Oil-based compositions and methods of making and use thereof

Abstract

The present invention provides novel compositions for treating malarial infections comprising prodrugs of ELQ-300 and an oil, wherein the composition can further comprise benzyl alcohol and / or benzyl benzoate, and methods of use thereof.

Description

TITLE OF THE INVENTIONOil-Based Compositions and Methods of Making and Use ThereofSTATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0001] This invention was made with government support under grant number 1R01AI141412-01A1 awarded by the National Institutes of Health (NIH). The Government has certain rights in this invention.BACKGROUND OF THE INVENTION

[0002] Malaria is an acute disease that can evolve quickly and be lethal in days; therefore, patients suspected of being infected should receive an urgent diagnosis and, if confirmed, prompt treatment. Malaria causes substantial morbidity and mortality and leads to an estimated USS 12 billion annual loss in economic activity in sub-Saharan Africa, where 95% of cases and 96% of deaths occur.

[0003] Given that there is no fully protective vaccine, chemotherapy is the only option available for treatment and prophylaxis. Most antimalarial drugs however are only partially efficacious and cause resistance quickly. The biggest problem is patient compliance, given that most affected are in impoverished areas, they do not have access to drugs for treatment and protection.

[0004] Chemoprophylactic medicines can provide significant economic and health benefit to populations, but they are only effective when users follow the prescribed dosage regimen. Non-adherence defeats the purpose of chemoprophylactics because, after an interval, plasma levels of the drug can fall below the concentration necessary for disease prevention (Stiratt, M. J., 2008, Current HIV / AIDS Reports, 5, 186; Trussel, J., 2013, Contraception, 88, 604). Long-acting chemoprophylactic formulations have been shown to improve adherence by reducing the number of user-controlled dosing events, which lowers or eliminates the probability of missing a dose. These kinds of dosage forms have the longest history of use in spacing childbirth (Winner, B. et al., 2012, New England Journal of Medicine, 366, 1998). More recently, they have been investigated for use in HIV pre-exposure prophylaxis (Krovi, S. A. et al.. 2021, Advanced Drug Delivery Reviews, 176, 113849).

[0005] Malaria (Nosten, F. et al., 2022, La Presse Medicale, 51) continues to cause significant numbers of deaths in regions where it is endemic. In 2021, there were an estimated 247 million cases of malaria worldwide resulting in an estimated 619,000 deaths, mostly in malaria-endemic countries (World Health Organization, 2022, World Malaria Report). These malaria-endemic regions, generally financially resource-challenged countries in the tropics, face difficulties in raising funds that can be allocated to healthcare. These regions are also where the economic costs of malaria are mostly felt (Andrade. M. V. et al., 2022, Malaria Journal, 21, 283). Even when medications are available, patient compliance during the treatment regimen of malaria is poor (Beer, N. et al., 2009, Trop. Med. Int. Health, 14, 766; Fogg, C. et al., 2004, Am. J. Trop. Med. Hyg., 71, 525; Khantikul. N. et al., 2009, J. Health Popul. Nutr., 27, 4). Adherence failure, which worsens disease and death rates, reduces the possibility of eliminating the malarial parasite and likely leads to the development of drug resistance (White, N. J., 2003, Proc. Biol. Sci., 270, 545). Suitably used (e.g., during times of increased mosquito breeding or in areas with increased prevalence of waterlogging), chemoprophylaxis appears to promise a reduction of the disease burden in malaria-endemic regions over a period of time by interfering with the reproductive cycle of the parasite (Macintyre, F. et al., 2018, Malaria Journal, 17, 402). Travelers to these areas could also benefit from a conveniently dosed antimalarial chemoprophylactic (Marasinghe, D. H. et al., 2020, CMAJ Open, 8, e60).

[0006] Medicines for Malaria Venture (MMV) has identified the need for long-acting injectable chemoprotection (LAI-C) against malaria by using formulation technologies with either parent or prodrugs. MMV has emphasized the need for developing potent new molecules, minimizing costs, and maximizing acceptability. These requirements have been stated by the MMV in the target product profile (TPP) for an injectable prophylactic medicine for malaria. The TPP states the need for the product to exhibit blood schizonticidal activity together with causal prophylactic activity and for dosing to occur not more than once every three months, an acceptable injection volume, suitable for intramuscular (IM) injection with minimal preparation, able to be administered with a 27-gauge needle, a cost of less than 5 USD per injection, and a shelflife of at least 2 years.

[0007] There is a need in the art for novel compositions and methods for treating and preventing malarial infections. The present invention addresses this unmet need in the art.BRIEF SUMMARY OF THE INVENTION

[0008] The present invention relates to, in part, a composition comprising a prodrug of ELQ-300 and an oil.

[0009] In some embodiments, the composition further comprises benzyl benzoate. In some embodiments, the concentration of benzyl benzoate is less than 40% (v / v). In some embodiments, the composition further comprises benzyl alcohol. In some embodiments, the prodrug of ELQ-300 is ELQ-331. In some embodiments, the oil is selected from sesame oil, cottonseed oil, or any combination thereof. In some embodiments, the solubility of the prodrug of ELQ-300 in the composition is at least 1 mg / mL. In some embodiments, the composition releases the prodrug of ELQ-300 for at least two months after administration to a subject. In some embodiments, the benzy l alcohol is a preservative.

[0010] In some embodiments, the concentration of benzyd alcohol is at least 10% (v / v). In some embodiments, the concentration of the oil is at least 50% (v / v). the concentration of the oil is between 40% (v / v) to 70% (v / v). In some embodiments, the concentration of benzy l benzoate is between 30% (v / v) and 50% (v / v). In some embodiments, the concentration of benzyl alcohol between 0% (v / v) and 20% (v / v).

[0011] In some embodiments, the oil is sesame oil, and the concentration of sesame oil is about 60% (v / v), and the composition further comprises benzyd benzoate, wherein the concentration of benzyl benzoate is about 40% (v / v). In some embodiments, the oil is sesame oil. and the concentration of sesame oil is about 50% (v / v), and the composition further comprises benzyl benzoate and benzyl alcohol, wherein the concentration of benzyl benzoate is about 40% (v / v) and the concentration of benzy l alcohol is about 10% (v / v). In some embodiments, the oil is cottonseed oil, and the concentration of cottonseed oil is about 60% (v / v), and the composition further comprises benzyl benzoate, wherein the concentration of benzyl benzoate is about 40% (v / v). In some embodiments, the oil is cottonseed oil, and the concentration of cottonseed oil is about 50% (v / v), and the composition further comprises benzyd benzoate and benzy l alcohol, wherein the concentration of benzyd benzoate is about 40% (v / v) and the concentration of benzyl alcohol is about 10% (v / v).

[0012] In some embodiments, the prodrug of ELQ-300 is ELQ-331; the concentration of ELQ-331 is about 3 mg / mL; the oil is sesame oil; the concentration of sesame oil is about 60% (v / v); and the composition further comprises about 40% (v / v) benzyl benzoate. In some embodiments, the prodrug of ELQ-300 is ELQ-331; the concentration of ELQ-331 is about 3mg / mL; the oil is sesame oil; the concentration of sesame oil is about 50% (v / v); and the composition further comprises about 40% (v / v) benzyl benzoate and about 10% (v / v) benzyl alcohol. In some embodiments, the prodrug of ELQ-300 is ELQ-331; the concentration of ELQ-331 is about 3 mg / mL; the oil is cottonseed oil; the concentration of cottonseed oil is about 60% (v / v); and the composition further comprises about 40% (v / v) benzyl benzoate. In some embodiments, the prodrug of ELQ-300 is ELQ-331; the concentration of ELQ-331 is about 3 mg / mL; the oil is cottonseed oil; the concentration of cottonseed oil is about 60% (v / v); and the composition further comprises about 40% (v / v) benzyl benzoate.

[0013] In some embodiments, the composition is injectable by syringe. In some embodiments, the composition has a viscosity of less than 17 cP at about 37 °C. In some embodiments, the composition has an osmolality between 200 mOsmol / L and 300 mOsmol / L.

[0014] The present invention further relates to, in part, a method of preventing or treating Plasmodium infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the instant composition.

[0015] In some embodiments, the therapeutically effective amount is about 12 mg / kg. In some embodiments, the method maintains a plasma concentration of at least 33 ng / rnL in the subject. In some embodiments, the method maintains an effective protective antimalarial concentration in the subject for at least 4 weeks. In some embodiments, the method maintains an effective protective antimalarial concentration in the subject for at least 56 days. In some embodiments, the composition remains present in the subject for at least 85 days. In some embodiments, the composition is administered using subcutaneous or intramuscular injection. In some embodiments, the composition is administered prophylactically or prior to Plasmodium infection. In some embodiments, the composition is administered before the blood stage of the Plasmodium life cycle. In some embodiments, the composition is administered prior to peak malaria season. In some embodiments, the composition is administered to the subject once annually. In some embodiments, the subject is protected from malaria for one year after administration.

[0016] The present invention further relates to, in part, a kit comprising a pre-filled syringe or cartridge loaded with the instant composition. In some embodiments, the kit further comprises an auto-injector. In some embodiments, the kit further comprises an instructional material.BRIEF DESCRIPTION OF THE DRAWINGS

[0017] For the purpose of illustrating the invention, there are depicted in the drawings certain embodiments of the invention. However, the invention is not limited to the precise arrangements and instrumentalities of the embodiments depicted in the drawings.

[0018] Fig. 1 comprises Fig. 1A and Fig. IB. Fig. 1 A depicts plunger-stopper break loose force (PBF), maximum force (Fmax), and dynamic glide force (DGF) for saline and formulations B-L. Fig. IB depicts total work of injection between the time when the probe touches the plunger and the time when the plunger stops moving for saline and formulations B-L. Formulation compositions are described elsewhere herein in Table 6. Values are reported as mean ± S.D.; n=3 measurements.

[0019] Fig. 2 comprises Fig. 2A through Fig. 2C. Fig. 2A depicts a representative in vitro release testing arrangement. Cumulative percent release profiles of ELQ-331 oil-based solution formulations with the oil floating on release medium model. Fig. 2B depicts percent release profiles for sesame oil formulations. Fig. 2C depicts percent release profiles for cottonseed oil formulations. Formulation compositions are described elsewhere herein in Table 6. Values are reported as mean ± S.D., n=6.

[0020] Fig. 3 depicts viscosity measurements of oil-based solution formulations of ELQ- 331. Formulations have an ELQ-331 concentration of 3 mg / ml. Values are from three measurements (mean ± S.D., n=3). Formulation compositions are described elsewhere herein in Table 7.

[0021] Fig. 4 depicts representative data showing the effect of drug loading on viscosity of ELQ-331 oil -based solution formulations. Formulations E, F, and G have ELQ-331 concentrations of 1, 3, and 30 mg / ml, respectively. The placebo is 100% sesame oil. Values are reported as mean ± S.D., n=3.

[0022] Fig. 5 depicts a representative force-distance plot (3 ml syringe with a 21G, 1" needle attached).

[0023] Fig. 6 depicts average cumulative release during in vitro release studies. Formulation compositions are described elsewhere herein in Table 7.

[0024] Fig. 7 depicts plasma concentrations of ELQ-300 in rats, administered ELQ-331 IM at a dose of 12.14 mg / kg, IM (the dose is the equivalent of 10.00 mg / ml ELQ-300). Each data point represents the mean and S.D. of n = 3 rats. Formulation F: 60% sesame oil, 40% benzylbenzoate, formulation H: 50% sesame oil, 40% benzyl benzoate, 10% benzyl alcohol. The minimum fully effective protective plasma concentration (MEPioo) of ELQ-300 is shown as a dotted line.

[0025] Fig. 8 depicts ELQ-300 concentrations after administration of 12. 14 mg / kg to Sprague Dawley rats (n=3) for Formulation H. ELQ-331 was below the lower limit of quantitation (LLOQ) in all samples, LLOQ = 1.00 ng / ml. The MEP100 is included on the graph at 33.25 ng / ml. The plasma drug concentration elimination curves intersected the MEPlOO at 1320 hr.

[0026] Fig. 9 depicts pharmacokinetic parameters for ELQ-300 after administration.DETAILED DESCRIPTION OF THE INVENTION

[0027] It is to be understood that the figures and descriptions of the present invention have been simplified to illustrate elements that are relevant for a clear understanding of the present invention, while eliminating, for the purpose of clarity, many other elements found in the art. Those of ordinary skill in the art may recognize that other elements and / or steps are desirable and / or required in implementing the present invention. However, because such elements and steps are well known in the art, and because they do not facilitate a better understanding of the present invention, a discussion of such elements and steps is not provided herein. The disclosure herein is directed to all such variations and modifications to such elements and methods known to those skilled in the art. Although any methods, materials and components similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described.Definitions

[0028] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods, materials and components similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described.

[0029] As used herein, each of the following terms has the meaning associated with it in this section.

[0030] The articles “a’' and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0031] “About” as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±20% or ±10%, more preferably ±5%, even more preferably ±1%, and still more preferably ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.

[0032] A disease or disorder is “alleviated” if the severity7of a sign or symptom of the disease or disorder, the frequency with which such a sign or symptom is experienced by a patient, or both, is reduced.

[0033] The terms “patient,” “subject,” or “individual” are used interchangeably herein, and refer to any animal, or cells thereof whether in vitro or in situ, amenable to the methods described herein. In a non-limiting embodiment, the patient, subject or individual is a human.

[0034] As used herein, the term “composition” refers to a mixture of at least one compound useful within the invention with a pharmaceutically acceptable carrier. The composition facilitates administration of the compound to a patient or subject. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary and topical administration.

[0035] A “therapeutic” treatment is a treatment administered to a subject who exhibits signs of pathology, for the purpose of diminishing or eliminating those signs.

[0036] A “prophylactic” treatment is a treatment administered to a subject with the purpose of preventing the occurrence or spread of a disease or infection.

[0037] As used herein, the term “treatment” or “treating” is defined as the application or administration of a therapeutic agent, i.e., a compound of the invention (alone or in combination with another pharmaceutical agent), to a patient, or application or administration of a therapeutic agent to an isolated tissue or cell line from a patient (e.g., for diagnosis or ex vivo applications), who has a condition contemplated herein, a sign or symptom of a condition contemplated herein or the potential to develop a condition contemplated herein, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect a condition contemplated herein, at least one sign or symptom of a condition contemplated herein or the potential to develop a condition contemplated herein. Such treatments may bespecifically tailored or modified, based on knowledge obtained from the field of pharmacogenomics.

[0038] As used herein, the terms “effective amount,” “pharmaceutically effective amount" and “therapeutically effective amount” refer to a nontoxic but sufficient amount of an agent to provide the desired biological result. That result may be reduction and / or alleviation of a sign, a symptom, or a cause of a disease or disorder, or any other desired alteration of a biological system. An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

[0039] As used herein, the term “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing an undesirable biological effect or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0040] As used herein, the language “pharmaceutically acceptable salt” refers to a salt of the administered compound prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids, organic acids, solvates, hydrates, or clathrates thereof. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, hexafluorophosphoric, citric, gluconic, benzoic, propionic, butyric, sulfosalicylic, maleic, lauric, malic, fumaric, succinic, tartaric, amsonic, pamoic, p-tolunenesulfonic, and mesylic. Appropriate organic acids may be selected, for example, from aliphatic, aromatic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, camphorsulfonic, citric, fumaric, gluconic, isethionic, lactic, malic, mucic, tartaric, para-toluenesulfonic, glycolic, glucuronic, maleic, furoic, glutamic, benzoic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, benzenesulfonic (besylate), stearic, sulfanilic, alginic. galacturonic, and the like. Furthermore, pharmaceutically acceptable salts include, by way of non-limiting example, alkaline earth metal salts (e.g., calcium or magnesium), alkali metal salts (e g., sodium-dependent or potassium), and ammonium salts.

[0041] As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or earner, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within theinvention within or to the patient such that it may perform its intended function. Typically, such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be ‘'acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the invention, and not injurious to the patient. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as com starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. As used herein, ‘'pharmaceutically acceptable earner” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound useful within the invention, and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions. The “pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound useful within the invention.Other additional ingredients that may be included in the compositions used in the practice of the invention are known in the art and described, for example in Remington's Pharmaceutical Sciences (Genaro, Ed.. Mack Publishing Co., 1985, Easton. PA), which is incorporated herein by reference.

[0042] An “effective amount” of a delivery vehicle is that amount sufficient to effectively bind or deliver a compound.

[0043] As used herein, the term “potency” refers to the dose needed to produce half the maximal response (ED50).

[0044] As used herein, the term “efficacy” refers to the maximal effect (Emax) achieved within an assay.

[0045] ‘‘Instructional material’', as that term is used herein, includes a publication, a recording, a diagram, or any other medium of expression which can be used to communicate the usefulness of the composition and / or formulation of the present invention in the kit for identifying, diagnosing, alleviating, preventing, or treating the various diseases or disorders recited herein. The instructional material of the kit may, for example, be affixed to a container that contains one or more components of the invention or be shipped together with a container that contains the one or more components of the invention. Alternatively, the instructional material may be shipped separately from the container with the intention that the recipient uses the instructional material and the components cooperatively.

[0046] Ranges: throughout this disclosure, various aspects of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4. from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.Description

[0047] The present invention arises from, in part, the identification of a novel composition uniquely enabled for treating and / or preventing infectious diseases including, but not limited to, malarial infections, and methods of use thereof. In certain embodiments, the present invention demonstrates unexpectedly enhanced release rates and prolonged intervals wherein efficacious doses are maintained in subjects.Compositions for Treating and / or Preventing Infectious Diseases

[0048] The present invention provides, in part, a composition for the treatment and prophylaxis of infectious diseases. In some embodiments, the composition includes at least one therapeutic compound such as ELQ-300 and / or a prodrug thereof. In some embodiments, the composition comprises ELQ-300 and / or a prodrug thereof. In some embodiments, the composition may further include a carrier, an oil, and / or a solvent.

[0049] As used herein, the term “prodrug’' refers to an agent that is converted into the parent drug in vivo. In some embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound. In some embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.

[0050] Exemplary' prodrugs of ELQ-300 include, but are not limited to, ELQ-331, ELQ- 494, ELQ-495. and ELQ-499. In certain embodiments, the prodrug of ELQ-300 is a compound having the structure of General Formula I,General Formula I wherein R represents a functional group comprising an alkylcarbonate. In some embodiments, R is a functional group which can be enzymatically converted to a carbonyl group. In some embodiments, the prodrug of ELQ-300 is ELQ-331.ELQ-331

[0051] In some embodiments, the concentration of the prodrug in the composition is at least about 0. 1 mg / mL. In some embodiments, the concentration of the prodrug in the composition is at least about 0.5 mg / mL. In some embodiments, the concentration of the prodrug in the composition is at least about 1 .0 mg / mL. In some embodiments, the concentration of the prodrug in the composition is at least about 1.5 mg / mL. In some embodiments, the concentration of the prodrug in the composition is at least about 2.0 mg / mL. In some embodiments, the concentration of the prodrug in the composition is at least about 2.5 mg / mL. In some embodiments, the concentration of the prodrug in the composition is at least about 3.0 mg / mL. In some embodiments, the concentration of the prodrug in the composition is at least about 3.5 mg / mL. In some embodiments, the concentration of the prodrug in thecomposition is at least about 4.0 mg / mL. In some embodiments, the concentration of the prodrug in the composition is at least about 4.5 mg / mL. In some embodiments, the concentration of the prodrug in the composition is at least about 5.0 mg / mL. In some embodiments, the concentration of the prodrug in the composition is at least about 10 mg / mL. In some embodiments, the concentration of the prodrug in the composition is at least about 15 mg / mL. In some embodiments, the concentration of the prodrug in the composition is at least about 20 mg / mL. In some embodiments, the concentration of the prodrug in the composition is at least about 25 mg / mL. In some embodiments, the concentration of the prodrug in the composition is at least about 30 mg / mL. In some embodiments, the concentration of the prodrug in the composition is at least about 35 mg / mL. In some embodiments, the concentration of the prodrug in the composition is at least about 40 mg / mL. In some embodiments, the concentration of the prodrug in the composition is at least about 45 mg / mL. In some embodiments, the concentration of the prodrug in the composition is at least about 50 mg / mL.

[0052] In some embodiments, the concentration of the prodrug in the composition is between about 0.1 mg / mL and about 50 mg / mL. In some embodiments, the concentration of the prodrug in the composition is between about 0. 1 mg / mL and about 45 mg / mL. In some embodiments, the concentration of the prodrug in the composition is between about 0.1 mg / mL and about 40 mg / mL. In some embodiments, the concentration of the prodrug in the composition is between about 0.1 mg / mL and about 35 mg / mL. In some embodiments, the concentration of the prodrug in the composition is between about 0. 1 mg / mL and about 30 mg / mL. In some embodiments, the concentration of the prodrug in the composition is between about 0.1 mg / mL and about 25 mg / mL. In some embodiments, the concentration of the prodrug in the composition is between about 0. 1 mg / mL and about 20 mg / mL. In some embodiments, the concentration of the prodrug in the composition is between about 0. 1 mg / mL and about 15 mg / mL. In some embodiments, the concentration of the prodrug in the composition is between about 0.1 mg / mL and about 10 mg / mL. In some embodiments, the concentration of the prodrug in the composition is betw een about 0. 1 mg / mL and about 5.0 mg / mL. In some embodiments, the concentration of the prodrug in the composition is between about 0.5 mg / mL and about 5.0 mg / mL. In some embodiments, the concentration of the prodrug in the composition is between 1.0 mg / mL and about 5.0 mg / mL. In some embodiments, the concentration of the prodrug in the composition is between about 1.5 mg / mL and about 4.5 mg / mL. In some embodiments, the concentration of the prodrug in thecomposition is between about 2.0 mg / mL and about 4.0 mg / rnL. In some embodiments, the concentration of the prodrug in the composition is between about 2.5 mg / mL and about 3.5 mg / mL. In some embodiments, the concentration of the prodrug in the composition is between about 2.5 mg / mL and about 3.0 mg / rnL. In some embodiments, the concentration of the prodrug in the composition is between about 3.0 mg / mL and about 3.5 mg / rnL.

[0053] In certain embodiments, the composition further comprises an oil. Exemplary oils which may be included in the present invention include, but are not limited to, sesame oil, cottonseed oil, com oil, peanut oil, castor oil, safflower oil, soybean oil, sunflower oil, olive oil, canola oil, coconut oil, palm oil, rapeseed oil, almond oil, beech nut oil, brazil nut oil, cashew oil, cobnut oil, hazelnut oil, macadamia oil, pecan oil, pine nut oil, pistachio oil, walnut oil, seed oil, and combinations thereof. In some embodiments, the oil is any commercially available oil. In some embodiments, the oil is sesame oil. In some embodiments, the oil is cottonseed oil.

[0054] In some embodiments, the concentration of the oil is at least about 1% (v / v). In some embodiments, the concentration of the oil is at least about 10% (v / v). In some embodiments, the concentration of the oil is at least about 20% (v / v). In some embodiments, the concentration of the oil is at least about 30% (v / v). In some embodiments, the concentration of the oil is at least about 40% (v / v). In some embodiments, the concentration of the oil is at least about 50% (v / v). In some embodiments, the concentration of the oil is at least about 60% (v / v). In some embodiments, the concentration of the oil is at least about 70% (v / v). In some embodiments, the concentration of the oil is at least about 80% (v / v). In some embodiments, the concentration of the oil is at least about 90% (v / v).

[0055] In some embodiments, the concentration of the oil is between about 20% (v / v) and about 90% (v / v). In some embodiments, the concentration of the oil is between about 25% (v / v) and about 85% (v / v). In some embodiments, the concentration of the oil is between about 30% (v / v) and about 80% (v / v). In some embodiments, the concentration of the oil is between about 35% (v / v) and about 75% (v / v). In some embodiments, the concentration of the oil is between about 40% (v / v) and about 70% (v / v). In some embodiments, the concentration of the oil is between about 40% (v / v) and about 65% (v / v). In some embodiments, the concentration of the oil is between about 40% (v / v) and about 60% (v / v). In some embodiments, the concentration of the oil is between about 45% (v / v) and about 55% (v / v). In some embodiments, the concentration of the oil is between about 45% (v / v) andabout 50% (v / v). In some embodiments, the concentration of the oil is between about 50% (v / v) and about 55% (v / v).

[0056] In some embodiments, the solubility of the prodrug of ELQ-300 in the oil is about 1 mg / rnL to about 30 mg / mL. In some embodiments, the solubility of the prodrug of ELQ-300 in the oil is about 5 mg / mL to about 30 mg / mL. In some embodiments, the solubility of the prodrug of ELQ-300 in the oil is about 10 mg / mL to about 30 mg / mL. In some embodiments, the solubility of the prodrug of ELQ-300 in the oil is about 15 mg / mL to about 30 mg / mL. In some embodiments, the solubility of the prodrug of ELQ-300 in the oil is about 20 mg / mL to about 30 mg / mL. In some embodiments, the solubility of the prodrug of ELQ-300 in the oil is about 25 mg / mL to about 30 mg / mL. In some embodiments, the solubility of the prodrug of ELQ-300 in the oil is less than about 5 mg / rnL. In some embodiments, the solubility of the prodrug of ELQ-300 in the oil is less than about 10 mg / mL. In some embodiments, the solubility of the prodrug of ELQ-300 in the oil is less than about 15 mg / mL. In some embodiments, the solubility of the prodrug of ELQ-300 in the oil is less than about 20 mg / mL. In some embodiments, the solubility of the prodrug of ELQ-300 in the oil is less than about 25 mg / mL. In some embodiments, the solubility of the prodrug of ELQ-300 in the oil is less than about 30 mg / mL.

[0057] In certain embodiments, the composition further comprises a solvent. In some embodiments, the solvent is an organic solvent. Exemplary solvents which may be included in the present invention include, but are not limited to, benzyl benzoate, polyethylene glycol, glycerin, alcohol, benzyl alcohol, and combinations thereof. In some embodiments, the solvent acts as a preservative. In some embodiments, the solvent enhances the solubility of ELQ-300 and / or the prodrug of ELQ-300 in the composition. In some embodiments, the solvent is benzyl benzoate. In some embodiments, the solvent is benzyl alcohol.

[0058] In some embodiments, the concentration of the solvent is at least about 1% (v / v). In some embodiments, the concentration of the solvent is at least about 10% (v / v). In some embodiments, the concentration of the solvent is at least about 20% (v / v). In some embodiments, the concentration of the solvent is at least about 30% (v / v). In some embodiments, the concentration of the solvent is at least about 40% (v / v). In some embodiments, the concentration of the solvent is at least about 50% (v / v). In some embodiments, the concentration of the solvent is at least about 60% (v / v). In some embodiments, the concentration of the solvent is at least about 70% (v / v). In someembodiments, the concentration of the solvent is at least about 80% (v / v). In some embodiments, the concentration of the solvent is at least about 90% (v / v).

[0059] In some embodiments, the solubility of the prodrug of ELQ-300 in the solvent is at least about 30 mg / mL. In some embodiments, the solubility of the prodrug of ELQ-300 in the solvent is at least about 50 mg / mL. In some embodiments, the solubility of the prodrug of ELQ-300 in the solvent is at least about 100 mg / mL. In some embodiments, the solubility of the prodrug of ELQ-300 in the solvent is at least about 150 mg / mL. In some embodiments, the solubility of the prodrug of ELQ-300 in the solvent is at least about 200 mg / mL. In some embodiments, the solubility of the prodrug of ELQ-300 in the solvent is at least about 250 mg / mL. In some embodiments, the solubility of the prodrug of ELQ-300 in the solvent is at least about 300 mg / mL. In some embodiments, the solubility of the prodrug of ELQ-300 in the solvent is at least about 350 mg / mL.

[0060] In some embodiments, the composition comprises a solvent, wherein the solvent is benzyl alcohol. In some embodiments, the composition comprises a solvent, wherein the solvent is benzyl benzoate. In some embodiments, the composition comprises a solvent, wherein the solvent comprises benzyd alcohol and benzyl benzoate. In some embodiments, the composition comprises a solvent, wherein the solvent is a combination of benzyl alcohol and benzyl benzoate.

[0061] In some embodiments, the composition comprises a solvent wherein the solvent is benzyd benzoate. In some embodiments, the concentration of benzyl benzoate is between 5% (v / v) and 50% (v / v), 10% (v / v) and 50% (v / v), 15% (v / v) and 50% (v / v), 20% (v / v) and 50% (v / v), 25% (v / v) and 50% (v / v), 30% (v / v) and 50% (v / v), 35% (v / v) and 50% (v / v), 40% (v / v) and 50% (v / v), or 45% (v / v) and 50% (v / v). In some embodiments, the concentration of benzyd benzoate is less than about 50% (v / v). In some embodiments, the concentration of benzyl benzoate is less than about 45% (v / v). In some embodiments, the concentration of benzyl benzoate is less than about 40% (v / v). In some embodiments, the concentration of benzyd benzoate is less than about 35% (v / v). In some embodiments, the concentration of benzy l benzoate is less than about 30% (v / v). In some embodiments, the concentration of benzy l benzoate is less than about 25% (v / v). In some embodiments, the concentration of benzyl benzoate is less than about 20% (v / v). In some embodiments, the concentration of benzyl benzoate is less than about 15% (v / v). In some embodiments, the concentration of benzy l benzoate is less than about 10% (v / v). In some embodiments, the concentration of benzyd benzoate is less than about 5% (v / v).

[0062] In some embodiments, the concentration of benzyl benzoate is between about 30% (v / v) and about 50% (v / v). In some embodiments, the concentration of benzyl benzoate is between about 35% (v / v) and about 45% (v / v). In some embodiments, the concentration of benzyl benzoate is between about 30% (v / v) and about 40% (v / v). In some embodiments, the concentration of benzyl benzoate is between about 35% (v / v) and about 40% (v / v). In some embodiments, the concentration of benzyl benzoate is between about 40% (v / v) and about 45% (v / v). In some embodiments, the concentration of benzyl benzoate is between about 40% (v / v) and about 50% (v / v).

[0063] In some embodiments, the composition comprises a solvent, wherein the solvent comprises benzyl alcohol. In some embodiments, the composition further comprises a solvent, wherein the solvent is benzyl alcohol. In some embodiments, the benzyl alcohol serves as a preservative. In some embodiments, the concentration of benzyl alcohol is between 1% (v / v) and 90% (v / v), 10% (v / v) and 90% (v / v), 20% (v / v) and 90% (v / v), 30% (v / v) and 90% (v / v), 40% (v / v) and 90% (v / v), 50% (v / v) and 90% (v / v), 60% (v / v) and 90% (v / v), 70% (v / v) and 90% (v / v), or 80% (v / v) and 90% (v / v). In some embodiments, the concentration of benzyl alcohol is at least about 1% (v / v). In some embodiments, the concentration of benzyl alcohol is at least about 10% (v / v). In some embodiments, the concentration of benzyl alcohol is at least about 20% (v / v). In some embodiments, the concentration of benzy l alcohol is at least about 30% (v / v). In some embodiments, the concentration of benzyl alcohol is at least about 40% (v / v). In some embodiments, the concentration of benzyl alcohol is at least about 50% (v / v). In some embodiments, the concentration of benzyl alcohol is at least about 60% (v / v). In some embodiments, the concentration of benzyl alcohol is at least about 70% (v / v). In some embodiments, the concentration of benzy l alcohol is at least about 80% (v / v). In some embodiments, the concentration of benzyl alcohol is at least about 90% (v / v).

[0064] In some embodiments, the concentration of benzyl alcohol is between about 0% (v / v) and about 20% (v / v). In some embodiments, the concentration of benzyl alcohol is between about 5% (v / v) and about 15% (v / v). In some embodiments, the concentration of benzyl alcohol is between about 0% (v / v) and about 10% (v / v). In some embodiments, the concentration of benzy l alcohol is between about 5% (v / v) and about 10% (v / v). In some embodiments, the concentration of benzyl alcohol is between about 10% (v / v) and about 15% (v / v). In some embodiments, the concentration of benzyl alcohol is between about 10% (v / v) and about 20% (v / v).

[0065] In some embodiments, the composition comprises sesame oil and a solvent, wherein the solvent comprises benzyl benzoate. In some embodiments, the concentration of sesame oil is about 60% (v / v) and the concentration of benzyl benzoate is about 40% (v / v). In some embodiments, the concentration of sesame oil is about 60% (v / v) and the concentration of benzyl benzoate is about 30% (v / v). In some embodiments, the concentration of sesame oil is about 60% (v / v) and the concentration of benzyl benzoate is about 20% (v / v). In some embodiments, the concentration of sesame oil is about 60% (v / v) and the concentration of benzyl benzoate is about 10% (v / v). In some embodiments, the concentration of sesame oil is about 60% (v / v) and the concentration of benzyl benzoate is about 5% (v / v). In some embodiments, the concentration of sesame oil is about 60% (v / v) and the concentration of benzyl benzoate is about 1% (v / v).

[0066] In some embodiments, the composition comprises sesame oil and a solvent, wherein the solvent comprises benzyl benzoate and benzyl alcohol. In some embodiments, the concentration of sesame oil is about 50% (v / v) and the concentration of benzyl benzoate is about 40% (v / v) and the concentration of benzyl alcohol is about 10% (v / v). In some embodiments, the concentration of sesame oil is about 50% (v / v) and the concentration of benzyl benzoate is about 30% (v / v) and the concentration of benzyl alcohol is about 20% (v / v). In some embodiments, the concentration of sesame oil is about 50% (v / v) and the concentration of benzyl benzoate is about 20% (v / v) and the concentration of benzyl alcohol is about 30% (v / v). In some embodiments, the concentration of sesame oil is about 50% (v / v) and the concentration of benzyl benzoate is about 10% (v / v) and the concentration of benzyl alcohol is about 40% (v / v).

[0067] In some embodiments, the composition comprises cottonseed oil and a solvent, wherein the solvent comprises benzyd benzoate. In some embodiments, the oil is cottonseed oil, and the concentration of cottonseed oil is about 60% (v / v), and the composition further comprises benzy l benzoate, wherein the concentration of benzy l benzoate is about 40% (v / v). In some embodiments, the oil is cottonseed oil, and the concentration of cottonseed oil is about 60% (v / v), and the composition further comprises benzyl benzoate, wherein the concentration of benzyl benzoate is about 30% (v / v). In some embodiments, the oil is cottonseed oil, and the concentration of cottonseed oil is about 60% (v / v), and the composition further comprises benzyl benzoate, wherein the concentration of benzyl benzoate is about 20% (v / v). In some embodiments, the oil is cottonseed oil, and theconcentration of cottonseed oil is about 60% (v / v), and the composition further comprises benzyl benzoate, wherein the concentration of benzyl benzoate is about 10% (v / v).

[0068] In some embodiments, the composition comprises cottonseed oil and a solvent, wherein the solvent comprises benzyl benzoate and benzyl alcohol. In some embodiments, the concentration of cottonseed oil is about 50% (v / v) and the concentration of benzyl benzoate is about 40% (v / v) and the concentration of benzy l alcohol is about 10% (v / v). In some embodiments, the concentration of cottonseed oil is about 50% (v / v) and the concentration of benzyl benzoate is about 30% (v / v) and the concentration of benzyl alcohol is about 20% (v / v). In some embodiments, the concentration of cottonseed oil is about 50% (v / v) and the concentration of benzyd benzoate is about 20% (v / v) and the concentration of benzy l alcohol is about 30% (v / v). In some embodiments, the concentration of cottonseed oil is about 50% (v / v) and the concentration of benzyl benzoate is about 10% (v / v) and the concentration of benzyl alcohol is about 40% (v / v).

[0069] In some embodiments, the solubility of the prodrug of ELQ-300 in the composition is between about 1 mg / mL and about 300 mg / mL. In some embodiments, the solubility of the prodrug of ELQ-300 in the composition is between about 1 mg / mL and about 250 mg / mL. In some embodiments, the solubility7of the prodrug of ELQ-300 in the composition is betw een about 1 mg / mL and about 200 mg / mL. In some embodiments, the solubility of the prodrug of ELQ-300 in the composition is between about 1 mg / mL and about 150 mg / mL. In some embodiments, the solubility of the prodrug of ELQ-300 in the composition is between about 1 mg / mL and about 100 mg / mL. In some embodiments, the solubility7of the prodrug of ELQ- 300 in the composition is between about 5 mg / mL and about 300 mg / mL. In some embodiments, the solubility of the prodrug of ELQ-300 in the composition is between about 5 mg / mL and about 250 mg / mL. In some embodiments, the solubility7of the prodrug of ELQ- 300 in the composition is between about 5 mg / mL and about 200 mg / mL. In some embodiments, the solubility of the prodrug of ELQ-300 in the composition is betw een about 5 mg / mL and about 150 mg / mL. In some embodiments, the solubility7of the prodrug of ELQ- 300 in the composition is between about 5 mg / mL and about 100 mg / mL. In some embodiments, the solubility of the prodrug of ELQ-300 in the composition is between about 10 mg / mL and about 300 mg / mL. In some embodiments, the solubility7of the prodrug of ELQ-300 in the composition is between about 10 mg / mL and about 250 mg / mL. In some embodiments, the solubility of the prodrug of ELQ-300 in the composition is between about 10 mg / mL and about 200 mg / mL. In some embodiments, the solubility of the prodrug ofELQ-300 in the composition is between about 10 mg / mL and about 150 mg / mL. In some embodiments, the solubility of the prodrug of ELQ-300 in the composition is between about 10 mg / mL and about 100 mg / mL.

[0070] In certain embodiments, the composition is injectable by syringe. In some embodiments, the composition has a viscosity of less than about 5 cP at about 37 °C. In some embodiments, the composition has a viscosity of less than about 10 cP at about 37 °C. In some embodiments, the composition has a viscosity of less than about 15 cP at about 37 °C. In some embodiments, the composition has a viscosity of less than about 17 cP at about 37 °C. In some embodiments, the composition has a viscosity of less than about 20 cP at about 37 °C.

[0071] In some embodiments, the composition has an osmolality between about 100 mOsmol / kg and about 500 mOsmol / kg. In some embodiments, the composition has an osmolality between about 100 mOsmol / kg and about 400 mOsmol / kg. In some embodiments, the composition has an osmolality between about 100 mOsmol / kg and about 300 mOsmol / kg. In some embodiments, the composition has an osmolality between about 200 mOsmol / kg and about 500 mOsmol / kg. In some embodiments, the composition has an osmolality' between about 300 mOsmol / kg and about 500 mOsmol / kg. In some embodiments, the composition has an osmolality between about 200 mOsmol / kg and about 300 mOsmol / kg. In some embodiments, the composition has an osmolality between about 200 mOsmol / kg and about 400 mOsmol / kg.

[0072] In certain embodiments, the composition releases the prodrug of ELQ-300 for at least one month after administration to a subject. In certain embodiments, the composition releases the prodrug of ELQ-300 for at least two months after administration to a subject. In certain embodiments, the composition releases the prodrug of ELQ-300 for at least three months after administration to a subject.Methods of Treating and / or Preventing Infectious Diseases

[0073] The present invention provides, in part, a method of treating and / or preventing an infectious disease. In certain embodiments, the method is uniquely effective against infectious diseases which are caused by a microorganism of the genus Plasmodium, including, but not limited to, P. falciparum, P. vivax, P. ovale wallikeri, P. ovcde curtisi, P.malariae, and P. knowlesi. In certain embodiments, the method comprises administering to a subject in need thereof the composition of the present invention.

[0074] In some embodiments, the therapeutically effective amount is at least about 1 mg / kg. In some embodiments, the therapeutically effective amount is at least about 5 mg / kg. In some embodiments, the therapeutically effective amount is at least about 10 mg / kg. In some embodiments, the therapeutically effective amount is at least about 12 mg / kg. In some embodiments, the therapeutically effective amount is at least about 15 mg / kg. In some embodiments, the therapeutically effective amount is at least about 20 mg / kg. In some embodiments, the therapeutically effective amount is at least about 25 mg / kg.

[0075] In some embodiments, the method maintains a plasma concentration of at least about 10 ng / mL in the subject. In some embodiments, the method maintains a plasma concentration of at least about 15 ng / mL in the subject. In some embodiments, the method maintains a plasma concentration of at least about 20 ng / mL in the subject. In some embodiments, the method maintains a plasma concentration of at least about 25 ng / mL in the subject. In some embodiments, the method maintains a plasma concentration of at least 30 ng / mL in the subject. In some embodiments, the method maintains a plasma concentration of at least 33 ng / mL in the subject. In some embodiments, the method maintains a plasma concentration of at least 35 ng / mL in the subject. In some embodiments, the method maintains a plasma concentration of at least about 40 ng / mL in the subject. In some embodiments, the method maintains a plasma concentration of at least about 50 ng / mL in the subject.

[0076] In some embodiments, the method maintains an effective protective antimalarial concentration in the subject for at least 1 day. In some embodiments, the method maintains an effective protective antimalarial concentration in the subject for at least 1 week. In some embodiments, the method maintains an effective protective antimalarial concentration in the subject for at least 4 weeks. In some embodiments, the method maintains an effective protective antimalarial concentration in the subject for at least 2 months. In some embodiments, the method maintains an effective protective antimalarial concentration in the subject for at least 56 days. In some embodiments, the method maintains an effective protective antimalarial concentration in the subject for at least 85 days.

[0077] In some embodiments, the composition is administered using subcutaneous or intramuscular injection. In some embodiments, the composition is administeredprophylactically or prior to Plasmodium infection. In some embodiments, the composition is administered before the blood stage of the Plasmodium life cycle. In some embodiments, the composition is administered prior to peak malaria season. Peak malaria seasons are determined by the location of the subject of interest.

[0078] In some embodiments, the subject is protected from malaria for at least one day after administration. In some embodiments, the subject is protected from malaria for at least one week after administration. In some embodiments, the subject is protected from malaria for at least one year after administration. In some embodiments, the subject is protected from malaria throughout an entire malaria season.Administration / Dosage / Formulations

[0079] In some embodiments, the composition of the present invention is administered once annually. In some embodiments, the composition is administered in any amount less than the therapeutically effective dose at a frequency higher than once a year. In some embodiments, the composition is administered at the therapeutically effective dose more than once a year. In some embodiments, the composition is administered in any amount over any desired time period such that the composition is therapeutically effective over the desired time period.

[0080] The regimen of administration may affect what constitutes an effective amount. The therapeutic formulations may be administered to the subject either before or after the onset of the infection. Further, the dosages of the therapeutic formulations may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.

[0081] Administration of the compositions of the present invention to a patient, such as a mammal, (e.g., human), may be carried out using known procedures, at dosages and for periods of time effective to treat a microbial infection in the patient. An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the state of the disease or disorder in the patient; the age, sex, and weight of the patient; and the ability of the therapeutic compound to treat a microbial infection in the patient. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily. In another example, the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A nonlimiting example of an effective dose range for a therapeutic compound of the invention isfrom about 1 mg / kg to about 5,000 mg / kg of body weight / per day. One of ordinary skill in the art would be able to assess the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation.

[0082] Actual dosage levels of the active ingredients (i.e.. the concentration of ELQ-300 and / or the prodrug of ELQ-300) in the compositions of this invention may be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without generating excessive side effects in the patient.

[0083] A medical professional, e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the composition required. For example, the physician or veterinarian could start with a dosage of the compound of the invention in the composition at a level that is lower than the level required to achieve the desired therapeutic effect, and then increase the dosage over time until the desired effect is achieved.

[0084] In some embodiments, the compositions of the invention are formulated using one or more additional pharmaceutically acceptable excipients or carriers. In some embodiments, the compositions of the invention comprise a therapeutically effective amount of a compound of the invention and an additional pharmaceutically acceptable carrier.

[0085] The additional carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), vegetable oils, and suitable mixtures thereof. The proper injectability may be maintained by the maintenance of the required particle size in the case of dispersion and by the use of surfactants or viscosity thinners. In some embodiments, it is useful to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable compositions can be achieved by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.

[0086] The therapeutically effective amount or dose of a compound of the present invention depends on the age, sex and weight of the patient, the current medical condition of the patient and the severity of the microbial infection in the patient being treated. The skilled artisan is able to determine appropriate doses depending on these and other factors.

[0087] Doses of the compound of the invention for administration may be in the range of from about 1 pg to about 10.000 mg, from about 20 pg to about 9,500 mg, from about 40 pg to about 9,000 mg, from about 75 pg to about 8,500 mg, from about 150 pg to about 7,500 mg, from about 200 pg to about 7,000 mg, from about 3050 pg to about 6,000 mg, from about 500 pg to about 5,000 mg, from about 750 pg to about 4,000 mg, from about 1 mg to about 3,000 mg, from about 10 mg to about 2,500 mg, from about 20 mg to about 2,000 mg, from about 25 mg to about 1,500 mg, from about 30 mg to about 1,000 mg, from about 40 mg to about 900 mg, from about 50 mg to about 800 mg, from about 60 mg to about 750 mg, from about 70 mg to about 600 mg, from about 80 mg to about 500 mg, and any and all whole or partial increments therebetween.

[0088] In some embodiments, the dose of a compound of the invention is from about 1 mg to about 2,500 mg. In some embodiments, a dose of a compound of the invention used in compositions described herein is less than about 10,000 mg, or less than about 8,000 mg, or less than about 6,000 mg, or less than about 5.000 mg, or less than about 3.000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg. Similarly, in some embodiments, the dosage of a second compound as described elsewhere herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg. or less than about 100 mg. or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or partial increments thereof.

[0089] The compounds for use in the method of the invention may be formulated in unit dosage form. The term “unit dosage form’7refers to physically discrete units suitable as unitary dosage for patients undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier.

[0090] It is readily apparent to one skilled in the art that the frequency of administration of the various combination compositions of the invention will vary- from individual to individual depending on many factors including, but not limited to, age, the disease or disorder to be treated, the severity of the disease or disorder to be treated, gender, overall health, and otherfactors. Thus, the invention should not be construed to be limited to any particular dosing regime and the precise dosage and composition to be administered to any patient is determined by the medical professional taking all other factors about the patient into account.

[0091] In the case wherein the patient's status does improve, upon the doctor's discretion the administration of the inhibitor of the invention is optionally given continuously; alternatively, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i. e. , a "drug holiday"). The length of the drug holiday optionally varies between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The dose reduction during a drug holiday includes from 10%-100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%. 65%. 70%. 75%. 80%. 85%. 90%. 95%. or 100%.

[0092] Once improvement of the patient's condition has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, may be reduced to a level at which the improved disease is retained. In some embodiments, a patient may require intermittent treatment on a long-term basis, or upon any recurrence of the disease or disorder.

[0093] Toxicity and therapeutic efficacy of such therapeutic regimens are optionally determined in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 (the dose lethal to 50% of the population) and the EDso (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio between LDso and EDso. The data obtained from cell culture assays and animal studies are optionally used in formulating a range of dosage for use in human. The dosage of such compounds hes preferably within a range of circulating concentrations that include the EDso with minimal toxicity. The dosage optionally varies within this range depending upon the dosage form employed and the route of administration utilized.

[0094] In some embodiments, the present invention is directed to a packaged composition comprising a container holding a therapeutically effective amount of a compound of the invention; and instructions for using the compound to treat or prevent a microbial infection in a patient.

[0095] Formulations may be employed in admixtures with additional conventional excipients, i.e.. pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration, known to the art. The pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and / or aromatic substances and the like. They may also be combined where desired with other active agents, e.g., other analgesic agents.

[0096] For parenteral administration, the compounds of the invention may be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration in a bolus dose and / or continuous infusion. Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing and / or dispersing agents may be used.Kits

[0097] The present invention also pertains to kits comprising compositions of the present invention. Such kits comprise various combinations of any composition and / or formulation described elsewhere herein in various forms and may optionally further comprise an instructional material.

[0098] In some embodiments, the present invention provides a kit comprising the composition described elsewhere herein, wherein the composition is loaded in the appropriate dosage amount in a pre-filled syringe. In some embodiments, the present invention further provides a kit comprising the composition described herein, wherein the composition is loaded in the appropriate dosage amount in a pre-filled cartridge. In some embodiments, the kit provides a pre-filled syringe which may be self-administered or administered by, but not limited to, an individual who does not have prior medical training. In some embodiments, the kit provides a pre-filled cartridge which may be inserted into an auto-injector, which is optionally further provided in the kit. In some embodiments, the kit provides a pre-filled cartridge which, once inserted into an auto-injector, may be self-administered or administered by, but not limited to, an individual who does not have prior medical training. In some embodiments, the kit provides an instructional material which effectively details how anycomposition and / or formulation provided in the kit may be self-administered or administered by, but not limited to, an individual who does not have prior medical training.Controlled Release Formulations and Drug Delivery Systems

[0099] In some embodiments, the formulations of the present invention may be, but are not limited to, short-term, rapid-offset, as well as controlled, for example, sustained release, delayed release and pulsatile release formulations.

[0100] The term sustained release refers to a drug formulation that provides for gradual release of a drug over an extended period of time, and that may, although not necessarily, result in substantially constant blood levels of a drug over an extended time period. The period of time may be as long as a day, a week, or a month or more and should be a release which is longer that the same amount of agent administered in bolus form. The term delayed release is used herein in its conventional sense to refer to a drug formulation that provides for an initial release of the drug after some delay following drug administration and that mat, although not necessarily, includes a delay of from about 10 minutes up to about 12 hours.

[0101] For sustained release, the compounds may be further formulated with a suitable polymer or hydrophobic material which provides sustained release properties to the compounds.

[0102] In some embodiments of the invention, the compounds of the invention are administered to a patient, alone or in combination with another pharmaceutical agent, using a sustained release formulation.

[0103] The term pulsatile release refers to a drug formulation that provides release of the drug in such a way as to produce pulsed plasma profiles of the drug after drug administration.

[0104] The term immediate release refers to a drug formulation that provides for release of the drug immediately after drug administration.

[0105] As used herein, short-term refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes and any or all whole or partial increments thereof after drug administration after drug administration.

[0106] As used herein, rapid-offset refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes, and any and all whole or partial increments thereof after drug administration.

[0107] Those skilled in the art recognize or are able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents were considered to be within the scope of this invention and covered by the claims appended hereto. For example, it should be understood, that modifications in reaction conditions, including but not limited to reaction times, reaction size / volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, e.g., nitrogen atmosphere, and reducing / oxi dizing agents, with art-recognized alternatives and using no more than routine experimentation, are within the scope of the present application.Preparation of the Compounds of the Invention

[0108] Compounds utilized in any methods of the present invention may be prepared using any synthetic method known by those skilled in the art. The following examples illustrate non-limiting embodiments of the invention.

[0109] In some embodiments, the compounds of the invention may exist as tautomers. All tautomers are included within the scope of the compounds presented herein.

[0110] In some embodiments, sites on, for example, the aromatic ring portion of compounds of the invention are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the aromatic ring structures may reduce, minimize or eliminate this metabolic pathway. In some embodiments, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a deuterium, a halogen, or an alk l group.[OHl] In some embodiments, the compounds described herein may be labeled by means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0112] The compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein and as described, for example, in Fieser & Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Suppiementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley andSons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March. Advanced Organic Chemistry 4thEd., (Wiley 1992); Carey & Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000, 2001), and Green & Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods for the preparation of compound as described herein are modified by the use of appropriate reagents and conditions, for the introduction of the various moieties found in the formula as provided herein.

[0113] Compounds described herein are synthesized using any suitable procedures starting from compounds that are available from commercial sources, or are prepared using procedures described herein.

[0114] In some embodiments, reactive functional groups, such as hydroxyl, amino, imino, thio or carboxy groups, are protected in order to avoid their unwanted participation in reactions. Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed. In another embodiment, each protective group is removable by a different means. Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal.

[0115] In some embodiments, protective groups are removed by acid, base, reducing conditions (such as, for example, hydrogenolysis), and / or oxidative conditions. Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and are used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile. Carboxylic acid and hydroxy reactive moieties are blocked with base labile groups such as, but not limited to, methyl, ethyl, and acetyl, in the presence of amines that are blocked with acid labile groups, such as t- uty l carbamate, or with carbamates that are both acid and base stable but hydrolytically removable.

[0116] In some embodiments, carboxylic acid and hydroxy reactive moieties are blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids are blocked with base labile groups such as Fmoc. Carboxylic acid reactive moieties are protected by conversion to simple ester compounds as exemplified herein, which include conversion to alkyl esters, or are blockedwith oxidatively-removable protective groups such as 2,4-dimethoxybenzyl, while coexisting amino groups are blocked with fluoride labile silyl carbamates.

[0117] Allyl blocking groups are useful in the presence of acid- and base- protecting groups since the former are stable and are subsequently removed by metal or pi-acid catalysts. For example, an allyl-blocked carboxylic acid is deprotected with a palladium-catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate is attached. As long as the residue is attached to the resin, that functional group is blocked and does not react. Once released from the resin, the functional group is available to react.

[0118] Typically blocking / protecting groups may be selected from:

[0119] Other protecting groups, plus a detailed description of techniques applicable to the creation of protecting groups and their removal are described in Greene & Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference for such disclosure.Combination Therapies

[0120] In certain embodiments, the composition or compounds of the present invention is used in combination with one or more additional compounds. In certain embodiments, these additional compounds may comprise compounds of the present invention or therapeuticagents known to treat, prevent, or reduce the symptoms or effects of an infectious disease, such as malarial infection and / or a Plasmodium infection. In certain embodiments, the composition of the present invention further comprises an additional therapeutic agent.

[0121] In some embodiments, administering the composition of the invention to the subject allows for administering a lower dose of the therapeutic agent compared to the dose of the therapeutic agent alone that is required to achieve similar results in treating the subject. For example, in some embodiments, the composition of the invention enhances the activity of the additional therapeutic compound, thereby allowing for a lower dose of the therapeutic compound to provide the same effect. In another embodiment, administering the composition of the invention to the subject allows for administering a lower dose of the therapeutic agent compared to the dose of the therapeutic agent alone that is required to achieve similar results in treating or preventing infection in the subject.

[0122] In some embodiments, the composition of the invention and the therapeutic agent are co-administered to the subject. In another embodiment, the composition of the invention and the therapeutic agent are co-formulated and co-administered to the subject.

[0123] It is to be understood that wherever values and ranges are provided herein, all values and ranges encompassed by these values and ranges, are meant to be encompassed within the scope of the present invention. Moreover, all values that fall within these ranges, as well as the upper or lower limits of a range of values, are also contemplated by the present application.EXAMPLES

[0124] The invention is now described with reference to the following Examples. These Examples are provided for the purpose of illustration only, and the invention is not limited to these Examples, but rather encompasses all variations that are evident as a result of the teachings provided herein.

[0125] The materials and methods employed in the experiments and the results of the experiments presented in this Example are now described.Example 1:

[0126] A few reports have described the use of small molecules as possible long-acting injectable chemoprophylactics (LAI-Cs) using existing approved small molecule drugs (Bakshi, R. P. et al., 2018, Nature Communications, 9, 315; Fan, Y. et al., 2022, Pharmaceutics, 14; Pooda, S. H. et al., 2023, Parasites & Vectors, 16, 66). However, commercially feasible LAI-C formulations have only become possible with the appearance of potent molecules that have the attributes necessary’ to support long-acting dosage forms. ELQ-331 (Smilkstein, M. J. et al.. 2019. Malaria Journal. 18, 291), a prodrug of ELQ-300 (Frueh, L. et al., 2017, ACS Infectious Diseases, 3, 728), appears to fulfil the requirements for an antimalarial LAI-C. ELQ-300 is active against liver stage, blood stage, and sexual forms of Plasmodium parasites (Nilsen, A. et al., 2013, Sci. Transl. Med., 5, 177ral37) and the ELQ-331 prodrug substantially enhances ELQ-300 exposure. As a result. ELQ-331 is a preclinical candidate in MMV's pipeline of malaria prophylactics (Pou, S. et al., 2021, Organic Process Research & Development, 25, 1841). The minimum fully effective protective plasma concentration of ELQ-300 (MEPioo) to prevent sporozoite-induced infection is about 80 nM in mice. Allometric scaling indicates that a dose of 2.5 mg / kg (translated to 175 mg for a 70 kg person) is a reasonable estimate of the required injectable dose for long term protection in humans (Smilkstein, M. J. et al., 2019, Malaria Journal, 18, 291).

[0127] The work reported herein formulates ELQ-331 into an LAI-C against malaria. As for all prophylactic medications, since the target group is a pool of healthy users, the risk profile is particularly important. The product was formulated with vehicles and excipients used in marketed products. An oil-based solution strategy was used to develop the formulation. Microspheres and liposome-based formulations were also considered; however, these multi -phase dosage forms are difficult to inject, present stability’ issues, have manufacturing challenges (e g., batch-to-batch variability), and require particle-size control. They also tend to have low drug loading, are difficult to sterilize, and may cause an inflammatory’ response (Bee, S.-L. et al., 2018, Polymer Reviews, 58, 495; Sharma, A., 1997, International Journal of Pharmaceutics, 154, 123). In contrast, a simpler, oil-based injectable formulation provides the advantages of straightforward manufacturing, long-term stability, suitability for terminal sterilization, and the possibility for drug depots with tailored delivery characteristics (Fredholt, K. et al., 2000, Eur. J. Pharm. Sci., 11, 231; Larsen S. W., 2009, AAPS J., 11, 762; Larsen, S. W. et al., 2012, Advances in Delivery Science and Technology’, 113).

[0128] Injected medications, formulated as solutions, cannot be retrieved from the body easily once injected. Earlier work (Potharaju, S. et al.. 2020, Pharm. Dev. Technol., 25, 625) reported on the formulation of ELQ-331 as oral suspensions or spray-dried dispersion (SDD) preparations that could possibly be compressed as tablets. Oral formulations can be used as a lead in regimen prior to the administration of the long-acting injections to guard against the possibility of unanticipated adverse reactions to ELQ-331 in some individuals.Materials and MethodsMethods

[0129] The prodrug (ELQ-331) and the active form (ELQ-300) were synthesized at the Veterans Administration Medical Center, Oregon Health & Science University (VAMC / OHSU) in Portland, OR, using previously reported procedures (Frueh, L. et al., 2017, ACS Infectious Diseases, 3, 728; Pou, S. et al., 2021, Organic Process Research & Development, 25, 1841).ELQ-331

[0130] Deionized (DI) water was obtained from a Millipore (Burlington, MA) waterpurification system. Analytical reagents were analytical research grade or better. Inactive ingredients in the formulation were USP / NF grade. Phosphate buffered saline (10X) was purchased from Alfa Aesar (Ward Hill, MA) and diluted to IX with DI water. Formic acid was purchased from EMD Millipore (Billerica, MA). Brij®35 was purchased from Acros Organics (Pittsburgh, PA). Glycerin was purchased from J. T. Baker (Pittsburgh, PA). Sesame oil, com oil, cottonseed oil, peanut oil, castor oil, safflower oil, soybean oil, benzy lalcohol, benzyl benzoate, and polyethylene glycols (300, 400, 3350, 4000) were obtained from Spectrum Chemical Company (Gardena. CA). Acetonitrile, methanol, ethanol, disposable syringes, and needles were purchased from VWR International (Radnor, PA).High Performance Liquid Chromatography (HPLC) Method

[0131] Chromatography was performed on an HP 1100 series HPLC system (Santa Clara, CA) controlled with ChemStation software (Agilent Technologies, Santa Clara, CA) as reported earlier (Potharaju et al.. 2020). The HPLC gradient is shown in the supplemental section (Table 1). Standards of ELQ-331 and ELQ-300 were injected during each run to quantify the prodrug and the active drug.Table 1. HPLC Gradient.Solubility of ELQ-331

[0132] The solubility of ELQ-331 in selected solvents, suitable for IM administration, was evaluated by a modified shake flask method. Excess quantity of ELQ-331 was added to each vehicle in glass vials followed by vortexing and overnight agitation at 25 °C on a VWR Model 3500 ADV orbital shaker (Radnor, PA) set to 200 rpm. The vortexing and agitation steps were repeated until saturated solutions were obtained. The vials were then agitated for an additional day. The saturated samples were centrifuged. The supernatant was collected, diluted with methanol, filtered through a 0.2 pm syringe filter, and analyzed by HPLC. Thesolubility of ELQ-331 in oil-based binary and ternary combinations was also determined using this procedure. Three replicates were performed for each solvent system.Preparation of oil-based solution formulations

[0133] The vehicle components were measured at the required volumes into a glass container. The container contents were blended with a magnetic stirrer until a homogenous solution was obtained. The active formulations were prepared by adding the required quantity of ELQ-331 to the oil or oil-solvent blend. The mixture was briefly sonicated. The vials were agitated, by vortexing and shaking, to dissolve the ELQ-331 completely and obtain the oilbased solution formulations.Characterization and testing of oil-based formulations

[0134] The oil-based solution formulations were characterized for appearance, assay, viscosity, density, injectability, and in vitro release.Appearance

[0135] The placebo and active formulations were visually evaluated for physical appearance, color, phase separation, and homogeneity at room temperature (RT), 25°C.Assay

[0136] The ELQ-331 oil injections were extracted and accurately diluted in methanol using volumetric flasks. The solutions were filtered through a 0.45 pm syringe filter. The formulations were analyzed for ELQ-331 and ELQ-300 by the HPLC method.Viscosity'

[0137] A cone and plate viscometer (Model DV3TLV, Brookfield Instruments, Middleboro, MA) was used to measure the viscosity of the formulations. The measurements were recorded at 25, 37. and 60 °C.Density

[0138] The density of each oil-based solution formulation was measured by weighing the formulation in a specific gravity flask at RT.Injectability parameters

[0139] The injectability of the formulations was determined with a Brookfield CT3-1500 texture analyzer (Middleboro, MA). The force was measured using an assembly to hold the syringe. The procedure used was similar to that reported by other authors (Burckbuchler, V. et al.. 2010, Eur. J. Pharm. Biopharm.. 76. 351; Zhang, Q. et al., 2018, AAPS PharmSciTech, 19. 1520). The syringe (BD Luer-Lok™ Tip, 3 ml) was positioned in the syringe test fixture (TA-STJ), sourced from the texture analyzer manufacturer, and held in place on the base table. A needle (BD Precision Glide 21G 1" Needle) was attached to the syringe. Testing was carried out at a speed of 1 mm / s. The loading force (N) required to displace the plunger was measured as a function of plunger displacement (mm). The plunger was depressed for a distance of 17 mm while the force (N) was measured. A force-distance plot was generated. The plunger-stopper break-loose force (PBF, the force required to initiate the movement of the plunger); maximum force (Fmax , the maximum force measured when the plunger completes displacing material from the front end of the syringe); dynamic glide force (DGF, the force required to maintain the movement of the plunger to extrude the content of the syringe); and the total work done (the work of injection between the time when the probe touches the plunger and the time when the plunger stops moving) were determined by the instrument's data processing software (Fig. 1).In vitro release study

[0140] The Oil Floating on Release Medium (OFRM) model was used for the in vitro drugrelease study to screen the formulations. The release medium was 2% w / v Brij 35 in phosphate buffered saline (PBS, pH 7.4), which was added to a glass bottle (Qorpak 120ml / 4 oz Beaker Bottle). A transfer pipette was cut at both ends and converted to a tube with the required length to be placed on the inside wall of the bottle (Fig. 2A). The tube was affixed to the wall with either a hot glue gun or tape. The oil-based solution formulation was carefully placed on the surface of the aqueous release medium. The tube, affixed to the inside wall, was used to collect samples without disturbing the oil layer. An ELQ-331 concentration of 3 mg / ml was used for the study samples, and a volume of 1 ml of the sample was used. The release system was agitated by placing the bottle on a VWR 3500 ADV orbital shaker in an Imperial III Incubator (Lab-Line Instruments, Melrose Park, IL) maintained at 37 °C. The speed of the shaker was set to 100 rpm. The oil formulation and aqueous phase were shakenbut not mixed with each other at this speed. Samples (1 ml) were collected through the tube from the aqueous phase at predetermined intervals. The collected samples were transferred to HPLC vials after filtration through a 0.45 pm syringe filter. The volume in the release container was replenished with 1 ml of fresh release medium (prewarmed to 37 °C) through the tube after each sample was collected. The collected samples were analyzed with the HPLC method described above. Sink condition was maintained during the study. Six replicates were performed for each formulation.Partition coefficient of oil formulations

[0141] The partition coefficients were calculated using Equation (1) (Schultz, K. et al., 1997, Int. J. Pharm., 157, 163) when equilibrium had been established between the oil-based solution formulations and the aqueous buffer in the in vitro release studies. p=(vaq) ~CaqVo (1)Caq Vaq

[0142] The total mass of drug used in the sample is M, Caq is the equilibrium drug concentration in the aqueous buffer, and Vaq, Vo are the volumes of aqueous and the oil phases, respectively.Short term accelerated stability testing

[0143] Two formulations, selected for the animal studies, were placed on short-term accelerated stability testing at 40 °C / 75% Relative Humidity (RH) for three months. At the end of three months, the formulations were assayed and visually examined for any changes compared to the same solutions at RT.Pharmacokinetic (PK) study

[0144] The general procedures for animal care and housing were in accordance with the recommendations of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC), the Guide for the Care and Use of Laboratory Animals (National Research Council), and the U.S. Department of Agriculture through the Animal Welfare Act and Animal Welfare regulations. Every effort was made to minimize pain and suffering in all animals used in this study.

[0145] Single jugular-vein catheterized (JVC) male Sprague Dawley (SD) rats sourced from Charles River Laboratories (Hollister, CA) were used. The age at first dose was 10-11 weeks. The rats were randomly assigned to treatment groups by computerized body weight stratification (Provantis® version 10.5.0.2), and each animal was identified by a unique ear punch. Water and food were provided ad libitum.

[0146] The concentration of ELQ-331 in the oil formulations used for the study was 12. 14 mg / ml (equivalent of 10.00 mg / ml of ELQ-300). The IM injection was administered in the hind back quadriceps of unfasted animals at two sites with a 25G 5 / 8" needle. A dose of 12.14 mg (ELQ-33 l) / kg was administered. No more than 0.2 ml was injected per site on one leg, and both legs were used. The animals were checked at least once daily during the course of the study for mortality or morbidity. The animals were examined for any altered clinical signs, including gross motor and behavioral activity and observable changes in appearance. The injection site was also routinely examined during the study duration of four weeks.Plasma collection

[0147] Blood samples were collected through the JVC port from each rat to K3EDTA- containing tubes at specified time points. Sodium fluoride (NaF) was added promptly to the blood samples by transferring 300 pl of whole blood, from the K EDTA tube, into a microcentrifuge tube containing 34 pl of 500 mM NaF. These mixtures were placed on wet ice until processed to plasma by centrifugation at 2-8 °C. The plasma samples were placed on dry ice prior to being frozen below -60 °C for storage. Further breakdown, post blood collection, of the prodrug ELQ-331 during sample processing and storage was prevented by NaF. Blood was also collected using other Institutional Animal Care and Use Committee (IACUC) approved methods: tail vein (for one rat on days 14 and 21) and retro-orbital sinus (for two rats on day 28). Anesthesia was used when blood was collected via retro-orbital sinus.Bioanalytical method

[0148] Drug levels of ELQ-300 and the prodrug ELQ-331 were determined in the collected plasma samples using a bioanalytical method reported earlier (Potharaju, S. et al., 2020, Pharm. Dev. Technol., 25, 625).Pharmacokinetic data analysis

[0149] Plasma drug-level data of ELQ-300 and ELQ-331 were analyzed using Phoenix WinNonlin® (v 8.3) by noncompartmental approaches. The following PK parameters and constants were determined: observed maximum plasma concentration (Cmax), time to reach maximum plasma concentration after the IM dose (Tmax), area under the plasma concentration-time curve (AUC), and mean residence time (MRT).Results and DiscussionPhysical attributes of the oil-based formulations

[0150] Oil vehicles for parenteral administration have to be inert, stable, syringeable, injectable, and safe (Spiegel, A. J., 1963, J. Pharm. Sci., 52, 917). Except for containing a drug (thus, not inert), the active oil formulation should have the same characteristics. The vegetable oils and vehicles tested in this study were selected based on published reports and from the US FDA inactive ingredient database. In addition to the vehicle, excipients are used in formulations to introduce or improve certain properties of the vehicle. These include preservatives (if intended for multi-dose administration), excipients to improve the ease of administration, and solvents to improve the solubility of the drug (Rowe, R. C. et al.. 2009, Handbook of Pharmaceutical Excipients). Some excipients perform more than one function. For example, benzyl alcohol, in addition to being a preservative, has local anesthetic properties and serves to reduce the viscosity of the oily vehicle (Nair, B., 2001, International Journal of Toxicology. 20, 23). For injectable products, where constraints of administration volume and limited selection (compared to oral or topical dosage forms) of excipients are possible, it appeared reasonable to limit experimental excipients and choose those that perform multiple roles.

[0151] The solubility of ELQ-331 ranged from 11.2 to 17.7 mg / ml in the vegetable oils tested, while in non-oil solvents, solubility was in the range of 0.4 to 330.9 mg / ml (Table 2). Among the materials tested, the solubility of ELQ-331 was the highest in benzyl alcohol (330.9 mg / ml) and the lowest in glycerin (0.4 mg / ml). Castor oil has a high viscosity (Table 3) and is expected to have low injectability properties. Since the solubility of ELQ-331 was not very much increased in castor oil, it was eliminated from the choice of oils. The viscosity of the other oils was similar enough that all were possible choices as the primary vehicle if a short-acting injection was being formulated.Table 2. Solubility of ELQ-331 in vegetable oils and solvents. Values, measured at 25 °C, are reported as mean ± S.D.. n=3.Table 3. Viscosity of Oils at 37 °C

[0152] The safety profile during the intended long duration (possibly greater than one month) residence at the site of injection was an important consideration in selecting suitable candidate oils and narrowing the choices (Wilkinson, J. et al., 2022, European Journal of Pharmaceutical Sciences, 178, 106253). Considerations of viscosity, safety during prolonged use, and prior precedent in approved products led to the choice of sesame oil and cottonseed oil for additional studies. These two oils were used to prepare binary and ternary combinations. The solvents in which the highest solubilities of ELQ-331 were obtained, benzyl alcohol and benzyd benzoate, were used as the additional components in the different combinations. The maximum concentrations of benzyl alcohol and benzyl benzoate were set at 10 and 40 % v / v, respectively, of the total volume in testing the different combinations.

[0153] The cosolvent formulations with benzyl alcohol and / or benzyl benzoate were colored yellow. The active formulations were similar in visual appearance to the corresponding placebo. The formulations of ELQ-331 and the placebo formulations were visually stable in color, physical appearance, and homogenous with no sign of phase separation at RT. The assay of the active formulations was within ±10% of the nominal concentration (Table 4). ELQ-300 was not observed when the prepared solutions were assayed by HPLC.

[0154] The solubility of ELQ-331 in the cosolvent formulations was more than twice that with oil alone (Table 5). When 5% of benzyl alcohol or benzyl benzoate was added to sesame oil, the solubility' increased by a factor of 2.6 and 2.3. For cottonseed oil, the increase with the addition of these excipients was 2.4X. The increase in solubility with increasing quantities of the benzyl benzoate / benzyl alcohol appeared to be linear. Based on the solubility results, seven formulations (indicated with asterisks in Table 5) were selected for additional studies. Six were selected based on the increased solubility compared to the oils; one formulation (Formulation C containing 98.8% sesame oil, 1.2% benzyl alcohol) w as prepared to enable comparison with a prior study (Smilkstein, M. J. et al., 2019, Malaria Journal, 18, 291). Two formulations contained ELQ-331 in sesame oil or cottonseed oil without additional excipients. Thus, nine formulations (Table 6, Table 7) were carried forward to additional studies. Formulations obtained by blending the two oils, and adding the excipients did not improve the solubilities compared to a single-oil formulation and were not tested further.Table 4. Composition and Assay of Prepared ELQ-331 Oil-based Solution FormulationsTable 5. Solubility of ELQ-331 in sesame and cottonseed oil-based cosolvent formulations.Values are reported as mean ± S.D., n=3.Table 6. Density, viscosity, and partition coefficient of oil-based solution ELQ-331 formulations. ELQ-331 concentration is 3 mg / ml.Table 7. Density of prepared ELQ-331 oil-based solution formulationsDensity is the average of three measurements.

[0155] Viscous liquids can be difficult to inject, and high forces of injection are required to move the plunger forward in the syringe barrel to displace the solution out of the needle and into the injection site. This can cause patient distress and may also have other undesired effects (Roberts, B. C. et al., 2022, Drug Delivery, 29, 43). As the oil was replaced with other excipients (Table 6), the viscosity of the ELQ-331 formulations decreased. The observed viscosity changes differed in sesame oil and cottonseed oil formulations with the addition of the excipients. Sesame oil-based formulations had a slightly higher viscosity compared to the corresponding cottonseed oil formulations. Testing was also performed at 25 and 60 °C in addition to 37 °C (Fig. 3). The viscosity7trend of the formulations was similar to that at 37 °C, with the sesame oil formulations having slightly higher viscosity values. The viscosity of formulations at different drug loadings in the formulation consisting of 60% sesame oil, 40% benzyl benzoate (placebo and drug loadings of 1, 3, and 30 mg / ml) were determined. Higher drug loading (up to 30 mg / ml) did not appear to significantly affect the viscosity of the sesame oil-based formulations. The increase in viscosity was less than 2 cP with the 30 mg / ml formulation compared to the placebo (Fig. 4). Commercial parenteral solutions have viscosities in the range of 29-60 cPs (Allahham, A. et al.. 2004, Int. J. Pharm. 270, 139) and concentrated biologicals have viscosities of 10-200 cPs (Zhang, Q. et al., 2018, AAPS PharmSciTech., 19, 1520). Since the viscosity of ELQ-331 formulations with 30 mg / ml is about 25 cPs, these formulations can be injected without causing significant pain or distress. It appears likely that even if additional ELQ-331 is loaded in the formulation, within the solubility7limits, the viscosity will be within the range for practical use. The density of the formulations ranged from 0.92 to 1.04 g / ml for the active formulations (Table 6). Replacement of oil with other cosolvents resulted in slightly increased density for both sesame oil and cottonseed oil.

[0156] While administering injections, withdrawal of the dose into the syringe from the primary container (syringeability7) and delivery to the administration site (injectability) are important parameters. This is especially true for formulations with high viscosity (Cilurzo, F. et al., 2011, AAPS PharmSciTech., 12, 604). While syringing and injecting are two different events, the term injectability is used to refer to the overall resistance of the liquid formulation to flow during either event. This includes the force required for injection, evenness of flow, and freedom from needle clogging. The measurement of injectability parameters of ELQ-331 oil-based solution formulations was performed by recording the force-distance plots (Fig. 5). The mean PBF, Fmax, DGF, and total w ork values were collected (Fig. 1A, Fig. IB). Low ervalues indicate better injectability. All oil-based formulations had higher values of PBF, Fmax, DGF. and total work when compared to saline. Combinations of the oils with benzyl benzoate or benzyl alcohol showed lower values for PBF, Fmax, and DGF than the oils alone. This also resulted in the total work of the injection sequence being lower for the cosolvent formulations. The cottonseed oil formulations had slightly better injectability values compared to corresponding sesame oil formulations when the concentration of the oils was greater than 50%. However, once the concentration was at 50%, the major contribution appeared to be due to the property of the cosolvents. The addition of cosolvents resulted in better injectability values for both series of oil formulations.

[0157] The highest value of Fmax is about 6 N when a 21G 1" needle is used for the test. The study allowed rank ordering of the different formulations. Since these values were obtained with a free-standing needle set up, the force when injecting into muscle is expected to be much higher. The results of the test indicate the likelihood of an uncomplicated and safe manual inj ection with these formulations in humans. Other authors have used the maximum force (when injected into air) of 30 N as a reasonable upper limit (Burckbuchler, V. et al., 2010, Eur. J. Pharm. Biopharm., 76, 351).In vitro release from oil formulations

[0158] Sustained release parenteral products do not have a specified standard method for drug-release testing. Reports in the literature have used a variety of methods to measure in vitro release of extended-release products. The OFRM model was used for the in vitro release studies. A suitable release medium is an important aspect in the in vitro release-method development for a poorly soluble drug. Factors such as sufficient solubility of drug in the release media to ensure sink conditions under experimental set up and stability of the drug in the release media were considered important aspects of the development phase of the method. A release media of 2% w7v Brij 35 in phosphate buffer saline, pH 7.4, was used. The solubility of ELQ-331 in this media is ~90 pg / ml. A volume sufficient to ensure sink conditions was used for the studies.

[0159] The release profiles of ELQ-331 formulations are shown in Fig. 2. All the formulations resulted in delayed in vitro release, but to varying degrees. The cumulative release was in the range of 9% to 27% over 42 days. Among the sesame oil formulations (Fig. 2B), drug release was higher when 100% oil w as used. Delayed release was greatest in formulations prepared in combination of co-solvents (benzyl alcohol, benzyl benzoate).Similar release trends were observed with cottonseed oil formulations in combination with co-sol vents (Fig. 2C). The difference in release between the 100% sesame and cottonseed oil formulation, using the AUC, was significant (p< 0.05). Sesame oil formulations in combination with co-solvents had similar or slightly more delayed release when compared with corresponding formulation prepared with cottonseed oil.

[0160] The conversion of ELQ-331 to ELQ-300 was monitored during the in vitro release studies (Fig. 6). The amount of conversion to ELQ-300 was minimal with oil-based formulations. The partition coefficient values between the oil vehicle and release medium for the ELQ-331 oil-based formulations were calculated (Table 6). The formulations that combined sesame oil with co-solvents had higher partition coefficient values compared to corresponding cottonseed oil formulations (p<0.001 for formulations F and K, p<0.01 for formulations H and L).

[0161] The in vivo performance of oil-based solution formulations is affected by various processes that are difficult to simulate with in vitro tests. These include physical factors (spreading and disappearance of the oil-based solution from the injection site) or physiological factors (blood flow at the site and depth of injection, shape, and surface area of oil depot at site of injection). Nevertheless, in vitro release tests allow the rank ordering of these different formulations. It is known that drug partitioning between the oil vehicle and the aqueous tissue fluid play an important part in modifying the drug release rate from oil-based solutions. Hence, it is possible to design oil-based formulations with customized release rate characteristics by modifying the partition coefficient. An increase in the partition coefficient can be achieved by increasing the drug partitioning to the oil phase of formulations by using mixtures of triglycerides / oils or by the addition of excipients such as nonaqueous vehicles. Oil-based solution formulations of ELQ-331 in combination with solvents (benzyl benzoate and benzyl alcohol) showed improved solubility, increased partition coefficient, and relatively delayed in vitro release. The observed release differences and the delayed release of ELQ-331 from the oil-based formulations appear to be primarily due to the change in oilwater partition coefficients by altering the oil vehicle composition. Over time, the cosolvents are also released from the oil, leading to a continous change in the formulation composition and the partition coefficient (Kalicharan, R. W., 2017, New Insights into Drug Absorption from Oil Depots). In summary, drug release and absorption from an oil depot is complex and may not be entirely described by simple models. Thus predicting the drug release and absorption from the injection site may prove difficult without in vivo studies.

[0162] In prior reported in vivo studies in mice (Smilkstein, M. J. et al., 2019, Malaria Journal, 18, 291), a single IM injection of 30 mg (ELQ-331) / kg in sesame oil and 1.2% benzyl alcohol (Table 6, Formulation C) maintained an ELQ-300 concentration above 100 nM and provided more than four months of causal prophylaxis against malaria. In in vitro release studies (Fig. 2), other formulations appeared to show a more delayed release, compared to Formulation C. These formulations with significantly enhanced solubility of ELQ-331 and an improvement in delayed release in vitro will allow higher ELQ-331 loading and were expected to achieve greater long-term release in in vivo studies.

[0163] The objective going into the PK study was to down-select two oil-based formulations from among the various possible oil combinations. Formulation H had the best injectability' (the lowest total work value during force testing) among the formulations tested and the highest calculated partition coefficient value. This led to the choice of formulation H as one of the two candidates. While K, L, and F had good results in the injectability tests, formulation F had a higher calculated partition value than K or L. Formulations F and H also showed the greatest delay in the ELQ-331 being converted to the ELQ-300 during the in vitro release study. Since the objective was to have a stable prolonged release formulation and the intent was to narrow down the field of formulations to two candidates for the PK study, the sesame oil formulations (F and H) were selected. No significant advantage was thought to be obtained by earn ing forward formulations of cottonseed oil.

[0164] The formulations stored at 40 °C for three months were visually like those stored at RT with no phase separation, precipitation, or visually discernible color changes. The assay values were similar to when initially tested at the time of manufacture.Pharmacokinetic study

[0165] The two oil-based formulations (Formulations F and H, see Table 6 for composition) used for the study were selected based on solubility, in vitro release studies, and inj ectability7parameters.

[0166] No animals were required to be euthanized prior to the study’s scheduled end points due to adverse health status. The trained personnel performing the injections did not report any difference from other aqueous-based injections while administering these oil-based formulations. The formulations were well tolerated by the rats used in the study. The animals showed no adverse clinical observations during the entire study from the test article injection,and no animals died. Any clinical observations (Table 7) during the study did not appear to be test-article related, since they were located distal from the IM administration site. Significantly, the IM injection sites showed no changes during the study. The concentrations of ELQ-331 were below the lower limit of quantitation (LLOQ, 1.00 ng / ml) in all plasma samples, indicating that ELQ-331 was efficiently and completely converted to ELQ-300 in vivo. The plasma concentrations of ELQ-300 (Fig. 7) were above the LLOQ throughout the study. The PK parameters (mean values) are shown in Table 8. Individual values are in the supplementary section (Table 9).Table 7. Individual clinical observations from PK parameters for ELQ-300 in Sprague Dawley rats administered ELQ-331 by IM injection.Table 8. Pharmacokinetic parameters for ELQ-300 in Sprague Daw-ley rats administered ELQ-331 by IM administration (mean ± S.D., n=3).Table 9. PK parameters for ELQ-300 in Sprague Dawley rats administered ELQ-331 by IM injection.#More than 20% of AUCiast values were extrapolated, which impacts the accuracy of these values.

[0167] The Tmax for ELQ-300 was from 8 to 48 hours. The mean peak plasma concentration of ELQ-300 (Cmax) was 268 ± 106 ng / ml (formulation F), and 216 ± 49 ng / ml (formulation H). The mean AUCiast values were 88,800 ± 11,700 h*ng / ml and 88,700 ± 10,400 h»ng / ml for formulations F and H, respectively. The AUCinf was also calculated for each group, but as much as 26% to 85% of each value was extrapolated, which impacts the accuracy of the calculation. The terminal ti / 2 values were 509 ± 262 h (formulation F) and 394 ± 39.5 h (formulation H). The MRTiast values were 262 ± 24. 1 h (formulation F) and 272 ± 13.3 h (formulation H). MRTinf were 718 ± 383 h (formulation F) and 575 ± 48.9 h (formulation H). There was no significant difference (p>0.05), using the AUCiast values, between the two tested formulations.

[0168] The MEP too of ELQ-300 is 80 nM. Plasma concentrations were well above this concentration for the duration of the study.

[0169] LAI-C, formulated as solutions, may require the addition of a lead-in phase dosage regimen to rule out the possibility of adverse reactions since the injections cannot be retrievedonce injected. The present injection formulation complements dosing strategies such as formulations of solid drug dispersions and SEDDS of ELQ-331 as reported previously (Potharaju, S. et al., 2020, Pharm. Dev. Technol., 25, 625).Plasma Drug Levels

[0170] Fig. 8 shows the plasma profiles of ELQ-330 for Formulation H. Plasma samples were collected out to either 85 or 112 days and concentrations of the base drug ELQ-300 and the prodrug ELQ-331 were determined. ELQ-331 concentrations were below the lower limit of quantitation (LLOQ = 1 ng / ml) in all samples collected on Day 1-112. Plasma concentrations of ELQ-300 were quantifiable in all three animals through Day 85 (2016 hr). By Day 112 (2664 hr), plasma concentrations of ELQ-300 were below the LLOQ in all three animals. Plasma concentrations of ELQ-300 were equal to or higher than the MEP100 (33.25 ng / ml) to 1320 hr after dose administration of ELQ-331 in Formula H. Plasma concentrations of ELQ-300 were quantifiable in all three rats through Day 85 (2016 hr). By Day 112 (2664 hr), plasma concentrations of ELQ-300 were below the LLOQ in all three animals.Pharmacokinetics Analysis

[0171] The results of the pharmacokinetics analysis are presented in Fig. 9. In animals, administered ELQ-331 in Formulation H, Cmax for ELQ-300 was 684 ± 255 ng / ml observed at 48 hr (Tmax). The mean AUCinf for Formulation H was 243,000 ± 60,100 hr*ng / ml.Conclusion

[0172] Thus, the present invention provides oil-based long-acting formulations of ELQ- 331, a new antimalarial drug. The formulations have acceptable viscosity and injectability properties, demonstrated increased drug solubility, and displayed sustained release. The formulations appear to be stable and suitable for IM administration. The simple manufacturing method can be scaled up easily. Based on a PK study in rats, these formulations show promise as delay ed-release IM injections to be used as a prophylactic against malaria. The studies also indicate the potential use of oil-based solution formulations as long-acting injectables for other drugs with properties like ELQ-331.

[0173] The disclosures of each and every' patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety. While this invention has been disclosed w ith reference to specific embodiments, it is apparent that other embodiments and variations of this invention may be devised by others skilled in the art without departing from the true spirit and scope of the invention. The appended claims are intended to be construed to include all such embodiments and equivalent variations.

Claims

CLAIMSWhat is claimed is:

1. A composition comprising a prodrug of ELQ-300 and an oil.

2. The composition of claim 1, wherein the composition further comprises benzy l benzoate.

3. The composition of claim 2, wherein the concentration of benzyl benzoate is less than 40% (v / v).

4. The composition of claim 1 , wherein the composition further comprises benzy l alcohol.

5. The composition of claim 1, wherein the prodrug of ELQ-300 is ELQ-331.

6. The composition of claim 1, wherein the oil is selected from sesame oil, cottonseed oil, or any combination thereof.

7. The composition of claim 1, wherein the solubility7of the prodrug of ELQ-300 in the composition is at least 5 mg / mL.

8. The composition of claim 1, wherein the composition releases the prodrug of ELQ-300 for at least two months after administration to a subject.

9. The composition of claim 4, wherein the benzyl alcohol is a preservative.

10. The composition of claim 4, wherein the concentration of benzy l alcohol is at least 10% (v / v).

11. The composition of claim 1, wherein the concentration of the oil is at least 50% (v / v).

12. The composition of claim 1, wherein the concentration of the oil is between 40% (v / v) to 70% (v / v).

13. The composition of claim 2, wherein the concentration of benzyl benzoate is between 30% (v / v) and 50% (v / v).

14. The composition of claim 4, wherein the concentration of benzy l alcohol between 0% (v / v) and 20% (v / v).

15. The composition of claim 1, wherein: the oil is sesame oil; the concentration of sesame oil is about 60% (v / v); and the composition further comprises about 40% (v / v) benzyd benzoate.

16. The composition of claim 1, wherein:the oil is sesame oil; the concentration of sesame oil is about 50% (v / v); and the composition further comprises about 40% (v / v) benzyl benzoate and about 10% (v / v) benzyl alcohol.

17. The composition of claim 1, wherein: the oil is cottonseed oil; the concentration of cottonseed oil is about 60% (v / v); and the composition further comprises about 40% (v / v) benzyl benzoate.

18. The composition of claim 1, wherein: the oil is cottonseed oil; the concentration of cottonseed oil is about 50% (v / v); and the composition further comprises about 40% (v / v) benzyl benzoate and about 10% (v / v) benzy l alcohol.

19. The composition of claim 1, wherein: the prodrug of ELQ-300 is ELQ-331; the concentration of ELQ-331 is about 3 mg / mL; the oil is sesame oil; the concentration of sesame oil is about 60% (v / v); and the composition further comprises about 40% (v / v) benzyl benzoate.

20. The composition of claim 1, wherein: the prodrug of ELQ-300 is ELQ-331 ; the concentration of ELQ-331 is about 3 mg / mL; the oil is sesame oil; the concentration of sesame oil is about 50% (v / v); and the composition further comprises about 40% (v / v) benzyl benzoate and about 10% (v / v) benzyd alcohol.

21. The composition of claim 1, wherein: the prodrug of ELQ-300 is ELQ-331; the concentration of ELQ-331 is about 3 mg / mL; the oil is cottonseed oil; the concentration of cottonseed oil is about 60% (v / v); and the composition further comprises about 40% (v / v) benzyl benzoate.

22. The composition of claim 1, wherein: the prodrug of ELQ-300 is ELQ-331;the concentration of ELQ-331 is about 3 mg / mL; the oil is cottonseed oil; the concentration of cottonseed oil is about 50% (v / v); and the composition further comprises about 40% (v / v) benzyl benzoate and about 10% (v / v) benzy l alcohol.

23. The composition of any one of claims 1-22, wherein the composition is injectable by syringe.

24. The composition of claim 23, wherein the composition has a viscosity of less than 17 cP at about 37 °C.

25. The composition of claim 23, wherein the composition has an osmolality between 200 mOsmol / L and 300 mOsmol / L.

26. A method of preventing or treating Plasmodium infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the composition of any of claims 1-25.

27. The method of claim 26, wherein the therapeutically effective amount is about 12 mg / kg.

28. The method of claim 26, wherein the method maintains a plasma concentration of at least 33 ng / mL in the subject.

29. The method of claim 26, wherein the method maintains an effective protective antimalarial plasma concentration in the subject for at least 4 weeks.

30. The method of claim 26, wherein the method maintains an effective protective antimalarial concentration in the subject for at least 56 days.

31. The method of claim 26, wherein the composition maintains an effective protective antimalarial in the subject for at least 85 days.

32. The method of claim 26, wherein the composition is administered using subcutaneous or intramuscular injection.

33. The method of claim 26, wherein the composition is administered prophylactically or prior to Plasmodium infection.

34. The method of claim 26, wherein the composition is administered before the blood stage of the Plasmodium life cycle.

35. The method of claim 26, wherein the composition is administered prior to peak malaria season.

36. The method of claim 26, wherein the composition is administered to the subject once annually.

37. The method of claim 26, wherein the subject is protected from malaria for one year after administration.

38. A kit comprising a pre-filled syringe or cartridge loaded with the composition of any of claims 1-25.

39. The kit of claim 38, further comprising an auto-injector.

40. The kit of claim 38, further comprising an instructional material.

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