Compositions and methods for treating obesity

Abstract

Compositions and methods for treating or preventing obesity are provided. The compositions use compounds which act as vitamin D receptor agonists / activators (VDRA), preferably Vit D or calcitriol analogs or derivatives. The disclosed compositions can administered to a subject in need thereof, to treat on or more symptoms of obesity. The compounds can be used to promote a healthy body composition and to avoid the risks associated with overweight and / or obesity, such as cardiovascular disease cancers, urinary incontinence, diabetes and the like. The disclosed compositions can also be used prophylactically to treat animals that are overweight with a risk of becoming obese or animals that are at risk of becoming overweight and are on a high fat diet.

Description

[0001]Attorney Docket #: YU 8869 PCT COMPOSITIONS AND METHODS FOR TREATING OBESITY CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Application No.63 / 606,866 filed December 6, 2023, which is hereby incorporated by reference in its entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with Government Support under 1R21DK094701 awarded by the National Institutes of Health. The Government has certain rights in the invention. FIELD OF THE INVENTION This invention is in the field of compounds to regulate obesity, and methods of using thereof. BACKGROUND OF THE INVENTION Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and / or increased health problems. Body mass index (BMI), a measurement which compares weight and height, defines people as overweight (pre-obese or overweight) if their BMI is between 25 and 30 kg / m2, and obese when it is greater than 30 kg / m2. Obesity is a leading preventable cause of death worldwide, with increasing prevalence in adults and children, and authorities view it as one of the most serious public health problems of the 21st century. Obesity increases the risk of many physical and mental disorders. Excessive body weight is associated with various diseases, particularly cardiovascular diseases, diabetes mellitus type 2, obstructive sleep apnea, certain types of cancer, and osteoarthritis. These diseases are either directly caused by obesity or indirectly related through mechanisms sharing a common cause such as a poor diet and / or a sedentary lifestyle. One of the strongest links is with type 2 diabetes. Excess body fat underlies 64% of cases of diabetes in men and 77% of cases in women. Increases in body fat alter the body's response to insulin, potentially leading to insulin resistance. Obesity is most commonly caused by a combination of excessive energy intake, lack 1 078245 / 00730 45698823.1 Attorney Docket #: YU 8869 PCT of physical activity, and genetic susceptibility, although a few cases are caused primarily by genes, endocrine disorders, medications or psychiatric illness. The inability to regulate consumption despite adverse health consequences, shares similarities with drug addiction and involves similar neural pathways. There remains a need for compositions and methods that effectively treat obesity, including preventing weight gain in subjects. It is an object of the present invention to provide compositions for treating obesity. It is also an object of the present invention o provide methos for treating obesity in subjects in need thereof. SUMMARY OF THE INVENTION Compositions and methods for treating or preventing obesity are provided. The compositions use compounds which act as vitamin D receptor agonists / activators (VDRA), preferably Vit D, calcitriol / calcitriol analogs or derivatives. Useful VDRA include, but are not limited to calcitriol, ercalcitriol, calciferol (ergocalciferol), calcidiol, calcipotriol, doxercalciferol, alfacalcidol, tacalcitol, paricalcitol, oxacalcitriol, falecalcitriol, eldecalcitol and secalciferol. In some forms, the VDRA is calcitriol or an analog / derivative thereof. The disclosed compounds can administered to a subject in need thereof for an effective amount of time, to treat on or more symptoms of obesity. The disclosed compounds can also be used prophylactically to treat animals that are overweight with a risk of becoming obese or animals that are at risk of becoming overweight, by administering effective amounts of VDRA to the subject to prevent weight gain resulting from food consumption. Thus, the compounds can be used prophylactically to promote a healthy body composition and to avoid the risks associated with overweight and / or obesity, such as cardiovascular disease cancers, urinary incontinence, diabetes and the like. In some forms, the formulation is administered intranasally. The formulation is administered for an effective amount of time to treat obesity, for example, for at least 5 days, at least 10 days, and up to one month, daily. In some forms, the forms, administration incudes a two dosage regimen, wherein the 2 078245 / 00730 45698823.1 Attorney Docket #: YU 8869 PCT first dosage regimen is a treatment regimen and the second dosage regimen is a maintenance regimen and the effective dose administered during the treatment regimen is at least twice the effective dose required for maintenance (of body weight). In some forms, the disclosed compositions include effective amounts of a vitamin D receptor agonists to increase dopamine release in dopaminergic neurons when administered to a subject in need thereof. In some forms, the disclosed compositions include effective amounts of a vitamin D receptor agonists to increase upregulate TH (tyrosine hydroxylase) and / or Slc6a3 (solute carrier family 6 member 3) gene expression or Drd2 (dopamine receptor D2) mRNA in nucleus accumbens. BRIEF DESCRIPTION OF THE DRAWINGS FIG.1A and 1B show the effect of calcitriol treatment compared to vehicle on animal body weight. Male C57BL / 6J were maintained for one year on a high fat diet prior to any manipulation. Daily oral calcitriol (1 µg / kg, n=5) significantly reduced body weight over time compared to vehicle treated mice (n=4). This significance was maintained after reducing the dose to 0.5 µg / kg beginning at day 32. Two-way repeated measures ANOVA revealed significant main effects of treatment F(1, 7)= 23.80 p=0.0018; time F(52, 364)= 9.279 p<0.0001; and a significant interaction of treatment x time F(52, 364)=18.75 p<0.0001. Bonferroni’s multiple comparison’s test showed initial significance *p<0.05 for days 14 and 15, and then increasing from **p=0.01 to ****p<0.0001 from day 16 to 23, and remaining at ****p<0.0001 through day 52. All error bars are S.E.M. FIG.1C shows the effect of calcitriol treatment on the body weight of chronically obese mice. FIG.1D shows in vivo mouse body weight data with semaglutide (reproduced from Gabery, JCI 2020). FIG.2 is a bar graph showing serum Ca+2levels at Day 53 in calcitriol treated vs. vehicle treated animals. On day 54, mice were sacrificed and serum was isolated from collected trunk blood. Calcium levels were assessed and revealed a non-significant difference between groups (two tailed unpaired t-test, t=2.148 p=0.0688. All error bars are S.E.M. FIG.3 is a line graph showing the effects of calcitriol in preventing weight gain in 3 078245 / 00730 45698823.1 Attorney Docket #: YU 8869 PCT mice fed a high fat diet. HF Diet switched from 35% to 45% kcal from fat on Day 32. Day 44 - last day of Calcitriol. All mice continued to receive Veh (M.C.T. oil, 2% EtOH, 0.1% saccharin) Day 60 - remove Veh. * P<0.05 (treatment*time) 2-way ANOVA; Bonferroni's posthoc (beginning Day 13). Adult male C57BL / 6J were maintained on standard chow prior to the start of the experiment. Treatment with either with oral calcitriol (1 µg / kg n=8) or vehicle (n=8) started concurrently with 35% HF diet exposure on day 0. Treatments were performed daily. Calcitriol caused an initial reduction in body weight which became significant by day 15, and then stabilized and gradually increased to day 32. On day 32, a 45% HF diet replaced the 35% diet, and treatments continued through day 44. On day 45 the calcitriol group began receiving vehicle instead, during which body weight rebounded to day 51, after which the rate of weight gain matched the original vehicle group. On day 60, treatments for all mice were discontinued, and body weight was monitored until day 66. Two-way repeated measures ANOVA revealed significant main effects of treatment F(1, 14)= 21.65 p=0.0004; time F(66, 924)= 83.82 p<0.0001; and a significant interaction of treatment x time F(66, 924)=15.59 p<0.0001. Bonferroni’s multiple comparison’s test showed initial significance *p<0.05 on day 15, and then increasing to ****p<0.0001 by day 36 and holding to day 61. Body weights through the remaining days stayed significant. All error bars are S.E.M. DETAILED DESCRIPTION OF THE INVENTION The disclosed compositions and methods are based at least on studies demonstrating the effective reduction of body weight in obese subjects and the prevention of weight gain by administration of a vitamin D receptor agonist, exemplified herein using calcitriol. I. DEFINITIONS “Aerosol” as used herein refers to any preparation of a fine mist of particles, which can be in solution or a suspension, whether or not it is produced using a propellant. “Analog” and “Derivative”, are used herein interchangeably, and refer to a compound that possesses the same pentacyclic core as a parent compound, but differs from the parent compound in bond order, in the absence or presence of one or more atoms and / or groups of atoms, and combinations thereof. The derivative can differ from the parent compound, for 4 078245 / 00730 45698823.1 Attorney Docket #: YU 8869 PCT example, in one or more substituents present on the pentacyclic core, which may include one or more atoms, functional groups, or substructures. The derivative can also differ from the parent compound in the bond order between atoms within the pentacyclic core. In general, a derivative can be imagined to be formed, at least theoretically, from the parent compound via chemical and / or physical processes.. “Amphiphilic” as used herein refers to a molecule combining hydrophilic and lipophilic (hydrophobic) properties. A “continuous phase” refers to the liquid in which solids are suspended or droplets of another liquid are dispersed, and is sometimes called the external phase. This also refers to the fluid phase of a colloid within which solid or fluid particles are distributed. If the continuous phase is water (or another hydrophilic solvent), water-soluble or hydrophilic drugs will dissolve in the continuous phase (as opposed to being dispersed). In a multiphase formulation (e.g., an emulsion), the discreet phase is suspended or dispersed in the continuous phase. A "cream" is a viscous liquid or semi-solid emulsion of either the “oil-in-water” or “water-in-oil type”. An "emulsion" is a composition containing a mixture of non-miscible components homogenously blended together. “Gel” as used herein is a colloid in which the dispersed phase has combined with the continuous phase to produce a semisolid material, such as jelly. “Hydrophilic” as used herein refers to substances that have strongly polar groups that readily interact with water. “Hydrophobic” as used herein refers to substances that lack an affinity for water; tending to repel and not absorb water as well as not dissolve in or mix with water. “Lipophilic” as used herein refers to compounds having an affinity for lipids. A "lotion" is a low- to medium-viscosity liquid formulation. "Oil" as used herein refers to a composition containing at least 95% wt. of a lipophilic substance. Examples of lipophilic substances include but are not limited to 5 078245 / 00730 45698823.1 Attorney Docket #: YU 8869 PCT naturally occurring and synthetic oils, fats, fatty acids, lecithins, triglycerides and combinations thereof. An “ointment” is a semisolid preparation containing an ointment base and optionally one or more active agents. “Parenteral administration”, as used herein, means administration by any method other than through the digestive tract or non-invasive topical or regional routes. "Patient" or "subject" to be treated as used herein refers to either a human or non- human animal. “Pharmaceutically acceptable” as used herein refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit / risk ratio. “Pharmaceutically acceptable salt”, as used herein, refers to derivatives of the compounds defined herein, wherein the parent compound is modified by making acid or base salts thereof. “Therapeutically effective” or “effective amount” as used herein means that the amount of the composition used is of sufficient quantity to ameliorate one or more causes or symptoms of a disease or disorder. Such amelioration only requires a reduction or alteration, not necessarily elimination. As used herein, the terms “therapeutically effective amount” “therapeutic amount” and “pharmaceutically effective amount” are synonymous. One of skill in the art can readily determine the proper therapeutic amount. As used herein, the term “treating” includes alleviating the symptoms associated with a specific disorder or condition and / or preventing or eliminating the symptoms. A “subject” or “patient” refers to a human, primate, non-human primate, laboratory animal, farm animal, livestock, or a domestic pet. II. COMPOSITIONS Compositions that are useful in the disclosed compositions contain compounds which act as vitamin D receptor agonists. 6 078245 / 00730 45698823.1 Attorney Docket #: YU 8869 PCT In some forms, the compositions include effective amounts of a vitamin D receptor agonists to increase the release of satiety signals (or signaling factors) when administered to a subject in need thereof. The physiological state at the end of a meal when further eating is inhibited by ‘fullness’ is termed satiety. Satiety, or between-meal satiety, ends as meal processing and absorptive signals wane and hunger initiates the next period of eating. The stomach and intestines provide post-ingestive information through the physical signals of stretch / distension as well as osmotic load, providing feedback related to meal quantity (Amin, et al., Hunger and Satiety Mechanisms and Their Potential Exploitation in the Regulation of Food Intake. Curr Obes Rep.2016 Mar;5(1):106-12. doi: 10.1007 / s13679-015-0184-5. PMID: 26762623; PMCID: PMC4796328). Although dozens of enzymes, hormones, and other factors are secreted by the GI tract in response to food in the lumen, only a handful are able to influence food intake directly. Most of these cause meals to terminate and hence are called satiety signals. Satiety signals are so named because when they are administered to animals before a meal, a decrease in the size of that meal is observed. Several other criteria must be met, however, before a hormone, neurotransmitter, or other internal signal is considered a satiety signal. For one, if the signal influences the size of normal meals, it should be the case that blocking or compromising its endogenous activity leads to increased meal size. That is, the administration of an antagonist to the signal or the generation of an animal lacking a receptor for the signal should be associated with consumption of greater than normal amounts of food. Another criterion is that the reduction of food intake caused by administration of the “satiety” signal should not be the consequence of illness or malaise, or of some sort of incapacitation, and the animal (or person) receiving the compound should engage in behaviors that occur when meals end naturally. That is, there are many reasons why the administration of an exogenous compound might cause an animal to eat less food, reasons that have little or nothing to do with normal satiety. Finally, the secretion of an endogenous satiety signal must be elicited by ingested food with a temporal profile consistent with contributing to the normal cessation of eating. These criteria are well accepted. CCK; Bombesin family (bombesin, gastrin releasing peptide or GRP, and neuromedin B); 7 078245 / 00730 45698823.1 Attorney Docket #: YU 8869 PCT Glucagon; Glucagon-like peptide-1; Glucagon-like peptide-2; Apolipoprotein A-IV Amylin; Somatostatin; Enterostatin and Peptide YY-(3–36) are non-limiting examples of satiety signals (Woods, Am J Physiol Gastrointest Liver Physiol, 286: G7–G13, 2004). In some forms, the disclosed compositions include effective amounts of a vitamin D receptor agonists to increase dopamine release in dopaminergic neurons when administered to a subject in need thereof. In some forms, the compositions include effective amounts of a vitamin D receptor agonists to increase / upregulate TH (tyrosine hydroxylase) and / or Slc6a3 (solute carrier family 6 member 3) gene expression or Drd2 (dopamine receptor D2) mRNA in nucleus accumbens. The tyrosine hydroxylase (TH) gene encodes a monoxygenase that catalyzes the rate limiting step in dopamine biosynthesis. Slc6a3 encodes a dopamine transporter which is a member of the sodium- and chloride-dependent neurotransmitter transporter family. Drd2 encodes the D2 subtype of the dopamine receptor. In some forms, the VDRA is further modified for targeted delivery to the brain and / or dopaminergic neurons. A. Vitamin D Receptor Agonists / Activators (VDRA) The vitamin D receptor (VDR also known as the calcitriol receptor) is a member of the nuclear receptor family of transcription factors. Calcitriol (the active form of vitamin D, 1,25-(OH)2vitamin D3) binds to VDR, which then forms a heterodimer with the retinoid-X receptor. The VDR heterodimer then enters the nucleus and binds to Vitamin D responsive elements (VDRE) in genomic DNA. In humans, the vitamin D receptor is encoded by the VDR gene located on chromosome 12q13.11.VDR is expressed in most tissues of the body, and regulates transcription of genes involved in intestinal and renal transport of calcium and other minerals. VDR activators initiate signaling through ligand binding to the ubiquitously-present VDR, followed by activation of downstream endocrine, paracrine, and / or autocrine loops to maintain homeostasis in the kidney, bone, immune, and cardiovascular systems. 8 078245 / 00730 45698823.1 Attorney Docket #: YU 8869 PCT In some forms, the VDRA is represented by the general formula: I. agonist is calcitriol (1,25-dihydroxycholecalciferol) and the 1-alpha,25-dihydroergocalciferol) is also a strong activator. Vitamin D, also known as calciferol, includes a group of fat-soluble seco-sterols. The two major forms are vitamin D2 and vitamin D3. Vitamin D2 (ergocalciferol) is largely human-made and added to foods, whereas vitamin D3 (cholecalciferol) is synthesized in the skin of humans from 7-dehydrocholesterol and is also consumed in the diet via the intake of animal-based foods. Both vitamin D3 and vitamin D2 are synthesized commercially. In some forms, the VDRA is calcitriol. In some forms the VDRA is ercalcitriol. Useful compounds include commercially available vitamin D derivatives such as, Calcidiol, Calcipotriol, Doxercalciferol, Alfacalcidol, Tacalcitol, Paricalcitol, Oxacalcitriol, Falecalcitriol, Eldecalcitol and Secalciferol. Calciferol (ergocalciferol) is vitamin D2, and its structure is shown below. 25-hydroxycholecalciferol, or 25- hydroxyvitamin D3(abbreviated 25(OH)D3) (its structure shown below), is produced in the liver by hydroxylation of vitamin D3 (cholecalciferol) by the enzyme vitamin D 25- 9 078245 / 00730 45698823.1 Attorney Docket #: YU 8869 PCT hydroxylase. hydroxylated by the enzyme 25(OH)D-1α-hydroxylase, primarily in the kidney, to form calcitriol (1,25-(OH)2D3), which is the active hormonal form of vitamin D. Calcipotriol, whose structure is shown below, is a vitamin D derivative synthesized in 1985 by the Léo Laboratories. Its mode of action is identical to that of 1-25 vitamin D3 (calcitriol), essentially by regulating the activity of genes capable of responding to vitamin D. . structure is shown below, is a synthetic vitamin D2 analog that undergoes metabolic activation in vivo to form 1α,25-dihydroxyvitamin D2 (1α,25- (OH)2D2), a naturally occurring, biologically active form of vitamin D2. . 1-hydroxycholecalciferol), whose structure is shown below, is an 10 078245 / 00730 45698823.1 Attorney Docket #: YU 8869 PCT analogue of vitamin D used for supplementation in humans and as a poultry feed additive. The chemical structure for Alfacalcidol is shown below. . Tacalcitol (1,24-dihydroxyvitamin D3) is a synthetic vitamin D3 analog. The chemical structure for Alfacalcidol is shown below. (Zemplar) is a synthetic vitamin D(2) analogue. The chemical structure for Paricalcitol is shown below. (OCT) is a vitamin D3 analog and a vitamin D receptor activator (VDRA). The chemical structure for 22-oxacalcitriol is shown below. 11 078245 / 00730 45698823.1 Attorney Docket #: YU 8869 PCT an of calcitriol. he 26 and 27 positions of vitamin D molecular structure of calcitriol were fluorinated with 3 atoms of fluorine each and the new compound was named falecalcitriol, whose structure is shown below. . was found to be 10 to 100 times more active compared with calcitriol depending on the target organs. Eldecalcitol (ED-71) is an orally active vitamin D3 analogue. The chemical structure for Eldecalcitol is shown below. . -24,25-Dihydroxyvitamin D3) is the major active metabolite of Vitamin D; its chemical structure is shown below. 12 078245 / 00730 45698823.1 Attorney Docket #: YU 8869 PCT or the following additional compounds 3a and 3b with structures in Seonne, et al., J. Med. Chem., 65:13112-13124 (2022) . but are not limited to Asentar, Becocalcidiol, Bonalfa, BPM-31543 (topical calcitriol) (Lacouture, et al., Annals of Oncology, Volume 29, viii606 - viii607 (2018), EB1089 (calcitriol analog- (1R,3S,5Z)-5- [(2E)-2-[(1R,3aS,7aR)-1-[(1R,2E,4E)-6-Ethyl-6-hydroxy-1-methyl-2,4-octadien-1-yl]- octahydro-7α-methyl-4H-inden-4-ylidene]ethylidene]-4-methylene-1,3-cyclohexanediol) (Blutt, et al., Cancer Res (2000) 60 (4): 779–782), CTAP-201, Dovonex, DP001 (2- Methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D3) Pandey, et al., Drugs R D. 2017;17(4):597-605), DP-R206 (ibandronate 150-mg / vitamin D324,000-IU; Jeon, et al., Volume 36, Issue 1, 2014, 48-57), DPS-101 (calcipotriol and niacinamide; Feely, et al., https: / / cdn.mdedge.com / files / s3fs-public / issues / articles / CT095030164.pdf), Edirol, Elocalcitol, Enstilar, Hectorol, Inecalcitol, LP0113, Lunacalcipol, Marduox, MC2-16 (calcipotriene), P-3073, SAR404460, Silkis, Sorilux, Taclonex Ointment, Taclonex Scalp, VS-105 (((1R,3R)-5-((E)-2-((3αS,7αS)-1-((R)-1-((S)-3-hydroxy-2,3-dimethylbutoxy)ethyl)- 7α-methyldihydro-1H-inden-4(2H,5H,6H,7H,7αH)-ylidene)ethylidene)-2- methylenecyclohexane-1,3-diol) and paricalcitol (19-nor-1α,25(OH)2D2) (Wu-Wong, et al., 13 078245 / 00730 45698823.1 Attorney Docket #: YU 8869 PCT Br J Pharmacol.2011, 164(2b):551–560); calciferol-lactone, GS1590 (Vitamin D3 polyunsaturated side-chain analogue; Segersten, et al., J Steroid Biochem Mol Biol. 2004;88(3):289-9), CH-5036249 (J Steroid Biochem Mol Biol, 2010, 121, 204, PMID:20304062, http: / / www.ncbi.nlm.nih.gov / pubmed / 20304062), ecalcidene, 1-alpha hydroxy-vitamin D5, VDR 4-1 (Sci Rep, 16 Aug 2017, PMID: 28814738, https: / / www.ncbi.nlm.nih.gov / pubmed / 28814738), and Wynzora® Cream (cream-based fixed dose combination of calcipotriene and betamethasone dipropionate) B. Formulations The compounds described herein can be formulated for enteral, parenteral, topical, or pulmonary administration. The compounds can be combined with one or more pharmaceutically acceptable carriers and / or excipients that are considered safe and effective and may be administered to an individual without causing undesirable biological side effects or unwanted interactions. The carrier is all components present in the pharmaceutical formulation other than the active ingredient or ingredients. The compounds disclosed herein can also be formulated for use as a disinfectant, for example, in a hospital environment. 1. Parenteral Formulations The compounds described herein can be formulated for parenteral administration. For example, parenteral administration may include administration to a patient intravenously, intradermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intravitreally, intratumorally, intramuscularly, subcutaneously, subconjunctivally, intravesicularly, intrapericardially, intraumbilically, by injection, and by infusion. Parenteral formulations can be prepared as aqueous compositions using techniques known in the art. Typically, such compositions can be prepared as injectable formulations, for example, liquid formulations such as solutions or suspensions; solid forms suitable for using to prepare solutions or suspensions upon the addition of a reconstitution medium prior to injection; emulsions, such as water-in-oil (w / o) emulsions, oil-in-water (o / w) emulsions, and microemulsions thereof, liposomes, or emulsomes. 14 078245 / 00730 45698823.1 Attorney Docket #: YU 8869 PCT Liquid formulations contain one or more weight loss agents dissolved or suspended in a liquid pharmaceutical carrier. Suitable liquid carriers include, but are not limited to distilled water, de-ionized water, pure or ultrapure water, saline, and other physiologically acceptable aqueous solutions containing salts and / or buffers, such as phosphate buffered saline (PBS), Ringer's solution, and isotonic sodium chloride, or any other aqueous solution acceptable for administration to an animal or human. Preferably, liquid formulations are isotonic relative to physiological fluids and of approximately the same pH, ranging e.g., from about pH 4.0 to about pH 7.4, more preferably from about pH 6.0 to pH 7.0. The liquid pharmaceutical carrier can include one or more physiologically compatible buffers, such as a phosphate buffers. One skilled in the art can readily determine a suitable saline content and pH for an aqueous solution for pulmonary administration. Liquid formulations may include one or more suspending agents, such as cellulose derivatives, sodium alginate, polyvinylpyrrolidone, gum tragacanth, or lecithin. Liquid formulations may also include one or more preservatives, such as ethyl or n-propyl p- hydroxybenzoate. In some cases the liquid formulation may contain one or more solvents that are low toxicity organic (i.e., nonaqueous) class 3 residual solvents, such as ethanol, acetone, ethyl acetate, tetrahydofuran, ethyl ether, and propanol. These solvents can be selected based on their ability to readily aerosolize the formulation. Any such solvent included in the liquid formulation should not detrimentally react with the one or more active agents present in the liquid formulation. The solvent should be sufficiently volatile to enable formation of an aerosol of the solution or suspension. Additional solvents or aerosolizing agents, such as a freon, alcohol, glycol, polyglycol, or fatty acid, can also be included in the liquid formulation as desired to increase the volatility and / or alter the aerosolizing behavior of the solution or suspension. 15 078245 / 00730 45698823.1 Attorney Docket #: YU 8869 PCT Liquid formulations may also contain minor amounts of polymers, surfactants, or other excipients well known to those of the art. In this context, “minor amounts” means no excipients are present that might adversely affect uptake of the one or The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, one or more polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), oils, such as vegetable oils (e.g., peanut oil, corn oil, sesame oil, etc.), and combinations thereof. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and / or by the use of surfactants. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Solutions and dispersions of the active compounds as the free acid or base or pharmacologically acceptable salts thereof can be prepared in water or another solvent or dispersing medium suitably mixed with one or more pharmaceutically acceptable excipients including, but not limited to, surfactants, dispersants, emulsifiers, pH modifying agents, viscosity modifying agents, and combination thereof. Suitable surfactants may be anionic, cationic, amphoteric or nonionic surface-active agents. Suitable anionic surfactants include, but are not limited to, those containing carboxylate, sulfonate and sulfate ions. Examples of anionic surfactants include sodium, potassium, ammonium of long chain alkyl sulfonates and alkyl aryl sulfonates such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium bis-(2-ethylthioxyl)-sulfosuccinate; and alkyl sulfates such as sodium lauryl sulfate. Cationic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzyl ammonium chloride, polyoxyethylene and coconut amine. Examples of nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4-oleate, sorbitan acylate, sucrose acylate, PEG-150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbates, polyoxyethylene octylphenylether, PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, Poloxamer® 401, stearoyl 16 078245 / 00730 45698823.1 Attorney Docket #: YU 8869 PCT monoisopropanolamide, and polyoxyethylene hydrogenated tallow amide. Examples of amphoteric surfactants include sodium N-dodecyl-.beta.-alanine, sodium N-lauryl-.beta.- iminodipropionate, myristoamphoacetate, lauryl betaine and lauryl sulfobetaine. The formulation can contain a preservative to prevent the growth of microorganisms. Suitable preservatives include, but are not limited to, parabens, chlorobutanol, phenol, sorbic acid, and thimerosal. The formulation may also contain an antioxidant to prevent degradation of the active agent(s). The formulation is typically buffered to a pH of 3-8 for parenteral administration upon reconstitution. Suitable buffers include, but are not limited to, phosphate buffers, acetate buffers, and citrate buffers. Water-soluble polymers are often used in formulations for parenteral administration. Suitable water-soluble polymers include, but are not limited to, polyvinylpyrrolidone, dextran, carboxymethylcellulose, and polyethylene glycol. Sterile injectable solutions can be prepared by incorporating the active compounds in the required amount in the appropriate solvent or dispersion medium with one or more of the excipients listed above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. The powders can be prepared in such a manner that the particles are porous in nature, which can increase dissolution of the particles. Methods for making porous particles are well known in the art. (a) Controlled Release Formulations The parenteral formulations described herein can be formulated for controlled release including immediate release, delayed release, extended release, pulsatile release, and combinations thereof. 17 078245 / 00730 45698823.1 Attorney Docket #: YU 8869 PCT 1. Nano- and microparticles For parenteral administration, the one or more compounds, and optional one or more additional active agents, can be incorporated into microparticles, nanoparticles, or combinations thereof that provide controlled release of the compounds and / or one or more additional active agents. In embodiments wherein the formulations contains two or more drugs, the drugs can be formulated for the same type of controlled release (e.g., delayed, extended, immediate, or pulsatile) or the drugs can be independently formulated for different types of release (e.g., immediate and delayed, immediate and extended, delayed and extended, delayed and pulsatile, etc.). For example, the compounds and / or one or more additional active agents can be incorporated into polymeric microparticles, which provide controlled release of the drug(s). Release of the drug(s) is controlled by diffusion of the drug(s) out of the microparticles and / or degradation of the polymeric particles by hydrolysis and / or enzymatic degradation. Suitable polymers include ethylcellulose and other natural or synthetic cellulose derivatives. Polymers, which are slowly soluble and form a gel in an aqueous environment, such as hydroxypropyl methylcellulose or polyethylene oxide, can also be suitable as materials for drug containing microparticles. Other polymers include, but are not limited to, polyanhydrides, poly(ester anhydrides), polyhydroxy acids, such as polylactide (PLA), polyglycolide (PGA), poly(lactide-co-glycolide) (PLGA), poly-3-hydroxybutyrate (PHB) and copolymers thereof, poly-4-hydroxybutyrate (P4HB) and copolymers thereof, polycaprolactone and copolymers thereof, and combinations thereof. Alternatively, the drug(s) can be incorporated into microparticles prepared from materials which are insoluble in aqueous solution or slowly soluble in aqueous solution, but are capable of degrading within the GI tract by means including enzymatic degradation, surfactant action of bile acids, and / or mechanical erosion. As used herein, the term “slowly soluble in water” refers to materials that are not dissolved in water within a period of 30 minutes. Preferred examples include fats, fatty substances, waxes, wax-like substances and mixtures thereof. Suitable fats and fatty substances include fatty alcohols (such as lauryl, myristyl stearyl, cetyl or cetostearyl alcohol), fatty acids and derivatives, including but not 18 078245 / 00730 45698823.1 Attorney Docket #: YU 8869 PCT limited to fatty acid esters, fatty acid glycerides (mono-, di- and tri-glycerides), and hydrogenated fats. Specific examples include, but are not limited to hydrogenated vegetable oil, hydrogenated cottonseed oil, hydrogenated castor oil, hydrogenated oils available under the trade name Sterotex®, stearic acid, cocoa butter, and stearyl alcohol. Suitable waxes and wax-like materials include natural or synthetic waxes, hydrocarbons, and normal waxes. Specific examples of waxes include beeswax, glycowax, castor wax, carnauba wax, paraffins and candelilla wax. As used herein, a wax-like material is defined as any material, which is normally solid at room temperature and has a melting point of from about 30 to 300ºC. In some cases, it may be desirable to alter the rate of water penetration into the microparticles. To this end, rate-controlling (wicking) agents can be formulated along with the fats or waxes listed above. Examples of rate-controlling materials include certain starch derivatives (e.g., waxy maltodextrin and drum dried corn starch), cellulose derivatives (e.g., hydroxypropylmethyl-cellulose, hydroxypropylcellulose, methylcellulose, and carboxymethyl-cellulose), alginic acid, lactose and talc. Additionally, a pharmaceutically acceptable surfactant (for example, lecithin) may be added to facilitate the degradation of such microparticles. Proteins, which are water insoluble, such as zein, can also be used as materials for the formation of drug containing microparticles. Additionally, proteins, polysaccharides and combinations thereof, which are water-soluble, can be formulated with drug into microparticles and subsequently cross-linked to form an insoluble network. For example, cyclodextrins can be complexed with individual drug molecules and subsequently cross- linked. 2. Method of making Nano- and Microparticles Encapsulation or incorporation of drug into carrier materials to produce drug- containing microparticles can be achieved through known pharmaceutical formulation techniques. In the case of formulation in fats, waxes or wax-like materials, the carrier material is typically heated above its melting temperature and the drug is added to form a mixture comprising drug particles suspended in the carrier material, drug dissolved in the carrier material, or a mixture thereof. Microparticles can be subsequently formulated through 19 078245 / 00730 45698823.1 Attorney Docket #: YU 8869 PCT several methods including, but not limited to, the processes of congealing, extrusion, spray chilling or aqueous dispersion. In a preferred process, wax is heated above its melting temperature, drug is added, and the molten wax-drug mixture is congealed under constant stirring as the mixture cools. Alternatively, the molten wax-drug mixture can be extruded and spheronized to form pellets or beads. These processes are known in the art. For some carrier materials it may be desirable to use a solvent evaporation technique to produce drug-containing microparticles. In this case drug and carrier material are co- dissolved in a mutual solvent and microparticles can subsequently be produced by several techniques including, but not limited to, forming an emulsion in water or other appropriate media, spray drying or by evaporating off the solvent from the bulk solution and milling the resulting material. In some embodiments, drug in a particulate form is homogeneously dispersed in a water-insoluble or slowly water soluble material. To minimize the size of the drug particles within the composition, the drug powder itself may be milled to generate fine particles prior to formulation. The process of jet milling, known in the pharmaceutical art, can be used for this purpose. In some embodiments drug in a particulate form is homogeneously dispersed in a wax or wax like substance by heating the wax or wax like substance above its melting point and adding the drug particles while stirring the mixture. In this case a pharmaceutically acceptable surfactant may be added to the mixture to facilitate the dispersion of the drug particles. The particles can also be coated with one or more modified release coatings. Solid esters of fatty acids, which are hydrolyzed by lipases, can be spray coated onto microparticles or drug particles. Zein is an example of a naturally water-insoluble protein. It can be coated onto drug containing microparticles or drug particles by spray coating or by wet granulation techniques. In addition to naturally water-insoluble materials, some substrates of digestive enzymes can be treated with cross-linking procedures, resulting in the formation of non- soluble networks. Many methods of cross-linking proteins, initiated by both chemical and physical means, have been reported. One of the most common methods to obtain cross- linking is the use of chemical cross-linking agents. Examples of chemical cross-linking 20 078245 / 00730 45698823.1 Attorney Docket #: YU 8869 PCT agents include aldehydes (gluteraldehyde and formaldehyde), epoxy compounds, carbodiimides, and genipin. In addition to these cross-linking agents, oxidized and native sugars have been used to cross-link gelatin. Cross-linking can also be accomplished using enzymatic means; for example, transglutaminase has been approved as a GRAS substance for cross-linking seafood products. Finally, cross-linking can be initiated by physical means such as thermal treatment, UV irradiation and gamma irradiation. To produce a coating layer of cross-linked protein surrounding drug containing microparticles or drug particles, a water-soluble protein can be spray coated onto the microparticles and subsequently cross-linked by the one of the methods described above. Alternatively, drug-containing microparticles can be microencapsulated within protein by coacervation-phase separation (for example, by the addition of salts) and subsequently cross- linked. Some suitable proteins for this purpose include gelatin, albumin, casein, and gluten. Polysaccharides can also be cross-linked to form a water-insoluble network. For many polysaccharides, this can be accomplished by reaction with calcium salts or multivalent cations, which cross-link the main polymer chains. Pectin, alginate, dextran, amylose and guar gum are subject to cross-linking in the presence of multivalent cations. Complexes between oppositely charged polysaccharides can also be formed; pectin and chitosan, for example, can be complexed via electrostatic interactions. (b) Injectable / Implantable formulations The compounds described herein can be incorporated into injectable / implantable solid or semi-solid implants, such as polymeric implants. In one embodiment, the compounds are incorporated into a polymer that is a liquid or paste at room temperature, but upon contact with aqueous medium, such as physiological fluids, exhibits an increase in viscosity to form a semi- solid or solid material. Exemplary polymers include, but are not limited to, hydroxyalkanoic acid polyesters derived from the copolymerization of at least one unsaturated hydroxy fatty acid copolymerized with hydroxyalkanoic acids. The polymer can be melted, mixed with the active substance and cast or injection molded into a device. Such melt fabrication require polymers having a melting point that is below the temperature at which the substance to be delivered and polymer degrade or become reactive. The device can also be prepared by solvent casting where 21 078245 / 00730 45698823.1 Attorney Docket #: YU 8869 PCT the polymer is dissolved in a solvent and the drug dissolved or dispersed in the polymer solution and the solvent is then evaporated. Solvent processes require that the polymer be soluble in organic solvents. Another method is compression molding of a mixed powder of the polymer and the drug or polymer particles loaded with the active agent. Alternatively, the compounds can be incorporated into a polymer matrix and molded, compressed, or extruded into a device that is a solid at room temperature. For example, the compounds can be incorporated into a biodegradable polymer, such as polyanhydrides, polyhydroalkanoic acids (PHAs), PLA, PGA, PLGA, polycaprolactone, polyesters, polyamides, polyorthoesters, polyphosphazenes, proteins and polysaccharides such as collagen, hyaluronic acid, albumin and gelatin, and combinations thereof and compressed into solid device, such as disks, or extruded into a device, such as rods. The release of the one or more compounds from the implant can be varied by selection of the polymer, the molecular weight of the polymer, and / or modification of the polymer to increase degradation, such as the formation of pores and / or incorporation of hydrolyzable linkages. Methods for modifying the properties of biodegradable polymers to vary the release profile of the compounds from the implant are well known in the art. 2. Enteral Formulations Suitable oral dosage forms include tablets, capsules, solutions, suspensions, syrups, and lozenges. Tablets can be made using compression or molding techniques well known in the art. Gelatin or non-gelatin capsules can prepared as hard or soft capsule shells, which can encapsulate liquid, solid, and semi-solid fill materials, using techniques well known in the art. Formulations may be prepared using a pharmaceutically acceptable carrier. As generally used herein “carrier” includes, but is not limited to, diluents, preservatives, binders, lubricants, disintegrators, swelling agents, fillers, stabilizers, and combinations thereof. Carrier also includes all components of the coating composition, which may include plasticizers, pigments, colorants, stabilizing agents, and glidants. Examples of suitable coating materials include, but are not limited to, cellulose polymers such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate and hydroxypropyl 22 078245 / 00730 45698823.1 Attorney Docket #: YU 8869 PCT methylcellulose acetate succinate; polyvinyl acetate phthalate, acrylic acid polymers and copolymers, and methacrylic resins that are commercially available under the trade name EUDRAGIT® (Roth Pharma, Westerstadt, Germany), zein, shellac, and polysaccharides. Additionally, the coating material may contain conventional carriers such as plasticizers, pigments, colorants, glidants, stabilization agents, pore formers and surfactants. “Diluents”, also referred to as "fillers," are typically necessary to increase the bulk of a solid dosage form so that a practical size is provided for compression of tablets or formation of beads and granules. Suitable diluents include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starches, pregelatinized starch, silicone dioxide, titanium oxide, magnesium aluminum silicate and powdered sugar. “Binders” are used to impart cohesive qualities to a solid dosage formulation, and thus ensure that a tablet or bead or granule remains intact after the formation of the dosage forms. Suitable binder materials include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums such as acacia, tragacanth, sodium alginate, cellulose, including hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, and veegum, and synthetic polymers such as acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid / polymethacrylic acid and polyvinylpyrrolidone. “Lubricants” are used to facilitate tablet manufacture. Examples of suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, glycerol behenate, polyethylene glycol, talc, and mineral oil. “Disintegrants” are used to facilitate dosage form disintegration or "breakup" after administration, and generally include, but are not limited to, starch, sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethylcellulose, hydroxypropyl cellulose, pregelatinized starch, clays, cellulose, alginine, gums or cross linked polymers, such as cross- linked PVP (Polyplasdone® XL from GAF Chemical Corp). 23 078245 / 00730 45698823.1 Attorney Docket #: YU 8869 PCT “Stabilizers” are used to inhibit or retard drug decomposition reactions, which include, by way of example, oxidative reactions. Suitable stabilizers include, but are not limited to, antioxidants, butylated hydroxytoluene (BHT); ascorbic acid, its salts and esters; Vitamin E, tocopherol and its salts; sulfites such as sodium metabisulphite; cysteine and its derivatives; citric acid; propyl gallate, and butylated hydroxyanisole (BHA). (a) Controlled Release Enteral Formulations Oral dosage forms, such as capsules, tablets, solutions, and suspensions, can for formulated for controlled release. For example, the one or more compounds and optional one or more additional active agents can be formulated into nanoparticles, microparticles, and combinations thereof, and encapsulated in a soft or hard gelatin or non-gelatin capsule or dispersed in a dispersing medium to form an oral suspension or syrup. The particles can be formed of the drug and a controlled release polymer or matrix. Alternatively, the drug particles can be coated with one or more controlled release coatings prior to incorporation in to the finished dosage form. In another embodiment, the one or more compounds and optional one or more additional active agents are dispersed in a matrix material, which gels or emulsifies upon contact with an aqueous medium, such as physiological fluids. In the case of gels, the matrix swells entrapping the active agents, which are released slowly over time by diffusion and / or degradation of the matrix material. Such matrices can be formulated as tablets or as fill materials for hard and soft capsules. In still another embodiment, the one or more compounds, and optional one or more additional active agents are formulated into a sold oral dosage form, such as a tablet or capsule, and the solid dosage form is coated with one or more controlled release coatings, such as a delayed release coatings or extended release coatings. The coating or coatings may also contain the compounds and / or additional active agents. (1) Extended release dosage forms The extended release formulations are generally prepared as diffusion or osmotic systems, which are known in the art. A diffusion system typically consists of two types of devices, a reservoir and a matrix, and is well known and described in the art. The matrix 24 078245 / 00730 45698823.1 Attorney Docket #: YU 8869 PCT devices are generally prepared by compressing the drug with a slowly dissolving polymer carrier into a tablet form. The three major types of materials used in the preparation of matrix devices are insoluble plastics, hydrophilic polymers, and fatty compounds. Plastic matrices include, but are not limited to, methyl acrylate-methyl methacrylate, polyvinyl chloride, and polyethylene. Hydrophilic polymers include, but are not limited to, cellulosic polymers such as methyl and ethyl cellulose, hydroxyalkylcelluloses such as hydroxypropyl-cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and Carbopol® 934, polyethylene oxides and mixtures thereof. Fatty compounds include, but are not limited to, various waxes such as carnauba wax and glyceryl tristearate and wax-type substances including hydrogenated castor oil or hydrogenated vegetable oil, or mixtures thereof. In certain preferred embodiments, the plastic material is a pharmaceutically acceptable acrylic polymer, including but not limited to, acrylic acid and methacrylic acid copolymers, methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamine copolymer poly(methyl methacrylate), poly(methacrylic acid)(anhydride), polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers. In certain preferred embodiments, the acrylic polymer is comprised of one or more ammonio methacrylate copolymers. Ammonio methacrylate copolymers are well known in the art, and are described in NF XVII as fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups. In one preferred embodiment, the acrylic polymer is an acrylic resin lacquer such as that which is commercially available from Rohm Pharma under the tradename EUDRAGIT t®. In further preferred embodiments, the acrylic polymer comprises a mixture of two acrylic resin lacquers commercially available from Rohm Pharma under the tradenames EUDRAGIT® RL30D and EUDRAGIT ® RS30D, respectively. EUDRAGIT® RL30D and EUDRAGIT ® RS30D are copolymers of acrylic and methacrylic esters with a low content of quaternary ammonium groups, the molar ratio of ammonium groups to the remaining neutral (meth)acrylic esters being 1:20 in EUDRAGIT ® RL30D and 1:40 in EUDRAGIT® 25 078245 / 00730 45698823.1 Attorney Docket #: YU 8869 PCT RS30D. The mean molecular weight is about 150,000. EUDRAGIT ® S-100 and EUDRAGIT ® L-100 are also preferred. The code designations RL (high permeability) and RS (low permeability) refer to the permeability properties of these agents. EUDRAGIT ® RL / RS mixtures are insoluble in water and in digestive fluids. However, multiparticulate systems formed to include the same are swellable and permeable in aqueous solutions and digestive fluids. The polymers described above such as EUDRAGIT ® RL / RS may be mixed together in any desired ratio in order to ultimately obtain a sustained-release formulation having a desirable dissolution profile. Desirable sustained-release multiparticulate systems may be obtained, for instance, from 100% EUDRAGIT® RL, 50% EUDRAGIT® RL and 50% EUDRAGIT t® RS, and 10% EUDRAGIT® RL and 90% EUDRAGIT® RS. One skilled in the art will recognize that other acrylic polymers may also be used, such as, for example, EUDRAGIT® L. Alternatively, extended release formulations can be prepared using osmotic systems or by applying a semi-permeable coating to the dosage form. In the latter case, the desired drug release profile can be achieved by combining low permeable and high permeable coating materials in suitable proportion. The devices with different drug release mechanisms described above can be combined in a final dosage form comprising single or multiple units. Examples of multiple units include, but are not limited to, multilayer tablets and capsules containing tablets, beads, or granules An immediate release portion can be added to the extended release system by means of either applying an immediate release layer on top of the extended release core using a coating or compression process or in a multiple unit system such as a capsule containing extended and immediate release beads. Extended release tablets containing hydrophilic polymers are prepared by techniques commonly known in the art such as direct compression, wet granulation, or dry granulation. Their formulations usually incorporate polymers, diluents, binders, and lubricants as well as the active pharmaceutical ingredient. The usual diluents include inert powdered substances such as starches, powdered cellulose, especially crystalline and microcrystalline cellulose, 26 078245 / 00730 45698823.1 Attorney Docket #: YU 8869 PCT sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders include substances such as starch, gelatin and sugars such as lactose, fructose, and glucose. Natural and synthetic gums, including acacia, alginates, methylcellulose, and polyvinylpyrrolidone can also be used. Polyethylene glycol, hydrophilic polymers, ethylcellulose and waxes can also serve as binders. A lubricant is necessary in a tablet formulation to prevent the tablet and punches from sticking in the die. The lubricant is chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils. Extended release tablets containing wax materials are generally prepared using methods known in the art such as a direct blend method, a congealing method, and an aqueous dispersion method. In the congealing method, the drug is mixed with a wax material and either spray- congealed or congealed and screened and processed. (2) Delayed release dosage forms Delayed release formulations can be created by coating a solid dosage form with a polymer film, which is insoluble in the acidic environment of the stomach, and soluble in the neutral environment of the small intestine. The delayed release dosage units can be prepared, for example, by coating a drug or a drug-containing composition with a selected coating material. The drug-containing composition may be, e.g., a tablet for incorporation into a capsule, a tablet for use as an inner core in a "coated core" dosage form, or a plurality of drug-containing beads, particles or granules, for incorporation into either a tablet or capsule. Preferred coating materials include bioerodible, gradually hydrolyzable, gradually water-soluble, and / or enzymatically degradable polymers, and may be conventional "enteric" polymers. Enteric polymers, as will be appreciated by those skilled in the art, become soluble in the higher pH environment of the lower gastrointestinal tract or slowly erode as the dosage form passes through the gastrointestinal tract, while enzymatically degradable polymers are degraded by bacterial enzymes present in the lower gastrointestinal tract, particularly in the colon. Suitable coating 27 078245 / 00730 45698823.1 Attorney Docket #: YU 8869 PCT materials for effecting delayed release include, but are not limited to, cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, methylcellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate and carboxymethylcellulose sodium; acrylic acid polymers and copolymers, preferably formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and / or ethyl methacrylate, and other methacrylic resins that are commercially available under the tradename Eudragit® (Rohm Pharma; Westerstadt, Germany), including EUDRAGIT® L30D-55 and L100-55 (soluble at pH 5.5 and above), EUDRAGIT® L-100 (soluble at pH 6.0 and above), EUDRAGIT® S (soluble at pH 7.0 and above, as a result of a higher degree of esterification), and EUDRAGITS® NE, RL and RS (water-insoluble polymers having different degrees of permeability and expandability); vinyl polymers and copolymers such as polyvinyl pyrrolidone, vinyl acetate, vinylacetate phthalate, vinylacetate crotonic acid copolymer, and ethylene-vinyl acetate copolymer; enzymatically degradable polymers such as azo polymers, pectin, chitosan, amylose and guar gum; zein and shellac. Combinations of different coating materials may also be used. Multi-layer coatings using different polymers may also be applied. The preferred coating weights for particular coating materials may be readily determined by those skilled in the art by evaluating individual release profiles for tablets, beads and granules prepared with different quantities of various coating materials. It is the combination of materials, method and form of application that produce the desired release characteristics, which one can determine only from the clinical studies. The coating composition may include conventional additives, such as plasticizers, pigments, colorants, stabilizing agents, glidants, etc. A plasticizer is normally present to reduce the fragility of the coating, and will generally represent about 10 wt. % to 50 wt. % relative to the dry weight of the polymer. Examples of typical plasticizers include polyethylene glycol, propylene glycol, triacetin, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, triethyl acetyl citrate, castor oil 28 078245 / 00730 45698823.1 Attorney Docket #: YU 8869 PCT and acetylated monoglycerides. A stabilizing agent is preferably used to stabilize particles in the dispersion. Typical stabilizing agents are nonionic emulsifiers such as sorbitan esters, polysorbates and polyvinylpyrrolidone. Glidants are recommended to reduce sticking effects during film formation and drying, and will generally represent approximately 25 wt. % to 100 wt. % of the polymer weight in the coating solution. One effective glidant is talc. Other glidants such as magnesium stearate and glycerol monostearates may also be used. Pigments such as titanium dioxide may also be used. Small quantities of an anti-foaming agent, such as a silicone (e.g., simethicone), may also be added to the coating composition. 3. Topical Formulations Suitable dosage forms for topical administration include creams, ointments, salves, sprays, gels, lotions, emulsions, and transdermal patches. The formulation may be formulated for transmucosal, transepithelial, transendothelial, or transdermal administration. The compounds can also be formulated for intranasal delivery, pulmonary delivery, or inhalation. In a preferred embodiment, the compounds are formulation for intranasal delivery. The compositions may further contain one or more chemical penetration enhancers, membrane permeability agents, membrane transport agents, emollients, surfactants, stabilizers, buffers, and combination thereof. In certain embodiments, it may be desirable to provide continuous delivery of one or more compounds to a patient in need thereof. For topical applications, repeated application can be done or a patch can be used to provide continuous administration of the compounds over an extended period of time “Buffers” are used to control pH of a composition. Preferably, the buffers buffer the composition from a pH of about 4 to a pH of about 7.5, more preferably from a pH of about 4 to a pH of about 7, and most preferably from a pH of about 5 to a pH of about 7. In a preferred embodiment, the buffer is triethanolamine. “Emollients” are an externally applied agent that softens or soothes skin and are generally known in the art and listed in compendia, such as the “Handbook of Pharmaceutical Excipients”, 4thEd., Pharmaceutical Press, 2003. These include, without limitation, almond oil, castor oil, ceratonia extract, cetostearoyl alcohol, cetyl alcohol, cetyl esters wax, 29 078245 / 00730 45698823.1 Attorney Docket #: YU 8869 PCT cholesterol, cottonseed oil, cyclomethicone, ethylene glycol palmitostearate, glycerin, glycerin monostearate, glyceryl monooleate, isopropyl myristate, isopropyl palmitate, lanolin, lecithin, light mineral oil, medium-chain triglycerides, mineral oil and lanolin alcohols, petrolatum, petrolatum and lanolin alcohols, soybean oil, starch, stearyl alcohol, sunflower oil, xylitol and combinations thereof. In one embodiment, the emollients are ethylhexylstearate and ethylhexyl palmitate. “Emulsifiers” are surface active substances which promote the suspension of one liquid in another and promote the formation of a stable mixture, or emulsion, of oil and water. Common emulsifiers are: metallic soaps, certain animal and vegetable oils, and various polar compounds. Suitable emulsifiers include acacia, anionic emulsifying wax, calcium stearate, carbomers, cetostearyl alcohol, cetyl alcohol, cholesterol, diethanolamine, ethylene glycol palmitostearate, glycerin monostearate, glyceryl monooleate, hydroxpropyl cellulose, hypromellose, lanolin, hydrous, lanolin alcohols, lecithin, medium-chain triglycerides, methylcellulose, mineral oil and lanolin alcohols, monobasic sodium phosphate, monoethanolamine, nonionic emulsifying wax, oleic acid, poloxamer, poloxamers, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, propylene glycol alginate, self- emulsifying glyceryl monostearate, sodium citrate dehydrate, sodium lauryl sulfate, sorbitan esters, stearic acid, sunflower oil, tragacanth, triethanolamine, xanthan gum and combinations thereof. In one embodiment, the emulsifier is glycerol stearate. “Penetration enhancers” are known in the art and include, but are not limited to, fatty alcohols, fatty acid esters, fatty acids, fatty alcohol ethers, amino acids, phospholipids, lecithins, cholate salts, enzymes, amines and amides, complexing agents (liposomes, cyclodextrins, modified celluloses, and diimides), macrocyclics, such as macrocylic lactones, ketones, and anhydrides and cyclic ureas, surfactants, N-methyl pyrrolidones and derivatives thereof, DMSO and related compounds, ionic compounds, azone and related compounds, and solvents, such as alcohols, ketones, amides, polyols (e.g., glycols). Examples of these classes are known in the art. 30 078245 / 00730 45698823.1 Attorney Docket #: YU 8869 PCT “Preservatives” can be used to prevent the growth of fungi and microorganisms. Suitable antifungal and antimicrobial agents include, but are not limited to, benzoic acid, butylparaben, ethyl paraben, methyl paraben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, and thimerosal. “Surfactants” are surface-active agents that lower surface tension and thereby increase the emulsifying, foaming, dispersing, spreading and wetting properties of a product. Suitable non-ionic surfactants include emulsifying wax, glyceryl monooleate, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polysorbate, sorbitan esters, benzyl alcohol, benzyl benzoate, cyclodextrins, glycerin monostearate, poloxamer, povidone and combinations thereof. In one embodiment, the non-ionic surfactant is stearyl alcohol. (a) Emulsions An emulsion is a preparation of one liquid distributed in small globules throughout the body of a second liquid. In particular embodiments, the non-miscible components of the emulsion include a lipophilic component and an aqueous component. The dispersed liquid is the discontinuous phase, and the dispersion medium is the continuous phase. When oil is the dispersed liquid and an aqueous solution is the continuous phase, it is known as an oil-in- water emulsion, whereas when water or aqueous solution is the dispersed phase and oil or oleaginous substance is the continuous phase, it is known as a water-in-oil emulsion. Either or both of the oil phase and the aqueous phase may contain one or more surfactants, emulsifiers, emulsion stabilizers, buffers, and other excipients. Preferred excipients include surfactants, especially non-ionic surfactants; emulsifying agents, especially emulsifying waxes; and liquid non-volatile non-aqueous materials, particularly glycols such as propylene glycol. The oil phase may contain other oily pharmaceutically approved excipients. For example, materials such as hydroxylated castor oil or sesame oil may be used in the oil phase as surfactants or emulsifiers. The oil phase may consist at least in part of a propellant, such as an HFA propellant. Either or both of the oil phase and the aqueous phase may contain one or more surfactants, emulsifiers, emulsion stabilizers, buffers, and other excipients. Preferred excipients include 31 078245 / 00730 45698823.1 Attorney Docket #: YU 8869 PCT surfactants, especially non-ionic surfactants; emulsifying agents, especially emulsifying waxes; and liquid non-volatile non-aqueous materials, particularly glycols such as propylene glycol. The oil phase may contain other oily pharmaceutically approved excipients. For example, materials such as hydroxylated castor oil or sesame oil may be used in the oil phase as surfactants or emulsifiers. A sub-set of emulsions are the self-emulsifying systems. These drug delivery systems are typically capsules (hard shell or soft shell) comprised of the drug dispersed or dissolved in a mixture of surfactant(s) and lipophilic liquids such as oils or other water immiscible liquids. When the capsule is exposed to an aqueous environment and the outer gelatin shell dissolves, contact between the aqueous medium and the capsule contents instantly generates very small emulsion droplets. These typically are in the size range of micelles or nanoparticles. No mixing force is required to generate the emulsion as is typically the case in emulsion formulation processes. (b) Lotions A lotion can contain finely powdered substances that are in soluble in the dispersion medium through the use of suspending agents and dispersing agents. Alternatively, lotions can have as the dispersed phase liquid substances that are immiscible with the vehicle and are usually dispersed by means of emulsifying agents or other suitable stabilizers. In one embodiment, the lotion is in the form of an emulsion having a viscosity of between 100 and 1000 centistokes. The fluidity of lotions permits rapid and uniform application over a wide surface area. Lotions are typically intended to dry on the skin leaving a thin coat of their medicinal components on the skin’s surface. (c) Creams Creams may contain emulsifying agents and / or other stabilizing agents. In one embodiment, the formulation is in the form of a cream having a viscosity of greater than 1000 centistokes, typically in the range of 20,000-50,000 centistokes. Creams are often time preferred over ointments, as they are generally easier to spread and easier to remove. The difference between a cream and a lotion is the viscosity, which is dependent on the amount / use of various oils and the percentage of water used to prepare the formulations. 32 078245 / 00730 45698823.1 Attorney Docket #: YU 8869 PCT Creams are typically thicker than lotions, may have various uses and often one uses more varied oils / butters, depending upon the desired effect upon the skin. In a cream formulation, the water-base percentage is about 60-75 % and the oil-base is about 20-30 % of the total, with the other percentages being the emulsifier agent, preservatives and additives for a total of 100 %. (d) Ointments Examples of suitable ointment bases include hydrocarbon bases (e.g., petrolatum, white petrolatum, yellow ointment, and mineral oil); absorption bases (hydrophilic petrolatum, anhydrous lanolin, lanolin, and cold cream); water-removable bases (e.g., hydrophilic ointment), and water-soluble bases (e.g., polyethylene glycol ointments). Pastes typically differ from ointments in that they contain a larger percentage of solids. Pastes are typically more absorptive and less greasy that ointments prepared with the same components. (e) Gels Gels are semisolid systems containing dispersions of small or large molecules in a liquid vehicle that is rendered semisolid by the action of a thickening agent or polymeric material dissolved or suspended in the liquid vehicle. The liquid may include a lipophilic component, an aqueous component or both. Some emulsions may be gels or otherwise include a gel component. Some gels, however, are not emulsions because they do not contain a homogenized blend of immiscible components. Suitable gelling agents include, but are not limited to, modified celluloses, such as hydroxypropyl cellulose and hydroxyethyl cellulose; Carbopol homopolymers and copolymers; and combinations thereof. Suitable solvents in the liquid vehicle include, but are not limited to, diglycol monoethyl ether; alklene glycols, such as propylene glycol; dimethyl isosorbide; alcohols, such as isopropyl alcohol and ethanol. The solvents are typically selected for their ability to dissolve the drug. Other additives, which improve the skin feel and / or emolliency of the formulation, may also be incorporated. Examples of such additives include, but are not limited, isopropyl myristate, ethyl acetate, C12-C15 alkyl benzoates, mineral oil, squalane, cyclomethicone, capric / caprylic triglycerides, and combinations thereof. 33 078245 / 00730 45698823.1 Attorney Docket #: YU 8869 PCT (f) Foams Foams consist of an emulsion in combination with a gaseous propellant. The gaseous propellant consists primarily of hydrofluoroalkanes (HFAs). Suitable propellants include HFAs such as 1,1,1,2-tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA 227), but mixtures and admixtures of these and other HFAs that are currently approved or may become approved for medical use are suitable. The propellants preferably are not hydrocarbon propellant gases, which can produce flammable or explosive vapors during spraying. Furthermore, the compositions preferably contain no volatile alcohols, which can produce flammable or explosive vapors during use. 4. Pulmonary Formulations In one embodiment, the compounds are formulated for pulmonary delivery, such as intranasal administration or oral inhalation. The respiratory tract is the structure involved in the exchange of gases between the atmosphere and the blood stream. The lungs are branching structures ultimately ending with the alveoli where the exchange of gases occurs. The alveolar surface area is the largest in the respiratory system and is where drug absorption occurs. The alveoli are covered by a thin epithelium without cilia or a mucus blanket and secrete surfactant phospholipids. The respiratory tract encompasses the upper airways, including the oropharynx and larynx, followed by the lower airways, which include the trachea followed by bifurcations into the bronchi and bronchioli. The upper and lower airways are called the conducting airways. The terminal bronchioli then divide into respiratory bronchiole, which then lead to the ultimate respiratory zone, the alveoli, or deep lung. The deep lung, or alveoli, is the primary target of inhaled therapeutic aerosols for systemic drug delivery. Pulmonary administration of therapeutic compositions including low molecular weight drugs has been observed, for example, beta-androgenic antagonists to treat asthma. Other therapeutic agents that are active in the lungs have been administered systemically and targeted via pulmonary absorption. Nasal delivery is considered to be a promising technique for administration of therapeutics for the following reasons: the nose has a large surface area available for drug absorption due to the coverage of the epithelial surface by numerous 34 078245 / 00730 45698823.1 Attorney Docket #: YU 8869 PCT microvilli, the sub epithelial layer is highly vascularized, the venous blood from the nose passes directly into the systemic circulation and therefore avoids the loss of drug by first-pass metabolism in the liver, it offers lower doses, more rapid attainment of therapeutic blood levels, quicker onset of pharmacological activity, fewer side effects, high total blood flow per cm3, porous endothelial basement membrane, and it is easily accessible. Carriers for pulmonary formulations can be divided into those for dry powder formulations and for administration as solutions. Aerosols for the delivery of therapeutic agents to the respiratory tract are known in the art. Aerosols can be produced using standard techniques, such as ultrasonication or high-pressure treatment. For administration via the upper respiratory tract, the formulation can be formulated into a solution, e.g., water or isotonic saline, buffered or un-buffered, or as a suspension, for intranasal administration as drops or as a spray. Preferably, such solutions or suspensions are isotonic relative to nasal secretions and of about the same pH, ranging e.g., from about pH 4.0 to about pH 7.4 or, from pH 6.0 to pH 7.0. Buffers should be physiologically compatible and include, simply by way of example, phosphate buffers. For example, a representative nasal decongestant is described as being buffered to a pH of about 6.2. One skilled in the art can readily determine a suitable saline content and pH for an innocuous aqueous solution for nasal and / or upper respiratory administration. Preferably, the aqueous solution is water, physiologically acceptable aqueous solutions containing salts and / or buffers, such as phosphate buffered saline (PBS), or any other aqueous solution acceptable for administration to an animal or human. Such solutions are well known to a person skilled in the art and include, but are not limited to, distilled water, de-ionized water, pure or ultrapure water, saline, phosphate-buffered saline (PBS). Other suitable aqueous vehicles include, but are not limited to, Ringer's solution and isotonic sodium chloride. Aqueous suspensions may include suspending agents such as cellulose derivatives, sodium alginate, polyvinyl-pyrrolidone and gum tragacanth, and a wetting agent such as lecithin. Suitable preservatives for aqueous suspensions include ethyl and n-propyl p- hydroxybenzoate. 35 078245 / 00730 45698823.1 Attorney Docket #: YU 8869 PCT Solvents that are low toxicity organic (i.e. nonaqueous) class 3 residual solvents, such as ethanol, acetone, ethyl acetate, tetrahydofuran, ethyl ether, and propanol may be used for the formulations. The solvent is selected based on its ability to readily aerosolize the formulation. The solvent should not detrimentally react with the compounds. An appropriate solvent should be used that dissolves the compounds or forms a suspension of the compounds. The solvent should be sufficiently volatile to enable formation of an aerosol of the solution or suspension. Additional solvents or aerosolizing agents, such as freons, can be added as desired to increase the volatility of the solution or suspension. In one embodiment, compositions may contain minor amounts of polymers, surfactants, or other excipients well known to those of the art. In this context, "minor amounts" means no excipients are present that might affect or mediate uptake of the compounds in the lungs and that the excipients that are present are present in amount that do not adversely affect uptake of compounds in the lungs. Dry lipid powders can be directly dispersed in ethanol because of their hydrophobic character. For lipids stored in organic solvents such as chloroform, the desired quantity of solution is placed in a vial, and the chloroform is evaporated under a stream of nitrogen to form a dry thin film on the surface of a glass vial. The film swells easily when reconstituted with ethanol. To fully disperse the lipid molecules in the organic solvent, the suspension is sonicated. Nonaqueous suspensions of lipids can also be prepared in absolute ethanol using a reusable PARI LC Jet+ nebulizer (PARI Respiratory Equipment, Monterey, CA). Dry powder formulations ("DPFs") with large particle size have improved flowability characteristics, such as less aggregation, easier aerosolization, and potentially less phagocytosis. Dry powder aerosols for inhalation therapy are generally produced with mean diameters primarily in the range of less than 5 microns, although a preferred range is between one and ten microns in aerodynamic diameter. Large "carrier" particles (containing no drug) have been co-delivered with therapeutic aerosols to aid in achieving efficient aerosolization among other possible benefits. Polymeric particles may be prepared using single and double emulsion solvent evaporation, spray drying, solvent extraction, solvent evaporation, phase separation, simple 36 078245 / 00730 45698823.1 Attorney Docket #: YU 8869 PCT and complex coacervation, interfacial polymerization, and other methods well known to those of ordinary skill in the art. Particles may be made using methods for making microspheres or microcapsules known in the art. The preferred methods of manufacture are by spray drying and freeze drying, which entails using a solution containing the surfactant, spraying to form droplets of the desired size, and removing the solvent. The particles may be fabricated with the appropriate material, surface roughness, diameter and tap density for localized delivery to selected regions of the respiratory tract such as the deep lung or upper airways. For example, higher density or larger particles may be used for upper airway delivery. Similarly, a mixture of different sized particles, provided with the same or different EGS may be administered to target different regions of the lung in one administration. Formulations for pulmonary delivery include unilamellar phospholipid vesicles, liposomes, or lipoprotein particles. Formulations and methods of making such formulations containing nucleic acid are well known to one of ordinary skill in the art. Liposomes are formed from commercially available phospholipids supplied by a variety of vendors including Avanti Polar Lipids, Inc. (Birmingham, Ala.). In one embodiment, the liposome can include a ligand molecule specific for a receptor on the surface of the target cell to direct the liposome to the target cell. III. METHODS OF USE Pharmaceutical formulations containing one or more of the VDRA described herein can be administered to induce weight loss in a pre-obese, obese, or morbidly obese patient, reduce body fat in a pre-obese, obese, or morbidly obese patient, reduce food intake in a pre- obese, obese, or morbidly obese patient, improve glucose homeostasis in a pre-obese, obese, or morbidly obese patient, prevent weight gain and / or prevent an increase in body mass index in a normal, pre-obese, obese, or morbidly obese patient, or combinations thereof. In certain embodiments, the pharmaceutical formulations are administered to a patient suffering from obesity (e.g., a pro-obese, obese, or morbidly obese patient), an obesity-related disease or disorder, diabetes, insulin-resistance syndrome, lypodystrpohy, nonalcoholic steatohepatitis, a cardiovascular disease, polycystic ovary syndrome, or a metabolic 37 078245 / 00730 45698823.1 Attorney Docket #: YU 8869 PCT syndrome. The disclosed pharmaceutical formulations may also be administered to patients suffering from a disease or disorder that causes obesity or predisposes a patient to become obese, such as Bardet-Biedl syndrome or a mutation in the gene encoding for the melanocortin receptor 4 (MC4R) protein (i.e., an MC4R mutation). A. Dosages The precise dosage administered to a patient will depend on many factors, including the physical characteristics of the patient (e.g., weight), the degree of severity of the disease or disorder to be treated, and the presence or absence of other complicating diseases or disorders and can be readily determined by the prescribing physician. In certain embodiments, the weight loss agent is administered at a dosage equivalent to an oral dosage of between about 0.005 mg and about 500 mg per kg of body weight per day, more preferably between about 0.05 mg and about 100 mg per kg of body weight per day, most preferably between about 0.1 mg and about 10 mg per kg of body weight per day. In particular embodiments, the weight loss agent is administered at a dosage equivalent to an oral dosage of between about 1.0 mg and 5.0 mg per kg of body weight per day. In some cases, a pharmaceutical formulation containing one or more of the weight loss agents is administered to a pre-obese, obese, or morbidly obese patient in a therapeutically effective amount to induce weight loss. In certain embodiments, a pharmaceutical formulation containing one or more of the weight loss agents is administered to a pre-obese, obese, or morbidly obese patient in a therapeutically effective amount to decrease body mass by at least 10%, more preferably by at least 15%, most preferably by at least 20%. In some cases, a pharmaceutical formulation containing one or more of the weight loss agents is administered to a pre-obese, obese, or morbidly obese patient in a therapeutically effective amount to reduce body fat. In certain embodiments, a pharmaceutical formulation containing one or more of the weight loss agents is administered to a pre-obese, obese, or morbidly obese patient in a therapeutically effective amount to decrease body fat by at least 10%, more preferably by at least 15%, most preferably by at least 20%. 38 078245 / 00730 45698823.1 Attorney Docket #: YU 8869 PCT In some forms, the disclosed compositions include effective amounts of a vitamin D receptor agonists to increase dopamine release in dopaminergic neurons when administered to a subject in need thereof. In some forms, the disclosed compositions include effective amounts of a vitamin D receptor agonists to increase upregulate TH (tyrosine hydroxylase) and / or Slc6a3 (solute carrier family 6 member 3) gene expression or Drd2 (dopamine receptor D2) mRNA in nucleus accumbens B. Therapeutic Administration Pharmaceutical formulations may be administered, for example, in a single dosage, as a continuous dosage, one or more times daily, or less frequently, such as once a week. The pharmaceutical formulations can be administered once a day or more than once a day, such as twice a day, three times a day, four times a day or more. In some forms, the formulation is administered intranasally for intranasal transport of the administered VDRA to the CNS. In these forms, the effective amount of the VDRA is less than the amount that would be required if the VDRA is delivered via a non-intranasal route, for example, orally. Intranasal transport is the direct transport of therapeutic agents from the nasal cavity to the brain. This is a mainly extracellular and transcellular transport, involving the olfactory and respiratory regions of the nasal cavity. The administered VDRA reaches the systemic circulation through intranasal instillation. Pharmacological agents can bypass the BBB during this transport and enter the CNS. Woesensel, et al., 2013 Aug 14;5(3):1020-48. doi: 10.3390 / cancers5031020. PMID: 24202332. In the case of formulations for intranasal administration, the uptake of active molecules in the brain is mainly formulated as nanoparticles. Nanoparticles are defined as having a size smaller than 1 µm. The pharmaceutical formulations are administered in an effective amount and for an effective period of time to elicit the desired therapeutic benefit. In certain embodiments, the pharmaceutical formulation is administered daily, bi-weekly, weekly, bi-monthly or monthly for a period of at least one week, two weeks, three weeks, four weeks, one month, two months, three months, four months, five months, six months, seven months, eight months, 39 078245 / 00730 45698823.1 Attorney Docket #: YU 8869 PCT nine months, ten months, eleven months, one year, or longer. The formulation is preferably administered for a period that is longer than 2, or 3 days. The formulation is administered for an effective amount of time to treat obesity, for example, for at least 5 days, at least 10 days, and up to one month, daily. In some forms, the forms, administration incudes a two dosage regimen, wherein the first dosage regimen is a treatment regimen and the second dosage regimen is a maintenance regimen and the effective dose administered during the treatment regimen is at least twice the effective dose required for maintenance (of body weight). In some forms, the treatment period is at least two weeks, and up to one month and the maintenance period commences after the end of the treatment period. The pharmaceutical formulations may also be administered prophylactically, e.g., to patients or subjects who are at risk for a disease or disorder such as diabetes or obesity. Thus, methods can also involve identifying a subject at risk for diabetes or obesity prior to administration of the formulations. The exact amount of the formulations required will vary from subject to subject, depending on the species, age, sex, weight and general condition of the subject, extent of the disease in the subject, route of administration, whether other drugs are included in the regimen, and the like. Thus, it is not possible to specify an exact dosages for every formulation. However, an appropriate dosage can be determined by one of ordinary skill in the art using only routine experimentation. For example, effective dosages and schedules for administering the compositions may be determined empirically, and making such determinations is within the skill in the art. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. C. Combination Therapy The disclosed formulations can be administered to a subject in need thereof alone or in combination with one or more additional active agents such as leptin, niacinamide, alendronate sodium, arsenic trioxide and / or pravastatin, calcium carbonate, docosahexaenoic 40 078245 / 00730 45698823.1 Attorney Docket #: YU 8869 PCT acid, Ro-23-6474 (C28H44O4), raloxifene, nandrolone decanoate, corticosteroids or a GLP- 1 pathway drug for example, a GLP-1 agonist. Glucagon-like peptide-1 (GLP-1) agonists (also known as GLP-1 receptor agonists, incretin mimetics, or GLP-1 analogs) represent a class of medications used to treat type 2 diabetes mellitus and, in some cases, obesity. Examples of drugs in this class include exenatide, lixisenatide, liraglutide, albiglutide, dulaglutide, and semaglutide.Other active agents can also include one or more vitamins, minerals, dietary supplements, nutraceutical agents, such as proteins, carbohydrates, amino acids, fatty acids, antioxidants, and plant or animal extracts, or combinations thereof. Suitable vitamins, minerals, nutraceutical agents, and dietary supplements are known in the art, and disclosed, for example, in Roberts et al., (Nutriceuticals: The Complete Encyclopedia of Supplements, Herbs, Vitamins, and Healing Foods, American Nutriceutical Association, 2001). Nutraceutical agents and dietary supplements are also disclosed in Physicians' Desk Reference for Nutritional Supplements, 1st Ed. (2001) and The Physicians' Desk Reference for Herbal Medicines, 1st Ed. (2001). The disclosed compositions and methods can be further understood in view of the following number paragraphs and non-limiting examples. 1. A method of treating obesity comprising administering to a subject in need thereof, a composition comprising a vitamin D receptor agonist (VDRA), for an effective amount of time, to treat on or more symptoms of obesity. 2. A method of preventing one or more symptoms associated with obesity in a subject, comprising administering to the subject, a composition comprising a vitamin D receptor agonist (VDRA),, optionally, wherein the subject is on a high fat diet. 3. The method of paragraph 1 or 2, wherein the VDRA includes the following core structure represented by the general formula: 41 078245 / 00730 45698823.1 Attorney Docket #: YU 8869 PCT I. 4. of paragraphs 1-3, wherein the VRDA is selected from the group calciferol (ergocalciferol), calcidiol, calcipotriol, doxercalciferol, alfacalcidol, tacalcitol, paricalcitol, oxacalcitriol, falecalcitriol, eldecalcitol and secalciferol. 5. The method of any one of paragraphs 1-4, wherein the VDRA is calcitriol. 6. The composition of any one of claims 1-4, wherein the VDRA is in an effective amount to increase the release of one or more satiety signals when administered to a subject in need thereof. 7. The method of any one of paragraphs 1-6 wherein the composition is administered for at least 10 days, and up to one month, optionally, daily. 8. The method of paragraph 7, wherein the composition is administered at a first effective dose for at least two week, followed by administration of a second effective dose (the maintenance dose), wherein the maintenance dose is at least half, a third or a quarter of the first effective dose. 9. The method of any one of paragraphs 1-8, wherein the composition is administered for at least one month. 10. The method of any one of paragraphs 1-9, wherein the composition is administered intranasally, optionally, in the form of a liquid. 11. The method of any one of paragraphs 1-10, wherein the subject’s daily body weight reduces following administration of the composition. 12. The method of any one of paragraphs 1-11 wherein VDRA is in an effective amount to increase dopamine release from dopaminergic neurons in the subject. 13. The method of any one of paragraphs 1-12, wherein VDRA is in an effective 42 078245 / 00730 45698823.1 Attorney Docket #: YU 8869 PCT amount to increase upregulate TH (tyrosine hydroxylase) and / or Slc6a3 (solute carrier family 6 member 3) gene expression in a subject or Drd2 (dopamine receptor D2) mRNA level in nucleus accumbens in the subject. 14. The method of any one of paragraphs 1-13, wherein the composition comprising the VRDA is administered alone or in combination with one or more additional active agents. 15. The method of paragraph 14, wherein the active agent is leptin. 16. The method of paragraph 15, wherein the active agent is Glucagon-like peptide-1 (GLP-1) agonist. 17. The method of paragraph 16, wherein the GLP-1 agonist is selected from the group consisting of dulaglutide, exenatide, semiglutide, liraglutide, and lixisenatide. 18. A composition for treating or preventing obesity comprising form of a vitamin D receptor agonists / activator (VDRA) in an effective amount to treat reduce one or mor symptoms associated with obesity, optionally, in a unit doage form, wherein the VDRA wherein the compound is present in the dosage formulation in a therapeutically effective amount to induce weight loss and / or reduce the body fat. 19. The composition of paragraph 18, wherein the VDRA includes the following core structure represented by the general formula: I. 20. 18 or 19, wherein the VRDA is selected from the group consisting of calcitriol, ercalcitriol, calciferol (ergocalciferol), calcidiol, calcipotriol, doxercalciferol, alfacalcidol, tacalcitol, paricalcitol, oxacalcitriol, falecalcitriol, eldecalcitol and secalciferol. 21. The composition of any one of paragraphs 18-20, wherein the VDRA is 43 078245 / 00730 45698823.1 Attorney Docket #: YU 8869 PCT calcitriol. 22. The composition of any one of paragraphs 18-21, wherein the VDRA is in an effective amount to increase the release of one or more satiety signals when administered to a subject in need thereof. 23. The composition of any one of paragraphs 18-22, wherein the VDRA is in an effective amount to increase dopamine release from dopaminergic neurons when administered to a subject in need thereof. 24. The composition of any one of paragraphs 18-23, wherein VDRA is in an effective amount to increase upregulate TH (tyrosine hydroxylase) and / or Slc6a3 (solute carrier family 6 member 3) gene expression in a subject or Drd2 (dopamine receptor D2) mRNA level in nucleus accumbens. 25. The composition of any one of paragraphs 18-24, wherein the dosage formulation is a pharmaceutically acceptable oral or intravenous dosage formulation. 26. The composition of any one of paragraphs 18-25, wherein the dosage formulation is a pharmaceutically acceptable oral dosage formulation selected from the group consisting of tablets, capsules, solutions, suspensions, syrups, and lozenges. 27. The composition of any one of paragraphs 18-25, wherein the dosage formulation is suitable for intranasal administration and comprises a pharmaceutically acceptable carrier for intranasal deliver. 28. The composition of any one of paragraphs 18-24, wherein the formulation is a liquid formulation. EXAMPLES Methods: Previously obese HF mice: Group housed male C57BL / 6J mice were provided ad libitum a high fat diet (35% kcal from fat; 5TLN Test Diet, Purina Mills Inc.) for one year prior to any subsequent experimentation. Prior to pharmacological manipulation, mice were single-housed and counterbalanced by weight into Veh (n=4) or Calcitriol (n=5) groups. Veh (98% oil, 2% EtOH, 0.1% saccharin) or Calcitriol (in vehicle) was delivered to their mouth cavity using a 44 078245 / 00730 45698823.1 Attorney Docket #: YU 8869 PCT metal feeding tube attached to a syringe. Mice readily consumed the palatable oral solution. Oral delivery and BW (body weight) measurements were conducted daily throughout the experiment. For days 1-31, the Calcitriol group was treated with 1 µg / kg, and for days 32-52 they received 0.5 µg / kg. On day 54, mice were sacrificed, various tissues were recovered, and serum from trunk blood was collected and stored at -80 for calcium level analysis. QuantiChrom Calcium Assay Kit (DICA-500, Bio-Assay Systems) was used per manufacturer instructions to assess calcium levels. Concurrent treatment with HFD: Male C57BL / 6J mice were single-housed and grouped by bodyweight into Veh or Calcitriol groups. On day 0, mice were treated orally with Veh (98% oil, 2% EtOH, 0.1% saccharin) or Calcitriol 1 µg / kg and their std. chow was replaced with a high fat diet (35% kcal from fat; 5TLN Test Diet, Purina Mills Inc.). Oral treatment was provided daily, and BW was assessed daily as well through day 31. On day 32, the diet was replaced with a higher fat content diet (45% kcal from fat, D12451 Research Diets Inc.) and daily oral treatment and BW measurements continued through day 44. On day 45, calcitriol was discontinued, and all mice received oral vehicle daily and BW was assessed through day 60. On day 61, oral treatment of vehicle was discontinued, and BW was assessed through day 66. Future intranasal delivery of calcitriol methods: Calcitriol will be presented (up to 20 µl) to the nasal entrance of awake mice with a metal feeding tube attached to a syringe. Various doses can be accommodated as needed with this volume with the goal of using reduced doses of daily calcitriol via this method. Body weight will be monitored with concurrent fat diet as well as with mice previously exposed to high fat diet. Results and Discussion Daily delivery of oral calcitriol works well as a non-invasive and minimally stressful treatment technique. Calcitriol robustly reduced bodyweight (BW) in mice previously exposed to a year of high fat (HF) diet and prevented BW gain in normal weight mice upon HF diet exposure over time. 45 078245 / 00730 45698823.1 Attorney Docket #: YU 8869 PCT In mice that had been previously exposed to their HF diet for one year prior to experimentation, daily oral calcitriol robustly reduced BW over time vs vehicle treated mice. This reduction was maintained and stabilized with a lower concentration of calcitriol (FIG. 1A and 1B). Thus, chronic Oral Administration of Calcitriol Reduces Body Weight During a High Fat Diet. Calcitriol treatment normalizes body weight in chronically obese mice (FIG. 1C), showing an approximately 20% reduction in body weight at 21 days. This degree of reduction is comparable to the amounts seen with a GLP-1 R agonis (semaglutide) t (FIG. 1D).. Serum calcium levels were found to be similar in both groups at the end of the experiment (FIG.2). These data provide evidence that calcitriol is sufficient to reduce body weight even after long-term obesity and its metabolic consequences. In the concurrent treatment paradigm, daily oral calcitriol prevented the corresponding BW gain observed in the vehicle treated mice, with both groups exposed to HF diets. This was observed with two different HF diets, with different nutritional compositions. Upon cessation of calcitriol treatment, the mice in the calcitriol group showed a brief rebound in BW, and then matched the same rate of BW gain observed in the vehicle group while maintaining significant separation (FIG.3). These data demonstrate the potential for calcitriol in prevention of weight gain during consumption of high fat and high fat / high-sugar diets. This could be relevant for pharmacogenetic approaches that target treatment for people with genetic propensity for weight gain. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of skill in the art to which the disclosed invention belongs. Publications cited herein and the materials for which they are cited are specifically incorporated by reference. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims. 46 078245 / 00730 45698823.1

Claims

Attorney Docket #: YU 8869 PCT We claim:

1. A method of treating obesity comprising administering to a subject in need thereof, a composition comprising a vitamin D receptor agonist (VDRA), for an effective amount of time, to treat on or more symptoms of obesity.

2. A method of preventing one or more symptoms associated with obesity in a subject, comprising administering to the subject, a composition comprising a vitamin D receptor agonist (VDRA),, optionally, wherein the subject is on a high fat diet.

3. The method of claim 1 or 2, wherein the VDRA includes the following core structure represented by the general formula: I. 4.or 2, wherein the VRDA is selected from the group consisting of calcitriol, ercalcitriol, calciferol (ergocalciferol), calcidiol, calcipotriol, doxercalciferol, alfacalcidol, tacalcitol, paricalcitol, oxacalcitriol, falecalcitriol, eldecalcitol and secalciferol.

5. The method of claim 1, wherein the VDRA is calcitriol.

6. The composition of claim 1, wherein the VDRA is in an effective amount to increase the release of one or more satiety signals when administered to a subject in need thereof.

7. The method of claim 1 wherein the composition is administered for at least 10 days, and up to one month, optionally, daily.

8. The method of claim 7, wherein the composition is administered at a first effective dose for at least two weeks, followed by administration of a second effective dose (the maintenance dose), wherein the maintenance dose is at least half, a third or a quarter of the first effective dose. 47 078245 / 0073045698823.1Attorney Docket #: YU 8869 PCT 9. The method of claim 7, wherein the composition is administered for at least one month.

10. The method of claim 1, wherein the composition is administered intranasally, optionally, in the form of a liquid.

11. The method of claim 1, wherein the subject’s daily body weight reduces following administration of the composition.

12. The method of claim 1 wherein VDRA is in an effective amount to increase dopamine release from dopaminergic neurons in the subject.

13. The method of claim 1, wherein VDRA is in an effective amount to increase upregulate TH (tyrosine hydroxylase) and / or Slc6a3 (solute carrier family 6 member 3) gene expression in a subject or Drd2 (dopamine receptor D2) mRNA level in nucleus accumbens in the subject.

14. The method of claim 1, wherein the composition comprising the VRDA is administered alone or in combination with one or more additional active agents.

15. The method of claim 14, wherein the active agent is leptin.

16. The method of claim15, wherein the active agent is Glucagon-like peptide-1 (GLP-1) agonist.

17. The method of claim 16, wherein the GLP-1 agonist is selected from the group consisting of dulaglutide, exenatide, semiglutide, liraglutide, and lixisenatide.

18. A composition for treating or preventing obesity comprising a unit dosoage form of a vitamin D receptor agonists / activator (VDRA) in an effective amount to treat reduce one or mor symptoms associated with obesity, optionally, wherein the VDRA wherein the compound is present in the dosage formulation in a therapeutically effective amount to induce weight loss and / or reduce the body fat..

19. The composition of claim 18, wherein the VDRA includes the following core structure represented by the general formula: 48 078245 / 0073045698823.1Attorney Docket #: YU 8869 PCT I.

20. 18 or 19, wherein the VRDA is selected from thegroup calciferol (ergocalciferol), calcidiol, calcipotriol, doxercalciferol, alfacalcidol, tacalcitol, paricalcitol, oxacalcitriol, falecalcitriol, eldecalcitol and secalciferol.

21. The composition of any one of claims 18-20, wherein the VDRA is calcitriol.

22. The composition of any one of claims 18-20, wherein the VDRA is in an effective amount to increase the release of one or more satiety signals when administered to a subject in need thereof.

23. The composition of any one of claims 18-20, wherein the VDRA is in an effective amount to increase dopamine release from dopaminergic neurons when administered to a subject in need thereof.

24. The composition of any one of claim 18-20, wherein VDRA is in an effective amount to increase upregulate TH (tyrosine hydroxylase) and / or Slc6a3 (solute carrier family 6 member 3) gene expression in a subject or Drd2 (dopamine receptor D2) mRNA level in nucleus accumbens.

25. The composition of any one of claims 18-20, wherein the dosage formulation is a pharmaceutically acceptable oral or intravenous dosage formulation.

26. The composition of any one of claims 18-20, wherein the dosage formulation is a pharmaceutically acceptable oral dosage formulation selected from the group consisting of tablets, capsules, solutions, suspensions, syrups, and lozenges.

27. The composition of any one of claims 18-20, wherein the dosage formulation is suitable for intranasal administration and comprises a pharmaceutically acceptable carrier for intranasal deliver. 49 078245 / 0073045698823.1Attorney Docket #: YU 8869 PCT 28. The composition of any one of claims 18-20, wherein the formulation is a liquid formulation. 50 078245 / 0073045698823.1

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