Use of aprepitant and cyclic dipeptide for weight control

Abstract

Disclosed herein include methods, compositions, and kits suitable for use in preventing, slowing the progression of or treating obesity and weight controlling. The method can comprise administering to a subject a composition comprising a neurokinin 1 receptor (NK1R) antagonist (e.g., aprepitant) and a cyclic dipeptide (e.g., cyclo(His-Pro)).

Description

USE OF APREPITANT AND CYCLIC DIPEPTIDE FOR WEIGHT CONTROLRELATED APPLICATIONS

[0001] The present application claims priority to U.S. Provisional Application No. 63 / 569635, filed on March 25, 2024, the content of this related application is incorporated herein by reference in its entirety for all purposes.BACKGROUNDField

[0002] The present disclosure relates generally to the fields of medicine. One aspect relates to the preventing, slowing the progression of or treating obesity using a neurokinin 1 receptor (NK1R) antagonist (e.g., aprepitant) and a cyclic dipeptide (e.g., cyclo(His-Pro)). Another aspect relates to weight controlling using a neurokinin 1 receptor (NK1R) antagonist (e.g., aprepitant) and a cyclic dipeptide (e.g., cyclo(His-Pro)).Description of the Related Art

[0003] Obesity is a disorder characterized by the accumulation of excess fat in the body. Obesity has been recognized as one of the leading causes of disease and is emerging as a global problem. Various methods of treating obesity and related conditions, involve administering certain medications or combinations thereof. For example, a number of references disclose the administration of certain weight loss medications that include an anticonvulsant, an opioid antagonist, glucagon-like peptide 1 (GLP-1) receptor agonist and / or a norepinephrine reuptake inhibitor (NRI) to a patient to affect weight loss.

[0004] Despite public health efforts and application of current anti-obesity agents, obesity is still increasingly prevalent in industrialized nations because of reasons such as the abundance of food and the reduced activity levels that accompany the movement of populations from rural to urban settings. Therefore, there is a need for improved weight loss agents and methods.SUMMARY

[0005] Disclosed herein include methods for preventing, slowing the progression of or treating obesity. In some embodiments, the method comprises administering to a subject in need thereof (i) aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug thereof, and (ii) a cyclic dipeptide, thereby preventing, slowing the progression of or treating obesity.

[0006] Disclosed herein include methods for controlling weight. In some embodiments, the method comprises administering to a subject in need thereof a compositioncomprising (i) aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug thereof, and (ii) a cyclic dipeptide, thereby reducing, maintaining or preventing increase of weight in the subject.

[0007] In some embodiments, the subject is administrated with a therapeutically or prophylactically effective amount of aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof. In some embodiments, the subject is administrated with a therapeutically or prophylactically effective amount of the cyclic dipeptide.

[0008] The subject can be a mammal. In some embodiments, the subject is a human. In some embodiments, the subject in need thereof is diagnosed with overweight or obesity. In some embodiments, the obesity is visceral obesity or abdominal obesity. In some embodiments, the subject in need thereof has a body mass index (BMI) of at least 25 kg / m2.

[0009] In some embodiments, the cyclic dipeptide is a histidine-containing, tyrosinecontaining and / or proline-containing cyclic dipeptide. In some embodiments, the cyclic dipeptide is cyclo(His-Pro), cyclo(D-8-acetoxyl-Pro-L-Leu) or cyclo(Pro-Gly).

[0010] In some embodiments, aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer thereof, and / or the cyclic dipeptide is formulated into a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients. In some embodiments, aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer thereof, and / or the cyclic dipeptide is administered to the subject by intravenous administration, nasal administration, pulmonary administration, oral administration, parenteral administration, or nebulization. In some embodiments, aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer thereof, and / or the cyclic dipeptide is administered to the subject by oral or intravenous administration. In some embodiments, aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer thereof, and / or the cyclic dipeptide is in the form of powder, pill, tablet, microtablet, pellet, micropellet, capsule, capsule containing microtablets, liquid, aerosols, or nanoparticles. In some embodiments, aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer thereof, and / or the cyclic dipeptide is administered to the subject once, twice, or three times a day. In some embodiments, aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer thereof, and / or the cyclic dipeptide is administered to the subject once every day, every two days, or every three days. In some embodiments, aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer thereof is administered to the subject at an effective daily dose of aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer thereof at from 10 mg to 250 mg. In some embodiments, the cyclic dipeptide is administered to the subject at an effective daily dose of the cyclic dipeptide at from 1 mg to 500 mg. In some embodiments, the subject is administrated with one or more additional therapeutic agents.

[0011] The method can further comprise measuring body weight and / or body mass index (BMI) of the subject before administering aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer thereof, and / or the cyclic dipeptide to the subject, after administering aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer thereof, and / or the cyclic dipeptide to the subject, or both. In some embodiments, administering aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer thereof, and the cyclic dipeptide reduces body weight and / or body mass index (BMI) by at least 10%. In some embodiments, the reduction of body weight and / or BMI is more than the additive reduction achieved by administrating aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer thereof along, or the cyclic dipeptide alone. In some embodiments, a change in body weight and / or body mass index (BMI) of the subject is by less than 10% for at least 3 months, optionally less than 2% for at least 6 months.

[0012] Disclosed herein include kits. In some embodiments, the kit comprises aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug thereof; a cyclic dipeptide; and a label indicating: (a) the kit is for preventing, slowing the progression of or treating obesity, and / or (b) the kit is for controlling weight.

[0013] Disclosed herein include compositions. In some embodiments, the composition comprises (i) aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug thereof, and (ii) a cyclic dipeptide for use in preventing, slowing the progression of or treating obesity in a subject. In some embodiments, the composition comprises(i) aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug thereof, and(ii) a cyclic dipeptide for use in controlling weight in a subject.

[0014] In some embodiments, the cyclic dipeptide is a histidine-containing, tyrosinecontaining and / or proline-containing cyclic dipeptide. In some embodiments, the cyclic dipeptide is cyclo(His-Pro) or cyclo(Pro-Gly).DETAILED DESCRIPTION

[0015] The illustrative embodiments described in the detailed description, and claims are not meant to be limiting. Other embodiments may be utilized, and other changes may be made, without departing from the spirit or scope of the subject matter presented herein. It will be readily understood that the aspects of the present disclosure, as generally described herein, can be arranged, substituted, combined, separated, and designed in a wide variety of different configurations, all of which are explicitly contemplated herein and made part of the disclosure herein.

[0016] All patents, published patent applications, other publications, and sequences from GenBank, and other databases referred to herein are incorporated by reference in theirentirety with respect to the related technology.

[0017] Disclosed herein include methods for preventing, slowing the progression of or treating obesity. In some embodiments, the method comprises administering to a subject in need thereof (i) a NK1R antagonist (e.g., aprepitant) or a pharmaceutically acceptable salt, solvate, stereoisomer thereof, and (ii) a cyclic dipeptide, thereby preventing, slowing the progression of or treating obesity.

[0018] Disclosed herein include methods for controlling weight. In some embodiments, the method comprises administering to a subject in need thereof a composition comprising (i) a NK1R antagonist (e.g., aprepitant) or a pharmaceutically acceptable salt, solvate, stereoisomer thereof, and (ii) a cyclic dipeptide, thereby reducing, maintaining or preventing increase of weight in the subject.

[0019] There are provided, in some embodiments, kits. The kit can comprise: a NK1R antagonist (e.g., aprepitant) or a pharmaceutically acceptable salt, solvate, stereoisomer thereof, a cyclic dipeptide, and a label indicating: (a) the kit is for preventing, slowing the progression of or treating obesity, and / or (b) the kit is for controlling weight.

[0020] There are provided, in some embodiments, compositions. The composition can comprise: (i) a NK1R antagonist (e.g., aprepitant) or a pharmaceutically acceptable salt, solvate, stereoisomer thereof, and (ii) a cyclic dipeptide for use in preventing, slowing the progression of or treating obesity in a subject. The composition can comprise: (i) a NK1R antagonist (e.g., aprepitant) or a pharmaceutically acceptable salt, solvate, stereoisomer thereof, and (ii) a cyclic dipeptide for use in controlling weight in a subject.Definitions

[0021] Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present disclosure belongs. See, e.g. Singleton et al., Dictionary of Microbiology and Molecular Biology 2nd ed., J. Wiley & Sons (New York, NY 1994); Sambrook et al., Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Press (Cold Spring Harbor, NY 1989). For purposes of the present disclosure, the following terms are defined below.

[0022] As used herein, a "subject" refers to an animal that is the object of treatment, observation or experiment. "Animals" include cold- and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals. "Mammal" includes, without limitation, mice; rats; rabbits; guinea pigs; dogs; cats; sheep; goats; cows; horses; primates, such as monkeys, chimpanzees, and apes, and, in particular, humans.

[0023] As used herein, a "patient" refers to a subject that is being treated by a medical professional, such as a Medical Doctor (z.e. Doctor of Allopathic medicine or Doctor ofOsteopathic medicine) or a Doctor of Veterinary Medicine, to attempt to cure, or at least ameliorate the effects of, a particular disease or disorder or to prevent the disease or disorder from occurring in the first place.

[0024] As used herein, "administration" or "administering" refers to a method of giving a dosage of a pharmaceutically active ingredient to a vertebrate.

[0025] As used herein, a "dosage" refers to the combined amount of the active ingredients (e.g., NK1R antagonist).

[0026] As used herein, a "unit dosage" refers to an amount of therapeutic agent administered to a patient in a single dose.

[0027] As used herein, a "daily dosage" refers to the total amount of therapeutic agent administered to a patient in a day,

[0028] As used herein, "therapeutically effective amount" or "pharmaceutically effective amount" is meant an amount of therapeutic agent, which has a therapeutic effect. The dosages of a pharmaceutically active ingredient which are useful in treatment are therapeutically effective amounts. Thus, as used herein, a therapeutically effective amount means an amount of therapeutic agent which produces the desired therapeutic effect as judged by clinical trial results and / or model animal studies.

[0029] As used herein, a "therapeutic effect" relieves, to some extent, one or more of the symptoms of a disease or disorder. For example, a therapeutic effect may be observed by a reduction of the subjective discomfort that is communicated by a subject (e.g., reduced discomfort noted in self-administered patient questionnaire). "Treat," "treatment," or "treating," as used herein refers to administering a therapeutic agent or pharmaceutical composition to a subject for prophylactic and / or therapeutic purposes. The term "prophylactic treatment" refers to treating a subject who does not yet exhibit symptoms of a disease or condition, but who is susceptible to, or otherwise at risk of, a particular disease or condition, whereby the treatment reduces the likelihood that the patient will develop the disease or condition. The term "therapeutic treatment" refers to administering treatment to a subject already suffering from a disease or condition.

[0030] As used herein, "body mass index" or "BMI" is calculated by dividing weight by height squared.Obesity

[0031] Obesity is a condition in which excess body fat has accumulated to such an extent that health may be negatively affected. It is commonly defined as a body mass index (BMI) of 30 kg / m2or higher. Overweight is distinguished and defined as a BMI between 25-29.9 kg / m2. In some embodiment, the subjects treated or to be treated with the method disclosed herein has a BMI of at least 23 kg / m2(e.g., at least 23 kg / m2, at least 23.5 kg / m2, at least 24 kg / m2, at least 24.5 kg / m2, at least 25 kg / m2, at least 25.5 kg / m2, at least 26 kg / m2, at least 26.5 kg / m2, at least 27 kg / m2, at least 27.5 kg / m2, at least 28 kg / m2, at least 28.5 kg / m2, at least 29 kg / m2, at least 29.5 kg / m2, at least 30 kg / m2, at least 30.5 kg / m2, at least 31 kg / m2, at least 31.5 kg / m2, at least 32 kg / m2, at least 32.5 kg / m2, at least 33 kg / m2, at least 33.5 kg / m2, at least 34 kg / m2, at least 34.5 kg / m2, at least 35 kg / m2, at least 35.5 kg / m2, at least 36 kg / m2, at least 36.5 kg / m2, at least 37 kg / m2, at least 37.5 kg / m2, at least 38 kg / m2, at least 38.5 kg / m2, at least 39 kg / m2, at least 39.5 kg / m2, at least 40 kg / m2, at least 40.5 kg / m2, at least 41 kg / m2, at least 41.5 kg / m2, at least 42 kg / m2, at least 42.5 kg / m2, at least 43 kg / m2, at least 43.5 kg / m2, at least 44 kg / m2, at least 44.5 kg / m2, at least 45 kg / m2, at least 45.5 kg / m2, at least 46 kg / m2, at least 46.5 kg / m2, at least 47 kg / m2, at least 47.5 kg / m2, at least 48 kg / m2, at least 48.5 kg / m2, at least 49 kg / m2, at least 49.5 kg / m2or at least 50 kg / m2).

[0032] Excessive body weight is associated with various diseases, particularly cardiovascular diseases, diabetes mellitus type 2, obstructive sleep apnea, certain types of cancer, and osteoarthritis. As a result, obesity has been found to reduce life expectancy. The primary treatment for obesity is dieting and physical exercise. If diet and exercise fail, antiobesity drugs and bariatric surgery may be recommended in severe cases.

[0033] The pathogenesis of obesity is multi -factorial and includes the control of feeding behavior, mechanisms of fat storage, the components of energy intake and expenditure, and genetic and psychological influences. Likewise, the treatment of obesity is generally multifactorial. Unfortunately, the mechanisms of fat storage and genetic influences are not, generally speaking, amenable to treatment. Moreover, the control of feeding behavior and psychological influences require prolonged treatment. Although the components of energy intake and expenditure are treatable, many obese individuals are resistant to or incapable of engaging in activities, which significantly increase their energy expenditure. Therefore, controlling energy intake is an attractive approach for the treatment of obesity. In some embodiments, the method disclosed herein does not require activities of controlling energy intake and expenditure.

[0034] In some embodiments, the subject in need thereof is diagnosed with overweight or obesity. In some embodiments, the obesity is visceral obesity or abdominal obesity.Methods of Preventing, Slowing the Progression of or Treating Obesity and Controlling Weight

[0035] Aprepitant is a highly selective antagonist of the G-protein coupled neurokinin-1 receptor (NK1R). NK1R is a member of the tachykinin receptor family thatpreferentially binds the tachykinin substance P (SP) (Ubaldi et al. "Emerging targets for addiction neuropharmacology: from mechanisms to therapeutics." Progress in brain research. Vol. 224. Elsevier, 2016. 251-284; incorporated herein by reference in its entirety). NKIRs are widely distributed on human pulmonary arterial blood vessels, on circular and longitudinal smooth muscle throughout the human gastrointestinal tract, and over ganglia of the myenteric plexus. These receptors have been also located in the placenta, thyroid gland, endothelial cells, immune cells (e.g., dendritic cells, macrophages, monocytes, and lymphocytes) and in platelets.

[0036] SP is an 11 -amino acid peptide that belongs to the tachykinin family of peptides. SP is the most abundant NK and is involved in many physiological processes, such as in the gastrointestinal, bronchial, and vascular systems. For example, the potent vasodilator action of SP is mediated primarily by binding to NK1 receptors on the endothelium of peripheral arterial blood vessels. Substance P (SP) receptors are present in thymocytes, B and T lymphocytes, macrophages, mast cells, and astrocytes (Berczi et al. "Neuropeptides in Immunoregulation." Insights to Neuroimmune Biology. Elsevier, 2016. 133-181; incorporated herein by reference in its entirety). SP is a major mediator of neurogenic inflammation and capable of inducing mast cell degranulation, plasma extravasation, and bronchoconstriction (Berczi et all). SP acts on lymphocytes, macrophages, and neutrophils (Berczi et all). Lymphocyte proliferation and lymphokine production are enhanced by SP, whereas the effect on immunoglobulin secretion is variable (Berczi et all). SP increased Fey and receptors, decreased C3b on eosinophils, released TNF-a from macrophages, and modified macrophage function during stress (Berczi et all).

[0037] More recently, SP is found to be abundant in the stomach, duodenum, and jejunum, all important areas for digestion and nutrient uptake, as well as in hypothalamic areas implicated in feeding behavior, such as the arcuate and ventromedial nuclei. Moreover, the presence of NK-1R in the hypothalamus and adipose tissue has also been discovered. The presence of SP in the hypothalamus and other areas of the brain that regulate feeding as well as in the stomach and small intestine evidences its role on appetite control and energy balance.

[0038] The glycosylation / phosphorylation of the NK1 receptor influences the NK1 receptor signaling. SP generates second messengers and affects many signaling pathways controlling the cell function: activation of phospholipases A2 / C, protein kinases A / C and adenylyl cyclase, synthesis of diacylglicerol / inositol triphosphate / arachidonic acid, mobilization of intracellular Ca2+generation of thromboxane / leukotrienes, phosphorylation of myosin regulatory light chain, and activation of Rho-associated protein-kinase (ROCK). SP, via the NK1 receptor, transactivates the epidermal growth factor receptor (EGFR) leading to the activation of mitogen-activated protein kinases (MAPK), extracellular signal-regulated kinases(ERK) 1 and 2, DNA synthesis and proliferation. SP exerts an antiapoptotic effect involving the Janus kinase 2 (JAK-2) and phosphoinositide 3 -kinase (PI3K)-mediated activation of the antiapoptotic molecule Akt (protein kinase B). SP activates p38, promotes the synthesis of proinflammatory cytokines (e.g., interleukin-6, interleukin-8) and activates proinflammatory transcription factors (e.g., nuclear factor kappa B (NF-KB) by mechanisms in which the activation of the Rho family kinases is involved).

[0039] The NK-1 receptor has been a therapeutic target for the treatment of functional gastrointestinal disorders (FGIDs), such as dyspepsia and irritable bowel syndrome (IBS). FGIDs are diagnosed by the presence of recurrent symptoms of abdominal pain or discomfort, and often subjects with IBS generally present with diarrhea or constipation. Evidence for the role of neurokinins in abdominal pain has been observed in a double-blind study in which the NK-1 antagonist (CJ-11,974) alleviated the discomfort associated with rectosigmoidal distension in patients with IBS. Both NK-1 and NK-2 receptor antagonists have been investigated for their potential use in alleviating symptoms of food allergy and IBS. The NK-2 receptor antagonist nepadutant (MEN 11420) effectively antagonized the motilitystimulating effect of neurokinin A without affecting basal gastrointestinal motility.

[0040] When released from intrinsic enteric or extrinsic primary afferent neurons, tachykinins, such as substance P, have the potential to influence both nerves and muscles by way of interactions with NK1, NK2, and NK3 receptors. Most prominent among the effects of tachykinins is their excitatory action on mammalian gastrointestinal motor activity by direct activation of the muscle through NK1 and / or NK2 receptors or by stimulation of excitatory enteric motor pathways through NK3 and / or NK1 receptors. In addition, tachykinins can inhibit motor activity by stimulating either inhibitory neuronal pathways or interrupting excitatory relays.

[0041] NK1 receptor antagonists have also been shown to be effective for vomiting and have, therefore, explored as antiemetic agents. The central conductor orchestrating the vomiting mechanism has been called the vomiting center (emetic center). Rather than being a distinct anatomical area this is considered more of a functional zone or a signal generating area in the medulla and comprises the reticular formation and the nucleus tractus solitarius. This center receives input from various areas of the body which include vagal afferents from the gastrointestinal (GI) tract, psychogenic stimuli from the cerebral cortex and stimuli from the vestibular and visual areas as well as the chemoreceptor trigger zone (CTZ). Chemoreceptors and mechanoreceptors in the GI tract can sense various chemical (e.g., medications) and mechanical stimuli. Afferent fibers take this signal to the emesis center, primarily via vagal pathways. Enterochromaffin cells (ECC) detect these various stimuli and release mediators thatstimulate the vagal pathways. A variety of chemical mediators (e.g., substance P acting on the NK1 receptor) are involved. SP can also impact gastric emptying and energy balance. Moreover, administration of the NK-1R pharmacologic inhibitor, CJ 012,255, ameliorates the weight gain induced by feeding with high-caloric content diets, and improves the ability to remove glucose from the blood and respond to insulin.

[0042] There are provided, in some embodiments, methods and compositions for preventing, slowing the progression of or treating obesity. In some embodiments, the method comprises: administering to a subject in need thereof (i) aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug thereof, and (ii) a cyclic dipeptide, thereby preventing, slowing the progression of or treating obesity. Disclosed herein include methods and compositions for controlling weight. In some embodiments, the method comprises: administering to a subject in need thereof a composition comprising (i) aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug thereof, and (ii) a cyclic dipeptide, thereby reducing, maintaining or preventing increase of weight in the subject.

[0043] In some embodiments, the composition comprises a therapeutically or prophylactically effective amount of a NK1R antagonist (e.g., aprepitant) or a pharmaceutically acceptable salt, solvate, stereoisomer thereof. In some embodiments, the composition comprises a therapeutically or prophylactically effective amount of a cyclic dipeptide (e.g., cyclo(His- Pro)). In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the subject in need thereof is diagnosed with overweight or obesity. In some embodiments, the obesity is visceral obesity or abdominal obesity. In some embodiments, the subject in need thereof has a body mass index (BMI) of at least 25 kg / m2.

[0044] In some embodiments, the method can comprise administering to the subject a weight loss medication (e.g., Ozempic®). The weight loss medication (e.g., Ozempic®) can be co-administered to the subject with the composition. The weight loss medication (e.g., Ozempic®) can be co-administered to the subject with the composition simultaneously. The weight loss medication (e.g., Ozempic®) can be administered to the subject before the administration of the composition, after the administration of the composition, or both. In certain embodiments, the subject is administered with the weight loss medication (e.g., Ozempic®) before being administered with the composition. In some embodiments, the weight loss medication (e.g., Ozempic®) is administered about, at least about or at most about 1 minute, 2, minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 2, hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 1 day, 2days, 3 days, 4 days, 5 days, 6 days, 1 week, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 2 weeks, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 3 weeks, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 1 month, 2 months, 3 months before the administration of the composition. The composition can comprise a weight loss medication (e.g., Ozempic®).

[0045] Administering the composition can result in an at least, or at least about, 2% (e.g., 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%,19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%,35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%,51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%,67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, or a number or a range between any two of these values) reduction in the body weight of the subject. In some embodiments, administering the composition can result in an at least, or at least about, 2% (e.g., 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%,36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%,52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%,68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, or a number or a range between any two of these values) reduction in BMI of the subject.

[0046] In some embodiments, administering the composition can maintain or prevent increase of weight and / or BMI of the subject. In some embodiments, administering the composition can result in a less than 2% (e.g., 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, or a number or a range between any two of these values) change in the weight of the subject over a period of time. In some embodiments, administering the composition can result in a less than 2% (e.g., 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, or a number or a range between any two of these values) change in BMI of the subject over a period of time. In some embodiments, the period of time is at least 1 month (e.g., 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, 4 years, or 5 years).

[0047] The method can comprise measuring body weight and / or body mass index(BMI) of the subject before administering aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer thereof, and / or the cyclic dipeptide to the subject, after administering aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer thereof, and / or the cyclic dipeptide to the subject, or both. In some embodiments, administering the composition reduces, maintains, or prevents increase of body weight and / or BMI of the subject.

[0048] As disclosed herein, co-administration of particular ratios and / or amounts of an NK1R antagonist (e.g., aprepitant) and a cyclic dipeptide (e.g., cyclo(His-Pro)) can result in synergistic effects in preventing, slowing the progression of or treating obesity. As disclosed herein, co-administration of particular ratios and / or amounts of an NK1R antagonist (e.g., aprepitant) and a cyclic dipeptide (e.g., cyclo(His-Pro)) can result in synergistic effects in controlling weight. These synergistic effects can be such that the one or more effects of the combination compositions are greater than the one or more effects of each component alone at a comparable dosing level, or they can be greater than the predicted sum of the effects of all of the components at a comparable dosing level, assuming that each component acts independently. The synergistic effect can be, be about, be greater than, or be greater than about, 5%, 10%, 20%, 30%, 50%, 75%, 100%, 110%, 120%, 150%, 200%, 250%, 350%, or 500% better than the effect of administrating one of the components alone, or the additive effects of each of the components when administered individually. The effect can be any of the measurable effects described herein. The composition comprising an NK1R antagonist (e.g., aprepitant) and a cyclic dipeptide (e.g., cyclo(His-Pro)) can be such that the synergistic effect is a reduction in body weight and / or BMI of the subject. In some embodiments, the body weight and / or BMI of the subject is reduced to a greater degree as compared to the sum of the effects of administering each component, determined as if each component exerted its effect independently, also referred to as the predicted additive effect herein. For example, if the NK1R antagonist (e.g., aprepitant) yields an effect of a 20% reduction in the BMI of the subject and the cyclic dipeptide (e.g., cyclo(His- Pro)) yields an effect of 10% reduction in the BMI of the subject, then the composition comprising both the NK1R antagonist (e.g., aprepitant) and the cyclic dipeptide (e.g., cyclo(His- Pro)) would have a synergistic effect if the combination composition's effect on BMI reduction was greater than 30%.

[0049] A synergistic combination composition can have an effect that is greater than the predicted additive effect of administering each component of the combination composition alone as if each component exerted its effect independently. For example, if the predicted additive effect is 70%, an actual effect of 140% is 70% greater than the predicted additive effect or is 1-fold greater than the predicted additive effect. The synergistic effect can be at least, or at least about, 20%, 50%, 75%, 90%, 100%, 150%, 200% or 300% greater than the predictedadditive effect. In some embodiments, the synergistic effect can be at least, or at least about, 0.2- , 0.5-, 0.9-, 1.1-, 1.5-, 1.7-, 2-, or 3-fold greater than the predicted additive effect.Therapeutic Agents

[0050] The NK1R antagonist can be or can include a selective NK1R antagonist. Non-limiting examples of NK1R antagonists include aprepitant (L-754030 or MK-(0)869), fosaprepitant (L-758298), befetupitant, casopitant (GW-679769), dapitant (RPR-100893), ezlopitant (CJ-11974), lanepitant (LY-303870), maropitant (CJ-11972), netupitant, nolpitantium (SR-140333), orvepitant (GW-823296), rolapitant (SCH-619734), SCH-720881 (active metabolite of rolapitant), serlopitant (MK-(0)594 or VPD-737), tradipitant (VLY-686 or LY- 686017), vestipitant (GW-597599), vofopitant (GR-205171), hydroxyphenyl propamidobenzoic acid, maltooligosaccharides (e.g., maltotetraose and maltopentaose), spantides (e.g., spantide I and II), AV-608, AV-818, AZD-2624, BIIF 1149 CL, CGP-49823, CJ-17493, CP-96345, CP- 99994, CP- 122721, DNK-333, FK-224, FK-888, GR-82334, GR-205171, GSK-424887, HSP- 117, KRP-103, L-703606, L-733060, L-736281, L-759274, L-760735, LY-686017, M516102, MDL-105212, MK-0303 (L-001182885), MK- 8478 (L-001983867), NKP-608, R-l 16031, R-l 16301, RP-67580, S-41744, SCH-206272, SCH-388714, SCH-900978, SLV-317, SSR-240600, T-2328, TA-5538, TAK-637, TKA-731, WIN-51708, ZD-4974, ZD-6021, cycloalkyl (including, but not limited to, cyclopentyl, cyclohexyl and cycloheptyl) tachykinin receptor antagonists disclosed in U.S. Patent No. 5,750,549, hydroxymethyl ether hydroisoindoline tachykinin receptor antagonists disclosed in U.S. Patent No. 8,124,633, and analogs, derivatives, prodrugs, metabolites and salts thereof. Non-limiting examples of NK1R antagonists also include Casopitant, CGP49823, CP-122,721, CP-96,345, CP-99,994, FK 888, GR 82334, GR 94800, GR203040, GR-205171, GSK1144814, GSK206136, GSK424887, GW679769, HSP- 117, L 703,606, L 732,138, L 733,060, L 742,694, L668,169, LY 303241, LY 303870, LY 306740, Maropitant, MEN 11149, Orvepitant, PD 154075, R-544, RP-67580, RPR 100893, SCH619734, Spantide II, Spantide III, Spendide, SR140333, Vestipitant, WIN-41,708, WIN- 62,577, and analogs, derivatives, prodrugs, metabolites and salts thereof. Non-limiting examples of NK1R antagonists also include FK 888(Fujisawa); GR 205171 (Glaxo Wellcome); LY 303870 (Lilly); MK 869 (Merck); GR82334 (Glaxo Wellcome); L758298 (Merck); L 733060 (Merck); L 741671 (Merck); L 742694 (Merck); PD 154075 (Parke-Davis); SI 8523 (Servier); SI 9752 (Servier); OT 7100 (Otsuka); WIN 51708 (Sterling Winthrop); NKP-608 A; TKA457; DNK333; CP-96345; CP-99994; CP122721; L-733060; L-741671; L742694; L-758298; L- 754030; GR-203040; GR-205171; RP-67580; RPR-100893 (dapitant); RPR-107880; RPR- 111905; FK-888; SDZ-NKT-343; MEN-10930; MEN-11149; S-18523; S-19752; PD-154075(CAM-4261); SR-140333; LY-303870 (lanepitant); EP-00652218; EP00585913; L-737488; CGP-49823; WIN-51708; SR-48968 (saredutant); SR-144190; YM383336; ZD-7944; MEN- 10627; GR-159897; RPR-106145; PD-147714 (CAM-2291); ZM253270; FK-224; MDL-1 05212 A; MDL-105172 A; L-743986; L-743986 analogs; S- 16474; SR-1 42801 (osanetant); PD- 161182; SB-223412; SB-222200; and analogs, derivatives, prodrugs, metabolites and salts thereof. In some embodiments, the NK1R antagonists comprise:(fosaprepitant).

[0051] Cyclodipeptides (CDPs), also known as 2, 5 -diketopiperazines (2,5-DKP), constitute a fascinating class of cyclic peptides pervasive in nature, arising as secondary metabolites or byproducts of protein metabolism in bacteria, fungi, and animals. These compact, highly stable molecules boast a remarkable diversity of biological and pharmacologicalactivities. Formed through the condensation of two a-amino acids, CDPs feature a piperazine 6- membered ring structure wherein the nitrogen atoms engage in amide linkages. Their nomenclature adopts a three-letter code for each constituent amino acid, augmented by a prefix denoting the absolute configuration, exemplified by cyclo(L-Xaa-L-Yaa). While both cis and trans isoforms exist, cis configurations predominate in nature. Through various amino acid modifications, CDPs acquire a spectrum of chemical and biological functionalities. Notably, their cyclic nature imparts enhanced stability, protease resistance, and conformational rigidity, augmenting their specificity in biological interactions. CDPs and their derivatives have a number of biological activities, including bacterial quorum sensing, antibacterial and antimicrobial effects, anticancer properties, and radical-scavenging capabilities. For example, the CDP -based compound plasminogen activator inhibitor- 1 (PAI-1) acts as a main serine protease inhibitor in humans, and cyclo(His-Pro), a metabolite of TRH precursor, is directly involved in the control of high blood glucose levels, among other functions. Moreover, they have garnered interest for their potential in facilitating the transport of biologically active compounds across the bloodbrain barrier.

[0052] Cyclo(L-His-L-Pro) (or Cyclo(L-histidyl-L-proline)), shown below was the first active CDP and detected in human urine in 1965. Cyclo(His-Pro), or CHP, is a homodetic cyclic peptide resulting from the formal condensation of both the amino and acid groups of L- histidine with the acid and amino groups of L-proline. It is a metabolite of thyrotropin-releasing hormone (TRH). It has a role as a human blood serum metabolite, a dopamine uptake inhibitor and an anti-inflammatory agent. For example, CHP exerts anti-inflammatory effects in vivo in the central nervous system by counteracting the lipopolysaccharide-induced reactive gliosis. CHP may exert its effect through nuclear factor kappa B (NF-KB) and nuclear factor-like 2 (Nrf2). Furthermore, like TRH, CHP can reduce food intake. However, it requires high doses of CHP to reduce food intake, if CHP is administered alone. One reason for this could be that the structure of the CHP molecule is not optimal. Thus, there have been attempts to improve the anorectic potency of CHP by modifying the structure of its molecule. An alternative possibility for the low CHP potency is that it achieves its anorectic effect by modulating neuronal responses to feeding-relevant neurotransmitters. Accordingly, CHP would not be effective when administered alone, but could be very potent when given in combination with an appropriate transmitter-related agent. Cyclo(His-Pro) is ubiquitous in the central nervous system (CNS) and has been found in the gastrointestinal tract and prostate, as well as in several body fluids such as blood, semen, cerebrospinal fluid, and urine.Cyclo(His-Pro)

[0053] In addition to cyclo(His-Pro), a number of CDPs exerts various functions in mammals. For example, cyclo(Pro-Gly) is the only other endogenous CDP reported in the CNS. Found in rat brain, it is a memory-facilitating substance with anxiolytic activity.

[0054] Some CDPs isolated from bacterial can also play a role in mammals. For example, CDPs with the DOPA catechol moiety showed significant radical-scavenging activity, which made them potential antioxidant agents. Cyclo(D-Tyr-D-Phe) isolated from Bacillus sp. N strain has been found to have antitumor property and it also exhibits antioxidant and antibacterial activity. Cyclo(D-8-acetoxyl-Pro-L-Leu), isolated from the Streptomyces sp. revealed preferable anti-lipase activity, and could be well bound with the catalytic pocket of the pancreatic lipase. Pancreatic lipase is an important enzyme in relation to the digestion of dietary triglycerides. Thus, its inhibition is a promising target in the context of obesity treatment. Cyclo(L-Phe-L-Pro), involved in quorum sensing of Vibrio strains, can inhibit cancer cell growth.

[0055] In addition to the activities in mammals discussed above, a greater number of CDPs play a role in quorum sensing in bacteria. Cyclo(L-Ala-L-Val), cyclo(L-Phe-L-Pro), cyclo(L-Pro-L-Tyr) were capable of activating the biosensor depending on their concentrations. These compounds inhibited the N-(3-oxohexanoyl)-L-homoserine lactone (3-oxo-C6-HSL)- mediated induction of bioluminescence, which suggested these CDPs competed for the same LuxR-binding area. Cyclo(L-Phe-L-Pro) enhanced the expression of the ToxR-dependent ompU genes in related Vibrio strains. Furthermore, cyclo(L-Phe-L-Pro) was reported to induce the expression of LeuO in a ToxR-dependent manner and increased the affinity of ToxR binding to the cis-acting element of leuO. Cyclo(L-Pro-L-Leu) and cyclo(L-Pro-L-Phe) produced by Vibrio sp. exhibit the ability to activate QS bioreporters. On the contrary, cyclo(L-Trp-L-Ser) and cyclo(L-Leu-L-Pro) inhibit quorum sensing in Chromobacterium violaceum and Serratia marcescens. respectively.

[0056] Bidirectional communication between the gut microbiome and the central nervous system (CNS) has been reported, raising the possibility that CDPs might also act on the CNS indirectly, by intervening in the human gut microbiome-brain axis. Without wishing to bebound by any particular theory, CDPs may regulate food intake and energy management by modulating activities of gut microbiome. In some embodiment, CDPs modulate gut microbiome through quorum sensing.

[0057] n some embodiments, the cyclic dipeptide is a histidine-containing, tyrosinecontaining and / or proline-containing cyclic dipeptide. In some embodiments, the cyclic dipeptide is cyclo(His-Pro), cyclo(D-8-acetoxyl-Pro-L-Leu), cyclo(Pro-Gly), cyclo(Phe-Pro), cyclo(Tyr-Pro), tyrvalin, phevalin, cyclo(Gly-L-Val), cyclo(Gly-D-Val), cyclo(Gly-L-Leu), cyclo(Gly-L-Ile), cyclo(L-Phe-L-Cys), cyclo(L-Tyr-L-Cys), cyclo(L-Pro-D-Arg), cyclo(D-Tyr- D-Phe), cyclo(L-Trp-L-Trp), cyclo(D-Pro-L-Leu), cyclo(L-Pro-L-Met), cyclo(D-Pro-L-Phe), cyclo(L-Pro-L-Tyr), cyclo(L-Leu-L-Pro), cyclo(D-Pro-D-Phe), cyclo(D-Pro-D-Val), cyclo(D- Pro-D-Ile), cyclo(D-Pro-D-Leu), cyclo(D-trans-4-OH-Pro-D-Phe), cyclo(D-Val-D-Leu), cyclo(L-Pro-L-Leu), cyclo(D-Leu-D-Arg), cyclo(L-Trp-L-Arg), cyclo(D-Trp-D-Arg), cyclo(D- Leu-D-His), cyclo(D-Pro-L-Tyr), cyclo(trans-4-OH-D-Pro-D-Phe), cyclo(L-Trp-L-Phe), cyclo(L-Trp-L-Pro), cyclo(L-Phe-L-Pro), cyclo(L-His-L-Phe), cyclo(L-His-L-Tyr), cyclo(L- Ala-L-Val), cyclo(L-Trp-L-Ser), cyclo(Pro-Ala), cyclo(Pro-Ile), cyclo(Pro-Leu), cyclo(Pro-Ser), cyclo(Pro-Glu), cyclo(Pro-Gln), cyclo(Pro-Cys), cyclo(Pro-Met), cyclo(Pro-Phe), cyclo(Pro- Trp), cyclo(Pro-Tyr), cyclo(Leu-Pro), cyclo(Val-Pro), cyclo(Leu-hydroxy-Pro), cyclo(Gly-Pro), cyclo(L-Ala-L-Pro), cyclo(L-Phe-trans-4-OH-L-Pro), cyclo(L-Pro-L-Leu), cyclo(4-trans- hydroxy-L-Pro-L-Leu), cyclo(4-trans-hydroxy-L-Pro-L-Phe), cyclo(L-Gly-L-Pro), cyclo(L-Arg- D-Pro), cyclo(L-Arg-L-Pro), cyclo(L-His-L-Pro), cyclo(L-Pro-L-Tyr), cyclo(D-Pro-L-Leu), cyclo(D-Pro-L-Phe), cyclo(D-Phe-L-Pro), cyclo(D-Pro-D-Phe). In some embodiments, the cyclic dipeptide comprises cyclic dipeptide derivatives (e.g., spiro-2, 5-diketopiperazine)

[0058] The CDP scaffold can be synthesized either by purely chemically means using different solid-phases or under reflux conditions in solution or more naturally, by biosynthetic enzymes called non-ribosomal peptide synthetases (NRPSs) and CDP synthases (CDPSs). Common chemical synthesis of CDPs includes the condensation of individual amino acids at high temperature. Dipeptides substituted with an amine at one terminus and an ester at the other can also spontaneously cyclize to form a 2,5-DKP. Non-enzymatic processes can also lead to the formation of functional CDPs in various organisms, for example, cyclo(L-His-L-Pro) is found throughout the central nervous systems of mammals.

[0059] In some embodiments, additional weight loss medication or anti -obesity agent is administrated to the subject. In some embodiments, the weight loss medication or anti -obesity agent is phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, a cholecystokinin-A agonist, a monoamine reuptake inhibitor (such as sibutramine), a sympathomimetic agent, a serotonergic agent (such as dexfenfluramine or fenfluramine), a dopamine agonist (such asbromocriptine), a melanocyte-stimulating hormone receptor agonist or mimetic, a melanocytestimulating hormone analog, a cannabinoid receptor antagonist, a melanin concentrating hormone antagonist, the OB protein (leptin), a leptin analog, a leptin receptor agonist, a galanin antagonist or a GI lipase inhibitor or decreaser (such as orlistat). Other anorectic agents include bombesin agonists, dehydroepiandrosterone or analogs thereof, glucocorticoid receptor agonists and antagonists, orexin receptor antagonists, urocortin binding protein antagonists, or agonists of the glucagon-like peptide- 1 receptor such as Exendin and ciliary neurotrophic factors such as Axokine.

[0060] In some embodiments, the weight loss medication is a glucagon-like peptide 1 (GLP-1) receptor agonist. A GLP-1 receptor agonist is a ligand capable of binding to the GLP- 1 receptor and producing a biological response similar to that of the endogenous ligand, GLP-1. Examples of GLP-1 receptor agonists include semaglutide (the active pharmaceutical ingredient in Ozempic®, Rybelsus® and Wegovy®), liraglutide (the active pharmaceutical ingredient in Victoza® and Saxenda®), tirzepatide (the active pharmaceutical ingredient in Mounjaro®) and dulaglutide (the active pharmaceutical ingredient in Trulicity®). The physical and chemical properties of the GLP-1 receptor agonists disclosed herein may be readily known to the person skilled in the art. For example, semaglutide is a GLP-1 receptor agonist also known as N626- { 18-[N-(17- carboxyheptadecanoyl)-L-y-glutamyl]-10-oxo-3,6, 12, 15-tetraoxa-9, 18- diazaoctadecanoyl}-[8- (2-amino-2-propanoic acid),34-L-arginine]human glucagon-like peptide 1. Semaglutide was described in W02006 / 097537 and in J. Med. Chem. 2015, 58, 18, 7370- 7380, which are incorporated by reference by their entirety. In some embodiments, the

[0061] In some embodiments, the method can comprise administering to the subject one or more additional therapeutic agents (e.g., antiemetic agents). The additional therapeutic agents (e.g., antiemetic agents) can be co-administered to the subject with the composition. The additional therapeutic agents (e.g., anti emetic agents) can be administered to the subject before the administration of the composition, after the administration of the composition, or both. The composition can comprise one or more additional therapeutic agents (e.g., antiemetic agents). The one or more additional therapeutic agents (e.g., antiemetic agents) can include one or more of the following:

[0062] (i) anti emetic agents, such as granisetron, ondansetron, AZ-001, AZ-004,Levadex, Zelrix, VR-147, ROX-828, COL- 144, BF-1, diphenhydramine and scopolamine;

[0063] (ii) diarrhea therapeutics, such as loperamide, digestive enzymes (lactase) and bismuth subsalicylate;

[0064] (iii) constipation therapeutics, such as linaclotide (Linzess®) or lubiprostone (Amitiza®), methylcellulose, polycarbophil, psyllium, mineral oil, glycerol, docusate sodium,sodium bicarbonate, sodium phosphate, magnesium citrate, magnesium oxide, magnesium sulfate, bisacodyl, sennosides, senna and castor oil; and / or

[0065] (iv) analgesics, such as hydrocodone, morphine, hydromorphone, oxycodone, codeine, levorphanol, meperidine, methadone, oxymorphone, buprenorphine, fentanyl and derivatives thereof, dipipanone, heroin, tramadol, etorphine, dihydroetorphine, butorphanol and levorphanol.

[0066] As disclosed herein, co-administration of particular ratios and / or amounts of an NK1R antagonist (e.g., aprepitant) and one or more additional therapeutic agents (e.g., antiemetic agents) can result in synergistic effects in preventing, slowing the progression of or treating obesity. As disclosed herein, co-administration of particular ratios and / or amounts of an NK1R antagonist (e.g., aprepitant) and one or more additional therapeutic agents (e.g., antiemetic agents) can result in synergistic effects in reducing, maintaining or preventing increase of weight in the subject. As disclosed herein, co-administration of particular ratios and / or amounts of a cyclic dipeptide (e.g., cyclo(His-Pro)) and one or more additional therapeutic agents (e.g., antiemetic agents) can result in synergistic effects in preventing, slowing the progression of or treating obesity. As disclosed herein, co-administration of particular ratios and / or amounts of cyclo(His-Pro) and one or more additional therapeutic agents (e.g., antiemetic agents) can result in synergistic effects in reducing, maintaining or preventing increase of weight in the subject.

[0067] These synergistic effects can be such that the one or more effects of the combination compositions are greater than the one or more effects of each component alone at a comparable dosing level, or they can be greater than the predicted sum of the effects of all of the components at a comparable dosing level, assuming that each component acts independently. The synergistic effect can be, be about, be greater than, or be greater than about, 5%, 10%, 20%, 30%, 50%, 75%, 100%, 110%, 120%, 150%, 200%, 250%, 350%, or 500% better than the effect of one of the components alone, or the additive effects of each of the components when administered individually. The effect can be any of the measurable effects described herein. The composition comprising a plurality of components can be such that the synergistic effect is a reduction in body weight and / or BMI that is reduced to a greater degree as compared to the sum of the effects of administering each component, determined as if each component exerted its effect independently, also referred to as the predicted additive effect herein. For example, if a composition comprising component (a) yields an effect of a 20% reduction in BMI in the subject and a composition comprising component (b) yields an effect of 10% reduction in BMI in the subject, then a composition comprising both component (a) and component (b) would have a synergistic effect if the combination composition's effect on the reduction of BMI was greaterthan 30%.

[0068] A synergistic combination composition can have an effect that is greater than the predicted additive effect of administering each component of the combination composition alone as if each component exerted its effect independently. For example, if the predicted additive effect is 70%, an actual effect of 140% is 70% greater than the predicted additive effect or is 1-fold greater than the predicted additive effect. The synergistic effect can be at least, or at least about, 20%, 50%, 75%, 90%, 100%, 150%, 200% or 300% greater than the predicted additive effect. In some embodiments, the synergistic effect can be at least, or at least about, 0.2- , 0.5-, 0.9-, 1.1-, 1.5-, 1.7-, 2-, or 3-fold greater than the predicted additive effect.

[0069] In some embodiments, the synergistic effect of the combination compositions can also allow for reduced dosing amounts, leading to reduced side effects to the subject and reduced cost of treatment. Furthermore, the synergistic effect can allow for results that are not achievable through any other treatments. Therefore, proper identification, specification, and use of combination compositions can allow for significant improvements in preventing, slowing the progression of or treating obesity, and / or controlling weight.Compositions and Methods of Administration

[0070] There are provided, in some embodiments, kits. The kit can comprise: a NK1R antagonist (e.g., aprepitant) or a pharmaceutically acceptable salt, solvate, stereoisomer thereof, a cyclic dipeptide (e.g., cyclo(His-Pro)), and a label indicating: 23. (a) the kit is for preventing, slowing the progression of or treating obesity, and / or 23. (b) the kit is for controlling weight.

[0071] There are provided, in some embodiments, compositions. The composition can comprise: a NK1R antagonist (e.g., aprepitant) or a pharmaceutically acceptable salt, solvate, stereoisomer thereof and a cyclic dipeptide (e.g., cyclo(His-Pro)), for use in preventing, slowing the progression of or treating obesity in a subject. The composition can comprise: a NK1R antagonist (e.g., aprepitant) or a pharmaceutically acceptable salt, solvate, stereoisomer thereof and a cyclic dipeptide (e.g., cyclo(His-Pro)), for use in controlling weight in a subject.

[0072] The composition can be a pharmaceutical composition comprising a NK1R antagonist (e.g., aprepitant) or a pharmaceutically acceptable salt, solvate, stereoisomer thereof, a cyclic dipeptide (e.g., cyclo(His-Pro)), and one or more pharmaceutically acceptable excipients. In some embodiments, the composition is administered to the subject by intravenous administration, nasal administration, pulmonary administration, oral administration, parenteral administration, or nebulization. In some embodiments, the composition is in the form of powder, pill, tablet, microtablet, pellet, micropellet, capsule, capsule containing microtablets, liquid,aerosols, or nanoparticles. In some embodiments, the composition is administered to the subject once, twice, or three times a day. In some embodiments, the composition is administered to the subject once every day, every two days, or every three days. In some embodiments, the composition is administered to the subject over the course of at least two weeks, at least three weeks, at least four weeks, or at least five weeks.

[0073] In some embodiments, the NK1R antagonist (e.g., aprepitant) and the cyclic dipeptide (e.g., cyclo(His-Pro)) can be administrated to the subject in need thereof simultaneously, separately, or sequentially. The NK1R antagonist and the cyclic dipeptide can be administered in any suitable order. For example, the NK1R antagonist can be administered followed by the cyclic dipeptide. Alternatively or in combination, the cyclic dipeptide can be administered followed by the NK1R antagonist. In some embodiments, the NK1R antagonist can be administered about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 12 hours, about 18 hours, about 24 hours (1 day), about 2 days, about 3 days, about 4 days, about 5 days, about 6 days (1 week), about 2 weeks, about 3 weeks, about 4 weeks (1 month), about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 5 months, or about 6 months the cyclic dipeptide. In some embodiments, the cyclic dipeptide can be administered about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 12 hours, about 18 hours, about 24 hours (1 day), about 2 days, about 3 days, about 4 days, about 5 days, about 6 days (1 week), about 2 weeks, about 3 weeks, about 4 weeks (1 month), about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 5 months, or about 6 months before the NK1R antagonist. NK1R antagonist (e.g., aprepitant) and an additional therapeutic agent can be, for example, coadministered simultaneously or sequentially. The cyclic dipeptide (e.g., cyclo(His-Pro)) and an additional therapeutic agent can be, for example, co-administered simultaneously or sequentially.

[0074] In some embodiments, aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer thereof is administered to the subject at an effective daily dose of aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer thereof at from 10 mg to 250 mg. In some embodiments, the cyclic dipeptide is administered to the subject at an effective daily dose of the cyclic dipeptide at from 1 mg to 500 mg.

[0075] The therapeutically effective amount and the frequency of administration of, and the length of treatment with, the NK1R antagonist (e.g., aprepitant) and the cyclic dipeptide (e.g., cyclo(His-Pro)) may depend on various factors, including the potency of the NK1R antagonist, the potency of the cyclic dipeptide, the mode of administration, the age, the BMI, the body weight, the general health, the gender and the diet of the subject, and the response of thesubject to the treatment, and can be determined by the treating physician.

[0076] In some embodiments, a therapeutically effective amount of the NK1R antagonist (e.g., aprepitant) for preventing, slowing the progression of or treating obesity as described herein is about 0.1-200 mg, 0.1-150 mg, 0.1-100 mg, 0.1-50 mg, 0.1-30 mg, 0.5-20 mg, 0.5-10 mg or 1-10 mg (e.g., per day or per dose), or as deemed appropriate by the treating physician, which can be administered in a single dose or in divided doses. In certain embodiments, the therapeutically effective dose (e.g., per day or per dose) of the NK1R antagonist (e.g., aprepitant) for preventing, slowing the progression of or treating obesity as described herein is about 0.1-1 mg (e.g., about 0.1 mg, 0.5 mg or 1 mg), about 1-5 mg (e.g., about 1 mg, 2 mg, 3 mg, 4 mg or 5 mg), about 5-10 mg (e.g., about 5 mg, 6 mg, 7 mg, 8 mg, 9 mg or 10 mg), about 10-20 mg (e.g., about 10 mg, 15 mg or 20 mg), about 20-30 mg (e.g., about 20 mg, 25 mg or 30 mg), about 30-40 mg (e.g., about 30 mg, 35 mg or 40 mg), about 40-50 mg (e.g., about 40 mg, 45 mg or 50 mg), about 50-100 mg (e.g., about 50 mg, 60 mg, 70 mg, 80 mg, 90 mg or 100 mg), about 100-150 mg (e.g., about 100 mg, 125 mg or 150 mg), or about 150-200 mg (e.g., about 150 mg, 175 mg or 200 mg). In some embodiments, the therapeutically effective dose of the NK1R antagonist (e.g., aprepitant) is administered one or more (e.g., two, three or more) times a day, or once every two or three days, or once, twice or thrice a week, or as deemed appropriate by the treating physician. In some embodiments, the composition comprises a therapeutically or prophylactically effective amount of aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer thereof.

[0077] In some embodiments, a therapeutically effective amount of the NK1R antagonist (e.g., aprepitant) for controlling weight as described herein is about 0.1-200 mg, 0.1- 150 mg, 0.1-100 mg, 0.1-50 mg, 0.1-30 mg, 0.5-20 mg, 0.5-10 mg or 1-10 mg (e.g., per day or per dose), or as deemed appropriate by the treating physician, which can be administered in a single dose or in divided doses. In certain embodiments, the therapeutically effective dose (e.g., per day or per dose) of the NK1R antagonist (e.g., aprepitant) for controlling weight as described herein is about 0.1-1 mg (e.g., about 0.1 mg, 0.5 mg or 1 mg), about 1-5 mg (e.g., about 1 mg, 2 mg, 3 mg, 4 mg or 5 mg), about 5-10 mg (e.g., about 5 mg, 6 mg, 7 mg, 8 mg, 9 mg or 10 mg), about 10-20 mg (e.g., about 10 mg, 15 mg or 20 mg), about 20-30 mg (e.g., about 20 mg, 25 mg or 30 mg), about 30-40 mg (e.g., about 30 mg, 35 mg or 40 mg), about 40-50 mg (e.g., about 40 mg, 45 mg or 50 mg), about 50-100 mg (e.g., about 50 mg, 60 mg, 70 mg, 80 mg, 90 mg or 100 mg), about 100-150 mg (e.g., about 100 mg, 125 mg or 150 mg), or about 150-200 mg (e.g., about 150 mg, 175 mg or 200 mg). In some embodiments, the therapeutically effective dose of the NK1R antagonist (e.g., aprepitant) is administered one or more (e.g., two, three or more) times a day, or once every two or three days, or once, twice or thrice a week, or asdeemed appropriate by the treating physician. In some embodiments, the composition comprises a therapeutically or prophylactically effective amount of aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer thereof.

[0078] In some embodiments, a therapeutically effective amount of the cyclic dipeptide (e.g., cyclo(His-Pro)) for preventing, slowing the progression of or treating obesity as described herein is about 0.1-200 mg, 0.1-150 mg, 0.1-100 mg, 0.1-50 mg, 0.1-30 mg, 0.5-20 mg, 0.5-10 mg or 1-10 mg (e.g., per day or per dose), or as deemed appropriate by the treating physician, which can be administered in a single dose or in divided doses. In certain embodiments, the therapeutically effective dose (e.g., per day or per dose) of the cyclic dipeptide (e.g., cyclo(His-Pro)) for preventing, slowing the progression of or treating obesity as described herein is about 0.1-1 mg (e.g., about 0.1 mg, 0.5 mg or 1 mg), about 1-5 mg (e.g., about 1 mg, 2 mg, 3 mg, 4 mg or 5 mg), about 5-10 mg (e.g., about 5 mg, 6 mg, 7 mg, 8 mg, 9 mg or 10 mg), about 10-20 mg (e.g., about 10 mg, 15 mg or 20 mg), about 20-30 mg (e.g., about 20 mg, 25 mg or 30 mg), about 30-40 mg (e.g., about 30 mg, 35 mg or 40 mg), about 40-50 mg (e.g., about 40 mg, 45 mg or 50 mg), about 50-100 mg (e.g., about 50 mg, 60 mg, 70 mg, 80 mg, 90 mg or 100 mg), about 100-150 mg (e.g., about 100 mg, 125 mg or 150 mg), about 150-200 mg (e.g., about 150 mg, 175 mg, or 200 mg), about 200-250 mg (e.g., about 200 mg, 225 mg, or 250 mg), about 250-300 mg (e.g., about 250 mg, 275 mg, or 300 mg), about 300-350 mg (e.g., about 300 mg, 325 mg, or 350 mg), about 350-400 mg (e.g., about 350 mg, 375 mg, or 400 mg), about 400-450 mg (e.g., about 400 mg or 450 mg), about 450-500 mg (e.g., about 450 mg or 500 mg). In some embodiments, the therapeutically effective dose of the cyclic dipeptide (e.g., cyclo(His-Pro)) is administered one or more (e.g., two, three or more) times a day, or once every two or three days, or once, twice or thrice a week, or as deemed appropriate by the treating physician. In some embodiments, the composition comprises a therapeutically or prophylactically effective amount of the cyclic dipeptide (e.g., cyclo(His-Pro)).

[0079] In some embodiments, a therapeutically effective amount of the cyclic dipeptide (e.g., cyclo(His-Pro)) for controlling weight as described herein is about 0.1-200 mg, 0.1-150 mg, 0.1-100 mg, 0.1-50 mg, 0.1-30 mg, 0.5-20 mg, 0.5-10 mg or 1-10 mg (e.g., per day or per dose), or as deemed appropriate by the treating physician, which can be administered in a single dose or in divided doses. In certain embodiments, the therapeutically effective dose (e.g., per day or per dose) of the cyclic dipeptide (e.g., cyclo(His-Pro)) for controlling weight as described herein is about 0.1-1 mg (e.g., about 0.1 mg, 0.5 mg or 1 mg), about 1-5 mg (e.g., about 1 mg, 2 mg, 3 mg, 4 mg or 5 mg), about 5-10 mg (e.g., about 5 mg, 6 mg, 7 mg, 8 mg, 9 mg or 10 mg), about 10-20 mg (e.g., about 10 mg, 15 mg or 20 mg), about 20-30 mg (e.g., about 20 mg, 25 mg or 30 mg), about 30-40 mg (e.g., about 30 mg, 35 mg or 40 mg), about 40-50 mg(e.g., about 40 mg, 45 mg or 50 mg), about 50-100 mg (e.g., about 50 mg, 60 mg, 70 mg, 80 mg, 90 mg or 100 mg), about 100-150 mg (e.g., about 100 mg, 125 mg or 150 mg), about 150-200 mg (e.g., about 150 mg, 175 mg, or 200 mg), about 200-250 mg (e.g., about 200 mg, 225 mg, or 250 mg), about 250-300 mg (e.g., about 250 mg, 275 mg, or 300 mg), about 300-350 mg (e.g., about 300 mg, 325 mg, or 350 mg), about 350-400 mg (e.g., about 350 mg, 375 mg, or 400 mg), about 400-450 mg (e.g., about 400 mg or 450 mg), about 450-500 mg (e.g., about 450 mg or 500 mg). In some embodiments, the therapeutically effective dose of the cyclic dipeptide (e.g., cyclo(His-Pro)) is administered one or more (e.g., two, three or more) times a day, or once every two or three days, or once, twice or thrice a week, or as deemed appropriate by the treating physician. In some embodiments, the composition comprises a therapeutically or prophylactically effective amount of the cyclic dipeptide (e.g., cyclo(His-Pro)).

[0080] The NK1R antagonist (e.g., aprepitant) can also be dosed in an irregular manner. For example, the NK1R antagonist can be administered once, twice or thrice in a period of two weeks, three weeks or a month in an irregular manner. Furthermore, the NK1R antagonist (e.g., aprepitant) can be taken pro re rata (as needed). For instance, the NK1R antagonist can be administered 1, 2, 3, 4, 5 or more times, whether in a regular or irregular manner, until reduction goal of the body weight and / or BMI of the subject is achieved. Once the reduction goal is achieved, dosing of the NK1R antagonist can optionally be discontinued. If the weigh and / or BMI of the subject increases again, administration of the NK1R antagonist, whether in a regular or irregular manner, can be resumed. The appropriate dosage of, frequency of dosing of and length of treatment with the NK1R antagonist can be determined by the treating physician.

[0081] The cyclic dipeptide (e.g., cyclo(His-Pro)) can also be dosed in an irregular manner. For example, the cyclic dipeptide can be administered once, twice or thrice in a period of two weeks, three weeks or a month in an irregular manner. Furthermore, the cyclic dipeptide (e.g., cyclo(His-Pro)) can be taken pro re rata (as needed). For instance, the cyclic dipeptide can be administered 1, 2, 3, 4, 5 or more times, whether in a regular or irregular manner, until reduction goal of the body weight and / or BMI of the subject is achieved. Once the reduction goal is achieved, dosing of the cyclic dipeptide can optionally be discontinued. If the weigh and / or BMI of the subject increases again, administration of the cyclic dipeptide, whether in a regular or irregular manner, can be resumed. The appropriate dosage of, frequency of dosing of and length of treatment with the cyclic dipeptide can be determined by the treating physician.

[0082] In some embodiments, the NK1R antagonist (e.g., aprepitant) is administered under a chronic dosing regimen. In certain embodiments, a therapeutically effective amount of the NK1R antagonist (e.g., aprepitant) is administered over a period of at least about 6 weeks, 2 months, 10 weeks, 3 months, 4 months, 5 months, 6 months, 1 year, 1.5 years, 2 years, 3 yearsor longer (e.g., at least about 6 weeks, 2 months, 3 months or 6 months).

[0083] In some embodiments, the cyclic dipeptide (e.g., cyclo(His-Pro)) is administered under a chronic dosing regimen. In certain embodiments, a therapeutically effective amount of the cyclic dipeptide (e.g., cyclo(His-Pro)) is administered over a period of at least about 6 weeks, 2 months, 10 weeks, 3 months, 4 months, 5 months, 6 months, 1 year, 1.5 years, 2 years, 3 years or longer (e.g., at least about 6 weeks, 2 months, 3 months or 6 months). In some embodiments, the cyclic dipeptide (e.g., cyclo(His-Pro)) is administered under the same dosing regimen as the NK1R antagonist (e.g., aprepitant). In some embodiments, the cyclic dipeptide (e.g., cyclo(His-Pro)) is administered under different dosing regimen from the NK1R antagonist (e.g., aprepitant).

[0084] The NK1R antagonist (e.g., aprepitant) and the cyclic dipeptide (e.g., cyclo(His-Pro)) can also be used prophylactically to relieve or prevent obesity and increase of body weight and / or BMI. The prophylactically effective amount of an NK1R antagonist (e.g., aprepitant) and the cyclic dipeptide (e.g., cyclo(His-Pro)) can be any therapeutically effective amount of the NK1R antagonist and the cyclic dipeptide described herein.

[0085] The NK1R antagonist (e.g., aprepitant) and the cyclic dipeptide (e.g., cyclo(His-Pro)) can be administered via any suitable route. Potential routes of administration of the NK1R antagonist and the cyclic dipeptide include without limitation oral, parenteral (including intramuscular, subcutaneous, intradermal, intravascular, intravenous, intraarterial, intramedullary and intrathecal), intracavitary, intraperitoneal, and topical (including dermal / epicutaneous, transdermal, mucosal, transmucosal, intranasal [e.g., by nasal spray or drop], intraocular [e.g., by eye drop], pulmonary [e.g., by oral or nasal inhalation], buccal, sublingual, rectal and vaginal). In certain embodiments, the NK1R antagonist (e.g., aprepitant) is administered orally (e.g., as a capsule or tablet, optionally with an enteric coating). In other embodiments, the NK1R antagonist (e.g., aprepitant) is administered parenterally (e.g., intravenously, subcutaneously or intradermally). In further embodiments, the NK1R antagonist (e.g., aprepitant) is administered topically (e.g., dermally / epicutaneously, transdermally, mucosally, transmucosally, buccally or sublingually). In some embodiments, the cyclic dipeptide (e.g., cyclo(His-Pro)) is administered via the same route as the NK1R antagonist (e.g., aprepitant). In some embodiments, the cyclic dipeptide (e.g., cyclo(His-Pro)) is administered via different route from the NK1R antagonist (e.g., aprepitant).

[0086] In additional embodiments, the NK1R antagonist (e.g., aprepitant) is administered without food. In some embodiments, the NK1R antagonist (e.g., aprepitant) is administered at least about 1 or 2 hours before or after a meal. In certain embodiments, the NK1R antagonist (e.g., aprepitant) is administered at least about 2 hours after an evening meal.The NK1R antagonist can also be taken substantially concurrently with food (e.g., within about 0.5, 1 or 2 hours before or after a meal, or with a meal).

[0087] In additional embodiments, the cyclic dipeptide (e.g., cyclo(His-Pro)) is administered without food. In some embodiments, the cyclic dipeptide (e.g., cyclo(His-Pro)) is administered at least about 1 or 2 hours before or after a meal. In certain embodiments, the cyclic dipeptide (e.g., cyclo(His-Pro)) is administered at least about 2 hours after an evening meal. The cyclic dipeptide can also be taken substantially concurrently with food (e.g., within about 0.5, 1 or 2 hours before or after a meal, or with a meal).

[0088] In some embodiments where a more rapid establishment of a therapeutic level of the NK1R antagonist (e.g., aprepitant) and the cyclic dipeptide (e.g., cyclo(His-Pro)) is desired, the NK1R antagonist and the cyclic dipeptide are administered under a dosing schedule in which a loading dose is administered, followed by (i) one or more additional loading doses and then one or more therapeutically effective maintenance doses, or (ii) one or more therapeutically effective maintenance doses without an additional loading dose, as deemed appropriate by the treating physician. A loading dose of a drug is typically larger (e.g., about 1.5, 2, 3, 4 or 5 times larger) than a subsequent maintenance dose and is designed to establish a therapeutic level of the drug more quickly. The one or more therapeutically effective maintenance doses can be any therapeutically effective dose described herein. In certain embodiments, the loading dose is about three times greater than the maintenance dose. In some embodiments, a loading dose of the NK1R antagonist (e.g., aprepitant) is administered, followed by administration of a maintenance dose of the NK1R antagonist after an appropriate time (e.g., after about 12 or 24 hours) and thereafter for the duration of therapy. For example, a loading dose of the NK1R antagonist is administered on day 1 and a maintenance dose is administered on day 2 and thereafter for the duration of therapy. In some embodiments, the NK1R antagonist (e.g., aprepitant) is administered in a loading, dose of about 1.5, 3, 15 or 30 mg (e.g., 3*about 0.5, 1, 5 or 10 mg) orally (e.g., as a tablet) on day 1, followed by a maintenance dose of about 0.5, 1, 5 or 10 mg orally (e.g., as a tablet) once daily, optionally at bedtime, for at least about 2 weeks, 1 month (4 weeks), 6 weeks, 2 months, 10 weeks, 3 months, 4 months, 5 months, 6 months, 1 year, 1.5 years, 2 years, 3 years or longer (e.g., at least about 6 weeks, 2 months, 3 months or 6 months). In certain embodiments, the NK1R antagonist (e.g., aprepitant) is administered in a loading dose of about 15 mg (e.g., 3*about 5 mg) orally (e.g., as a tablet) on day 1, followed by a maintenance dose of about 5 mg orally (e.g., as a tablet) once daily, optionally at bedtime, for at least about 2 weeks, 1 month, 6 weeks, 2 months, 3 months, 6 months, 1 year, 1.5 years, 2 years, 3 years or longer (e.g., at least about 6 weeks, 2 months, 3 months or 6 months).

[0089] In certain embodiments, the loading dose is about three times greater than the maintenance dose. In some embodiments, a loading dose of the cyclic dipeptide (e.g., cyclo(His- Pro)) is administered, followed by administration of a maintenance dose of the cyclic dipeptide after an appropriate time (e.g., after about 12 or 24 hours) and thereafter for the duration of therapy. For example, a loading dose of the cyclic dipeptide is administered on day 1 and a maintenance dose is administered on day 2 and thereafter for the duration of therapy. In some embodiments, the cyclic dipeptide (e.g., cyclo(His-Pro)) is administered in a loading dose of about 1.5, 3, 15 or 30 mg (e.g., 3*about 0.5, 1, 5 or 10 mg) orally (e.g., as a tablet) on day 1, followed by a maintenance dose of about 0.5, 1, 5 or 10 mg orally (e.g., as a tablet) once daily, optionally at bedtime, for at least about 2 weeks, 1 month (4 weeks), 6 weeks, 2 months, 10 weeks, 3 months, 4 months, 5 months, 6 months, 1 year, 1.5 years, 2 years, 3 years or longer (e.g., at least about 6 weeks, 2 months, 3 months or 6 months). In certain embodiments, the cyclic dipeptide (e.g., cyclo(His-Pro)) is administered in a loading dose of about 15 mg (e.g., 3*about 5 mg) orally (e.g., as a tablet) on day 1, followed by a maintenance dose of about 5 mg orally (e.g., as a tablet) once daily, optionally at bedtime, for at least about 2 weeks, 1 month, 6 weeks, 2 months, 3 months, 6 months, 1 year, 1.5 years, 2 years, 3 years or longer (e.g., at least about 6 weeks, 2 months, 3 months or 6 months).

[0090] In some embodiments, a first loading dose of the NK1R antagonist (e.g., aprepitant) and / or the cyclic dipeptide (e.g., cyclo(His-Pro)) is administered on day 1, a second loading dose is administered on day 2, and a maintenance dose is administered on day 3 and thereafter for the duration of therapy. In certain embodiment, the first loading dose is about three times greater than the maintenance dose, and the second loading dose is about two times greater than the maintenance dose.

[0091] As disclosed herein, the therapeutic agent (e.g., NK1R antagonist and the cyclic dipeptide) can be formulated for administration in a pharmaceutical composition comprising a physiologically acceptable surface active agents, carriers, diluents, excipients, smoothing agents, suspension agents, film forming substances, coating assistants, or a combination thereof. In some embodiments, the therapeutic agent (e.g., NK1R antagonist and the cyclic dipeptide) are formulated for administration with a pharmaceutically acceptable carrier or diluent. The therapeutic agent (e.g., NK1R antagonist and the cyclic dipeptide) can be formulated as a medicament with a standard pharmaceutically acceptable carrier(s) and / or excipient(s) as is routine in the pharmaceutical art. The exact nature of the formulation will depend upon several factors including the desired route of administration. In some embodiments, the NK1R antagonist is formulated for oral, intravenous, intragastric, intravascular or intraperitoneal administration. In some embodiments, the cyclic dipeptide isformulated for oral, intravenous, intragastric, intravascular or intraperitoneal administration. The cyclic dipeptide can be formulated the same as or differently from the NK1R antagonist. Standard pharmaceutical formulation techniques may be used, such as those disclosed in Remington's The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (2005), incorporated herein by reference in its entirety.

[0092] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. In addition, various adjuvants such as are commonly used in the art may be included. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds.) (1990); Goodman and Gilman' s: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press, which is incorporated herein by reference in its entirety.

[0093] Some examples of substances, which can serve as pharmaceutically- acceptable carriers or components thereof, are sugars, such as lactose, glucose and sucrose: starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyi cellulose, powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, com oil and oil of theobroraa; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; aiginic acid; emulsifiers, such as the TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.

[0094] The choice of a pharmaceutically acceptable carrier to be used in conjunction with the subject therapeutic agent is basically determined by the way the composition is to be administered.

[0095] The compositions described herein are preferably provided in unit dosage form. As used herein, a "unit dosage form" is a composition containing an amount of a therapeutic agent (e.g., NK1R antagonist and the cyclic dipeptide) that is suitable for administration to an animal, preferably mammal subject, in a single dose, according to good medical practice. The preparation of a single or unit dosage form, however, does not imply that the dosage form is administered once per day or once per course of therapy. Such dosage forms are contemplated to be administered once, twice, thrice or more per day and may beadministered as infusion over a period of time (e.g., from about 30 minutes to about 2-6 hours), or administered as a continuous infusion, and may be given more than once during a course of therapy, though a single administration is not specifically excluded. The skilled artisan will recognize that the formulation does not specifically contemplate the entire course of therapy and such decisions are left for those skilled in the art of treatment rather than formulation.

[0096] The compositions useful as described above may be in any of a variety of suitable forms for a variety of routes for administration, for example, for oral, nasal, rectal, topical (including transdermal), ocular, intracerebral, intracranial, intrathecal, intra-arterial, intravenous, intramuscular, or other parental routes of administration. The skilled artisan will appreciate that oral and nasal compositions include compositions that are administered by inhalation, and made using available methodologies. Depending upon the particular route of administration desired, a variety of pharmaceutically acceptable carriers well-known in the art may be used. Pharmaceutically acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropies, surface-active agents, and encapsulating substances. Optional pharmaceutically active materials may be included, which do not substantially interfere with the inhibitory activity of the therapeutic agent (e.g., NK1R antagonist and cyclic dipeptide). The amount of carrier employed in conjunction with the therapeutic agent (e.g., NK1R antagonist and cyclic dipeptide) is sufficient to provide a practical quantity of material for administration per unit dose of the therapeutic agent (e.g., NK1R antagonist and cyclic dipeptide). Techniques and compositions for making dosage forms useful in the methods described herein are described in the following references, ail incorporated by reference herein: Modern Pharmaceutics, 4th Ed., Chapters 9 and 10 (Banker & Rhodes, editors, 2002); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989), and Ansel, Introduction to Pharmaceutical Dosage Forms 8th Edition (2004).

[0097] Various oral dosage forms can be used, including such solid forms as tablets, capsules, and granules. Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.

[0098] The pharmaceutically acceptable carriers suitable for the preparation of unit dosage forms for peroral administration is well-known in the art. Tablets typically compriseconventional pharmaceutically compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmelose; lubricants such as magnesium stearate, stearic acid and talc. Glidants such as silicon dioxide can be used to improve flow characteristics of the powder mixture. Coloring agents, such as the FD&C dyes, can be added for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets. Capsules typically comprise one or more solid diluents disclosed above. The selection of carrier components depends on secondary considerations like taste, cost, and shelf stability, which are not critical, and can be readily made by a person skilled in the art.

[0099] Peroral compositions also include liquid solutions, emulsions, suspensions, and the like. The pharmaceutically acceptable carriers suitable for preparation of such compositions are well known in the art. Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For a suspension, typical suspending agents include sodium carboxymethyl cellulose, AVICEL RC-591, tragacanth and sodium alginate; typical wetting agents include lecithin and polvsorbate 80; and typical preservatives include methyl paraben and sodium benzoate. Peroral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and colorants disclosed above.

[0100] Other compositions useful for attaining systemic delivery of the subject therapeutic agents include sublingual, buccal and nasal dosage forms. Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included.

[0101] For topical use, creams, ointments, gels, solutions or suspensions, etc., containing the therapeutic agent (e.g., NK1R antagonist and cyclic dipeptide) disclosed herein are employed. Topical formulations may generally be comprised of a pharmaceutical carrier, cosolvent, emulsifier, penetration enhancer, preservative system, and emollient.

[0102] For intravenous administration, the therapeutic agent (e.g., NK1R antagonist and cyclic dipeptide) and compositions described herein may be dissolved or dispersed in a pharmaceutically acceptable diluent, such as a saline or dextrose solution. Suitable excipients may be included to achieve the desired pH, including but not limited to NaOH, sodium carbonate, sodium acetate, HC1, and citric acid. In various embodiments, the pH of the final composition ranges from 2 to 8, or preferably from 4 to 7. Antioxidant excipients may includesodium bisulfite, acetone sodium bisulfite, sodium formaldehyde, suifoxylate, thiourea, and EDTA. Other non-limiting examples of suitable excipients found in the final intravenous composition may include sodium or potassium phosphates, citric acid, tartaric acid, gelatin, and carbohydrates such as dextrose, mannitol, and dextran. Further acceptable excipients are described in Powell, et al., Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52 238-31 1 and Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J Pharm Sci and Tech 2011, 65 287-332, both of which are incorporated herein by reference in their entirety. Antimicrobial agents may also be included to achieve a bacteriostatic or fungistatic solution, including but not limited to phenyl mercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol.

[0103] The compositions for intravenous administration may be provided to caregivers in the form of one or more solids that are reconstituted with a suitable diluent such as sterile water, saline or dextrose in water shortly prior to administration. In other embodiments, the compositions are provided in solution ready to administer parenterally. In still other embodiments, the compositions are provided in a solution that is further diluted prior to administration. In embodiments that include administering a combination of a therapeutic agent (e.g., NK1R antagonist and cyclic dipeptide) described herein and another agent, the combination may be provided to caregivers as a mixture, or the caregivers may mix the two agents prior to administration, or the two agents may be administered separately.

[0104] In non-human animal studies, applications of potential products are commenced at higher dosage levels, with dosage being decreased until the desired effect is no longer achieved or adverse side effects disappear. The dosage may range broadly, depending upon the desired effects and the therapeutic indication. Typically, dosages may be between about 0.1 mg / kg and 4000 mg / kg body weight, preferably between about 80 mg / kg and 1600 mg / kg body weight. Alternatively, dosages may be based and calculated upon the surface area of the patient, as understood by those of skill in the art.

[0105] Depending on the severity and responsiveness of the condition to be treated, dosing can also be a single administration of a slow-release composition, with course of treatment lasting from several days to several weeks or until cure is effected or diminution of the disease state is achieved. The amount of a composition to be administered will, of course, be dependent on many factors including the subject being treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician. The therapeutic agent (e.g., NK1R antagonist and cyclic dipeptide) or combination of therapeutic agents disclosed herein may be administered orally or via injection at a dose from 0, 1 mg / kg to 4000 mg / kg of thepati ent's body weight per day. The dose range for adult humans is generally from 1 g to 100 g / day. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of the therapeutic agent (e.g., NK1R antagonist and cyclic dipeptide) or combination of therapeutic agents disclosed herein which is effective at such dosage or as a multiple of the same, for instance, units containing 1 g to 60 g (for example, from about 5 g to 20 g, from about 10 g to 50 g, from about 20 g to 40 g, or from about 25 g to 35 g). The precise amount of therapeutic agent administered to a patient will be the responsibility of the attendant physician. However, the dose employed will depend on a number of factors, including the age and sex of the patient, the precise disorder being treated, and its severity. Additionally, the route of administration may vary depending on the condition and its severity. A typical dose of the therapeutic agent (e.g., NK1R antagonist and cyclic dipeptide) can be from 0,02 g to 1.25 g per kg of body weight, for example from 0.1 g to 0.5 g per kg of body weight, depending on such parameters. In some embodiments, a dosage of the therapeutic agent (e.g., NK1R antagonist and cyclic dipeptide) can be from 1 g to 100 g, for example, from 10 g to 80 g, from 15 g to 60 g, from 20 g to 40 g, or from 25 g to 35 g. In A physician will be able to determine the required dosage of the therapeutic agent (e.g., NK1R antagonist and cyclic dipeptide) for any particular subject.

[0106] The exact formulation, route of administration and dosage for the pharmaceutical compositions of the therapeutic agent (e.g., NK1R antagonist and cyclic dipeptide) or combination of therapeutic agents disclosed herein can be chosen by the individual physician in view of the patient’s condition. (See e.g., Fingl et al. 1975, in "The Pharmacological Basis of Therapeutics," which is hereby incorporated herein by reference, with particular reference to Ch. 1). Typically, the dose range of the composition administered to the patient can be from about 0.1 to about 4000 mg / kg of the patient's body weight. The dosage may be a single one or a series of two or more given in the course of one or more days, as is needed by the patient. In instances where human dosages for therapeutic agents have been established for at least some condition, the present disclosure will use those same dosages, or dosages that are between about 0.1 % and about 5000%, more preferably between about 25% and about 1000% of the established human dosage. Where no human dosage is established, as will be the case for newly discovered pharmaceutical compounds, a suitable human dosage can be inferred from EDso or ID50 values, or other appropriate values derived from in vitro or in vivo studies, as qualified by toxicity studies and efficacy studies in animals.

[0107] It should be noted that the attending physician would know how to and when to terminate, interrupt, or adjust administration due to toxicity or organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if theclinical response were not adequate (precluding toxicity). The magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the condition to be treated and to the route of administration. The severity of the condition may, for example, be evaluated, in part, by standard prognostic evaluation methods. Further, the dose and perhaps dose frequency, will also vary according to the age, body weight, and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine.

[0108] Although the exact dosage will be determined on a drug-by-drug basis, in most cases, some generalizations regarding the dosage can be made. In cases of administration of a pharmaceutically acceptable salt, dosages may be calculated as the free base. In some embodiments, the composition is administered 1 to 4 times per day. Alternatively, the compositions disclosed herein may be administered by continuous intravenous infusion, e.g., at a dose of each active ingredient up to 100 g per day. As will be understood by those of skill in the art, in certain situations it may be necessary to administer the compositions disclosed herein in amounts that exceed, or even far exceed, the above-stated, preferred dosage range in order to effectively and aggressively treat particularly aggressive diseases or infections. In some embodiments, the therapeutic agent (e.g., NK1R antagonist and cyclic dipeptide) or combination of therapeutic agents disclosed herein will be administered for a period of continuous therapy, for example for a week or more, or for months or years.

[0109] In some embodiments, the dosing regimen of the therapeutic agent (e.g., NK1R antagonist and cyclic dipeptide) or combination of therapeutic agents disclosed herein is administered for a period of time, which time period can be, for example, from at least about 1 week to at least about 4 weeks, from at least about 4 weeks to at least about 8 weeks, from at least about 4 weeks to at least about 12 weeks, from at least about 4 weeks to at least about 16 weeks, or longer. The dosing regimen of the therapeutic agent (e.g., NK1R antagonist and cyclic dipeptide) or combination of therapeutic agents disclosed herein can be administered three times a day, twice a day, daily, every other day, three times a week, every other week, three times per month, once monthly, substantially continuously or continuously.

[0110] The NK1R antagonist (e.g., aprepitant) can be administered alone or in the form of a composition (e.g., a pharmaceutical composition). In some embodiments, a pharmaceutical composition comprises an NK1R antagonist (e.g., aprepitant) or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, prodrug or metabolite thereof, and one or more pharmaceutically acceptable carriers or excipients. The cyclic dipeptide (e.g., cyclo(His-Pro)) can be administered alone or in the form of a composition (e.g., a pharmaceutical composition). In some embodiments, a pharmaceutical composition comprises a cyclic dipeptide (e.g., cyclo(His-Pro)), and one or more pharmaceutically acceptable carriers orexcipients. The composition can optionally contain one or more additional therapeutic agents as described herein. A pharmaceutical composition contains a therapeutically effective amount of a therapeutic agent (e.g., an NK1R antagonist, such as aprepitant and a cyclic dipeptide, such as cyclo(His-Pro)) and one or more pharmaceutically acceptable carriers or excipients, and is formulated for administration to a subject for therapeutic use. For purposes of the content of a pharmaceutical composition, the terms "therapeutic agent", "active ingredient", "active agent" and "drug" encompass prodrugs.[OHl] A pharmaceutical composition contains a therapeutic agent (e.g., an NK1R antagonist, such as aprepitant and a cyclic dipeptide, such as cyclo(His-Pro)) in substantially pure form. In some embodiments, the purity of the therapeutic agent is at least about 95%, 96%, 97%, 98% or 99%. In certain embodiments, the purity of the therapeutic agent is at least about 98% or 99%. In addition, a pharmaceutical composition is substantially free of contaminants or impurities. In some embodiments, the level of contaminants or impurities other than residual solvent in a pharmaceutical composition is no more than about 5%, 4%, 3%, 2% or 1% relative to the combined weight of the intended active and inactive ingredients. In certain embodiments, the level of contaminants or impurities other than residual solvent in a pharmaceutical composition is no more than about 2% or 1% relative to the combined weight of the intended active and inactive ingredients. Pharmaceutical compositions generally are prepared according to current good manufacturing practice (GMP), as recommended or required by, e.g., the Federal Food, Drug, and Cosmetic Act §501(a)(2)(B) and the International Conference on Harmonisation Q7 Guideline.

[0112] Pharmaceutically acceptable carriers and excipients include pharmaceutically acceptable materials, vehicles and substances. Non-limiting examples of excipients include liquid and solid fillers, diluents, binders, lubricants, glidants, solubilizers, surfactants, dispersing agents, disintegration agents, emulsifying agents, wetting agents, suspending agents, thickeners, solvents, isotonic agents, buffers, pH adjusters, stabilizers, preservatives, antioxidants, antimicrobial agents, antibacterial agents, antifungal agents, absorption- delaying agents, sweetening agents, flavoring agents, coloring agents, adjuvants, encapsulating materials and coating materials. The use of such excipients in pharmaceutical formulations is known in the art. For example, conventional vehicles and carriers include without limitation oils (e.g., vegetable oils, such as sesame oil), aqueous solvents (e.g., saline, phosphate-buffered saline [PBS] and isotonic solutions [e.g., Ringer's solution]), and solvents (e.g., dimethyl sulfoxide [DMSO] and alcohols [e.g., ethanol, glycerol and propylene glycol]). Except insofar as any conventional carrier or excipient is incompatible with the active ingredient, the disclosure encompasses the use of conventional carriers and excipients in formulations containing a therapeutic agent (e.g.,an NK1R antagonist, such as aprepitant). See, e.g., Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (Philadelphia, Pennsylvania

[2005] ); Handbook of Pharmaceutical Excipients, 5th Ed., Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association (2005); Handbook of Pharmaceutical Additives, 3rd Ed., Ash and Ash, Eds., Gower Publishing Co. (2007); and Pharmaceutical Preformulation and Formulation, Gibson, Ed., CRC Press (Boca Raton, Florida, 2004).

[0113] Proper formulation can depend on various factors, such as the mode of administration chosen. Potential modes of administration of pharmaceutical compositions comprising an NK1R antagonist (e.g., aprepitant) and a cyclic dipeptide (e.g., cyclo(His-Pro)) include without limitation oral, parenteral (including intramuscular, subcutaneous, intradermal, intravascular, intravenous, intraarterial, intraperitoneal, intramedullary, intrathecal and topical), intracavitary, and topical (including dermal / epicutaneous, transdermal, mucosal, transmucosal, intranasal e.g., by nasal spray or drop], pulmonary [e.g., by oral or nasal inhalation], buccal, sublingual, rectal [e.g., by suppository], and vaginal [e.g., by suppository]).

[0114] As an example, formulations of an NK1R antagonist (e.g., aprepitant) and a cyclic dipeptide (e.g., cyclo(His-Pro)) suitable for oral administration can be presented as, e.g., boluses; tablets, capsules, pills, cachets or lozenges; as powders or granules; as semisolids, electuaries, pastes or gels; as solutions or suspensions in an aqueous liquid or / and a non-aqueous liquid; or as oil-in-water liquid emulsions or water- in-oil liquid emulsions.

[0115] Tablets can contain an NK1R antagonist (e.g., aprepitant) and a cyclic dipeptide (e.g., cyclo(His-Pro)) in admixture with, e.g., a filler or inert diluent (e.g., calcium carbonate, calcium phosphate, lactose, mannitol or microcrystalline cellulose), a binding agent (e.g., a starch, gelatin, acacia, alginic acid or a salt thereof, or microcrystalline cellulose), a lubricating agent (e.g., stearic acid, magnesium stearate, talc or silicon dioxide), and a disintegrating agent (e.g., crospovidone, croscarmellose sodium or colloidal silica), and optionally a surfactant (e.g., sodium lauryl sulfate). The tablets can be uncoated or can be coated with, e.g., an enteric coating that protects the active ingredient from the acidic environment of the stomach, or with a material that delays disintegration and absorption of the active ingredient in the gastrointestinal tract and thereby provides a sustained action over a longer time period. In certain embodiments, a tablet comprises an NK1R antagonist (e.g., aprepitant) and a cyclic dipeptide (e.g., cyclo(His-Pro)), mannitol, microcrystalline cellulose, magnesium stearate, silicon dioxide, croscarmellose sodium and sodium lauryl sulfate, and optionally lactose monohydrate, and the tablet is optionally film-coated (e.g., with Opadry®).

[0116] Push-fit capsules or two-piece hard gelatin capsules can contain an NK1R antagonist (e.g., aprepitant) and a cyclic dipeptide (e.g., cyclo(His-Pro)) in admixture with, e.g.,a filler or inert solid diluent (e.g., calcium carbonate, calcium phosphate, kaolin or lactose), a binder (e.g., a starch), a glidant or lubricant (e.g., talc or magnesium stearate), and a disintegrant (e.g., crospovidone), and optionally a stabilizer or / and a preservative. For soft capsules or single-piece gelatin capsules, an NK1R antagonist (e.g., aprepitant) and a cyclic dipeptide (e.g., cyclo(His-Pro)) can be dissolved or suspended in a suitable liquid (e.g., liquid polyethylene glycol or an oil medium, such as a fatty oil, peanut oil, olive oil or liquid paraffin), and the liquid-filled capsules can contain one or more other liquid excipients or / and semi- solid excipients, such as a stabilizer or / and an amphiphilic agent (e.g., a fatty acid ester of glycerol, propylene glycol or sorbitol).

[0117] Compositions for oral administration can also be formulated as solutions or suspensions in an aqueous liquid or / and a non-aqueous liquid, or as oil-in-water liquid emulsions or water-in-oil liquid emulsions. Dispersible powder or granules of an NK1R antagonist (e.g., aprepitant) and a cyclic dipeptide (e.g., cyclo(His-Pro)) can be mixed with any suitable combination of an aqueous liquid, an organic solvent or / and an oil and any suitable excipients (e.g., any combination of a dispersing agent, a wetting agent, a suspending agent, an emulsifying agent or / and a preservative) to form a solution, suspension or emulsion.

[0118] In some embodiments, an NK1R antagonist (e.g., aprepitant) and a cyclic dipeptide (e.g., cyclo(His-Pro)) is contained in an amphiphilic vehicle of a liquid or semi-solid formulation for oral administration which provides improved solubility, stability and bioavailability of the NK1R antagonist and the cyclic dipeptide, as described in US 2010 / 0209496. The amphiphilic vehicle contains a solution, suspension, emulsion (e.g., oil-in- water emulsion) or semi-solid mixture of the NK1R antagonist (e.g., aprepitant) and the cyclic dipeptide (e.g., cyclo(His-Pro)) admixed with liquid or / and semi-solid excipients which fills an encapsulated dosage form (e.g., a hard gelatin capsule or a soft gelatin capsule containing a plasticizer [e.g., glycerol or / and sorbitol]). In some embodiments, the amphiphilic vehicle comprises an amphiphilic agent selected from fatty acid esters of glycerol (glycerin), propylene glycol and sorbitol. In certain embodiments, the amphiphilic agent is selected from mono- and di-glycerides of Cs-Cn saturated fatty acids. In some embodiments, the amphiphilic agent is selected from CAPMUL® MCM, CAPMUL® MCM 8, CAPMUL® MCM 10, IMWITOR® 308, IMWITOR® 624, IMWITOR® 742, IMWITOR® 988, CAPRYOL™ PGMC, CAPRYOL™ 90, L AUROGLYCOL™ 90, CAPTEX® 200, CRILL™ 1, CRILL™ 4, PECEOL® and MAIS INE™ 35-1. In some embodiments, the amphiphilic vehicle further comprises propylene glycol, a propylene glycol- sparing agent (e.g., ethanol or / and glycerol), or an antioxidant (e.g., butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate or / and sodium sulfite), or any combination thereof. In additional embodiments, the amphiphilic vehiclecontains on a weight basis about 0.1-5% of the NK1R antagonist (e.g., aprepitant) and the cyclic dipeptide (e.g., cyclo(His-Pro)), about 50-90% of the amphiphilic agent, about 5-40% of propylene glycol, about 5-20% of the propylene glycol- sparing agent, and about 0.01-0.5% of the antioxidant.

[0119] An NK1R antagonist (e.g., aprepitant) and a cyclic dipeptide (e.g., cyclo(His- Pro)) can also be formulated for parenteral administration by injection or infusion to circumvent gastrointestinal absorption and first-pass metabolism. A representative parenteral route is intravenous.

[0120] Additional advantages of intravenous administration include direct administration of a therapeutic agent into systemic circulation to achieve a rapid systemic effect, and the ability to administer the agent continuously or / and in a large volume if desired. Formulations for injection or infusion can be in the form of, e.g., solutions, suspensions or emulsions in oily or aqueous vehicles, and can contain excipients such as suspending agents, dispersing agents or / and stabilizing agents. For example, aqueous or non-aqueous (e.g., oily) sterile injection solutions can contain an NK1R antagonist (e.g., aprepitant) and a cyclic dipeptide (e.g., cyclo(His-Pro)) along with excipients such as an antioxidant, a buffer, a bacteriostat and solutes that render the formulation isotonic with the blood of the subject. Aqueous or non-aqueous sterile suspensions can contain an NK1R antagonist (e.g., aprepitant) and a cyclic dipeptide (e.g., cyclo(His-Pro)) along with excipients such as a suspending agent and a thickening agent, and optionally a stabilizer and an agent that increases the solubility of the NK1R antagonist and the cyclic dipeptide (e.g., cyclo(His-Pro)) to allow for the preparation of a more concentrated solution or suspension. As another example, a sterile aqueous solution for injection or infusion (e.g., subcutaneously or intravenously) can contain an NK1R antagonist (e.g., aprepitant), a cyclic dipeptide (e.g., cyclo(His-Pro)), NaCl, a buffering agent (e.g., sodium citrate), a preservative (e.g., meta-cresol), and optionally a base (e.g., NaOH) or / and an acid (e.g., HC1) to adjust pH.

[0121] For topical administration, an NK1R antagonist (e.g., aprepitant) and a cyclic dipeptide (e.g., cyclo(His-Pro)) can be formulated as, e.g., a buccal or sublingual tablet or pill. Advantages of a buccal or sublingual tablet or pill include avoidance of first-pass metabolism and circumvention of gastrointestinal absorption. A buccal or sublingual tablet or pill can also be designed to provide faster release of the NK-1R antagonist and the cyclic dipeptide (e.g., cyclo(His-Pro)) for more rapid uptake of it into systemic circulation. In addition to a therapeutically effective amount of the NK1R antagonist (e.g., aprepitant) and a cyclic dipeptide (e.g., cyclo(His-Pro)), the buccal or sublingual tablet or pill can contain suitable excipients, including without limitation any combination of fillers and diluents (e.g., mannitol and sorbitol),binding agents (e.g., sodium carbonate), wetting agents (e.g., sodium carbonate), disintegrants (e.g., crospovidone and croscarmellose sodium), lubricants (e.g., silicon dioxide [including colloidal silicon dioxide] and sodium stearyl fumarate), stabilizers (e.g., sodium bicarbonate), flavoring agents (e.g., spearmint flavor), sweetening agents (e.g., sucralose), and coloring agents (e.g., yellow iron oxide).

[0122] For topical administration, an NK1R antagonist (e.g., aprepitant) and a cyclic dipeptide (e.g., cyclo(His-Pro)) can also be formulated for intranasal administration. The nasal mucosa provides a big surface area, a porous endothelium, a highly vascular subepithelial layer and a high absorption rate, and hence allows for high bioavailability. Moreover, intranasal administration avoids first-pass metabolism and can introduce a significant concentration of the NK1R antagonist and the cyclic dipeptide to the central nervous system, allowing the NK1R antagonist and the cyclic dipeptide to block the central cough reflex via the nucleus tractus solitarius in the cough center in the medulla oblongata, where vagal afferent nerves terminate. An intranasal solution or suspension formulation can comprise an NK1R antagonist (e.g., aprepitant) and a cyclic dipeptide (e.g., cyclo(His-Pro)) along with excipients such as a solubility enhancer (e.g., propylene glycol), a humectant (e.g., mannitol or sorbitol), a buffer and water, and optionally a preservative (e.g., benzalkonium chloride), a mucoadhesive agent (e.g., hydroxyethylcellulose) or / and a penetration enhancer. In certain embodiments, a nasal spray formulation comprises an NK1R antagonist (e.g., aprepitant), a cyclic dipeptide (e.g., cyclo(His- Pro)), microcrystalline cellulose, sodium carboxymethylcellulose, dextrose and water, and optionally an acid (e.g., HC1) to adjust pH. An intranasal solution or suspension formulation can be administered to the nasal cavity by any suitable means, including but not limited to a dropper, a pipette, or spray using, e.g., a metering atomizing spray pump.

[0123] An additional mode of topical administration is pulmonary, including by oral inhalation and nasal inhalation, which is described in detail below.

[0124] Other suitable topical formulations and dosage forms include without limitation ointments, creams, gels, lotions, pastes and the like, as described in Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (Philadelphia, Pennsylvania, 2005).

[0125] Ointments are semi-solid preparations that are typically based on petrolatum or a petroleum derivative. Creams are viscous liquids or semi-solid emulsions, either oil-in- water or water-in-oil. Cream bases are water-washable, and contain an oil phase, an emulsifier and an aqueous phase. The oil phase, also called the "internal" phase, generally comprises petrolatum and a fatty alcohol (e.g., cetyl or stearyl alcohol). The aqueous phase typically, although not necessarily, exceeds the oil phase in volume, and usually contains a humectant. Theemulsifier in a cream formulation is generally a non-ionic, anionic, cationic or amphoteric surfactant. Gels are semi-solid, suspension-type systems. Single-phase gels contain organic macromolecules (polymers) distributed substantially uniformly throughout the carrier liquid, which is typically aqueous but can also contain an alcohol (e.g., ethanol or isopropanol) and optionally an oil. Lotions are preparations to be applied to the skin surface without friction, and are typically liquid or semi-liquid preparations in which solid particles, including the active agent, are present in a water or alcohol base. Lotions are usually suspensions of finely divided solids and typically contain suspending agents to produce better dispersion as well as compounds useful for localizing and holding the active agent in contact with the skin. Pastes are semi-solid dosage forms in which the active agent is suspended in a suitable base. Depending on the nature of the base, pastes are divided between fatty pastes or those made from single-phase aqueous gels.

[0126] Various excipients can be included in a topical formulation. For example, solvents, including a suitable amount of an alcohol, can be used to solubilize the active agent. Other optional excipients include without limitation gelling agents, thickening agents, emulsifiers, surfactants, stabilizers, buffers, antioxidants, preservatives, cooling agents (e.g., menthol), opacifiers, fragrances and colorants. For an active agent having a low rate of permeation through the skin or mucosal tissue, a topical formulation can contain a permeation enhancer to increase the permeation of the active agent through the skin or mucosal tissue. A topical formulation can also contain an irritation-mitigating excipient that reduces any irritation to the skin or mucosa caused by the active agent, the permeation enhancer or any other component of the formulation.

[0127] In some embodiments, an NK1R antagonist (e.g., aprepitant) and a cyclic dipeptide (e.g., cyclo(His-Pro)) is delivered from a sustained-release composition. As used herein, the term "sustained-release composition" encompasses sustained-release, prolonged- release, extended-release, slow-release and controlled-release compositions, systems and devices. Use of a sustained-release composition can have benefits, such as an improved profile of the amount of the drug or an active metabolite thereof delivered to the target site(s) over a time period, including delivery of a therapeutically effective amount of the drug or an active metabolite thereof over a prolonged time period. In certain embodiments, the sustained-release composition delivers the NK1R antagonist and the cyclic dipeptide over a period of at least about 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months or longer. In some embodiments, the sustained-release composition is a drug-encapsulation system, such as nanoparticles, microparticles or a capsule made of, e.g., a biodegradable polymer or / and a hydrogel. In certain embodiments, the sustained-release composition comprises a hydrogel.Non-limiting examples of polymers of which a hydrogel can be composed include polyvinyl alcohol, acrylate polymers (e.g., sodium poly acrylate), and other homopolymers and copolymers having a relatively large number of hydrophilic groups (e.g., hydroxyl or / and carboxylate groups). In other embodiments, the sustained-release drug-encapsulation system comprises a membrane- enclosed reservoir, wherein the reservoir contains a drug and the membrane is permeable to the drug. Such a drug-delivery system can be in the form of, e.g., a transdermal patch.

[0128] In some embodiments, the sustained-release composition is an oral dosage form, such as a tablet or capsule. For example, a drug can be embedded in an insoluble porous matrix such that the dissolving drag must make its way out of the matrix before it can be absorbed through the gastrointestinal tract. Alternatively, a drug can be embedded in a matrix that swells to form a gel through which the drug exits. Sustained release can also be achieved by way of a single-layer or multi-layer osmotic controlled-release oral delivery system (OROS). An OROS is a tablet with a semi-permeable outer membrane and one or more small laser- drilled holes in it. As the tablet passes through the body, water is absorbed through the semipermeable membrane via osmosis, and the resulting osmotic pressure pushes the drug out through the hole(s) in the tablet and into the gastrointestinal tract where it can be absorbed.

[0129] In further embodiments, the sustained-release composition is formulated as polymeric nanoparticles or microparticles, wherein the polymeric particles can be delivered, e.g., by inhalation or injection or from an implant. In some embodiments, the polymeric implant or polymeric nanoparticles or microparticles are composed of a biodegradable polymer. In certain embodiments, the biodegradable polymer comprises lactic acid or / and glycolic acid [e.g., an L-lactic acid-based copolymer, such as poly(L-lactide-co-glycolide) or poly(L-lactic acid-co- D,L-2-hydroxyoctanoic acid)]. For example, biodegradable polymeric microspheres composed of polylactic acid or / and polyglycolic acid can serve as sustained-release pulmonary drugdelivery systems. The biodegradable polymer of the polymeric implant or polymeric nanoparticles or microparticles can be selected so that the polymer substantially completely degrades around the time the period of treatment is expected to end, and so that the byproducts of the polymer's degradation, like the polymer, are biocompatible.

[0130] For a delayed or sustained release of an NK1R antagonist (e.g., aprepitant) and a cyclic dipeptide (e.g., cyclo(His-Pro)), a composition can also be formulated as a depot that can be implanted in or injected into a subject, e.g., intramuscularly or subcutaneously. A depot formulation can be designed to deliver the NK1R antagonist and the cyclic dipeptide over a longer period of time, e.g., over a period of at least about 1 week, 2 weeks, 3 weeks, 1 month, 6 weeks, 2 months, 3 months or longer. For example, the NK1R antagonist can be formulatedwith a polymeric material (e.g., polyethylene glycol (PEG), polylactic acid (PLA) or polyglycolic acid (PGA), or a copolymer thereof (e.g., PLGA)), a hydrophobic material (e.g., as an emulsion in an oil) or / and an ion-exchange resin, or as a sparingly soluble derivative (e.g., a sparingly soluble salt). As an illustrative example, an NK1R antagonist (e.g., aprepitant) and a cyclic dipeptide (e.g., cyclo(His-Pro)) can be incorporated or embedded in sustained-release microparticles composed of PLGA and formulated as a monthly depot.

[0131] An NK1R antagonist (e.g., aprepitant) and a cyclic dipeptide (e.g., cyclo(His- Pro)) can also be contained or dispersed in a matrix material. The matrix material can comprise a polymer (e.g., ethylene-vinyl acetate) and controls the release of the compound by controlling dissolution or / and diffusion of the compound from, e.g., a reservoir, and can enhance the stability of the compound while contained in the reservoir. Such a release system can be designed as a sustained-release system, can be configured as, e.g., a transdermal or transmucosal patch, and can contain an excipient that can accelerate the compound's release, such as a water- swellable material (e.g., a hydrogel) that aids in expelling the compound out of the reservoir. For example, U.S. Patent Nos. 4,144,317 and 5,797,898 describe examples of such a release system.

[0132] The release system can provide a temporally modulated release profile (e.g., pulsatile release) when time variation in plasma levels is desired, or a more continuous or consistent release profile when a constant plasma level is desired. Pulsatile release can be achieved from an individual reservoir or from a plurality of reservoirs. For example, where each reservoir provides a single pulse, multiple pulses ("pulsatile" release) are achieved by temporally staggering the single pulse release from each of multiple reservoirs.

[0133] Alternatively, multiple pulses can be achieved from a single reservoir by incorporating several layers of a release system and other materials into a single reservoir. Continuous release can be achieved by incorporating a release system that degrades, dissolves, or allows diffusion of a compound through it over an extended time period. In addition, continuous release can be approximated by releasing several pulses of a compound in rapid succession ("digital" release). An active release system can be used alone or in conjunction with a passive release system, as described in U.S. Patent No. 5,797,898.

[0134] In addition, pharmaceutical compositions comprising an NK1R antagonist (e.g., aprepitant) and a cyclic dipeptide (e.g., cyclo(His-Pro)) can be formulated as, e.g., liposomes, micelles (e.g., those composed of biodegradable natural or / and synthetic polymers, such as lactosomes), microspheres, microparticles or nanoparticles, whether or not designed for sustained release. For example, liposomes can be used as sustained release pulmonary drugdelivery systems that deliver drugs to the alveolar surface for treatment of systemic diseases.

[0135] The pharmaceutical compositions can be manufactured in any suitablemanner known in the art, e.g., by means of conventional mixing, dissolving, suspending, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compressing processes.

[0136] A pharmaceutical composition can be presented in unit dosage form as a single dose wherein all active and inactive ingredients are combined in a suitable system, and components do not need to be mixed to form the composition to be administered. The unit dosage form can contain an effective dose, or an appropriate fraction thereof, of a therapeutic agent (e.g., an NK1R antagonist, such as aprepitant and a cyclic dipeptide, such as cyclo(His- Pro)). Representative examples of a unit dosage form include a tablet, capsule or pill for oral administration, and powder in a vial or ampoule for oral or nasal inhalation.

[0137] Alternatively, a pharmaceutical composition can be presented as a kit, wherein the active ingredient, excipients and carriers (e.g., solvents) are provided in two or more separate containers (e.g., ampoules, vials, tubes, bottles or syringes) and need to be combined to form the composition to be administered. The kit can contain instructions for storing, preparing and administering the composition (e.g., a solution to be injected intravenously).

[0138] A kit can contain all active and inactive ingredients in unit dosage form or the active ingredient and inactive ingredients in two or more separate containers, and can contain instructions for using the pharmaceutical composition.

[0139] In some embodiments, a kit contains an NK1R antagonist (e.g., aprepitant) or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, prodrug or metabolite thereof, a cyclic dipeptide (e.g., cyclo(His-Pro)) and instructions for administering the compound. In certain embodiments, the compound is contained or incorporated in, or provided by, a device or system configured for pulmonary delivery of the compound by oral inhalation, such as a metered-dose inhaler, a dry powder inhaler or a nebulizer.

[0140] An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a transparent plastic material.

[0141] It may be desirable to provide a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on the card, e.g., as follows “First Week, Monday, Tuesday, etc. . . . Second Week, Monday, Tuesday, . . . ” etc. Other variations of memory aids will be readily apparent. A “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of Formula I compound can consist of one tablet orcapsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa. The memory aid should reflect this.

[0142] In another specific embodiment of the invention, a dispenser designed to dispense the daily doses one at a time in the order of their intended use is provided. For example, the dispenser is equipped with a memory aid, so as to further facilitate compliance with the regimen. An example of such a memory aid is a mechanical counter which indicates the number of daily doses that has been dispensed. Another example of such a memory aid is a battery-powered micro-chip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and / or reminds one when the next dose is to be taken.

[0143] Oral or nasal inhalation can be achieved by means of, e.g., a metered-dose inhaler (MDI), a nebulizer or a dry powder inhaler (DPI). For example, an NK1R antagonist (e.g., aprepitant) and a cyclic dipeptide (e.g., cyclo(His-Pro)) can be formulated for aerosol administration to the respiratory tract by oral or nasal inhalation. The drug is delivered in a small particle size (e.g., between about 0.5 micron and about 5 microns), which can be obtained by micronization, to improve, e.g., drug deposition in the lungs and drug suspension stability. The drug can be provided in a pressurized pack with a suitable propellant, such as a hydrofluoroalkane (HF A, e.g., 1,1,1,2-tetrafluoroethane [HFA-134a]), a chlorofluorocarbon (CFC, e.g., dichlorodifluoromethane, tri chlorofluoromethane or dichlorotetrafluoroethane), or a suitable gas (e.g., oxygen, compressed air or carbon dioxide). The drug in the aerosol formulation is dissolved, or more often suspended, in the propellant for delivery to the lungs. The aerosol can contain excipients such as a surfactant (which enhances penetration into the lungs by reducing the high surface tension forces at the air-water interface within the alveoli, may also emulsify, solubilize or / and stabilize the drug, and can be, e.g., a phospholipid such as lecithin) or / and a stabilizer. For example, an MDI formulation can comprise an NK1R antagonist (e.g., aprepitant), a propellant (e.g., an HFA such as 1,1,1,2-tetrafluoroethane), a surfactant (e.g., a fatty acid such as oleic acid), and a co-solvent (e.g., an alcohol such as ethanol). The MDI formulation can optionally contain a dissolved gas (e.g., CO2). After device actuation, the bursting of CO2 bubbles within the emitted aerosol droplets breaks up the droplets into smaller droplets, thereby increasing the respirable fraction of drug. As another example, a nebulizer formulation can comprise an NK1R antagonist (e.g., aprepitant), a cyclic dipeptide (e.g., cyclo(His-Pro)), a surfactant (e.g., a Tween® such as polysorbate 80), a chelator or preservative (e.g., edetate disodium), an isotonicity agent (e.g., sodium chloride), pH buffering agents (e.g., citric acid / sodium citrate), and water. The drug can be delivered by means of, e.g., a nebulizer or an MDI with or without a spacer, and the drug dose delivered can be controlled by ametering chamber (nebulizer) or a metering valve (MDI).

[0144] For oral or nasal inhalation using a dry powder inhaler (DPI), an NK1R antagonist (e.g., aprepitant) and a cyclic dipeptide (e.g., cyclo(His-Pro)) can be provided in the form of a dry micronized powder, where the drug particles are of a certain small size (e.g., between about 0.5 micron and about 5 microns) to improve, e.g., aerodynamic properties of the dispersed powder and drug deposition in the lungs. Particles between about 0.5 micron and about 5 microns deposit by sedimentation in the terminal bronchioles and the alveolar regions. By contrast, the majority of larger particles (> 5 microns) do not follow the stream of air into the many bifurcations of the airways, but rather deposit by impaction in the upper airways, including the oropharyngeal region of the throat. A DPI formulation can contain the drug particles alone or blended with a powder of a suitable larger base / carrier, such as lactose, starch, a starch derivative (e.g., hydroxypropylmethyl cellulose) or poly vinylpyrrolidine. The carrier particles enhance flow, reduce aggregation, improve dose uniformity and aid in dispersion of the drug particles. A DPI formulation can optionally contain an excipient such as magnesium stearate or / and leucine that improves the performance of the formulation by interfering with inter-particle bonding (by anti-adherent action). The powder formulation can be provided in unit dose form, such as a capsule (e.g., a gelatin capsule) or a cartridge in a blister pack, which can be manually loaded or pre-loaded in an inhaler. The drug particles can be drawn into the lungs by placing the mouthpiece or nosepiece of the inhaler into the mouth or nose, taking a sharp, deep inhalation to create turbulent airflow, and holding the breath for a period of time (e.g., about 5-10 seconds) to allow the drug particles to settle down in the bronchioles and the alveolar regions.

[0145] Lactose (e.g., alpha-lactose monohydrate) is the most commonly used carrier in DPI formulations. Other carriers for DPI formulations include without limitation glucose, mannitol (e.g., crystallized mannitol [Pearlitol 110 C] and spray-dried mannitol [Pearlitol 100 SD]), maltitol (e.g., crystallized maltitol [Maltisorb P90]), sorbitol and xylitol.

[0146] Dry powder inhalers can be classified by dose type into single-unit dose (including disposable and reusable) and multi-dose (including multi-dose reservoirs and multiunit dose). In a single-unit dose DPI, the formulation can be a powder mix of a micronized drug powder and a carrier and can be supplied in individual capsules, which are inserted into the inhaler for a single dose and are removed and discarded after use. The capsule body containing the dose falls into the device, while the cap is retained in the entry port for subsequent disposal. As the user inhales, the portion of the capsule containing the drug experiences erratic motion in the airstream, causing dislodged particles to be entrained and subsequently inhaled. Particle deaggregation is caused mainly by turbulence promoted by the grid upstream of the mouthpiece ornosepiece. Examples of single-unit dose DPIs include without limitation Aerolizer®, AIR®, Conix One® (foil seal), Diskhaler®, Diskus®, Handihaler®, Microhaler®, Rotahaler® and Turbo spin®.

[0147] In at least some of the previously described embodiments, one or more elements used in an embodiment can interchangeably be used in another embodiment unless such a replacement is not technically feasible. It will be appreciated by those skilled in the art that various other omissions, additions and modifications may be made to the methods and structures described above without departing from the scope of the claimed subject matter. All such modifications and changes are intended to fall within the scope of the subject matter, as defined by the appended claims.

[0148] With respect to the use of substantially any plural and / or singular terms herein, those having skill in the art can translate from the plural to the singular and / or from the singular to the plural as is appropriate to the context and / or application. The various singular / plural permutations may be expressly set forth herein for sake of clarity. As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. Any reference to “or” herein is intended to encompass “and / or” unless otherwise stated.

[0149] It will be understood by those within the art that, in general, terms used herein, and especially in the appended claims (e.g., bodies of the appended claims) are generally intended as “open” terms (e.g., the term “including” should be interpreted as “including but not limited to,” the term “having” should be interpreted as “having at least,” the term “includes” should be interpreted as “includes but is not limited to,” etc.). It will be further understood by those within the art that if a specific number of an introduced claim recitation is intended, such an intent will be explicitly recited in the claim, and in the absence of such recitation no such intent is present. For example, as an aid to understanding, the following appended claims may contain usage of the introductory phrases “at least one” and “one or more” to introduce claim recitations. However, the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles “a” or “an” limits any particular claim containing such introduced claim recitation to embodiments containing only one such recitation, even when the same claim includes the introductory phrases “one or more” or “at least one” and indefinite articles such as “a” or “an” (e.g., “a” and / or “an” should be interpreted to mean “at least one” or “one or more”); the same holds true for the use of definite articles used to introduce claim recitations. In addition, even if a specific number of an introduced claim recitation is explicitly recited, those skilled in the art will recognize that such recitation should be interpretedto mean at least the recited number (e.g., the bare recitation of “two recitations,” without other modifiers, means at least two recitations, or two or more recitations). Furthermore, in those instances where a convention analogous to “at least one of A, B, and C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., “ a system having at least one of A, B, and C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). In those instances where a convention analogous to “at least one of A, B, or C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., “ a system having at least one of A, B, or C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). It will be further understood by those within the art that virtually any disjunctive word and / or phrase presenting two or more alternative terms, whether in the description, or claims, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms.

[0150] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0151] As will be understood by one skilled in the art, for any and all purposes, such as in terms of providing a written description, all ranges disclosed herein also encompass any and all possible sub-ranges and combinations of sub-ranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like include the number recited and refer to ranges which can be subsequently broken down into sub-ranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 articles refers to groups having 1, 2, or 3 articles. Similarly, a group having 1-5 articles refers to groups having 1, 2, 3, 4, or 5 articles, and so forth.

[0152] While various aspects and embodiments have been disclosed herein, other aspects and embodiments will be apparent to those skilled in the art. The various aspects and embodiments disclosed herein are for purposes of illustration and are not intended to be limiting, with the true scope and spirit being indicated by the following claims.

Claims

WHAT IS CLAIMED IS:

1. A method of preventing, slowing the progression of or treating obesity, comprising administering to a subject in need thereof (i) aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug thereof, and (ii) a cyclic dipeptide, thereby preventing, slowing the progression of or treating obesity.

2. A method of controlling weight, comprising administering to a subject in need thereof a composition comprising (i) aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug thereof, and (ii) a cyclic dipeptide, thereby reducing, maintaining or preventing increase of weight in the subject.

3. The method of any one of claims 1-2, wherein the subject is administrated with a therapeutically or prophylactically effective amount of aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

4. The method of any one of claims 1-3, wherein the subject is administrated with a therapeutically or prophylactically effective amount of the cyclic dipeptide.

5. The method of any one of claims 1-4, wherein the subject is a mammal.

6. The method of any one of claims 1-5, wherein the subject is a human.

7. The method of any one of claims 1-6, wherein the subject in need thereof is diagnosed with overweight or obesity, optionally wherein the obesity is visceral obesity or abdominal obesity.

8. The method of any one of claims 1-7, wherein the subject in need thereof has a body mass index (BMI) of at least 25 kg / m2.

9. The method of any one of claims 1-8, wherein the cyclic dipeptide is a histidine- containing, tyrosine-containing and / or proline-containing cyclic dipeptide.

10. The method of any one of claims 1-9, wherein the cyclic dipeptide is cyclo(His- Pro), cyclo(D-8-acetoxyl-Pro-L-Leu) or cyclo(Pro-Gly).

11. The method of any one of claims 1-10, wherein aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer thereof, and / or the cyclic dipeptide is formulated into a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients.

12. The method of any one of claims 1-11, wherein aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer thereof, and / or the cyclic dipeptide is administered to the subject by intravenous administration, nasal administration, pulmonary administration, oral administration, parenteral administration, or nebulization.

13. The method of any one of claims 1-12, wherein aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer thereof, and / or the cyclic dipeptide is administered to the subject by oral or intravenous administration.

14. The method of any one of claims 1-13, wherein aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer thereof, and / or the cyclic dipeptide is in the form of powder, pill, tablet, microtablet, pellet, micropellet, capsule, capsule containing microtablets, liquid, aerosols, or nanoparticles.

15. The method of any one of claims 1-14, wherein aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer thereof, and / or the cyclic dipeptide is administered to the subject once, twice, or three times a day.

16. The method of any one of claims 1-15, wherein aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer thereof, and / or the cyclic dipeptide is administered to the subject once every day, every two days, or every three days.

17. The method of any one of claims 1-16, wherein aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer thereof is administered to the subject at an effective daily dose of aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer thereof at from 10 mg to 250 mg.

18. The method of any one of claims 1-17, wherein the cyclic dipeptide is administered to the subject at an effective daily dose of the cyclic dipeptide at from 1 mg to 500 mg.

19. The method of any one of claims 1-18, wherein the subject is administrated with one or more additional therapeutic agents.

20. The method of any one of claims 1-19, further comprising measuring body weight and / or body mass index (BMI) of the subject before administering aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer thereof, and / or the cyclic dipeptide to the subject, after administering aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer thereof, and / or the cyclic dipeptide to the subject, or both.

21. The method of any one of claims 1-20, wherein administering aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer thereof, and the cyclic dipeptide reduces body weight and / or body mass index (BMI) by at least 10%.

22. The method of any one of claims 1-21, wherein the reduction of body weight and / or body mass index (BMI) is more than the additive reduction achieved by administrating aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer thereof along, or the cyclic dipeptide alone.

23. The method of any one of claims 2-22, wherein a change in body weight and / or body mass index (BMI) of the subject is by less than 10% for at least 3 months, optionally less than 2% for at least 6 months.

24. A kit, comprisingaprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug thereof; a cyclic dipeptide; and a label indicating:(a) the kit is for preventing, slowing the progression of or treating obesity, and / or(b) the kit is for controlling weight.

25. A composition comprising (i) aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug thereof, and (ii) a cyclic dipeptide for use in preventing, slowing the progression of or treating obesity in a subject.

26. A composition comprising (i) aprepitant or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug thereof, and (ii) a cyclic dipeptide for use in controlling weight in a subject.

27. The kit and composition of any one of claims 24-26, wherein the cyclic dipeptide is a histidine-containing, tyrosine-containing and / or proline-containing cyclic dipeptide.

28. The kit and composition of any one of claims 24-27, wherein the cyclic dipeptide is cyclo(His-Pro) or cyclo(Pro-Gly).

Images