 mM, 19 mM or 20 mM.

[0083] In some embodiments of any of the aspects, the IL, e.g., CAGE, is a gel, or a shear-thinning Newtonian gel.

[0084] In some embodiments of any of the aspects, the compositions described herein further comprise n-methyl-pyrrolidone. In some embodiments of any of the aspects, the n-methyl-pyrrolidone is at a concentration of about 10% to about 80% v/v. In some embodiments of any of the aspects, the n-methyl-pyrrolidone is at a concentration of 10% to 80% v/v. In some embodiments of any of the aspects, the n-methyl-pyrrolidone is at a concentration of about 15% to about 60% v/v. In some embodiments of any of the aspects, the n-methyl-pyrrolidone is at a concentration of 15% to 60% v/v. In some embodiments of any of the aspects, the n-methyl-pyrrolidone is at a concentration of about 20% to about 50% v/v. In some embodiments of any of the aspects, the n-methyl-pyrrolidone is at a concentration of 20% to 50% v/v.

[0085] In some embodiments of any of the aspects, the n-methyl-pyrrolidone is at a concentration of about 10% to about 45% v/v. In some embodiments of any of the aspects, the n-methyl-pyrrolidone is at a concentration of 10% to 45% v/v. In some embodiments of any of the aspects, the n-methyl- pyrrolidone is at a concentration of about 25% to about 45% v/v. In some embodiments of any of the aspects, the n-methyl-pyrrolidone is at a concentration of 25% to 45% v/v. In some embodiments of any of the aspects, the n-methyl-pyrrolidone is at a concentration of about 30% to about 45% v/v. In some embodiments of any of the aspects, the n-methyl-pyrrolidone is at a concentration of 30% to 45% v/v.

[0086] In some embodiments of any of the aspects, the n-methyl-pyrrolidone is at a concentration of at least about 10% v/v. In some embodiments of any of the aspects, the n-methyl-pyrrolidone is at a concentration of at least 10% v/v. In some embodiments of any of the aspects, the n-methyl- pyrrolidone is at a concentration of at least about 20% v/v. In some embodiments of any of the aspects, the n-methyl-pyrrolidone is at a concentration of at least 20% v/v. In some embodiments of any of the aspects, the n-methyl-pyrrolidone is at a concentration of at least about 30% v/v. In some embodiments of any of the aspects, the n-methyl-pyrrolidone is at a concentration of at least 30% v/v. In some embodiments of any of the aspects, the n-methyl-pyrrolidone is at a concentration of at least about 35% v/v. In some embodiments of any of the aspects, the n-methyl-pyrrolidone is at a concentration of at least 35% v/v. In some embodiments of any of the aspects, the n-methyl- pyrrolidone is at a concentration of at least about 40% v/v. In some embodiments of any of the aspects, the n-methyl-pyrrolidone is at a concentration of at least 40% v/v. In some embodiments of any of the aspects, the n-methyl-pyrrolidone is at a concentration of at least about 45% v/v. In some embodiments of any of the aspects, the n-methyl-pyrrolidone is at a concentration of at least 45% v/v. [0087] In some embodiments of any of the aspects, the n-methyl-pyrrolidone is at a concentration of about 42.7% v/v. In some embodiments of any of the aspects, the n-methyl-pyrrolidone is at a concentration of 42.7% v/v.

[0088] In some embodiments of any of the aspects, the compositions described herein further comprise polyethylene glycol. In some embodiments of any of the aspects, the polyethylene glycol comprises or consists of PEG 3350. In some embodiments of any of the aspects, the polyethylene glycol is at a concentration of about 5 mg/mL to about 50 mg/mL. In some embodiments of any of the aspects, the polyethylene glycol is at a concentration of 5 mg/mL to 50 mg/mL. In some embodiments of any of the aspects, the polyethylene glycol is at a concentration of about 10 mg/mL to about 50 mg/mL. In some embodiments of any of the aspects, the polyethylene glycol is at a concentration of 10 mg/mL to 50 mg/mL. In some embodiments of any of the aspects, the polyethylene glycol is at a concentration of about 25 mg/mL to about 35 mg/mL. In some embodiments of any of the aspects, the polyethylene glycol is at a concentration of 25 mg/mL to 35 mg/mL. In some embodiments of any of the aspects, the polyethylene glycol is at a concentration of about 28.8 mg/mL. In some embodiments of any of the aspects, the polyethylene glycol is at a concentration of 28.8 mg/mL.

[0089] In some embodiments of any of the aspects, the composition comprises sodium metabisulfite. In some embodiments of any of the aspects, the sodium metabisulfite is present at about 1% w/v. In some embodiments of any of the aspects, the sodium metabisulfite is present at 1% w/v. In some embodiments of any of the aspects, the sodium metabisulfite is present at about 0.5% w/v. In some embodiments of any of the aspects, the sodium metabisulfite is present at 0.5% w/v. In some embodiments of any of the aspects, the sodium metabisulfite is present at about 0.3% w/v. In some embodiments of any of the aspects, the sodium metabisulfite is present at 0.3% w/v. In some embodiments of any of the aspects, the sodium metabisulfite is present at about 0.2% w/v. In some embodiments of any of the aspects, the sodium metabisulfite is present at 0.2% w/v. In some embodiments of any of the aspects, the sodium metabisulfite is present at about 0.1% w/v. In some embodiments of any of the aspects, the sodium bimetasulfite is present at 0.1% w/v. In some embodiments of any of the aspects, the sodium metabisulfite is present at about 0.3 mg/mL to about 30 mg/mL. In some embodiments of any of the aspects, the sodium bimetasulfite is present at 0.3 mg/mL to 30 mg/mL. In some embodiments of any of the aspects, the sodium metabisulfite is present at about 1.5mg/mL to about 6 mg/mL. In some embodiments of any of the aspects, the sodium bimetasulfite is present at 1.5 mg/mL to 6 mg/mL. In some embodiments of any of the aspects, the sodium metabisulfite is present at about 3 mg/mL. In some embodiments of any of the aspects, the sodium bimetasulfite is present at 3 mg/mL.

[0090] As used herein, “in combination with” refers to two or more substances being present in the same formulation in any molecular or physical arrangement, e.g, in an admixture, in a solution, in a mixture, in a suspension, in a colloid, in an emulsion. The formulation can be a homogeneous or heterogenous mixture. In some embodiments of any of the aspects, the active compound(s) can be comprised by a superstructure, e.g., nanoparticles, liposomes, vectors, cells, scaffolds, or the like, said superstructure is which in solution, mixture, admixture, suspension, etc., with the IL.

[0091] In some embodiments of any of the aspects, the composition comprises a further active agent or ingredient, e.g., a drug, e.g., a drug for a middle ear condition or disease. As used herein, an “active compound” or “active agent” is any agent which will exert an effect on a target cell or organism. The terms “compound” and “agent” refer to any entity which is normally not present or not present at the levels being administered and/or provided to a cell, tissue or subject. An agent can be selected from a group comprising: chemicals; small organic or inorganic molecules; signaling molecules; nucleic acid sequences; nucleic acid analogues; proteins; peptides; enzymes; aptamers; peptidomimetic, peptide derivative, peptide analogs, antibodies; intrabodies; biological macromolecules, extracts made from biological materials such as bacteria, plants, fungi, or animal cells or tissues; naturally occurring or synthetic compositions or functional fragments thereof. In some embodiments, the agent is any chemical, entity or moiety, including without limitation synthetic and naturally-occurring non- proteinaceous entities. Agents can be known to have a desired activity and/or property, or can be selected from a library of diverse compounds.

[0092] As used herein, the term “small molecule” refers to a chemical agent which can include, but is not limited to, a peptide, a peptidomimetic, an amino acid, an amino acid analog, a polynucleotide, a polynucleotide analog, an aptamer, a nucleotide, a nucleotide analog, an organic or inorganic compound (i.e., including heteroorganic and organometallic compounds) having a molecular weight less than about 10,000 grams per mole, organic or inorganic compounds having a molecular weight less than about 5,000 grams per mole, organic or inorganic compounds having a molecular weight less than about 1,000 grams per mole, organic or inorganic compounds having a molecular weight less than about 500 grams per mole, and salts, esters, and other pharmaceutically acceptable forms of such compounds.

[0093] In some embodiments of any of the aspects, the active compound can be a therapeutic compound or drug, e.g., an agent or compound which is therapeutically effective for the treatment of at least one condition in a subject. Therapeutic compounds are known in the art for a variety of conditions, see, e.g., the database available on the world wide web at drugs.com or the catalog of FDA-approved compounds available on the world wide web at catalog.data.gov/dataset/drugsfda- database; each of which is incorporated by reference herein in its entirety.

[0094] In some embodiments of any of the aspects, the active compound is a compound with low water solubility. In some embodiments of any of the aspects, the active compound is a therapeutic compound with low water solubility. Exemplary active agents can include, but are not limited to: domperidone, apomorphine, ciproflaxcin, telmisartan, repaglinide, atazenavir, imatinib, fenofibrate, clopidogrel, rosuvastatin, paclitaxel, docetaxel, cefuroxime axetil, zafirlukast, nelfmavir, quinapril, itraconzaole, itraconazole, tacrolimus, lopinavir, ritonavir, nabilone, nimodipine, etravirine, teniposide, dihydroergotamine, doxycycline, methocarabamil, lorazepam, chlordiazepoxide, lorazepam, propanidid, carbamazepine, gabapentinin, modafmil, piroxicam, doxorubicin, cisplatin, estrogen, insulin, SN-28, oxaliplatin, epirubicin, aripriprazole, mitomycine, diclofenac sodium, chlodizepoxide, meloxicam, alfaxalone, cisapride, indomethacine, omeprazole, danazol, atovaquone, sirolimus, aprepitant, rapamycin, megestrol, morphine, dexmethyl-phenidate, methyl phenidate, tizanidine, camptothecin, vinpocentine, 5-FU, calcitonin, clozapine, cylcosporin A, idarubicin, nimulsulide, progesterone, tetracycline, cyclosporine, porphyrins, minoxidil, anthracyclines, acyclovir, amphotericin B, daunorubicin, cytarabin, estradiol, amikacin, nystatin, terbutalinesulphite, vincristine, prostaglandin, propofol, cyclosporine A, etomidate, flurbiprofen, calcitrol, fcofazimine, doxercalciferol, dronabionol, dutasteride, isotretionoin, saquinavir, sirolimus, tritionoin, tipranavir, and valprioic acid. Further exemplary known active agents with known low water solubility are discussed in the art, e.g., in Kalepu et al. Acta Pharmaceutical Sinica B 2015 5:442-453; Ashford M, Chapter 20: Bioavailability - physicochemical and dosage form factors, in Aulton’s Pharmaceutics: The design and manufacture of medicines 8th Ed., Aulton ME & Taylor KMG (eds.) Elsevier,

London, 2018, 319-338; Formulating Poorly Water Soluble Drugs, Williams RO, et al. (eds), American Association of Pharmaceutical Scientists, Arlington, VA and Springer, New York, NY, 2012; Kanikkannan J Anal Pharm Res 2018 7(1): 00198; each of which is incorporated by reference herein in its entirety.

[0095] In some embodiments of any of the aspects, the active agent is apomorphine. Apomorphine is an aporphine compound that exhibits non-selective dopamine agonist activity, 5-HT₂ antagonism, and alpha-adrenergic receptor antagonism. It is used to treat Parkinson’s disease, e.g., particularly the refractory motor fluctuations and intermittent episodes of hypomobility exhibited by Parkinson’s patients. Apomorphine is depicted in Formula I. In some embodiments of any of the aspects, the Apomorphine comprises, consists of, or consists essentially of R-(-)-Apomorphine hydrochloride hemihydrate. In some embodiments of any of the aspects, the Apomorphine comprises, consists of, or consists essentially of R-(-)-Apomorphine hydrochloride. In some embodiments of any of the aspects, the Apomorphine comprises, consists of, or consists essentially of R-(-)-Apomorphine. Existing formulations of Apomorphine include APOKYN™, IXENSE™, SPONTANE™, and UPRIMA™. These existing formulations are limited by the bolus-dosing effects they exhibit, requiring constant infusion and/or several administrations in a single day to ensure that the patient continues to receive a therapeutic effect. Improved formulations that provide sustained release can improve the treatment efficacy and treatment compliance associated with Apomorphine.

Formula I

[0096] In some embodiments of any of the aspects, the Apomorphine is at a concentration of at least about 1 mg/mL. In some embodiments of any of the aspects, the Apomorphine is at a concentration of at least 1 mg/mL. In some embodiments of any of the aspects, the Apomorphine is at a concentration of at least about 10 mg/mL. In some embodiments of any of the aspects, the Apomorphine is at a concentration of at least 10 mg/mL. In some embodiments of any of the aspects, the Apomorphine is at a concentration of at least about 20 mg/mL. In some embodiments of any of the aspects, the Apomorphine is at a concentration of at least 20 mg/mL. In some embodiments of any of the aspects, the Apomorphine is at a concentration of at least about 30 mg/mL. In some embodiments of any of the aspects, the Apomorphine is at a concentration of at least 30 mg/mL. In some embodiments of any of the aspects, the Apomorphine is at a concentration of at least about 40 mg/mL. In some embodiments of any of the aspects, the Apomorphine is at a concentration of at least 40 mg/mL. In some embodiments of any of the aspects, the Apomorphine is at a concentration of at least about 50 mg/mL. In some embodiments of any of the aspects, the Apomorphine is at a concentration of at least 50 mg/mL. In some embodiments of any of the aspects, the Apomorphine is at a concentration of at least about 60 mg/mL. In some embodiments of any of the aspects, the Apomorphine is at a concentration of at least 60 mg/mL.

[0097] In some embodiments of any of the aspects, the Apomorphine is at a concentration of from about 1 to about 20 mg/mL. In some embodiments of any of the aspects, the Apomorphine is at a concentration of from 1 to 20 mg/mL. In some embodiments of any of the aspects, the Apomorphine is at a concentration of from about 9 to about 11 mg/mL. In some embodiments of any of the aspects, the Apomorphine is at a concentration of from 9 to 11 mg/mL.

[0098] In some embodiments of any of the aspects, the Apomorphine is at a concentration of from about 15 to about 60 mg/mL. In some embodiments of any of the aspects, the Apomorphine is at a concentration of from 15 to 60 mg/mL. In some embodiments of any of the aspects, the Apomorphine is at a concentration of from about 20 to about 40 mg/mL. In some embodiments of any of the aspects, the Apomorphine is at a concentration of from 20 to 40 mg/mL. In some embodiments of any of the aspects, the Apomorphine is at a concentration of from about 30 mg/mL. In some embodiments of any of the aspects, the Apomorphine is at a concentration of 30 mg/mL.

[0099] In some embodiments of any of the aspects, the Apomorphine is at a concentration of from about 30 to about 70 mg/mL. In some embodiments of any of the aspects, the Apomorphine is at a concentration of from 30 to 70 mg/mL. In some embodiments of any of the aspects, the Apomorphine is at a concentration of from about 40 to about 50 mg/mL. In some embodiments of any of the aspects, the Apomorphine is at a concentration of from 40 to 50 mg/mL. In some embodiments of any of the aspects, the Apomorphine is at a concentration of from about 45 to about 55 mg/mL. In some embodiments of any of the aspects, the Apomorphine is at a concentration of from 45 to 55 mg/mL. In some embodiments of any of the aspects, the Apomorphine is at a concentration of from about 35 to about 45 mg/mL. In some embodiments of any of the aspects, the Apomorphine is at a concentration of from 35 to 45 mg/mL.

[00100] In some embodiments of any of the aspects, the compositions described herein further comprise choline bicarbonate. In some embodiments of any of the aspects, the choline bicarbonate is at a concentration of about 100 to about 800 mM. In some embodiments of any of the aspects, the choline bicarbonate is at a concentration of 100 to 800 mM. In some embodiments of any of the aspects, the choline bicarbonate is at a concentration of about 150 to about 500 mM. In some embodiments of any of the aspects, the choline bicarbonate is at a concentration of 150 to 500 mM. In some embodiments of any of the aspects, the choline bicarbonate is at a concentration of about 180 to about 220 mM. In some embodiments of any of the aspects, the choline bicarbonate is at a concentration of 180 to 200 mM. In some embodiments of any of the aspects, the choline bicarbonate is at a concentration of about 200 mM. In some embodiments of any of the aspects, the choline bicarbonate is at a concentration of 200 mM. In some embodiments of any of the aspects, the choline bicarbonate is at a concentration of about 360 to about 440 mM. In some embodiments of any of the aspects, the choline bicarbonate is at a concentration of 360 to 440 mM. In some embodiments of any of the aspects, the choline bicarbonate is at a concentration of about 400 mM. In some embodiments of any of the aspects, the choline bicarbonate is at a concentration of 400 mM. In some embodiments of any of the aspects, the choline bicarbonate is at a concentration of about 500 mM. In some embodiments of any of the aspects, the choline bicarbonate is at a concentration of 500 mM. In some embodiments of any of the aspects, the choline bicarbonate is at a concentration of about 600 mM. In some embodiments of any of the aspects, the choline bicarbonate is at a concentration of 600 mM. In some embodiments of any of the aspects, the choline bicarbonate is at a concentration of about 700 mM. In some embodiments of any of the aspects, the choline bicarbonate is at a concentration of 700 mM. In some embodiments of any of the aspects, the choline bicarbonate is at a concentration of about 800 mM. In some embodiments of any of the aspects, the choline bicarbonate is at a concentration of 800 mM.

[00101] In some embodiments of any of the aspects, the composition further comprises an antioxidant. Suitable antioxidants include but not limited to ascorbic acid and its salts, ascorbyl palmitate, methionine, citric acid, erythorbic acid, fumaric acid, malic acid, monothioglycolate, phosphoric acid, potassium metabisulfite, sodium metabisulfite, propionic acid, propyl gallate, edetic acid, and its salts (e.g., disodium EDTA) and sodium sulfite. In one of the aspects, the antioxidant is sodium metabisulfite, and the concentration is in the range of from about 0.1 to about 5 mg/ml, or from about 0.5 to about 4 mg/ml or from about 1 to about 3 mg/ml.

[00102] In some embodiments of any of the aspects, the composition comprises methionine. In some embodiments of any of the aspects, the methionine is present at about 2% w/v. In some embodiments of any of the aspects, the methionine is present at 2% w/v. In some embodiments of any of the aspects, the methionine is present at about 1.5% w/v. In some embodiments of any of the aspects, the methionine is present at 1.5% w/v. In some embodiments of any of the aspects, the methionine is present at about 1% w/v. In some embodiments of any of the aspects, the methionine is present at 1% w/v. In some embodiments of any of the aspects, the methionine is present at about 0.5% w/v. In some embodiments of any of the aspects, the methionine is present at 0.5% w/v.

[00103] In some embodiments of any of the aspects, the composition comprises ascorbic acid. In some embodiments of any of the aspects, the ascorbic acid is present at about 2% w/v. In some embodiments of any of the aspects, the ascorbic acid is present at 2% w/v. In some embodiments of any of the aspects, the ascorbic acid is present at about 1.5% w/v. In some embodiments of any of the aspects, the ascorbic acid is present at 1.5% w/v. In some embodiments of any of the aspects, the ascorbic acid is present at about 1% w/v. In some embodiments of any of the aspects, the ascorbic acid is present at 1% w/v. In some embodiments of any of the aspects, the ascorbic acid is present at about 0.5% w/v. In some embodiments of any of the aspects, the ascorbic acid is present at 0.5% w/v. [00104] In one aspect of any of the embodiments, provided herein is a composition, wherein the IL is 10% IL with a catiomanion ratio of 1:2, and the composition further comprises n-methyl-pyrrolidone. In one aspect of any of the embodiments, provided herein is a composition, wherein the CAGE is the IL is 10% IL with a catiomanion ratio of 1:2, and the composition further comprises n-methyl- pyrrolidone and at least one antioxidant. In one aspect of any of the embodiments, provided herein is a composition, wherein the IL is 10% IL with a catiomanion ratio of 1:2, and the composition further comprises n-methyl-pyrrolidone, sodium metabisulfite, and polyethylene glycol.

[00105] In one aspect of any of the embodiments, provided herein is a composition, wherein the IL is 10% IL with a catiomanion ratio of 1:2, and the composition further comprises n-methyl-pyrrolidone at a concentration of at least about 35% v/v. In one aspect of any of the embodiments, provided herein is a composition, wherein the IL is 10% IL with a catiomanion ratio of 1:2, and the composition further comprises n-methyl-pyrrolidone at a concentration of at least about 35% v/v, and at least one antioxidant. In one aspect of any of the embodiments, provided herein is a composition, wherein the IL is 10% IL with a cation: anion ratio of 1:2, and the composition further comprises n- methyl-pyrrolidone at a concentration of at least about 35% v/v, sodium metabisulfite, and polyethylene glycol.

[00106] In one aspect of any of the embodiments, provided herein is a composition, wherein the IL is 10% IL with a catiomanion ratio of 1:2, and the composition further comprises n-methyl-pyrrolidone at a concentration of about 42.7% v/v. In one aspect of any of the embodiments, provided herein is a composition, wherein the IL is 10% IL with a catiomanion ratio of 1:2, and the composition further comprises n-methyl-pyrrolidone at a concentration of about 42.7% v/v, and at least one antioxidant. In one aspect of any of the embodiments, provided herein is a composition, wherein the IL is 10% IL with a catiomanion ratio of 1:2 and the composition further comprises n-methyl-pyrrolidone at a concentration of about 42.7% v/v, sodium metabisulfite, and polyethylene glycol.

[00107] In one aspect of any of the embodiments, provided herein is a composition, wherein the IL is 10% IL with a catiomanion ratio of 1:2, and the composition further comprises n-methyl-pyrrolidone and at least one active agent. In one aspect of any of the embodiments, provided herein is a composition, wherein the IL is 10% IL with a catiomanion ratio of 1:2, and the composition further comprises n-methyl-pyrrolidone, at least one active agent, and at least one antioxidant. In one aspect of any of the embodiments, provided herein is a composition, wherein the IL is 10% IL with a catiomanion ratio of 1:2, and the composition further comprises n-methyl-pyrrolidone, sodium metabisulfite, polyethylene glycol, and at least one active agent.

[00108] In one aspect of any of the embodiments, provided herein is a composition, wherein the IL is 10% IL with a catiomanion ratio of 1:2, and the composition further comprises n-methyl-pyrrolidone at a concentration of at least about 35% v/v, and at least one active agent. In one aspect of any of the embodiments, provided herein is a composition, wherein the IL is 10% IL with a catiomanion ratio of 1:2, and the composition further comprises n-methyl-pyrrolidone at a concentration of at least about 35% v/v, and at least one antioxidant and at least one active agent. In one aspect of any of the embodiments, provided herein is a composition, wherein the IL is 10% IL with a catiomanion ratio of 1:2, and the composition further comprises n-methyl-pyrrolidone at a concentration of at least about 35% v/v, and further comprises sodium metabisulfite, polyethylene glycol, and at least one active agent.

[00109] In one aspect of any of the embodiments, provided herein is a composition, wherein the IL is 10% IL with a catiomanion ratio of 1:2, and the composition further comprises n-methyl-pyrrolidone at a concentration of about 42.7% v/v, and at least one active agent. In one aspect of any of the embodiments, provided herein is a composition, wherein the IL is 10% IL with a catiomanion ratio of 1:2, and the composition further comprises n-methyl-pyrrolidone at a concentration of about 42.7% v/v, and at least one antioxidant and at least one active agent. In one aspect of any of the embodiments, provided herein is a composition, wherein the IL is 10% IL with a catiomanion ratio of 1:2, and the composition further comprises n-methyl-pyrrolidone at a concentration of about 42.7% v/v, and further comprises sodium metabisulfite, polyethylene glycol, and at least one active agent. [00110] In one aspect of any of the embodiments, provided herein is a composition, wherein the IL is 10% IL with a catiomanion ratio of 1:2, the Apomorphine is at a concentration of 30 mg/mL, and the composition further comprises n-methyl-pyrrolidone. In one aspect of any of the embodiments, provided herein is a composition, wherein the IL is 10% IL with a catiomanion ratio of 1:2, the Apomorphine is at a concentration of 30 mg/mL, and the composition further comprises n-methyl- pyrrolidone and at least one antioxidant. In one aspect of any of the embodiments, provided herein is a composition, wherein the IL is 10% IL with a catiomanion ratio of 1:2 the Apomorphine is at a concentration of 30 mg/mL, and the composition further comprises n-methyl-pyrrolidone, sodium metabisulfite, and polyethylene glycol.

[00111] In one aspect of any of the embodiments, provided herein is a composition, wherein the IL is 10% IL with a catiomanion ratio of 1:2, the Apomorphine is at a concentration of 30 mg/mL, and the composition further comprises n-methyl-pyrrolidone at a concentration of at least about 35% v/v. In one aspect of any of the embodiments, provided herein is a composition, wherein the IL is 10% IL with a catiomanion ratio of 1 :2, the Apomorphine is at a concentration of 30 mg/mL, and the composition further comprises n-methyl-pyrrolidone at a concentration of at least about 35% v/v, and at least one antioxidant. In one aspect of any of the embodiments, provided herein is a composition, wherein the IL is 10% IL with a catiomanion ratio of 1:2, the Apomorphine is at a concentration of 30 mg/mL, and the composition further comprises n-methyl-pyrrolidone at a concentration of at least about 35% v/v, sodium metabisulfite, and polyethylene glycol.

[00112] In one aspect of any of the embodiments, provided herein is a composition, wherein the IL is 10% IL with a catiomanion ratio of 1:2, the Apomorphine is at a concentration of 30 mg/mL, and the composition further comprises n-methyl-pyrrolidone at a concentration of about 42.7% v/v. In one aspect of any of the embodiments, provided herein is a composition, wherein the IL is 10% IL with a catiomanion ratio of 1:2, the Apomorphine is at a concentration of 30 mg/mL, and the composition further comprises n-methyl-pyrrolidone at a concentration of about 42.7% v/v, and at least one antioxidant. In one aspect of any of the embodiments, provided herein is a composition, wherein the IL is 10% IL with a catiomanion ratio of 1:2, the Apomorphine is at a concentration of 30 mg/mL, and the composition further comprises n-methyl-pyrrolidone at a concentration of about 42.7% v/v, sodium metabisulfite, and polyethylene glycol.

[00113] In one aspect of any of the embodiments, provided herein is a composition, wherein the CAGE is 10% CAGE 1:2, and the composition further comprises n-methyl-pyrrolidone. In one aspect of any of the embodiments, provided herein is a composition, wherein the CAGE is 10% CAGE 1:2, and the composition further comprises n-methyl-pyrrolidone and at least one antioxidant. In one aspect of any of the embodiments, provided herein is a composition, wherein the CAGE is 10%

CAGE 1:2, and the composition further comprises n-methyl-pyrrolidone, sodium metabisulfite, and polyethylene glycol.

[00114] In one aspect of any of the embodiments, provided herein is a composition, wherein the CAGE is 10% CAGE 1:2, and the composition further comprises n-methyl-pyrrolidone at a concentration of at least about 35% v/v. In one aspect of any of the embodiments, provided herein is a composition, wherein the CAGE is 10% CAGE 1:2, and the composition further comprises n- methyl-pyrrolidone at a concentration of at least about 35% v/v, and at least one antioxidant. In one aspect of any of the embodiments, provided herein is a composition, wherein the CAGE is 10%

CAGE 1:2, and the composition further comprises n-methyl-pyrrolidone at a concentration of at least about 35% v/v, sodium metabisulfite, and polyethylene glycol.

[00115] In one aspect of any of the embodiments, provided herein is a composition, wherein the CAGE is 10% CAGE 1:2, and the composition further comprises n-methyl-pyrrolidone at a concentration of about 42.7% v/v. In one aspect of any of the embodiments, provided herein is a composition, wherein the CAGE is 10% CAGE 1:2, and the composition further comprises n-methyl- pyrrolidone at a concentration of about 42.7% v/v, and at least one antioxidant. In one aspect of any of the embodiments, provided herein is a composition, wherein the CAGE is 10% CAGE 1:2, and the composition further comprises n-methyl-pyrrolidone at a concentration of about 42.7% v/v, sodium metabisulfite, and polyethylene glycol.

[00116] In one aspect of any of the embodiments, provided herein is a composition, wherein the CAGE is 10% CAGE 1:2, and the composition further comprises n-methyl-pyrrolidone and at least one active agent. In one aspect of any of the embodiments, provided herein is a composition, wherein the CAGE is 10% CAGE 1:2, and the composition further comprises n-methyl-pyrrolidone, at least one active agent, and at least one antioxidant. In one aspect of any of the embodiments, provided herein is a composition, wherein the CAGE is 10% CAGE 1:2, and the composition further comprises n-methyl-pyrrolidone, sodium metabisulfite, polyethylene glycol, and at least one active agent.

[00117] In one aspect of any of the embodiments, provided herein is a composition, wherein the CAGE is 10% CAGE 1:2, and the composition further comprises n-methyl-pyrrolidone at a concentration of at least about 35% v/v, and at least one active agent. In one aspect of any of the embodiments, provided herein is a composition, wherein the CAGE is 10% CAGE 1:2, and the composition further comprises n-methyl-pyrrolidone at a concentration of at least about 35% v/v, and at least one antioxidant and at least one active agent. In one aspect of any of the embodiments, provided herein is a composition, wherein the CAGE is 10% CAGE 1:2, and the composition further comprises n-methyl-pyrrolidone at a concentration of at least about 35% v/v, and further comprises sodium metabisulfite, polyethylene glycol, and at least one active agent.

[00118] In one aspect of any of the embodiments, provided herein is a composition, wherein the CAGE is 10% CAGE 1:2, and the composition further comprises n-methyl-pyrrolidone at a concentration of about 42.7% v/v, and at least one active agent. In one aspect of any of the embodiments, provided herein is a composition, wherein the CAGE is 10% CAGE 1:2, and the composition further comprises n-methyl-pyrrolidone at a concentration of about 42.7% v/v, and at least one antioxidant and at least one active agent. In one aspect of any of the embodiments, provided herein is a composition, wherein the CAGE is 10% CAGE 1:2, and the composition further comprises n-methyl-pyrrolidone at a concentration of about 42.7% v/v, and further comprises sodium metabisulfite, polyethylene glycol, and at least one active agent.

[00119] In one aspect of any of the embodiments, provided herein is a composition, wherein the CAGE is 10% CAGE 1 :2, the Apomorphine is at a concentration of 30 mg/mL, and the composition further comprises n-methyl-pyrrolidone. In one aspect of any of the embodiments, provided herein is a composition, wherein the CAGE is 10% CAGE 1 : 2, the Apomorphine is at a concentration of 30 mg/mL, and the composition further comprises n-methyl-pyrrolidone and at least one antioxidant. In one aspect of any of the embodiments, provided herein is a composition, wherein the CAGE is 10% CAGE 1 : 2, the Apomorphine is at a concentration of 30 mg/mL, and the composition further comprises n-methyl-pyrrolidone, sodium metabisulfite, and polyethylene glycol.

[00120] In one aspect of any of the embodiments, provided herein is a composition, wherein the CAGE is 10% CAGE 1 :2, the Apomorphine is at a concentration of 30 mg/mL, and the composition further comprises n-methyl-pyrrolidone at a concentration of at least about 35% v/v. In one aspect of any of the embodiments, provided herein is a composition, wherein the CAGE is 10% CAGE 1 :2, the Apomorphine is at a concentration of 30 mg/mL, and the composition further comprises n-methyl- pyrrolidone at a concentration of at least about 35% v/v, and at least one antioxidant. In one aspect of any of the embodiments, provided herein is a composition, wherein the CAGE is 10% CAGE 1 :2, the Apomorphine is at a concentration of 30 mg/mL, and the composition further comprises n-methyl- pyrrolidone at a concentration of at least about 35% v/v, sodium metabisulfite, and polyethylene glycol.

[00121] In one aspect of any of the embodiments, provided herein is a composition, wherein the CAGE is 10% CAGE 1 :2, the Apomorphine is at a concentration of 30 mg/mL, and the composition further comprises n-methyl-pyrrolidone at a concentration of about 42.7% v/v. In one aspect of any of the embodiments, provided herein is a composition, wherein the CAGE is 10% CAGE 1:2, the Apomorphine is at a concentration of 30 mg/mL, and the composition further comprises n-methyl- pyrrolidone at a concentration of about 42.7% v/v, and at least one antioxidant. In one aspect of any of the embodiments, provided herein is a composition, wherein the CAGE is 10% CAGE 1:2, the Apomorphine is at a concentration of 30 mg/mL, and the composition further comprises n-methyl- pyrrolidone at a concentration of about 42.7% v/v, sodium metabisulfite, and polyethylene glycol. [00122] In some embodiments of any of the aspects, the composition further comprises DMSO. [00123] In some embodiments, the composition comprises a pH between about 3 to about 5. In some embodiments, the composition comprises a pH of less than about 4. In some embodiments, the composition comprises a pH of less than 4.

[00124] In some embodiments of any of the aspects, a component or element of a composition is present at the stated concentration or within 5% thereof, thereby accounting for minor errors, inaccuracies, or deviations in measurement, mixing, and/or solubility. In some embodiments of any of the aspects, a component or element of a composition is present at the stated concentration or within 1% thereof, thereby accounting for minor errors, inaccuracies, or deviations in measurement, mixing, and/or solubility.

[00125] In some embodiments of any of the aspects, the compositions described herein are formulated for subcutaneous administration. In some embodiments of any of the aspects, the technology described herein relates to a pharmaceutical composition comprising a composition as described herein, and optionally a pharmaceutically acceptable carrier. In some embodiments, the active ingredients of the pharmaceutical composition comprise a composition as described herein. In some embodiments, the active ingredients of the pharmaceutical composition consisting essentially of a composition as described herein. In some embodiments, the active ingredients of the pharmaceutical composition consisting of a composition as described herein. Pharmaceutically acceptable carriers and diluents include saline, aqueous buffer solutions, solvents and/or dispersion media. The use of such carriers and diluents is well known in the art. Some non-limiting examples of materials which can serve as pharmaceutically -acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, methylcellulose, ethyl cellulose, microcrystalline cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) lubricating agents, such as magnesium stearate, sodium lauryl sulfate and talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol (PEG); (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates and/or polyanhydrides; (22) bulking agents, such as polypeptides and amino acids (23) serum component, such as serum albumin, HDL and LDL; (22) C2- C12 alcohols, such as ethanol; and (23) other non-toxic compatible substances employed in pharmaceutical formulations. Wetting agents, coloring agents, release agents, coating agents, sweetening agents, flavoring agents, perfuming agents, preservatives, and antioxidants can also be present in the formulation. The terms such as "excipient," "carrier," "pharmaceutically acceptable carrier," or the like are used interchangeably herein. In some embodiments, the carrier inhibits the degradation of the active agent, e.g., Apomorphine, as described herein. [00126] In some embodiments of any of the aspects, the pharmaceutical composition comprising a composition as described herein can be a parenteral dose form. Since the administration of parenteral dosage forms typically bypasses the patient's natural defenses against contaminants, parenteral dosage forms are preferably sterile or capable of being sterilized before administration to a patient. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions. In addition, controlled-release parenteral dosage forms can be prepared for the administration of a patient, including, but not limited to, DUROS^®-type dosage forms and dose-dumping. [00127] In some embodiments of any of the aspects, the parenteral composition comprises a therapeutically effective amount of and active agent or a pharmaceutically acceptable salt or a derivative thereof; at least one carrier, wherein the said carrier comprise of one or more ionic component, salt component or a mixture thereof; and pharmaceutically acceptable excipients; wherein the excipient include, but is not limited to, antimicrobial, antioxidant, co-solvent, complexing agent, buffering agent, stabilizer and/or combinations thereof. [00128] In some embodiments of any of the aspects, the parenteral composition a co-solvent. The cosolvent is a solvent or a mixture of solvents or water-soluble solid. The co-solvent may be selected, for instance, from an alcohol or a polyol such as diols, triols, mannitol, or a polyether, or a mixture thereof. Suitable co-solvents include ethanol, isopropanol, N-methyl pyrrolidone, dimethyl sulfoxide, polyethoxylated sorbitan, sorbitan esters, vitamin E derivatives such as Vitamin E TPGS, a diol such as propylene glycol, polyethylene glycol, or a triol such as glycerol, or may have more than three hydroxyl groups such as mannitol, maltitol or cyclodextrin derivatives such hydroxypropyl-β- cyclodextrin (HPβCD) or sulfobutyl-β-cyclodextrin (SBβCD), polyoxyethylene glycols or polyoxyethylene glycol derivatives, such as polyoxyethylene glycol 400, SOLUTOL® HS15 or CREMOPHOR ® ELP. [00129] Suitable vehicles that can be used to provide parenteral dosage forms are well known to those skilled in the art. Examples include, without limitation: sterile water; water for injection USP; saline solution; glucose solution; aqueous vehicles such as but not limited to, sodium chloride injection, Ringer's injection, dextrose Injection, dextrose, and sodium chloride injection, and lactated Ringer's injection; water-miscible vehicles such as but not limited to, ethyl alcohol, polyethylene glycol, and propylene glycol; and non-aqueous vehicles such as but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate. Compounds that alter or modify the solubility of a pharmaceutically acceptable salt of an ingredient described herein can also be incorporated into the parenteral dosage forms of the disclosure, including conventional and controlled-release parenteral dosage forms.

[00130] In some embodiments, a composition is in the form of a concentrate.

[00131] In another embodiment, a composition as disclosed herein, or a pharmaceutically acceptable salt or solvate thereof can be administered in a vesicle, in particular, a liposome (see Langer, "New Methods of Drug Delivery," Science 249: 1527-1533 (1990); Lopez-Berestein, "Treatment of Systemic Fungal Infections with Liposomal-Amphotericin B," Liposomes in the Therapy of Infectious Disease and Cancer, pp. 317-327 (1989); and Treat et al., "Liposome encapsulated doxorubicin - preliminary results of Phase I and Phase II trials" Liposomes in the Therapy of Infectious Disease and Cancer, pp. 353-365 (1989). Compositions, as disclosed herein invention, can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi -lamellar hydrated liquid crystals, which are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients and the like. The preferred lipids are natural and synthetic phospholipids, and phosphatidylcholines (lecithins) used separately or together. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.

[00132] In some embodiments, a composition as disclosed herein, or a pharmaceutically acceptable salt or solvate thereof can be topically administered via a nanoparticle or microparticle. See, for example, Allen et al. Biochim. Biophys. Acta 19993 1150:9-16, Wissing et al. Adv. Drug. Deliv. Rev. 200456:1257-1272, and Tochilin, Nanoparticulates as Drug Carriers, Imperial College Press (2006); the contents of each of which is incorporated by reference herein in its entirety.

[00133] In some embodiments, a composition as disclosed herein and a pharmaceutically acceptable salt and solvate thereof can be administered by controlled-release or sustained-release means or by delivery devices that are known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; and 5,733,566, each of which is incorporated herein by reference. Such dosage forms can be used to provide controlled- or sustained-release of one or more active ingredients using, for example, hydroxypropylmethylcellulose, ethylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profde in varying proportions. Suitable controlled- or sustained- release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the composition as disclosed herein.

[00134] Conventional dosage forms generally provide rapid or immediate drug release from the formulation. Depending on the pharmacology and pharmacokinetics of the drug, the use of conventional dosage forms can lead to wide fluctuations in the concentrations of the drug in a patient's blood and other tissues. These fluctuations can impact a number of parameters, such as dose frequency, the onset of action, duration of efficacy, maintenance of therapeutic blood levels, toxicity, side effects, and the like. Advantageously, controlled-re lease formulations can be used to control a drug's onset of action, duration of action, plasma levels within the therapeutic window, and peak blood levels. In particular, controlled- or extended-release dosage forms or formulations can be used to ensure that the maximum effectiveness of a drug is achieved while minimizing potential adverse effects and safety concerns, which can occur both from under-dosing a drug (i.e., going below the minimum therapeutic levels) as well as exceeding the toxicity level for the drug. In some embodiments, the composition can be administered in a sustained release formulation.

[00135] Controlled- or sustained-release pharmaceutical compositions can have a common goal of improving drug therapy over that achieved by their non-controlled or non-sustained release counterparts. In one embodiment, a controlled- or sustained-release composition comprises a minimal amount of a composition as disclosed herein or a pharmaceutically acceptable salt or solvate thereof to cure or control the condition in a minimum amount of time. Advantages of controlled- or sustained- release compositions include extended activity of the drug, reduced dosage frequency, and increased patient compliance. In addition, controlled- or sustained-release compositions can favorably affect the time of onset of action or other characteristics, such as blood or skin levels of a composition as disclosed herein and can thus reduce the occurrence of adverse side effects.

[00136] Controlled- or sustained-release compositions can be designed to immediately release an amount of a composition as disclosed herein or a pharmaceutically acceptable salt or solvate thereof that promptly produces the desired therapeutic or prophylactic effect, and gradually and continually release other amounts of a composition as disclosed herein, or a second therapeutic agent or a pharmaceutically acceptable salt or solvate thereof to maintain this level of therapeutic or prophylactic effect over an extended period of time. To maintain a constant level of a composition as disclosed herein at the desired site (e.g., site of hypomobility), the composition or a pharmaceutically acceptable salt or solvate thereof can be released from the dosage form at a rate that will replace the amount of composition being metabolized or broken down or excreted from the body. Controlled- or sustained- release of an active ingredient can be stimulated by various conditions, including but not limited to, changes in pH, changes in temperature, concentration or availability of enzymes, concentration or availability of water, or other physiological conditions or compounds. [00137] A further aspect of the present embodiments relates to a method of treating or alleviating Parkinson's disease or related symptoms in a subject in need thereof; the said method comprising administering a composition described herein comprising an effective amount of Apomorphine or a pharmaceutically acceptable salt thereof.

[00138] An aspect of the present embodiments relates to a method of treating Parkinson’s disease in a subject in need thereof, by administering to the subject composition described herein, comprising a therapeutically effective amount of Apomorphine or a pharmaceutically acceptable salt or a derivative thereof; at least one carrier, and pharmaceutically acceptable excipients.

[00139] In yet another embodiment, a composition as disclosed herein or a pharmaceutically acceptable salt or solvate thereof can be delivered in a controlled-release system or sustained-release system (see, e.g., Goodson, "Dental Applications," pp. 1 15-138 in Medical Applications of Controlled Release, Vol. 2, Applications and Evaluation, Langer and Wise, eds., CRC Press (1984), hereafter "Goodson"). Other controlled- or sustained-release systems discussed in the review by Langer, Science 249: 1527-1533 (1990) can be used. In one embodiment, a pump can be used (Langer, Science 249:1527-1533 (1990); Sefton, "Implantable Pumps," in CRC Crit. Rev. Biomed. Eng. 1_4(3):201 -240 (1987); Buchwald et al, "Long-term, Continuous Intravenous Heparin Administration by an Implantable Infusion Pump in Ambulatory Patients with Recurrent Venous Thrombosis," Surgery 88:507-516 (1980); and Saudek et al, "A Preliminary Trial of the Programmable Implantable Medication System for Insulin Delivery," New Engl. J. Med. 321 :574- 579 (1989)). In another embodiment, polymeric materials can be used (see Goodson; Smolen et ah, "Drug Product Design and Performance," Controlled Drug Bioavailability Vol. 1, John Wiley & Sons, New York (1984); Langer et ah, "Chemical and Physical Structure of Polymers as Carriers for Controlled Release of Bioactive Agents: A Review," J. Macromol. Sci. Rev. Macromol. Chem. C23(l):61-126 (1983); Levy et al, "Inhibition of Calcification of Bioprosthetic Heart Valves by Local Controlled-Release Diphosphonate," Science 228: 190-192 (1985); During et ak, "Controlled Release of Dopamine from a Polymeric Brain Implant: In Vivo Characterization," Ann. Neurol. 25:351-356 (1989); and Howard et ak, "Intracerebral drug delivery in rats with lesion-induced memory deficits,"

J. Neurosurg. 71: 105 (1989)). In yet another embodiment, a controlled- or sustained-release system comprising a composition as disclosed herein can be placed in proximity of the hypomobility or affected muscle, thus requiring only a fraction of the systemic dose.

[00140] As described herein, Apomorphine is used to treat hypomobility and/or refractory motor fluctuations in Parkinson’s patients. In one aspect of any of the embodiments described herein is a method of treating a subject with Apomorphine, the method comprising administering composition as described herein to the subject, e.g., subcutaneously. In one aspect of any of the embodiments described herein is a method of treating a subject in need of Apomorphine, the method comprising administering composition as described herein comprising apomorphine to the subject, e.g., subcutaneously. In some embodiments of any of the aspects, the subject or subject in need of Apomorphine is a subject who has or is diagnosed as having hypomobility and/or refractory motor fluctuations. In some embodiments of any of the aspects, the subject or subject in need of Apomorphine is a subject who has or is diagnosed as having Parkinson’s disease.

[00141] As demonstrated herein, the compositions provided herein can provide sustained release of one or more active agents. Accordingly, in some embodiments of any of the aspects, a method described herein comprises administering a dose of the composition described herein no more than twice per day. In some embodiments of any of the aspects, a method described herein comprises administering a dose of the composition described herein no more than once per day. In some embodiments of any of the aspects, a method described herein comprises administering at least 1 mL of a composition described herein.

[00142] In some embodiments, the composition described herein delivers an effective amount of an active agent to a subject over a period of up to about 30 days. In some embodiments, the composition described herein delivers an effective amount of an active agent to a subject over a period of about 6 hours up to about 36 hours. In some embodiments, the composition described herein delivers an effective amount of an active agent to a subject over a period of about 8 hours up to about 24 hours. In some embodiments, the composition described herein delivers an effective amount of an active agent to a subject over a period of about 8 hours up to about 18 hours. In some embodiments, the composition described herein delivers an effective amount of an active agent to a subject over a period of about 8 hours up to about 12 hours.

[00143] In some embodiments, the composition described herein delivers an effective amount of an active agent to a subject in need thereof at a rate of from about 0. lmg/hour to about lOmg/hour. In some embodiments, the composition described herein delivers an effective amount of an active agent to a subject in need thereof at a rate of from about 0.5 mg/hour to about 8 mg/hour. In some embodiments, the composition described herein delivers an effective amount of an active agent to a subject in need thereof at a rate of from about 1 mg/hour to about 7 mg/hour. In some embodiments, the composition described herein delivers an effective amount of an active agent to a subject in need thereof at a rate of from about 1 μg/kg/hour to about 200 μg/kg/hour. In some embodiments, the composition described herein delivers an effective amount of an active agent to a subject in need thereof at a rate of from about 10 μg/kg/hour to about 180 μg/kg/hour. In some embodiments, the composition described herein delivers an effective amount of an active agent to a subject in need thereof at a rate of from about 15 μg/kg/hour to about 150 μg/kg/hour.In some embodiments, the composition described herein delivers an effective amount of an active agent to a subject in need thereof at a rate of from about 20 μg/kg/hour to about 120 μg/kg/hour.

[00144] In some embodiments of any of the aspects, a method described herein comprises administering a dose of a composition described herein comprising at least 5 mg of An active agent. In some embodiments of any of the aspects, a method described herein comprises administering a dose of a composition described herein comprising at least 10 mg of An active agent. In some embodiments of any of the aspects, a method described herein comprises administering a dose of a composition described herein comprising at least 20 mg of An active agent. In some embodiments of any of the aspects, a method described herein comprises administering a dose of a composition described herein comprising at least 30 mg of An active agent. In some embodiments of any of the aspects, a method described herein comprises administering a dose of a composition described herein comprising at least 40 mg of An active agent. In some embodiments of any of the aspects, a method described herein comprises administering a dose of a composition described herein comprising at least 50 mg of An active agent. In some embodiments of any of the aspects, a method described herein comprises administering a dose of a composition described herein comprising at least 60 mg of An active agent. In some embodiments of any of the aspects, a method described herein comprises administering a dose of a composition described herein comprising at least 70 mg of An active agent. [00145] In some embodiments of any of the aspects, a method described herein comprises administering a dose of a composition described herein comprising at least 5 mg of Apomorphine. In some embodiments of any of the aspects, a method described herein comprises administering a dose of a composition described herein comprising at least 10 mg of Apomorphine. In some embodiments of any of the aspects, a method described herein comprises administering a dose of a composition described herein comprising at least 20 mg of Apomorphine. In some embodiments of any of the aspects, a method described herein comprises administering a dose of a composition described herein comprising at least 30 mg of Apomorphine. In some embodiments of any of the aspects, a method described herein comprises administering a dose of a composition described herein comprising at least 40 mg of Apomorphine. In some embodiments of any of the aspects, a method described herein comprises administering a dose of a composition described herein comprising at least 50 mg of Apomorphine. In some embodiments of any of the aspects, a method described herein comprises administering a dose of a composition described herein comprising at least 60 mg of Apomorphine.

In some embodiments of any of the aspects, a method described herein comprises administering a dose of a composition described herein comprising at least 70 mg of Apomorphine.

[00146] In some embodiments of any of the aspects, a method described herein comprises administering a dose of a composition described herein comprising about 10 mg of Apomorphine. In some embodiments of any of the aspects, a method described herein comprises administering a dose of a composition described herein comprising 10 mg of Apomorphine. In some embodiments of any of the aspects, a method described herein comprises administering a dose of a composition described herein comprising about 20 mg of Apomorphine. In some embodiments of any of the aspects, a method described herein comprises administering a dose of a composition described herein comprising 20 mg of Apomorphine. In some embodiments of any of the aspects, a method described herein comprises administering a dose of a composition described herein comprising about 30 mg of Apomorphine. In some embodiments of any of the aspects, a method described herein comprises administering a dose of a composition described herein comprising 30 mg of Apomorphine. In some embodiments of any of the aspects, a method described herein comprises administering a dose of a composition described herein comprising about 40 mg of Apomorphine. In some embodiments of any of the aspects, a method described herein comprises administering a dose of a composition described herein comprising 40 mg of Apomorphine. In some embodiments of any of the aspects, a method described herein comprises administering a dose of a composition described herein comprising about 50 mg of Apomorphine. In some embodiments of any of the aspects, a method described herein comprises administering a dose of a composition described herein comprising 50 mg of Apomorphine. In some embodiments of any of the aspects, a method described herein comprises administering a dose of a composition described herein comprising about 60 mg of Apomorphine. In some embodiments of any of the aspects, a method described herein comprises administering a dose of a composition described herein comprising 60 mg of Apomorphine.

[00147] In some embodiments, the methods described herein relate to treating a subject having or diagnosed as having, e.g., Parkinson’s disease, with a composition as described herein. Subjects having Parkinson’s disease can be identified by a physician using current methods of diagnosing Parkinson’s disease. Symptoms and/or complications of Parkinson’s disease which characterize these conditions and aid in diagnosis are well known in the art and include but are not limited to, tremor, bradykinesia, rigidity, and postural instability as well as neuropsychiatric problems (such as changes in mood, cognition, behavior, and/or thought), and sleep difficulties. Tests that may aid in the diagnosis of, e.g., Parkinson’s disease include, but are not limited to, levodopa testing, neurological examination, and MRI, PET, or SPECT scans. A family history of Parkinson’s disease can also aid in determining if a subject is likely to have Parkinson’s disease or in making a diagnosis of Parkinson’s disease.

[00148] The compositions and methods described herein can be administered to a subject having or diagnosed as having a condition described herein. In some embodiments, the methods described herein comprise administering an effective amount of compositions described herein to a subject to alleviate a symptom of a condition. As used herein, "alleviating a symptom of a condition" is ameliorating any symptom associated with the condition. As compared with an equivalent untreated control, such reduction is by at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, 99% or more as measured by any standard technique. A variety of means for administering the compositions described herein to subjects are known to those of skill in the art. Such methods can include but are not limited to, oral, parenteral, intravenous, intramuscular, subcutaneous, transdermal, airway (aerosol), pulmonary, cutaneous, or topical administration. Administration can be local or systemic. In some embodiments of any of the aspects, the administration is subcutaneous. In some embodiments of any of the aspects, the administration is intramuscular.

[00149] The term “effective amount" as used herein refers to the amount of a composition needed to alleviate at least one or more symptoms of the disease or disorder and relates to a sufficient amount of pharmacological composition to provide the desired effect. The term "therapeutically effective amount" therefore refers to an amount of a composition that is sufficient to provide a particular effect when administered to a typical subject. An effective amount as used herein, in various contexts, would also include an amount sufficient to delay the development of a symptom of the disease, alter the course of a symptom disease (for example but not limited to, slowing the progression of a symptom of the disease), or reverse a symptom of the disease. Thus, it is not generally practicable to specify an exact “effective amount." However, for any given case, an appropriate “effective amount" can be determined by one of ordinary skill in the art using only routine experimentation.

[00150] Effective amounts, toxicity, and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dosage can vary depending upon the dosage form employed and the route of administration utilized. The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio LD50/ED50. Compositions and methods that exhibit large therapeutic indices are preferred. A therapeutically effective dose can be estimated initially from cell culture assays. Also, a dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e.. the concentration of the active ingredient which achieves a half-maximal inhibition of symptoms) as determined in cell culture, or in an appropriate animal model. Levels in plasma can be measured, for example, by high-performance liquid chromatography. The effects of any particular dosage can be monitored by a suitable bioassay, e.g., an assay for dopamine agonism, among others. The dosage can be determined by a physician and adjusted, as necessary, to suit the observed effects of the treatment.

[00151] Pharmaceutical compositions comprising a composition as described herein can also be formulated to be suitable for oral administration, for example as discrete dosage forms, such as but not limited to, tablets (including without limitation scored or coated tablets), pills, caplets, capsules, chewable tablets, powder packets, cachets, troches, wafers, aerosol sprays, or liquids, such as but not limited to, syrups, elixirs, solutions or suspensions in an aqueous liquid, a non-aqueous liquid, an oil- in-water emulsion, or a water-in-oil emulsion. Such compositions contain a predetermined amount of the pharmaceutically acceptable salt of the disclosed compounds and may be prepared by methods of pharmacy well known to those skilled in the art. See generally, Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams, and Wilkins, Philadelphia, PA. (2005). [00152] In some embodiments of any of the aspects, the composition described herein is administered as a monotherapy, e.g., another treatment for e.g., Parkinson’s disease or the hypomobility is not administered to the subject.

[00153] In some embodiments, a composition as disclosed herein, or in combination (i.e., co administered) with one or more additional pharmaceutical agents (i.e., a second therapeutic agent). In some embodiments, the second therapeutic agent is an antiemetic. In some embodiments, the antiemetic is administered prior to the administration of the composition described herein, e.g., at least 1 day, at least 2 days, at least 3 days, at least 7 days, at least 10 days, at least 14 days, at least 21 days or at least 30 days prior. A non-limiting exemplary antiemetic is a trimethobenzamide.

[00154] In some embodiments, the effective amount of the second therapeutic agent when used with composition is less than the effective amount of the second therapeutic agent when used alone (or not in the presence or in combination with a composition described herein). In some embodiments, a composition and second therapeutic agent are synergistic in that they work together with such that one agent increases the effectiveness of the other. For example, the administration of a composition described herein increases the effectiveness of the administration of the second therapeutic agent, such that the effective dose of a second therapeutic agent is lower in the presence of the composition described herein (and higher in the absence of the composition). In some embodiments, the combined effect of a composition described herein, and a second therapeutic agent is greater than when each of these agents is used alone. Synergistic effects are typically detected when the composition described herein and second therapeutic agent work by different mechanisms, so together they form a stronger effect than then they are used individually. In some embodiments, a composition described herein and second therapeutic agent are additive in that combined effect of a composition described herein and second therapeutic agent is equal to the sum of the effect when these two agents are used alone. Additive effects are typically detected when the composition described herein and second therapeutic agent work by the same or similar mechanism.

[00155] Combination therapy includes administration of a single pharmaceutical dosage formulation containing one or more composition described herein as disclosed herein and one or more additional pharmaceutical agents, as well as administration of a composition described herein and each additional pharmaceutical agent, in its own separate pharmaceutical dosage formulation. For example, a composition described herein and one or more additional pharmaceutical agents may be administered to the patient together, in a single dosage composition having a fixed ratio of each active ingredient, or each agent may be administered in separate dosage formulations.

[00156] In certain embodiments, an effective dose of a composition, as described herein, can be administered to a patient once. In certain embodiments, an effective dose of a composition can be administered to a patient repeatedly. In some embodiments, after an initial treatment regimen, the treatments can be administered on a less frequent basis. For example, after treatment biweekly for three months, treatment can be repeated once per month, for six months or a year or longer. Treatment according to the methods described herein can reduce levels of a marker or symptom of a condition, e.g., by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80 % or at least 90% or more.

[00157] The dosage of a composition, as described herein, can be determined by a physician and adjusted, as necessary, to suit the observed effects of the treatment. With respect to duration and frequency of treatment, it is typical for skilled clinicians to monitor subjects in order to determine when the treatment is providing therapeutic benefit, and to determine whether to increase or decrease the dosage, increase or decrease administration frequency, discontinue treatment, resume treatment, or make other alterations to the treatment regimen. The dosing schedule can vary from once a week to daily depending on a number of clinical factors, such as the subject's sensitivity to the active ingredient(s). The desired dose or amount of activation can be administered at one time or divided into sub-doses, e.g., 2-4 sub-doses and administered over a period of time, e.g., at appropriate intervals throughout the day or other appropriate schedule. In some embodiments, the administration can be chronic, e.g., one or more doses and/or treatments daily over a period of weeks or months. Examples of dosing and/or treatment schedules are administration daily, twice daily, three times daily or four or more times daily over a period of 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months, or more. A composition can be administered over a period of time, such as over 5 minutes, 10 minutes, 15 minutes, 20 minutes, or 25 minutes period.

[00158] The dosage ranges for the administration of a composition, according to the methods described herein depend upon, for example, the form of the composition, its potency, and the extent to which symptoms, markers, or indicators of a condition described herein are desired to be reduced, for example, the percentage reduction desired for symptom reduction or the extent to which, for example, dopamine agonism are desired to be induced. The dosage should not be so large as to cause adverse side effects. Generally, the dosage will vary with the age, condition, and sex of the patient and can be determined by one of skill in the art. The dosage can also be adjusted by the individual physician in the event of any complication.

[00159] Suitable effective dosage amounts, however, will, in one embodiment, range from about 0.01 mg/kg of body weight to about 2500 mg/kg of body weight. In another embodiment, effective dosage amounts will be about 100 mg/kg of body weight or less. In one embodiment, the effective dosage amount ranges from about 0.01 mg/kg of body weight to about 100 mg/kg of body weight of the active ingredient; in another embodiment, about 0.02 mg/kg of body weight to about 50 mg/kg of body weight; and in another embodiment, about 0.025 mg/kg of body weight to about 20 mg/kg of body weight. In some embodiments, a composition, as disclosed herein is administered in an effective amount, e.g., a therapeutically effective amount. [00160] The efficacy of composition in, e.g., the treatment of a condition described herein or to induce a response as described herein (e.g., dopamine agonism) can be determined by the skilled clinician. However, a treatment is considered “effective treatment," as the term is used herein, if one or more of the signs or symptoms of a condition described herein are altered in a beneficial manner, other clinically accepted symptoms are improved, or even ameliorated, or the desired response is induced, e.g., by at least 10% following treatment according to the methods described herein.

Efficacy can be assessed, for example, by measuring a marker, indicator, symptom, and/or the incidence of a condition treated according to the methods described herein or any other measurable parameter appropriate, e.g., dopamine agonism. Efficacy can also be measured by a failure of an individual to worsen as assessed by hospitalization, or need for medical interventions (i.e., the progression of the disease is halted). Methods of measuring these indicators are known to those of skill in the art and/or are described herein. Treatment includes any treatment of a disease in an individual or an animal (some non-limiting examples include a human or an animal) and includes: (1) inhibiting the disease, e.g., preventing a worsening of symptoms; or (2) relieving the severity of the disease, e.g., causing regression of symptoms. An effective amount for the treatment of a disease means that amount which, when administered to a subject in need thereof, is sufficient to result in effective treatment as that term is defined herein, for that disease. The efficacy of an agent can be determined by assessing the physical indicators of a condition or desired response. It is well within the ability of one skilled in the art to monitor the efficacy of administration and/or treatment by measuring any one of such parameters, or any combination of parameters. The efficacy can be assessed in animal models of a condition described herein, for example, the treatment of a mouse model of the conditions described herein. When using an experimental animal model, the efficacy of treatment is evidenced when a statistically significant change in a marker is observed, e.g., dopamine agonism.

[00161] For convenience, the meaning of some terms and phrases used in the specification, examples, and appended claims, are provided below. Unless stated otherwise, or implicit from context, the following terms and phrases include the meanings provided below. The definitions are provided to aid in describing particular embodiments and are not intended to limit the claimed invention, because the scope of the invention is limited only by the claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. If there is an apparent discrepancy between the usage of a term in the art and its definition provided herein, the definition provided within the specification shall prevail.

[00162] For convenience, certain terms employed herein, in the specification, examples and appended claims are collected here. [00163] As used herein, the term "substantially immiscible" refers to two or more liquids that do not form a homogenous mixture when they are in contact with each other. In some embodiments, when two or more substantially immiscible liquids are in contact with each other, one of the liquids can have a partial solubility (e.g., no more than 10% or lower) in another substantially immiscible liquid. The term "homogenous mixture" as used herein means that all components and/or liquids in a mixture are readily present in a single phase. For instance, one or more of the components and/or liquids do not separate into different phases even when the mixture is left stationary for an extended period of time (e.g., at least about 6 hours or longer, including, e.g., at least about 12 hours, at least about 18 hours, at least about 24 hours, or longer). When referring to miscibility of the droplets and the carrier liquid, the term "substantially immiscible" refers to a liquid (e.g., a thin liquid layer) forming at least the outer surface of the droplets and the carrier liquid that do not form a homogenous mixture when they are in contact with each other.

[00164] As used herein and throughout the specification, the term "droplet" refers to a finite volume of matter comprising at least one liquid or at least one liquid phase, including, e.g., at least two or more liquids or liquid phases. The droplets can be of any dimension, configuration, and/or shape. It will be understood by one of ordinary skill in the art that droplets usually exhibit a distribution of droplet sizes around the indicated "size." Unless otherwise stated, the term "droplet size" or "size" as used herein refers to the mode of a size distribution of droplets, i.e., the value that occurs most frequently in the size distribution. Methods for measuring the droplet size are known to a skilled artisan, e.g., by dynamic light scattering (such as photo-correlation spectroscopy, laser diffraction, low-angle laser light scattering (LALLS), and medium-angle laser light scattering (MALLS)), light obscuration methods (such as Coulter analysis method), or other techniques (such as rheology, and light or electron microscopy).

[00165] The terms “decrease,” “reduced,” “reduction,” or “inhibit” are all used herein to mean a decrease by a statistically significant amount. In some embodiments, “reduce,” “reduction" or “decrease" or “inhibit” typically means a decrease by at least 10% as compared to a reference level (e.g., the absence of a given treatment or agent) and can include, for example, a decrease by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or more. As used herein,

“reduction” or “inhibition” does not encompass a complete inhibition or reduction as compared to a reference level. “Complete inhibition” is a 100% inhibition as compared to a reference level. A decrease can be preferably down to a level accepted as within the range of normal for an individual without a given disorder. [00166] The terms “increased,” “increase,” “enhance,” or “activate” are all used herein to mean an increase by a statically significant amount. In some embodiments, the terms “increased,” “increase,” “enhance,” or “activate” can mean an increase of at least 10% as compared to a reference level, for example, an increase of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% increase or any increase between 10-100% as compared to a reference level, or at least about a 2-fold, or at least about a 3 -fold, or at least about a 4-fold, or at least about a 5-fold or at least about a 10-fold increase, or any increase between 2-fold and 10-fold or greater as compared to a reference level. In the context of a marker or symptom, an “increase” is a statistically significant increase in such level.

[00167] As used herein, a "subject" means a human or animal. Usually, the animal is a vertebrate such as a primate, rodent, domestic animal, or game animal. Primates include chimpanzees, cynomolgus monkeys, spider monkeys, and macaques, e.g., Rhesus. Rodents include mice, rats, woodchucks, ferrets, rabbits, and hamsters. Domestic and game animals include cows, horses, pigs, deer, bison, buffalo, feline species, e.g., domestic cat, canine species, e.g., dog, fox, wolf, avian species, e.g., chicken, emu, ostrich, and fish, e.g., trout, catfish, and salmon. In some embodiments, the subject is a mammal, e.g., a primate, e.g., a human. The terms “individual,” “patient,” and “subject” are used interchangeably herein.

[00168] Preferably, the subject is a mammal. The mammal can be a human, non-human primate, mouse, rat, dog, cat, horse, or cow, but is not limited to these examples. Mammals other than humans can be advantageously used as subjects that represent animal models of a condition described herein, e.g., Parkinson’s disease. A subject can be male or female.

[00169] A subject can be one who has been previously diagnosed with or identified as suffering from or having a condition in need of treatment (e.g., Parkinson’s disease) or one or more complications related to such a condition, and optionally, have already undergone treatment for the condition or the one or more complications related to the condition. Alternatively, a subject can also be one who has not been previously diagnosed as having the condition or one or more complications related to the condition. For example, a subject can be one who exhibits one or more risk factors for the condition or one or more complications related to the condition of a subject who does not exhibit risk factors. [00170] A “subject in need” of treatment for a particular condition can be a subject having that condition, diagnosed as having that condition, or at risk of developing that condition.

[00171] As used herein, the terms "treat,” "treatment," "treating,” or “amelioration” refer to therapeutic treatments, wherein the object is to reverse, alleviate, ameliorate, inhibit, slow down or stop the progression or severity of a condition associated with a disease or disorder, e.g., Parkinson’s disease. The term “treating" includes reducing or alleviating at least one adverse effect or symptom of a condition, disease, or disorder. Treatment is generally “effective" if one or more symptoms or clinical markers are reduced. Alternatively, treatment is “effective" if the progression of a disease is reduced or halted. That is, “treatment" includes not just the improvement of symptoms or markers, but also a cessation of, or at least slowing of, progress or worsening of symptoms compared to what would be expected in the absence of treatment. Beneficial or desired clinical results include, but are not limited to, alleviation of one or more symptom(s), diminishment of the extent of disease, stabilized (/. e. , not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, remission (whether partial or total), and/or decreased mortality, whether detectable or undetectable. The term "treatment" of a disease also includes providing relief from the symptoms or side-effects of the disease (including palliative treatment).

[00172] As used herein, the term “pharmaceutical composition” refers to a composition described herein (e.g., one comprising an active agent) in combination with a pharmaceutically acceptable carrier, e.g., a carrier commonly used in the pharmaceutical industry. The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. In some embodiments of any of the aspects, a pharmaceutically acceptable carrier can be a carrier other than water. In some embodiments of any of the aspects, a pharmaceutically acceptable carrier can be a cream, emulsion, gel, liposome, nanoparticle, and/or ointment. In some embodiments of any of the aspects, a pharmaceutically acceptable carrier can be an artificial or engineered carrier, e.g., a carrier that the active ingredient would not be found to occur in nature.

[00173] As used herein, the term "administering," refers to the placement of a compound as disclosed herein into a subject by a method or route which results in at least partial delivery of the agent at the desired site. Pharmaceutical compositions comprising the compounds disclosed herein can be administered by any appropriate route which results in effective treatment in the subject. In some embodiments, administration comprises human physical activity, e.g., an injection, an act of ingestion, an act of application, and/or manipulation of a delivery device or machine. Such activity can be performed, e.g., by a medical professional and/or the subject being treated.

[00174] As used herein, “contacting" refers to any suitable means for delivering, or exposing, an agent to at least one cell. Exemplary delivery methods include, but are not limited to, direct delivery to the cell culture medium, perfusion, injection, or another delivery method well known to one skilled in the art. In some embodiments, contacting comprises human physical activity, e.g., an injection, an act of dispensing, mixing, and/or decanting, and/or manipulation of a delivery device or machine. [00175] The term “statistically significant" or “significantly" refers to statistical significance and generally means a two standard deviation (2SD) or greater difference. [00176] Other than in the operating examples, or where otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions used herein should be understood as modified in all instances by the term “about.” The term “about” when used in connection with percentages can mean ±1%.

[00177] As used herein, the term “comprising” means that other elements can also be present in addition to the defined elements presented. The use of “comprising” indicates inclusion rather than limitation.

[00178] The term "consisting of' refers to compositions, methods, and respective components thereof as described herein, which are exclusive of any element not recited in that description of the embodiment.

[00179] As used herein, the term "consisting essentially of' refers to those elements required for a given embodiment. The term permits the presence of additional elements that do not materially affect the basic and novel or functional characteristic(s) of that embodiment of the invention.

[00180] The singular terms "a," "an," and "the" include plural referents unless context clearly indicates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly indicates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below. The abbreviation, "e.g.," is used herein to indicate a non-limiting example. Thus, the abbreviation "e.g." is synonymous with the term "for example."

[00181] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group can be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified, thus fulfilling the written description of all Markush groups used in the appended claims.

[00182] Unless otherwise defined herein, scientific and technical terms used in connection with the present application shall have the meanings that are commonly understood by those of ordinary skill in the art to which this disclosure belongs. It should be understood that this invention is not limited to the particular methodology, protocols, and reagents, etc., described herein and as such can vary. The terminology used herein is for the purpose of describing specific embodiments only and is not intended to limit the scope of the present invention, which is defined solely by the claims. Definitions of common terms in molecular biology can be found in The Merck Manual of Diagnosis and Therapy, 20th Edition, published by Merck Sharp & Dohme Corp., 2018 (ISBN 0911910190, 978- 0911910421); Robert S. Porter et al. (eds.), The Encyclopedia of Molecular Cell Biology and Molecular Medicine, published by Blackwell Science Ltd., 1999-2012 (ISBN 9783527600908); and Robert A. Meyers (ed.), Molecular Biology and Biotechnology: a Comprehensive Desk Reference, published by VCH Publishers, Inc., 1995 (ISBN 1-56081-569-8); Immunology by Wemer Luttmann, published by Elsevier, 2006; Janeway's Immunobiology, Kenneth Murphy, Allan Mowat, Casey Weaver (eds.), W. W. Norton & Company, 2016 (ISBN 0815345054, 978-0815345053); Lewin's Genes XI, published by Jones & Bartlett Publishers, 2014 (ISBN-1449659055); Michael Richard Green and Joseph Sambrook, Molecular Cloning: A Laboratory Manual, 4th ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., USA (2012) (ISBN 1936113414); Davis et ak, Basic Methods in Molecular Biology, Elsevier Science Publishing, Inc., New York, USA (2012) (ISBN 044460149X); Laboratory Methods in Enzymology: DNA, Jon Lorsch (ed.) Elsevier, 2013 (ISBN 0124199542); Current Protocols in Molecular Biology (CPMB), Frederick M. Ausubel (ed.), John Wiley and Sons, 2014 (ISBN 047150338X, 9780471503385), Current Protocols in Protein Science (CPPS), John E. Coligan (ed.), John Wiley and Sons, Inc., 2005; and Current Protocols in Immunology (CPI) (John E. Coligan, ADA M Kruisbeek, David H Margulies, Ethan M Shevach, Warren Strobe, (eds.) John Wiley and Sons, Inc., 2003 (ISBN 0471142735, 9780471142737), the contents of which are all incorporated by reference herein in their entireties.

[00183] Other terms are defined herein within the description of the various aspects of the invention. [00184] All patents and other publications; including literature references, issued patents, published patent applications, and co-pending patent applications; cited throughout this application are expressly incorporated herein by reference for the purpose of describing and disclosing, for example, the methodologies described in such publications that might be used in connection with the technology described herein. These publications are provided solely for their disclosure prior to the filing date of the present application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention or for any other reason. All statements as to the date or representation as to the contents of these documents are based on the information available to the applicants and do not constitute any admission as to the correctness of the dates or contents of these documents.

[00185] The description of embodiments of the disclosure is not intended to be exhaustive or to limit the disclosure to the precise form disclosed. While specific embodiments of, and examples for, the disclosure are described herein for illustrative purposes, various equivalent modifications are possible within the scope of the disclosure, as those skilled in the relevant art will recognize. For example, while method steps or functions are presented in a given order, alternative embodiments may perform functions in a different order, or functions may be performed substantially concurrently. The teachings of the disclosure provided herein can be applied to other procedures or methods as appropriate. The various embodiments described herein can be combined to provide further embodiments. Aspects of the disclosure can be modified, if necessary, to employ the compositions, functions, and concepts of the above references and application to provide yet further embodiments of the disclosure. These and other changes can be made to the disclosure in light of the detailed description. All such modifications are intended to be included within the scope of the appended claims.

[00186] Specific elements of any of the foregoing embodiments can be combined or substituted for elements in other embodiments. Furthermore, while advantages associated with certain embodiments of the disclosure have been described in the context of these embodiments, other embodiments may also exhibit such advantages, and not all embodiments need necessarily exhibit such advantages to fall within the scope of the disclosure.

[00187] In some embodiments, the present technology may be defined in any of the following numbered paragraphs:

1. A composition comprising an ionic liquid and n-methyl-pyrrolidone.

2. The composition of paragraph 1, further comprising at least one active agent.

3. The composition of paragraph 1 or 2, further comprising polyethylene glycol.

4. The composition of paragraph 1, comprising the ionic liquid, n-methyl-pyrrolidone and polyethylene glycol.

5. The composition of paragraph 1, comprising the ionic liquid, n-methyl-pyrrolidone; polyethylene glycol; and at least one active agent.

6. The composition of any of the preceding paragraphs, wherein the ionic liquid is 1-90% v/v with a cation: anion ratio such that there is more anion than cation.

7. The composition of any of the preceding paragraphs, wherein the ionic liquid has a cation: anion ratio in which there is at least twice as much anion as cation.

8. The composition of any of the preceding paragraphs, wherein the ionic liquid has a cation: anion ratio in which there is at least four times as much anion as cation.

9. The composition of any of the preceding paragraphs, wherein the ionic liquid is 1-90% v/v with a cation: anion ratio of 1:2.

10. The composition of any of the preceding paragraphs, wherein the ionic liquid is 1-55% v/v.

11. The composition of any of the preceding paragraphs, wherein the ionic liquid is 5-20% v/v.

12. The composition of any of the preceding paragraphs, wherein the ionic liquid is 10% v/v.

13. The composition of any of the preceding paragraphs, wherein the ionic liquid has an anion with a LogP of 1.0 or greater.

14. The composition of any of the preceding paragraphs, wherein the ionic liquid has an anion with a LogP of 2.0 or greater.

15. The composition of any of the preceding paragraphs, wherein the ionic liquid has an anion with a LogP of 3.0 or greater.

16. The composition of any of the preceding paragraphs, wherein the anion of the ionic liquid is geranate or geranic acid. The composition of any of the preceding paragraphs, wherein the ionic liquid has an cation comprising a quaternary ammonium. The composition of any of the preceding paragraphs, wherein the cation is choline or one of C1-C7. The composition of any of the preceding paragraphs, wherein the ionic liquid is CAGE. The composition of any of the preceding paragraphs, wherein the n-methyl-pyrrolidone is present at least about 35% v/v. The composition of any of the preceding paragraphs, wherein the n-methyl-pyrrolidone is present at less than 45% v/v. The composition of any of the preceding paragraphs, wherein the n-methyl-pyrrolidone is present at 1-45% v/v. The composition of any of the preceding paragraphs, wherein the n-methyl-pyrrolidone is present at least about 35% v/v, and the CAGE is 1-90% v/v CAGE at a ratio of choline :geranate such that there is more geranate than choline present. The composition of any of the preceding paragraphs, wherein the n-methyl-pyrrolidone is present at least about 35% v/v, and the CAGE is 10% CAGE 1:2. The composition of any of the preceding paragraphs, wherein the n-methyl-pyrrolidone is present at about 42.7% v/v, and the CAGE is 10% CAGE 1:2. The composition of any of the preceding paragraphs, wherein the polyethylene glycol is PEG 3350 present at about 10 to about 50 mg/mL. The composition of any of the preceding paragraphs, wherein the polyethylene glycol is PEG 3350 present at about 28.8 mg/mL. The composition of any of the preceding paragraphs, wherein the active agent is present at 20 mg/mL or greater. The composition of any of the preceding paragraphs, wherein the active agent is present at 30 mg/mL or greater. The composition of any of the preceding paragraphs, wherein the active agent is present at 40 mg/mL or greater. The composition of any of the preceding paragraphs, wherein the active agent is present at 50 mg/mL or greater. The composition of any of the preceding paragraphs, wherein the active agent is apomorphine. The composition of paragraph 32, wherein the apomorphine is at a concentration of 30 mg/mL. 34. The composition of any of the preceding paragraphs, further comprising sodium metabisulfite.

35. The composition of any of the preceding paragraphs, wherein the sodium metabisulfite is present at about 1% w/v.

36. The composition of any of the preceding paragraphs, wherein the sodium metabisulfite is present at about 0.3% w/v.

37. The composition of any of the preceding paragraphs, wherein the sodium metabisulfite is present at about 3 mg/mL.

38. The composition of any of the preceding paragraphs formulated for subcutaneous administration.

39. A method of treating Parkinson’s Disease in a subject in need thereof, the method comprising subcutaneously administering a therapeutically effective dose of a composition of any of the preceding paragraphs, wherein the composition comprises apomorphine.

40. The method of paragraph 39, wherein the administration is daily or no more frequent than daily.

41. The method of paragraph 40, wherein the administration is every other day or no more frequent than every other day.

42. The method of any of paragraphs 39-41, wherein the dosing regime comprises a 60 mg apomorphine dose on Day 1, a 30 mg apomorphine dose on Day 3, and an 18 mg apomorphine dose every 48 hours thereafter for the duration of treatment.

[00188] In some embodiments, the present technology may be defined in any of the following numbered paragraphs:

1. A composition comprising an ionic liquid and n-methyl-pyrrolidone.

3. The composition of paragraph 1 or 2, further comprising polyethylene glycol.

6. The composition of any one of the preceding paragraphs, wherein the ionic liquid is 1-90% v/v with a cation: anion ratio such that there is more anion than cation.

7. The composition of any one of the preceding paragraphs, wherein the ionic liquid has a cation: anion ratio in which there is at least twice as much anion as cation.

8. The composition of any one of the preceding paragraphs, wherein the ionic liquid has a cation: anion ratio in which there is at least four times as much anion as cation. The composition of any one of the preceding paragraphs, wherein the ionic liquid is 1-90% v/v with a cation: anion ratio of 1 :2. The composition of any one of the preceding paragraphs, wherein the ionic liquid is 1-55% v/v. The composition of any one of the preceding paragraphs, wherein the ionic liquid is 5-20% v/v. The composition of any one of the preceding paragraphs, wherein the ionic liquid is 10% v/v. The composition of any one of the preceding paragraphs, wherein the ionic liquid has an anion with a LogP of 1.0 or greater. The composition of any one of the preceding paragraphs, wherein the ionic liquid has an anion with a LogP of 2.0 or greater. The composition of any one of the preceding paragraphs, wherein the ionic liquid has an anion with a LogP of 3.0 or greater. The composition of any one of the preceding paragraphs, wherein the anion of the ionic liquid is geranate or geranic acid. The composition of any one of the preceding paragraphs, wherein the ionic liquid has a cation comprising a quaternary ammonium. The composition of any one of the preceding paragraphs, wherein the cation is choline or one of C1-C7. The composition of any one of the preceding paragraphs, wherein the ionic liquid is CAGE. The composition of any one of the preceding paragraphs, wherein the n-methyl-pyrrolidone is present at least about 35% v/v. The composition of any one of the preceding paragraphs, wherein the n-methyl-pyrrolidone is present at less than 45% v/v. The composition of any one of the preceding paragraphs, wherein the n-methyl-pyrrolidone is present at 1-45% v/v. The composition of any one of the preceding paragraphs, wherein the n-methyl-pyrrolidone is present at least about 35% v/v, and the CAGE is 1-90% v/v CAGE at a ratio of choline: geranate such that there is more geranate than choline present. The composition of any one of the preceding paragraphs, wherein the n-methyl-pyrrolidone is present at least about 35% v/v, and the CAGE is 10% CAGE 1:2. The composition of any one of the preceding paragraphs, wherein the n-methyl-pyrrolidone is present at about 42.7% v/v, and the CAGE is 10% CAGE 1:2. The composition of any one of the preceding paragraphs, wherein the polyethylene glycol is PEG 3350 present at about 10 to about 50 mg/mL. The composition of any one of the preceding paragraphs, wherein the polyethylene glycol is PEG 3350 present at about 28.8 mg/mL. The composition of any one of the preceding paragraphs, wherein the active agent is present at 20 mg/mL or greater. The composition of any one of the preceding paragraphs, wherein the active agent is present at 30 mg/mL or greater. The composition of any one of the preceding paragraphs, wherein the active agent is present at 40 mg/mL or greater. The composition of any one of the preceding paragraphs, wherein the active agent is present at 50 mg/mL or greater. The composition of any one of the preceding paragraphs, wherein the active agent is apomorphine. The composition of paragraph 32, wherein the apomorphine is at a concentration of 30 mg/mL. The composition of any one of the preceding paragraphs, further comprising sodium metabisulfite. The composition of any one of the preceding paragraphs, wherein the sodium metabisulfite is present at about 1% w/v. The composition of any one of the preceding paragraphs, wherein the sodium metabisulfite is present at about 0.3% w/v. The composition of any one of the preceding paragraphs, wherein the sodium metabisulfite is present at about 3 mg/mL. The composition of any one of the preceding paragraphs formulated for subcutaneous administration. A method of treating Parkinson’s Disease in a subject in need thereof, the method comprising subcutaneously administering a therapeutically effective dose of a composition of any of the preceding paragraphs, wherein the composition comprises apomorphine. The method of paragraph 39, wherein the administration is daily or no more frequent than daily. The method of paragraph 40, wherein the administration is every other day or no more frequent than every other day. The method of any one of paragraphs 39-41, wherein the dosing regime comprises a 60 mg apomorphine dose on Day 1, a 30 mg apomorphine dose on Day 3, and an 18 mg apomorphine dose every 48 hours thereafter for the duration of treatment. A composition of any one of paragraphs 1-38, wherein the composition comprises apomorphine, for use in a method of treating Parkinson’s Disease in a subject in need thereof, the method comprising subcutaneously administering a therapeutically effective dose of the composition,.

44. The composition of paragraph 43, wherein the administration is daily or no more frequent than daily.

45. The composition of paragraph 43, wherein the administration is every other day or no more frequent than every other day.

46. The composition of any one of paragraphs 43-45, wherein the dosing regime comprises a 60 mg apomorphine dose on Day 1, a 30 mg apomorphine dose on Day 3, and an 18 mg apomorphine dose every 48 hours thereafter for the duration of treatment.

[00189] The technology described herein is further illustrated by the following examples, which in no way should be construed as being further limiting.

EXAMPLES

Example 1

[00190] Apomorphine, a dopamine agonist, is a highly effective therapy to prevent intermittent off episodes in advanced Parkinson’s disease. However, its short systemic half-life necessitates 3 injections per day. Such a frequent dosing regimen imposes a significant compliance challenge, especially given the nature of the disease. Described herein is a first of its kind deep eutectic-based formulation that slows the release of apomorphine after subcutaneous injection and extends its pharmacokinetics to convert the current three-injections-a-day injection therapy into every-other-day therapy. The formulation comprises a homogeneous mixture of a deep eutectic solvent choline- geranate, a co-solvent n-methyl-pyrrolidone, a stabilizer polyethylene glycol, and water, which spontaneously emulsifies into a microemulsion upon injection in the subcutaneous space, thereby entrapping apomorphine and significantly slowing its release. Ex vivo studies with gels and rat skin demonstrate the mechanism of action. In vivo pharmacokinetics studies in rats confirmed extended sustained release and improvement over the clinical comparator. In vivo pharmacokinetics, supported by a pharmacokinetic simulation, demonstrate that the deep eutectic formulation reported here allows maintenance of the therapeutic drug concentration in plasma in humans with a dosing regimen of approximately three injections per week compared to the current clinical practice of three injections per day.

[00191] Parkinson’s disease (PD) is a progressive disorder of the central nervous system that affects motor control. While subcutaneous injection of apomorphine (Apokyn) is clinically used to alleviate intermittent episodes of dyskinesia, the treatment requires multiple injections of the drug per day, significantly deterring patient compliance. Described herein is a deep eutectic-based ternary solvent system that self-emulsifses in situ following subcutaneous injection and entraps apomorphine, allowing a remarkable improvement in duration of the drug in vivo, e.g., over the clinical comparator. The results from the animal studies support the self-emulsifying system as a potent, long-lasting therapeutic for Parkinson’s disease patients and potentially for other therapeutics that have a similar delivery challenge. [00192] Introduction [00193] Parkinson’s disease (PD), the second most common neurodegenerative disease, is characterized by dopamine deficiency arising from the progressive loss of dopaminergic neurons in the pars compacta of the substantia nigra. Multiple motor- as well as non-motor symptoms, such as rigidity, tremor, bradykinesia, and cognitive dysfunction, are associated with PD (1). While a number of disease-modifying therapies to treat PD are currently in clinical trials (2, 3), the approved therapies comprise only those that treat the symptoms. Among these, apomorphine (APO) is a leading drug given to alleviate short intermittent periods of motor complications like dyskinesia, often developed in advanced PD after long-term prior treatment with oral levodopa (4). Apomorphine has poor oral bioavailability and high first pass metabolism, thus leaving subcutaneous injections as the only viable administration mode (Apokyn). However, short half-life (69.7 ^ 25.8 min) of APO in the systemic circulation necessitates frequent injections of Apokyn, three times a day, at the onset of individual off episodes (5). This poses a significant challenge with patient compliance in terms of pain, infection, emetic side effect, inaccurate dosing, lack of manual dexterity, or even inability to self-inject (6-9). [00194] Two notable strategies have been evaluated in clinical trials to mitigate the shortcomings of frequent subcutaneous APO injection. Kynmobi™, an FDA-approved sublingual film containing APO, allows rapid absorption of the drug via buccal administration (10, 11). However, it lacks a mechanism for sustained release, and thus still requires repeated on-demand administration and induces fluctuations in blood concentrations. Continuous subcutaneous infusion of APO has also been explored as an alternative. The subcutaneous pump aims to maintain therapeutic concentrations of APO in systemic circulation and has shown shortened duration of total daily off episodes in clinical trials. However, this approach is hindered by the complexity of use and local site reactions (12-14). Furthermore, this product recently received Refusal to File from the FDA. Many other pre-clinical and clinical formulations of APO have attempted to achieve non-invasive administration and prolonged pharmacokinetics (15, 16), for example, pro-drug modification for oral delivery (17) or encapsulation in microemulsion for transdermal delivery (18); however, the utility of these approaches is limited by low bioavailability compared to subcutaneous injections. Thus, the development of a safe and simple sustained release formulation of APO remains an unmet clinical need. [00195] From a scientific perspective, APO represents one of the most challenging drugs to formulate; it has limited water solubility, is highly susceptible to oxidation, exhibits short plasma half- life (5, 19), and has a tight therapeutic window with a minimum effective concentration (MEC) of 4 ng/mL and a maximum tolerated concentration (MTC) of 10 ng/mL in humans. Use of a large number of sustained release technologies including microspheres (20, 21), depots (11), liposomes (22), and polymeric as well as solid lipid nanoparticles (23, 24) among others, has been attempted with APO. However, the multiple physicochemical, biological, and clinical constraints have posed a hurdle in delivering APO in a safe and sufficiently sustained manner. Consequently, no long-acting formulation of APO is currently available. [00196] Described herein is a novel strategy for achieving extended release of APO based simultaneously on the differential miscibility of a deep eutectic solvent choline and geranic acid (CAGE_1:2) in two solvents, water and n-methyl pyrrolidone (NMP), as well as the differential solubility of APO in each of these three solvents. The formulation was designed to be a homogenous, stable solution of APO in a three-component system (CAGE_1:2/NMP/water). However, upon subcutaneous injection, NMP rapidly diffuses away, and the formulation self-emulsifies into a dispersion of CAGE_1:2 in water while trapping APO in it, thereby achieving sustained release (Figure 1). This design increased the timescale of APO pharmacokinetics, converting the current clinical standard of three-times-a-day formulation into an every-other-day formulation. While achieving this goal, three essential constraints were satisfied including: increased solubility of APO from 10 mg/mL in Apokyn to 30 mg/mL to support long-lasting delivery from a single dose; stability of APO against oxidation; and the use of all components, other than CAGE_1:2, at concentrations already listed in other FDA-approved subcutaneous products, thus facilitating the potential for translation of this strategy. This formulation is referred to herein as self-emulsifying, apomorphine-releasing therapeutic (SEAPORT). Provided herein are the design strategy, ex vivo assessment, in vivo pharmacokinetics in rats, and safety in rats. [00197] Results [00198] High solubility and stability of apomorphine in SEAPORT [00199] A ternary phase diagram shows that CAGE_1:2 exhibits concentration-dependent miscibility with water (Figure 6A). Specifically, a CAGE_1:2/water mixture forms an emulsion at a concentration of 10% v/v (inlet images), which was selected as the concentration of choice. The phase diagram also shows that addition of greater than 35% v/v NMP, an organic solvent in the FDA list of inactive ingredients in approved subcutaneous products, completely solubilizes 10% v/v CAGE_1:2-in-water emulsion to form a homogenous solution. An NMP concentration of 42.7% v/v was selected based on its concentration used in an FDA-approved product (ELIGARD ^). This ternary system was used as the base of SEAPORT. APO was solubilized at a concentration of 30 mg/mL in a mixture of 10% v/v CAGE_1:2, 42.7% v/v NMP and 47.3% v/v water (SEAPORT).3 mg/mL sodium metabisulfite (SMB) and 28.8 mg/mL polyethylene glycol MW 3350 (PEG 3350) were added as an antioxidant and a stabilizer, respectively (Figure 2A). [00200] The concentration of APO in SEAPORT was confirmed using LC-MS, which remained consistent at over 90% of the initial concentration over 7 days of incubation at 4^oC, 25^oC, and 37^oC (Figures 2B, 2C) with one exception of 37^oC on day 2 (Figure 6B). SEAPORT remained stable and homogenous with no apparent phase separation over 7 days of incubation at 4^oC, 25^oC, and 37^oC (Figure 6C). A stress-aging condition at 37^oC darkened the color of SEAPORT, but a similar color change was observed in SEAPORT w/o APO, thus indicating that the color was due to the inactive ingredients in the formulation. The absence of antioxidant SMB resulted in oxidation of APO and a color change to dark blue/green, which was indirectly measured via colorimetric absorbance assay (Figures 7C, 7D). SEAPORT containing 3 mg/mL SMB was sufficient to prevent oxidation of APO for at least 7 days even in stress-aging 37^oC condition (Figure 7E). [00201] Sustained release of apomorphine from SEAPORT ex vivo [00202] The ability of SEAPORT to provide sustained release of APO was tested ex vivo using rat skin as a model. The release was compared against an Apokyn-mimicking formulation, that is, 10 mg/mL APO in water with antioxidants (referred to as rApokyn) as the reference formulation. A variant of SEAPORT without CAGE_1:2 (SEAPORT w/o CAGE_1:2) was also used as a control to assess whether CAGE_1:2 played a role in achieving sustained release from SEAPORT. The apparatus was designed to detect APO diffusing out of the formulation, through the surrounding tissue, and into the saline medium (Figure 3A). rApokyn exhibited a burst release with nearly 50% of the injected dose released in the first 6 hours (Figure 3B, 7A). In contrast, SEAPORT suppressed the early burst release and allowed nearly zero order release kinetics, leading up to 40% of the injected dose released after 24 hours. SEAPORT w/o CAGE_1:2 demonstrated a release profile comparable to rApokyn, indicating that CAGE_1:2 plays a critical role in the observed controlled release of APO from SEAPORT. These quantitative measurements of release were also consistent with the visual observations in the rat skin injected with the formulations, where accumulation of oxidized APO in controls was clearly observed at the boundary of the skin by 48 hours while only minimal color was observed in the SEAPORT group (Figure 7B). [00203] To gain further insights into the behavior of APO in the subcutaneous tissue, SEAPORT was also studied in an agarose gel with high water content to mimic the subcutaneous space. A hollow channel was created at the center of the agarose gel and filled with the formulations to allow spontaneous mixing with water from the agarose gel (Figure 3C). Delivery of SEAPORT in the gel led to the formation of a emulsified depot that was visible by the transition of the clear formulation to an opaque mixture (Figure 3D). The clearance of APO from the center channel of the agarose gel was significantly slower for SEAPORT than for SEAPORT w/o CAGE_1:2 (Figure 3E). Release from rat skin as well as gel confirmed that SEAPORT slows the release of APO from the injected site. [00204] Emulsification of SEAPORT slows the diffusion of apomorphine [00205] SEAPORT incubated in the agarose gel model was used to assess the behavior of subcutaneously injected formulation. Dynamic light scattering (DLS) and cryogenic transmission electron microscopy (cryo-TEM) were used to characterize the formulation. Prior to injection, SEAPORT exhibited 10-30 nm nanoclusters, possibly from the association between APO and CAGE_1:2 (Figure 4A, 4B). Upon incubation in the agarose gel, the formulation generated large, micron-sized emulsions (Figure 4A, 4B). Transition of aggregates from 10-30 nm to micron-sized clusters upon injection into the gel was consistent with the visual observation that the formulation transitioned from transparent to milky (Figure 3D). Consistent with the ex vivo release, there was no apparent generation of emulsions from SEAPORT w/o CAGE_1:2. [00206] The emulsification process of SEAPORT was further characterized using ATR-FTIR spectra based on the characteristic peaks of NMP and CAGE_1:2. NMP exhibited a ν(C=O) peak at 1679 cm^-1 in neat NMP and at 1645 cm^-1 in SEAPORT. CAGE_1:2 showed a characteristic v(C=C) peak at 1650 cm^-1 that overlapped with the NMP peak, and an additional distinct peak at 1675 cm^-1 (Figure 4C). The intensities of peaks at 1645 cm^-1 (NMP and CAGE_1:2) and 1675 cm^-1 (CAGE_1:2) can thus be used to assess the evolution of the formulation. In both SEAPORT and SEAPORT w/o APO, the intensity of the peak at 1645 cm^-1 decreased over the course of 8 mins of incubation in agarose gel. A much smaller decrease in the peak intensity at 1675 cm^-1 was observed, resulting in a comparable ratio of peak heights at 1645 cm^-1 and 1675 cm^-1 between that of SEAPORT and neat CAGE_1:2 within 8 mins of incubation (Figure 9A). Meanwhile, SEAPORT w/o CAGE_1:2 showed no decrease in the 1645 cm^-1 peak, indicative of no change in the formulation composition. This indicates that upon injection into the gel, SEAPORT undergoes displacement of NMP with a high amount of CAGE_1:2 potentially due to phase separation of CAGE_1:2 from SEAPORT into emulsions. [00207] Diffusion-ordered spectroscopy (DOSY) further showed a significant decrease in the diffusivity of APO from emulsified SEAPORT in agarose gel compared to that from rApokyn in agarose gel (Figure 4D, 9B, 9C). Interestingly, SEAPORT formulation itself also decreased the diffusivity of APO without emulsification in comparison to rApokyn, potentially due to nanoclustering of APO with CAGE_1:2 (Figures 9D, 9E, and 9F). Collectively, these data confirm slower diffusion of APO from emulsified SEAPORT and provide a potential mechanism of its sustained release. [00208] Extended pharmacokinetics of apomorphine from SEAPORT in rats [00209] In vivo pharmacokinetics of APO from subcutaneously injected SEAPORT was measured in rats with rApokyn and SEAPORT w/o CAGE_1:2 as controls. rApokyn exhibited a burst release with t_max of 10 min, and a nearly complete elimination by 4 hours post administration (Figure 5A). In contrast, SEAPORT exhibited two peaks of plasma APO concentration. The time of the first peak corresponded closely to the t_max of rApokyn, but the second peak appeared at 4 hours post injection and represented the maximum concentration. In addition, the second peak led to sustained delivery of APO with plasma concentrations detectable even at 24 hours. The existence of two peaks is likely attributed to the presence of two forms of APO in the subcutaneous SEAPORT depot, namely the smaller burst of free APO present outside of the emulsions, followed by a slower release of APO trapped inside the emulsions. This is further supported by the absence of a second peak in the SEAPORT w/o CAGE_1:2 group. The C_max was comparable between all three groups, but the AUC of SEAPORT was significantly greater than that of rApokyn (Figure 5B, 5C). Moreover, the time at which the APO concentration dropped to 10% of C_max was significantly greater in SEAPORT than in either rApokyn or SEAPORT w/o CAGE_1:2, indicating that SEAPORT exhibits sustained release in vivo via CAGE_1:2-mediated extended pharmacokinetics and can maintain effective APO concentrations in plasma longer than Apokyn (Figure 5D). [00210] Safety of SEAPORT was assessed by blinded histological evaluation of subcutaneous tissues on days 1 and 7 post administration at a dose of 7.5 mg APO/kg (corresponding to 0.25 mL SEAPORT/kg). This dose is substantially higher than the expected dose in humans (0.01 mL/kg or 1 mL per 70 kg subject), thus providing a large margin in safety assessment. No toxicity from SEAPORT was noted in the tissue based on several criteria including inflammation, fibrosis, ulceration, necrosis, edema, and hyperkeratosis (Figure 5E). [00211] Compartmental modeling and simulation of multiple SEAPORT doses in humans [00212] Pharmacokinetic modeling of SEAPORT was performed to assess how the observed pharmacokinetics can be used to design a long-lasting dosing regimen of APO in humans with the goal of minimizing the number of injections and time spent outside the therapeutic window. Compartmental modeling were used, consisting of fast- and slow-acting compartments of SEAPORT in the subcutaneous space evidenced by pharmacokinetics in rats, and the vasculature compartment (Figure 6A). The parameters of the model were the fraction of APO in the slow-releasing compartment (F), two distinct rates of APO release from the two depot compartments (k_f and k_s), and rate of APO elimination from the bloodstream (k_e). First-order kinetics were assumed for all compartments. [00213] Using the rate constants, a dosing regimen was designed to achieve a satisfactory pharmacokinetic profile of APO in humans with SEAPORT compared to rApokyn (Figure 6C, 10A). According to the simulation, a regimen based on an injection every 48 hours, specifically with a starting dose of 60 mg (2 mL SEAPORT) followed by a second dose of 30 mg (1 mL SEAPORT) at 48 hours and then subsequent doses of 18 mg (0.6 mL SEAPORT) every 48 hours thereafter, is sufficient to maintain long-term APO concentration in the blood above the MEC. A 30-day simulation showed injections of the reference formulation (aqueous APO at 10 mg/mL) every 8 hours is able to maintain APO concentration between the MEC and MTC only for a total of less than 100 hours over 27 days starting at day 3 post injection (Figure 7D, 10B, 10C). Meanwhile, APO concentration from SEAPORT never fell below the MEC or rose above the MTC during the same time window. This represents a significant advance in the dosing frequency to achieve patient compliance compared to Apokyn that requires multiple injections per day. [00214] Discussion [00215] Apomorphine exhibits rapid drug absorption from the subcutaneous tissue, which has driven subcutaneous injection as the major administration route for the drug (5). However, there are still critical hurdles to subcutaneous administration of APO. APO exhibits rapid metabolism and clearance following its C_max at 10 mins with a half-life of around 33 min and duration of clinical response of around 45-60 min (5, 26, 27). This requires intermittent, frequent injections and leads to patient non- compliance, which calls for a novel formulation of APO allowing sustained release and thus less frequent injection to subcutaneous tissue. [00216] Self-emulsifying drug delivery systems (SEDDS) are homogeneous mixtures of oils, surfactants, and co-solvents that emulsify upon aqueous dilution to improve lipophilic drug solubility, absorption, and controlled release (28, 29). The majority of SEDDS have been developed to increase oral bioavailability, including FDA-approved Sandimmune Neoral. Described herein is the first SEDDS using a deep eutectic solvent as the emulsifier for sustained release in subcutaneous tissue. [00217] SEAPORT exploits differential miscibility of three solvents; CAGE_1:2, NMP and water_, and simultaneously, differential solubility of APO in these solvents. At the concentrations used in SEAPORT, these solvents form a homogenous clear solution, although nanoclusters of APO and CAGE_1:2 were observed in DLS. Upon injection in the subcutaneous space, the deep eutectic solvent in SEAPORT self-emulsifies in situ due to quick diffusion of co-solvent NMP and leads to the formation of a depot comprised largely of CAGE_1:2 that traps APO for sustained release. [00218] The concentration of NMP in SEAPORT falls within the specified concentration in the FDA’s database for inactive ingredients in approved drug products. It is also important to note that all excipients with the exception of CAGE_1:2 are also included in the FDA-approved inactive ingredient list and are used below the specified concentrations. CAGE_1:2 itself has been tested for safety in topical applications and has been tested in the clinic (32). This facilitates the clinical translation of SEAPORT formulation. [00219] Pharmacokinetics of APO in SEAPORT from rats showed the presence of two distinct rates of release. The second release is characterized by a slower decay in plasma concentration of APO, confirming the slow-releasing component. The first release closely overlapped with the initial burst from rApokyn, indicating that SEAPORT can have the fast-releasing component responsible for partial burst release. While SEAPORT was developed to provide sustained release of APO, the early absorption of APO outside of emulsion also offers an important clinical benefit. Specifically, the fast “onset” in addition to extended pharmacokinetics would provide patients with a therapeutic outcome over a wider time window that includes the time period immediately after injection. [00220] The studies reported here demonstrate that a novel deep eutectic-based formulation offers a solution to the long-lasting challenge of APO delivery for treating PD. SEAPORT is a homogenous, clear solution that can be prepared in a single-step process at a large scale. Pharmacokinetic studies in rats showed prolonged duration of higher APO concentration in plasma in comparison to the clinical comparator. Safety studies reported here demonstrate that a single administration of SEAPORT administered at a large excess was well tolerated in rats. [00221] Materials and Methods [00222] Materials [00223] Choline bicarbonate, geranic acid, sodium metabisulfite, poly(ethylene glycol) M_n 3350, boldine, N-methyl-pyrrolidinone, methanol [high-performance liquid chromatography (HPLC) grade, 99.8% purity], and acetonitrile [high-performance liquid chromatography (HPLC) grade, 99.8% purity] were obtained from Millipore Sigma (St. Louis, MO). D₂O and N-methyl-2-pyrrolidinone-d9 were obtained from Cambridge Isotope Laboratories (Tewksbury, MA). Pierce^TM formic acid, agarose (Thermo Fisher Scientific), and benzyl alcohol (Alfa Aesar) were used as received. Apomorphine hydrochloride was provided by Dr. Reddy’s Laboratories, Ltd. [00224] Deep eutectic solvent synthesis [00225] Choline bicarbonate and geranic acid were reacted via salt metathesis reaction in 1:2 molar ratio at 40^oC for 12 hours. Water produced from the reaction was removed using rotary evaporator at 20 mbar at 60^oC for 4 hours and additional drying in a vacuum oven at 60^oC for 48 hours. The resulting product was stored at room temperature until use.¹H NMR showed consistent spectrum with previous literature (33). [00226] Reference Apokyn formulation (rApokyn) [00227] Apokyn was reproduced using the composition listed in Apokyn’s FDA label, and used as the clinical comparator (reference formulation). Briefly, 10 mg of apomorphine hydrochloride, 1 mg sodium metabisulfite, and 5 mg benzyl alcohol were dissolved in 1 mL of water. The pH of the final formulation was adjusted to pH 4.0 using hydrochloric acid. [00228] SEAPORT formulation [00229] SEAPORT formulation was prepared by dissolving 30 mg of apomorphine hydrochloride, 3 mg sodium metabisulfite, and 28.8 mg poly(ethylene glycol) M_n 3350 in 42.7% n-methyl-2- pyrrolidinone, 10% CAGE_1:2, and 47.3% H₂O by volume. The mixture was vigorously vortexed for 1 min to yield a homogeneous preparation. SEAPORT w/o CAGE_1:2 control formulation was prepared by replacing 10% v/v CAGE_1:2 with H₂O. [00230] SEAPORT solubility and stability [00231] The amount of APO solubilized in the formulation as well as the remaining soluble APO following incubation at 4^oC, 25^oC, and 37^oC were detected via Agilent 1290™ ultra high performance liquid chromatography equipped with Agilent G6135B™ electrospray ionization – mass spectrometry detector (UPLC-MS). Agilent SB-Phenyl reversed-phase column (4.6 x 150 mm, 5 µm) protected by a guard column (ZORBAX™, 4.6 × 12.5 mm, 5 μm) was maintained at 30°C. Samples were prepared in 50:50 v/v 0.9% NaCl in water:100 ng/mL boldine (internal standard) in methanol. APO and boldine were eluted using 0.1% v/v formic acid in water as mobile phase A and 0.1% v/v formic acid in acetonitrile as mobile phase B in isocratic mode at 0.5 mL/min with 65% mobile phase A. Positive selected ion monitoring (SIM) mode was used to detect APO and boldine at m/z of 268.3 and 327.4, respectively. [00232] To determine the level of APO oxidation over time, the change in color of formulations incubated at 4°C, 25°C, and 37°C were observed on day 1, 3, 5, and 7. Absorbance due to dark blue color from oxidized APO was detected at 600 nm using plate reader (Biotek Neo2™). [00233] Ex vivo APO release [00234] Skin (5 cm x 10 cm) harvested from the dorsal side of euthanized Wistar rats was used to study APO release from SEAPORT ex vivo (Fig.8C).50 µL of specified formulations was injected using an insulin syringe in the fat, subcutaneous layer by inserting the needle (28G) from the stratum corneum until the tip of the needle was visible through the translucent layer of fat tissue (Figure 3A). Injection resulted in immediate formation of a small bleb (Figure 8D). Following injection, the skin was cut around the injection site with an approximately 3-5 mm margin in all directions, placed in each well of a 12-well plate containing 1 mL of 0.9% w/v NaCl and 0.01% w/v gentamicin in water, and incubated at 37°C with a parafilm cover. The entire 1 mL was collected and replaced with a fresh 1 mL of 0.9% w/v NaCl and 0.01% gentamicin in water at pre-determined timepoints. The amount of APO in the release medium was quantified via UPLC-MS with the same method used in SEAPORT characterization. [00235] SEAPORT emulsion characterization [00236] Agarose gel was used to mimic self-emulsification of SEAPORT in subcutaneous tissue.3 mL of 36% w/v agarose gel was prepared by heating 1080 mg of agarose with 3 mL H₂O absorbed in a 20-mL glass scintillation vial for 35 sec and placing it in a 65°C oven overnight. N-methyl-2- pyrollidinone-d9 and D₂O were used in the preparation of both SEAPORT and agarose gel for NMR. A 100-µL, hollow compartment at the center of the agarose channel was created by punching the gel removed from the oven with the back end of a glass Pasteur pipette. A similar method was followed to create the agarose gel with a hollow center channel in a 24-well plate to capture a video of the emulsification following the injection of SEAPORT via inverted microscope with a CCD camera (Olympus CKX53™ / HCImage™ software). [00237] 100 µL of specified formulations was placed in the hollow compartment, incubated for pre- determined timepoints, and removed for further characterization. The physical structure of the formulation and emulsion was measured using dynamic light scattering (Malvern ZetaSizer Nano ZS™) and visualized with cryogenic transmission electron microscopy (FEI Tecnai Arctica™ operated at 200 kV) without any dilution of samples. Diffusion-ordered spectroscopy (DOSY) NMR (Bruker AVANCE NEO 400B™, 16 scans, 3 sec delay) was used to measure the diffusion coefficient of APO in rApokyn and SEAPORT immediately after their formulation as well as 20 min post- incubation in the agarose gel. Smaller and thinner 36% w/v agarose gel was prepared to obtain Fourier-transform infrared (FT-IR) spectra of the formulation and emulsion in real-time. Agarose gel was mounted on Bruker ALPHA ATR-FTIR and the formulation was placed in the hollow compartment for time-course detection (64 scans at each timepoint). To determine the peak heights at 1645 cm^-1 and 1675 cm^-1, the IR spectrum was deconvoluted using the FITYK 1.3.1 software with Voigt type function for mathematical processing. [00238] Pharmacokinetics and toxicity in rats [00239] All experiments were performed according to the approved protocols by the Institutional Animal Care and Use Committee (IACUC) of the Faculty of Arts and Sciences (FAS), Harvard University. Male Wistar rats weighing between 300 – 350 g were subcutaneously injected with rApokyn (2.5 mg APO/kg), SEAPORT (7.5 mg APO/kg) or SEAPORT w/o CAGE_1:2 (7.5 mg APO/kg) in the dorsal flank, and blood was collected at pre-determined timepoints.95 µL of separated plasma was mixed with 5 µL of 15% w/v sodium metabisulfite in 0.2N HCl, and APO was extracted using 1:3 v/v plasma:50 ng/mL boldine in methanol. The separation of APO with boldine as internal standard was performed using an Agilent 1290 HPLC system with the same column as used in SEAPORT characterization. Mobile phase A was water with 0.1% (v/v) formic acid and mobile phase B was acetonitrile with 0.1% (v/v) formic acid. Online mass spectrometry detection was performed using an Agilent 6460 triple quadrupole mass spectrometer in positive electrospray ionization mode. Quantification was accomplished employing multiple reaction monitoring (MRM) by monitoring the transitions for APO 268.1/191.1 and boldine 328.2/265.1. The amount of APO in the samples was quantified using corresponding external calibration standard curves generated with pure standards. Detailed LC conditions are provided in supplemental information. In addition, tissue around the injection site was harvested from the stratum corneum to muscle layer on day 1 and 7, fixed with paraformaldehyde, sectioned, and stained with hematoxylin and eosin to observe toxicity from SEAPORT and SEAPORT w/o CAGE_1:2 formulations. [00240] Statistical analysis [00241] All results are expressed as mean ± standard deviation unless specified otherwise. All statistical analyses were performed in GraphPad Prism9™. Two-tailed Student’s t-test was used for comparisons between two groups, while one-way ANOVA with post-hoc testing (Dunnett’s multiple comparison) was performed to either compare between multiple groups or to compare each group to a control group. Statistical significance is defined as *p < 0.05, **p < 0.01, ***p < 0.001. [00242] Method of APO separation by triple-quadrupole LC-MS/MS. LC conditions: LC column: Agilent SB-Phenyl column (4.6 x 150 mm) heated to 30^oC Solvent A: water (0.1% formic acid) Solvent B: acetonitrile (0.1% formic acid) Flow rate: 0.5 mL/min 5uL injection Gradient: 0.00min 5% B 6.00min 100%B 7.00min 100%B 7.10min 5%B 10.0min 5%B Mass Spectrometer Parameters: Pos mode ionization Gas temp: 350C Gas flow: 12 L/min Nebulizer: 35psi Sheath gas temp: 400C Sheath gas flow: 12 L/min Capillary voltage: 3500V Nozzle voltage: 500V Cell accelerator voltage: 4V Apomorphine: Fragmentor: 100 Collision energy: 21 Boldine: Fragmentor: 110 Collision energy: 33 [00243] References 1. J. Jankovic, Parkinson's disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry 79, 368-376 (2008). 2. V. L. Dawson, T. M. Dawson, Promising disease-modifying therapies for Parkinson's disease. Sci Transl Med 11 (2019). 3. K. McFarthing et al., Parkinson's Disease Drug Therapies in the Clinical Trial Pipeline: 2020. J Parkinsons Dis 10, 757-774 (2020). 4. P. Jenner, R. Katzenschlager, Apomorphine - pharmacological properties and clinical trials in Parkinson's disease. Parkinsonism Relat Disord 33 Suppl 1, S13-S21 (2016). E. Nicolle el al, Pharmacokinetics of apomorphine in parkinsonian patients. Fundam Clin Pharmacol 7, 245-252 (1993). D. Deffond, F. Durif, M. Toumilhac, Apomorphine in treatment of Parkinson's disease: comparison between subcutaneous and sublingual routes. J Neurol Neurosurg Psychiatry 56, 101-103 (1993). A. J. Lees, The on-off phenomenon. J Neurol Neurosurg Psychiatry Suppl, 29-37 (1989). K. Pietz, P. Hagell, P. Odin, Subcutaneous apomorphine in late stage Parkinson's disease: a long term follow up. J Neurol Neurosurg Psychiatry 65, 709-716 (1998). P. Rossi, C. Colosimo, E. Moro, P. Tonali, A. Albanese, Acute challenge with apomorphine and levodopa in Parkinsonism. 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Kinget, Intranasal bioavailability of apomorphine from carboxymethylcellulose-based drug delivery systems. IntJPharm 202, 125-131 (2000). C. J. Wen, L. W. Zhang, S. A. Al-Suwayeh, T. C. Yen, J. Y. Fang, Theranostic liposomes loaded with quantum dots and apomorphine for brain targeting and bioimaging. IntJ Nanomedicine 7, 1599-1611 (2012). J. P. K. Tan et al, Effective encapsulation of apomorphine into biodegradable polymeric nanoparticles through a reversible chemical bond for delivery across the blood-brain barrier. Nanomedicine 17, 236-245 (2019). M. J. Tsai et al. , Oral apomorphine delivery from solid lipid nanoparticles with different monostearate emulsifiers: pharmacokinetic and behavioral evaluations. JPharm Sci 100, 547- 557 (2011). Y. Ramot et al, ND0701, A Novel Formulation of Apomorphine for Subcutaneous Infusion, in Comparison to a Commercial Apomorphine Formulation: 28-Day Pharmacokinetic Study in Minipigs and a Phase I Study in Healthy Volunteers to Assess the Safety, Tolerability, Pharmacokinetics and Relative Bioavailability. CNS Drugs 32, 443-454 (2018). S. T. Gancher, W. R. Woodward, B. Boucher, J. G. Nutt, Peripheral pharmacokinetics of apomorphine in humans. Ann Neurol 26, 232-238 (1989). P. A. LeWitt, Subcutaneously administered apomorphine: pharmacokinetics and metabolism. Neurology 62, S8-11 (2004). R. N. Gursoy, S. Benita, Self-emulsifying drug delivery systems (SEDDS) for improved oral delivery of lipophilic drugs. Biomed Pharmacother 58, 173-182 (2004). A. Malkawi et al, Self-Emulsifying Drug Delivery Systems: Hydrophobic Drug Polymer Complexes Provide a Sustained Release in Vitro. Mol Pharm 17, 3709-3719 (2020). S. R. 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Claims

What is claimed herein is:

1. A composition comprising an ionic liquid and n-methyl-pyrrolidone.

2. The composition of claim 1, further comprising at least one active agent.

3. The composition of claim 1 or 2, further comprising polyethylene glycol.

4. The composition of claim 1, comprising the ionic liquid, n-methyl-pyrrolidone and polyethylene glycol.

5. The composition of claim 1, comprising the ionic liquid, n-methyl-pyrrolidone; polyethylene glycol; and at least one active agent.

6. The composition of any one of the preceding claims, wherein the ionic liquid is 1-90% v/v with a cation: anion ratio such that there is more anion than cation.

7. The composition of any one of the preceding claims, wherein the ionic liquid has a cation: anion ratio in which there is at least twice as much anion as cation.

8. The composition of any one of the preceding claims, wherein the ionic liquid has a cation: anion ratio in which there is at least four times as much anion as cation.

9. The composition of any one of the preceding claims, wherein the ionic liquid is 1-90% v/v with a cation: anion ratio of 1:2.

10. The composition of any one of the preceding claims, wherein the ionic liquid is 1-55% v/v.

11. The composition of any one of the preceding claims, wherein the ionic liquid is 5-20% v/v.

12. The composition of any one of the preceding claims, wherein the ionic liquid is 10% v/v.

13. The composition of any one of the preceding claims, wherein the ionic liquid has an anion with a LogP of 1.0 or greater.

14. The composition of any one of the preceding claims, wherein the ionic liquid has an anion with a LogP of 2.0 or greater.

15. The composition of any one of the preceding claims, wherein the ionic liquid has an anion with a LogP of 3.0 or greater.

16. The composition of any one of the preceding claims, wherein the anion of the ionic liquid is geranate or geranic acid.

17. The composition of any one of the preceding claims, wherein the ionic liquid has a cation comprising a quaternary ammonium.

18. The composition of any one of the preceding claims, wherein the cation is choline or one of C1-C7.

19. The composition of any one of the preceding claims, wherein the ionic liquid is CAGE.

20. The composition of any one of the preceding claims, wherein the n-methyl-pyrrolidone is present at least about 35% v/v.

21. The composition of any one of the preceding claims, wherein the n-methyl-pyrrolidone is present at less than 45% v/v.

22. The composition of any one of the preceding claims, wherein the n-methyl-pyrrolidone is present at 1-45% v/v.

23. The composition of any one of the preceding claims, wherein the n-methyl-pyrrolidone is present at least about 35% v/v, and the CAGE is 1-90% v/v CAGE at a ratio of choline :geranate such that there is more geranate than choline present.

24. The composition of any one of the preceding claims, wherein the n-methyl-pyrrolidone is present at least about 35% v/v, and the CAGE is 10% CAGE 1:2.

25. The composition of any one of the preceding claims, wherein the n-methyl-pyrrolidone is present at about 42.7% v/v, and the CAGE is 10% CAGE 1:2.

26. The composition of any one of the preceding claims, wherein the polyethylene glycol is PEG 3350 present at about 10 to about 50 mg/mL.

27. The composition of any one of the preceding claims, wherein the polyethylene glycol is PEG 3350 present at about 28.8 mg/mL.

28. The composition of any one of the preceding claims, wherein the active agent is present at 20 mg/mL or greater.

29. The composition of any one of the preceding claims, wherein the active agent is present at 30 mg/mL or greater.

30. The composition of any one of the preceding claims, wherein the active agent is present at 40 mg/mL or greater.

31. The composition of any one of the preceding claims, wherein the active agent is present at 50 mg/mL or greater.

32. The composition of any one of the preceding claims, wherein the active agent is apomorphine.

33. The composition of claim 32, wherein the apomorphine is at a concentration of 30 mg/mL.

34. The composition of any one of the preceding claims, further comprising sodium metabisulfite.

35. The composition of any one of the preceding claims, wherein the sodium metabisulfite is present at about 1% w/v.

36. The composition of any one of the preceding claims, wherein the sodium metabisulfite is present at about 0.3% w/v.

37. The composition of any one of the preceding claims, wherein the sodium metabisulfite is present at about 3 mg/mL.

38. The composition of any one of the preceding claims formulated for subcutaneous administration.

39. A method of treating Parkinson’s Disease in a subject in need thereof, the method comprising subcutaneously administering a therapeutically effective dose of a composition of any of the preceding claims, wherein the composition comprises apomorphine.

40. The method of claim 39, wherein the administration is daily or no more frequent than daily.

41. The method of claim 40, wherein the administration is every other day or no more frequent than every other day.

42. The method of any one of claims 39-41, wherein the dosing regime comprises a 60 mg apomorphine dose on Day 1, a 30 mg apomorphine dose on Day 3, and an 18 mg apomorphine dose every 48 hours thereafter for the duration of treatment.

43. A composition of any one of claims 1-38, wherein the composition comprises apomorphine, for use in a method of treating Parkinson’s Disease in a subject in need thereof, the method comprising subcutaneously administering a therapeutically effective dose of the composition,.

44. The composition of claim 43, wherein the administration is daily or no more frequent than daily.

45. The composition of claim 43, wherein the administration is every other day or no more frequent than every other day.

46. The composition of any one of claims 43-45, wherein the dosing regime comprises a 60 mg apomorphine dose on Day 1, a 30 mg apomorphine dose on Day 3, and an 18 mg apomorphine dose every 48 hours thereafter for the duration of treatment.