Compositions and Their Uses in Food Intake Modulation

Related Applications

[0001] This application claims priority of U.S. Provisional Patent Application No. 63/336,587, filed April 29, 2022, the entire content of which is hereby incorporated by reference.

Field

[0002] Described herein are compositions having food intake (e.g., consumption) modulatory activity, and uses thereof.

Background

[0003] Previous methods of modulating caloric intake include intraperitoneal injection of a drug to reduce body weight (Int. J. Obes. 2013 May;37(5):685-92), feed additives (EP2368440B1), physically sealing the nasal cavity, for example, with a cream or powder (US2005/037031A1), nasal device prophylactics applied by the subject (US2008/0092896A1), or applying a sprayable liquid onto or within a food substance (US2011/0189335A1). What is needed are non-invasive methods of modulating caloric intake in order to address a number of existing needs, including weight control (whether weight gain or weight loss) to aid in the continuing health and survival of an organism. Without being bound by theory, non-invasive methods may be more readily adopted due, in part, to ease of use, thereby leading to commercial success and compliance continued by subjects in need of such caloric intake modulation as compared to invasive methods, including those described above.

Summary

[0004] Described herein are compositions comprising one or more of indole, cis- 3-hexenol, trans-2-hexenal, or octanoic acid, or a salt thereof.

[0005] Also described herein are methods of using such compositions.

Brief Description of the Drawings

[0006] Fig. 1 shows elicitation of increases or decreases on food consumption upon odorant exposure.

[0007] Fig. 2 shows that octanoic acid (OCA) and indole (IND) elicit significant changes in food intake across a broad concentration range.

Detailed Description

[0008] As described in Example 1, below, compositions described herein have food (caloric) intake modulating activity. Definitions

[0009] Certain terms, whether used alone or as part of a phrase or another term, are defined below.

[0010] The articles "a" and "an" refer to one or to more than one of the grammatical object of the article.

[0011] Numerical values relating to measurements are subject to measurement errors that place limits on their accuracy. For this reason, all numerical values provided herein, unless otherwise indicated, are to be understood as being modified by the term "about." Accordingly, the last decimal place of a numerical value provided herein indicates its degree of accuracy. Where no other error margins are given, the maximum margin is ascertained by applying the rounding-off convention to the last decimal place or last significant digit when a decimal is not present in the given numerical value.

[0012] The term "amelioration" means a lessening of severity of at least one indicator of a condition or disease, such as a delay or slowing in the progression of one or more indicators of a condition or disease. The severity of indicators may be determined by subjective or objective measures which are known to those skilled in the art.

[0013] The terms "composition" and "pharmaceutical composition" refer to a mixture of at least one compound described herein with a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a patient or subject. Multiple techniques of administering a compound exist including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

[0014] The terms "effective amount" and "therapeutically effective amount" refer to an amount of active ingredient, such as a compound described herein, administered to a subject, either as a single dose or as part of a series of doses, which produces a desired effect. In general, the effective amount can be estimated initially either in cell culture assays or in mammalian animal models, for example, in non-human primates, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in non-human subjects and human subjects.

[0015] The term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition or carrier, such as a liquid filler, solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent, or encapsulating material, involved in carrying or transporting at least one compound described herein within or to the patient such that the compound may perform its intended function. A given carrier must be "acceptable" in the sense of being compatible with the other ingredients of a particular formulation, including the compounds described herein, and not injurious to the patient. Other ingredients that may be included in the pharmaceutical compositions described herein are known in the art and described, for example, in "Remington's Pharmaceutical Sciences" (Genaro (Ed.), Mack Publishing Co., 1985), the entire content of which is incorporated herein by reference.

[0016] The term "pharmaceutically acceptable salt" refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Pharmaceutically acceptable salts can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two solvents. Lists of suitable salts are found in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (P. Henrich Stahl & Camille G. Wermuth (Eds.), VHCA & Wiley-VCH, 2002), the entire content of which is incorporated herein by reference.

[0017] The term "refractory disease" refers to a disease that continues to progress during treatment with a pharmaceutical ingredient other than the compounds provided herein, partially responds to the other treatment, or transiently responds to the other treatment. The term may be applied to each of the diseases referred to herein.

[0018] The terms "treatment" or "treating" refer to the application of one or more specific procedures used for the amelioration of a disease. A "prophylactic" treatment, refers to reducing the rate of progression of the disease or condition being treated, delaying the onset of that disease or condition, or reducing the severity of its onset.

[0019] Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein is intended merely to better illuminate the described subject matter and does not pose a limitation on the scope of the subject matter otherwise claimed. No language in the specification should be construed as indicating any nonclaimed element essential to practicing the described subject matter.

[0020] Groupings of alternative elements or embodiments of this disclosure are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. Furthermore, a recited member of a group may be included in, or excluded from, another recited group for reasons of convenience or patentability.

[0021] Reference made to a patent document or other publication in this specification serves as an incorporation herein by reference of the entire content of such document or publication.

[0022] Embodiments of this disclosure are illustrative. Accordingly, the present disclosure is not limited to that precisely as shown and described.

Compositions

[0023] It has been found that the amount of food consumed by an organism can be modulated (i.e., increase or decrease) through environmental exposure to specific odorants. In some embodiments, this is useful in the pet and farmed animal farm industry. In some embodiments, this is useful in addressing eating disorders or modulating food or caloric intake in animals, including livestock, pets, and humans. In some embodiments, decreasing the desire to eat by stimulating odorant sensation may be useful as a pest (including, without limitation, arthropods, such as insects and arachnids, or mammals, such as rodents) deterrent. Odorants that lead to decreases in food consumption could also be used for weight management purposes, and odorants eliciting increases in food intake would not only increase production yield (though increases in weight gain), but also has the potential of increasing the survival rate of animals (including, without limitations, livestock, including, without limitation, ruminants or others, such as ovine, bovine, porcine, caprine, equine, cervine, canine, feline, murine, poultry, or camel) during weaning.

[0024] Thus, in some embodiments, the compositions provided herein can be translated to the pet or agropecuary industry to increase or decrease food palatability and food intake in a non-invasive way, e.g., merely by stimulation of olfactory sensation. [0025] Thus, in some embodiments, described herein are compositions, comprising one or more odorant components selected from: indole - IND; ethyl butyrate

- EBT; trimethylamine - TMA; vanillin - VAN; heptylamine - HEP; hexanol - HXO; hexanethiol - HXT; linalool - LIN; isoamylamine - IAA; ambrettolide - AMB; cis-3-hexenol

- C3H; 2-methylbutylamine - 2MB; 2-ethyl-3,5 (or 6) dimethylpyrazine - EDM; (+)- menthone - +MNT; trans-2-hexenal - T2H; octanoic acid - OCA. As shown in Fig. 1, these odorants modulate food intake (increase or decrease). In some embodiments, the one or more odorant components is selected from indole, cis-3-hexenol, trans-2- hexenal, or octanoic acid, or a salt thereof. Each component, independently, may be at a concentration of about 8.5 pM to about 85 mM (e.g., about 8.5 pM, about 85 pM, about 850 pM, about 8.5 mM, or about 85 mM, or any range therebetween). In some embodiments, the compositions comprise at least two different components selected from indole, cis-3-hexenol, trans-2-hexenal, or octanoic acid. The compositions may be pharmaceutical compositions, and may include one or more pharmaceutically acceptable carriers. In some embodiments the salt is a pharmaceutically acceptable salt.

[0026] In some embodiments, when formulated for administration (for example, inhalation, ingestion, or topical) to a subject in need thereof, the amount of odorant component(s) is a non-toxic amount for the subject. In some embodiments, administration to the subject may include administering by diffusing a non-toxic amount of the odorant component(s) into the atmosphere that the subject is respiring. Thus, in some embodiments, the compositions herein may be provided as a mixture of the odorant compound(s) in substantially purified form, optionally blended with ethanol or an aqueous ethanolic solution, which may be used as a liquid drop dosage in a standard atmospheric diffuser device or nebulizer. In other embodiments, the compositions herein may be formulated as a cream for topical application to the subject such that the odorant compound is nasally inhaled by the subject, thereby effecting the intended caloric intake modulation activity.

[0027] Articles of manufacture are described, which comprise the compositions provided herein. The articles of manufacture may include forms of the compounds or compositions suitable for administration or storage. In some embodiments, the article of manufacture may take the form of, and also may be administered as, an ingestible, an inhalable (for example, nasally inhalable or orally inhalable, or both), or a topically depositable article. In some embodiments, the form may be an orally ingestible article. In some embodiments, the form may be an orally or nasally inhalable article. In some embodiments, the form is a liquid form, which may be an aerosol or may evaporate to a gas that is inhaled (for example, nasally inhaled) by a subject in need thereof.

[0028] The present compounds and associated materials can be finished as a commercial product by the usual steps performed in the present field, for example by appropriate sterilization and packaging steps. For example, the material can be treated by UV/vis irradiation (200-500 nm), for example using photo-initiators with different absorption wavelengths (e.g., Irgacure 184, 2959), preferably water-soluble initiators (e.g., Irgacure 2959). Such irradiation is usually performed for an irradiation time of 1- 60 min, but longer irradiation times may be applied, depending on the specific method. The material according to the present disclosure can be finally sterile-wrapped so as to retain sterility until use and packaged (e.g., by the addition of specific product information leaflets) into suitable containers (boxes, etc.).

[0029] According to further embodiments, the present compounds can also be provided in kit form combined with other components necessary for administration of the material to the subject. For example, disclosed kits, such as for use in the treatment of eating disorders, can further comprise, for example, administration materials. [0030] The kits are designed in various forms based on the specific deficiencies they are designed to treat.

[0031] The compositions provided herein may be prepared and placed in a container for storage at ambient or elevated temperature. When the composition is stored in a polyolefin plastic container as compared to a polyvinyl chloride plastic container, discoloration of the compound or composition may be reduced, whether dissolved or suspended in a liquid composition (e.g., an aqueous or organic liquid solution), or as a solid. Without wishing to be bound by theory, the container may reduce exposure of the container's contents to electromagnetic radiation, whether visible light (e.g., having a wavelength of about 380-780 nm) or ultraviolet (UV) light (e.g., having a wavelength of about 190-320 nm (UV B light) or about 320-380 nm (UV A light)). Some containers also include the capacity to reduce exposure of the container's contents to infrared light, or a second component with such a capacity. The containers that may be used include those made from a polyolefin such as polyethylene, polypropylene, polyethylene terephthalate, polycarbonate, polymethylpentene, polybutene, or a combination thereof, especially polyethylene, polypropylene, or a combination thereof. In some embodiments, the container is a glass container. The container may further be disposed within a second container, for example, a paper, cardboard, paperboard, metallic film, or foil, or a combination thereof, container to further reduce exposure of the container's contents to UV, visible, or infrared light. Compositions benefiting from reduced discoloration, decomposition, or both during storage, include solutions or suspensions that include a composition provided herein, which may be useful in, for example, a device that diffuses the composition into the atmosphere around the subject. In some embodiments the device provides an aerosol of the composition. The compositions provided herein may need storage lasting up to, or longer than, three months; in some cases up to, or longer than one year. The containers may be in any form suitable to contain the contents; for example, a bag, a bottle, a box, a pressurized container, or a combination thereof.

[0032] In some embodiments, provided herein are packaged compositions, or packaged pharmaceutical compositions, e.g., kits, comprising a container housing an effective amount of a composition described herein, and instructions for using the composition in accordance with one or more of the methods provided herein.

Composition Preparation

[0033] The compositions described herein include compounds that are commercially available. Compositions described herein may be prepared by, for example, adding an aliquot or amount of the desired components and mixing components together to arrive at the desired composition. Methods

[0034] In some embodiments, provided herein are methods of modulating food intake (e.g., consumption or caloric intake) in a subject in need thereof, comprising administering to the subject an effective amount of a composition or article of manufacture described herein. In some embodiments, provided herein are methods of treating an eating disorder or eating-related disease in a subject in need thereof, comprising administering to the subject an effective amount of a composition or article of manufacture described herein. In some embodiments, the eating disorder or eating- related disease is refractory. In some embodiments, the composition comprises one or more of indole, cis-3-hexenol, trans-2-hexenal, or octanoic acid. In some embodiments, the composition comprises at least two of indole, cis-3-hexenol, trans-2-hexenal, or octanoic acid.

[0035] In some embodiments, provided herein are methods of modulating caloric intake in a subject in need thereof, comprising administering an effective amount of a composition or article of manufacture provided herein, wherein the composition or article of manufacture modulates olfaction in the subject to bring about the caloric intake modulation.

[0036] A composition described herein can be administered in combination with one or more additional active ingredients. The composition can be administered concurrently with, prior to, or subsequent to one or more additional active ingredients, which may be useful as, e.g., combination therapies. In some embodiments, the combination therapy is a composition provided herein further comprising one or more additional active ingredients.

[0037] While the methods as described refer to the compositions described herein, the compositions may be used in conjunction with these methods in the form of a pharmaceutical composition or an article of manufacture as well.

[0038] In some embodiments of these methods, the amount of a compound administered, of the compositions provided herein, is such that the compound's concentration at the target site (e.g., odor receptors in the subject's nasal cavity or taste buds on the subject's tongue) is at least about the corresponding Kd or IC50 for such target site. Actual dosage levels of the active ingredients (e.g., the compounds of the compositions described herein), the compositions, or the pharmaceutical compositions provided herein may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired response (e.g., therapeutic response) for a particular subject, composition, and mode of administration, without being toxic to the subject. In particular, the selected dosage level will depend upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health, and prior medical history of the subject being treated, and like factors well-known in the medical arts. A medical doctor, e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0039] Routes of administration for the compounds include, without limitation, oral, nasal, sublingual, or topical. In some embodiments, the oral or nasal route of administration is an oral inhalational or nasal inhalational route of administration. The compositions for use as described herein may be formulated for administration by any suitable route to achieve the particular method being applied.

[0040] The following examples further illustrate aspects of the present disclosure. However, they are in no way a limitation of the teachings or disclosure as described herein.

Examples

Example 1. Odor-Induced Food Intake Assay

[0041] Commercially available wild-type C57BL6/J male mice are used to quantify the amount of food consumed in the presence of different odorants. Briefly, after an adaptation period to the animal housing facility, and 2 hours prior to testing the food consumption the food is removed to bring all animals to a similar state of hunger. The amount of food consumed is tested in 2 consecutive weeks, testing their baseline in the first week and how odorant exposure affects each animal's respective food intake.

[0042] These 'odor-induced food-intake assays' are used to test 16 odorants of different chemical structures and perceived odors at a concentration of 85,000 pM (85 mM) (Fig. 1). Odorants C3H, T2H and OCA elicit a significant increase in food intake, and odorant IND significantly decreases the amount of food consumed in its presence.

[0043] Additional assays are performed to test whether concentration impacts odor-induced food-intake. These assays are performed on two additional descending concentrations (850 pM and 8.5 pM) for 4 odorants (IND, C3H, T2H and OCA) that have a significant effect on food intake at 85,000 pM, and 4 additional odorants (TMA, HEP, IAA and VAN) that do not elicit significant changes. It is found that at the lower concentrations, only OCA and IND odorants elicit a significant increase or decrease in food intake, respectively, and only at 850 pM.

[0044] Detailed method for acute odor-induced food intake assays.

[0045] Step 1 : Order 7-week-old male C57BI6/J mice from Jackson Laboratories. [0046] Step 2: Separate them upon arrival and house them individually for 5-7 days in the host facility for acclimatization.

[0047] Step 3: On the day of testing, remove the food for the last 2 hours of the light cycle (5-7PM), but leave the water in.

[0048] Step 4: At the onset of the dark cycle, bring the mice, in their home cages, to the test room [lit with red lights] and let them habituate to the test room for 15 minutes.

[0049] Step 5: Weigh each mouse and transfer them into new cages (individually housed), along with the water, but without any bedding. Let the mice habituate to the new test cage for 15-30 min.

[0050] Step 6: After the habituation period, do the following [simultaneously]: On the cage wall, hang a tea ball containing a cotton ball, scented with 50 pL of water (this serves a the control/baseline exposure); in the middle of the cage floor, place a small petri dish containing 2-3 food pellets [between 2-3 grams total weight]. Prepare the petri dishes containing the weighed food pellets, while the mice are fasting.

[0051] Step 7: Let the assay run for 60 minutes.

[0052] Step 8: 60 minutes after the tea ball + food is placed in the test cage, place the mice back in their home cages.

[0053] Step 9: Proceed to the quantification of the amount of food consumed at 'baseline': collect the petri dish containing the remainder of the pellets, along with any chewed off food crumbs dispersed in the cage floor, and weigh it. Subtract this from the original food weight to quantify how much was consumed. The same scale is used for all of the experiments.

[0054] Step 10: Put the animals in their home cages and individually house for a week.

[0055] Step 11: Repeat steps 4-9, but this time for step 6 hang a tea ball containing a cotton ball, scented with 50 pL of the test odor (dissolved in H2O at 85 mM). For odors that do not dissolve well in H2O, prepare a IM solution in DMSO, and further dilute from that stock in H2O (always shake the Eppendorf vigorously before pipetting the odorant solution into the cotton ball).

[0056] Step 12: Calculate the difference (A) of food consumption (in grams) at 'baseline' and the odor testing day.

[0057] Fig. 1— Odorant exposure can elicit increases or decreases on food consumption.

[0058] The 'food intake assay' is used to assess the ability of 16 different odorants to elicit changes (A) in food consumption (g; grams). Results are presented as Tukey plots, where the horizontal bar represents the median (N=8-24 mice per odor tested). Cyan or red colored bars indicate responses significantly higher or lower from a 'no odor' control (water, H2O), respectively (Mann Whitney test; two-tailed, P < 0.05). [0059] Odorant abbreviations are as follows: indole - IND; ethyl butyrate - EBT; trimethylamine - TMA; vanillin - VAN; water - H2O; heptylamine - HEP; hexanol - HXO; hexanethiol - HXT; linalool - LIN; isoamylamine - IAA; ambrettolide - AMB; cis-3-hexenol

- C3H; 2-methylbutylamine - 2MB; 2-ethyl-3,5 (or 6) dimethylpyrazine - EDM; (+)- menthone - +MNT; trans-2-hexenal - T2H; octanoic acid - OCA.

[0060] Fig. 2— Octanoic acid (OCA) and indole (IND) elicit significant changes in food intake across a broad concentration range (850-85,000 pM).

[0061] The 'food intake assay' is used to assess the ability of 8 different odorants to elicit changes (A) in food consumption (g; grams) across 3 different concentrations. Results are presented as Tukey plots, where the horizontal bar represents the median (N=8-24 mice per odor tested). Cyan or red colored bars indicate responses significantly higher or lower from a 'no odor' control (water, H20), respectively (Mann Whitney test; two-tailed, P < 0.05).

[0062] Odorant abbreviations are as follows: octanoic acid - OCA; (+)-menthone

- +MNT; trans-2-hexenal - T2H; trimethylamine - TMA; heptylamine - HEP; isoamylamine - IAA; vanillin - VAN; indole - IND; water - H2O.