WO2019199731A1

WO2019199731A1 - Amphetamine prodrug and crystalline froms thereof

Info

Publication number: WO2019199731A1
Application number: PCT/US2019/026464
Authority: WO
Inventors: Helge A. Reisch; Datong Tang; Kishore Ramachandran
Original assignee: Shire Pharmaceuticals Inc.
Priority date: 2018-04-10
Filing date: 2019-04-09
Publication date: 2019-10-17

Abstract

The present invention relates to crystalline forms of amphetamine-homoarginine conjugate 1- homoarginine-d-amphetamine, which is an amphetamine prodrug useful in the treatment of various diseases and conditions, and symptoms associated therewith.

Description

AMPHETAMINE PRODRUG AND CRYSTALLINE FORMS THEREOF

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 62/655,792, filed April 10, 2018, the disclosure of which is herein incorporated by reference in its entirety.

FIELD OF INVENTION

[0002] The present invention relates to a novel amphetamine prodrug which is an amphetamine- homoarginine conjugate l-homoarginine-d-amphetamine carbamate, and crystalline forms thereof, which are useful for treatment of various conditions and disorders, and symptoms associated therewith.

BACKGROUND OF THE INVENTION

[0003] Stimulants, including amphetamine and its derivatives, enhance the activity of the sympathetic nervous system and/or central nervous system (CNS) and are prescribed for the treatment of a range of conditions and disorders predominantly encompassing, for example, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), fatigue, inattention, cognitive disfunction, obesity, narcolepsy, appetite suppression, depression, anxiety and wakefulness.

[0004] Prodrugs of the stimulant amphetamine (i.e., l-phenylpropan -2-amine), including homoarginine-prodrugs of amphetamine, have been shown to be useful in the treatment of various disorders and conditions, and symptoms associated therewith, including those described above. Furthermore, homoarginine-amphetamine conjugates may provide additional advantages, such as the reduction of amphetamine side effects in a human subject.

[0005] One particular amphetamine-homoarginine conjugate is l-homoarginine-d-amphetamine, which is represented by the following chemical formula:

[0006] The l-homoarginine-d-amphetamine, as well as its preparation and use, has been described in U.S. Patent No. 7,776,917; 7,772,222; and 8,101,661; and U.S. Patent Publication No. 2014/0171510, each of which are hereby incorporated by reference in their entirety for all purposes. For the development of a drug candidate, it is typically advantageous to employ a form of the drug having desirable properties with respect to preparation, purification, reproducibility, stability, bioavailability, and/or other characteristics. Accordingly, novel forms of l-homoarginine-d-amphetamine help satisfy the ongoing need for the development of stimulants for the treatment of a range of conditions and disorders, and symptoms associated therewith.

SUMMARY OF THE INVENTION

[0007] The present invention provides l-homoarginine-d-amphetamine carbamate, according to Formula I:

[0008] The present invention further provides a crystalline form of l-homoarginine-d- amphetamine carbamate which is Form I as described herein.

[0009] The present invention further provides a crystalline form of l-homoarginine-d- amphetamine carbamate according to Formula I.

[00010] The present invention further provides a crystalline form of 1- homoarginine-d-amphetamine carbamate according to Formula I which is hydrated or solvated.

[00011] The present invention further provides a crystalline form of l-homoarginine-d- amphetamine carbamate according to Formula I which is a hydrate.

[00012] The present invention further provides a crystalline form of l-homoarginine-d- amphetamine carbamate according to Formula I which is a solvate, e.g., an ethanolate. [00013] The present invention further provides a composition comprising a compound 1- homoarginine-d-amphetamine carbamate according to Formula I and at least one pharmaceutically acceptable carrier.

[00014] The present invention further provides a composition comprising a crystalline form of a compound of Formula I of the invention and at least one pharmaceutically acceptable carrier.

[00015] The present invention further provides a process for preparing a compound of Formula I according to the invention.

[00016] The present invention further provides a process for preparing a crystalline form of a compound of Formula I of the invention.

[00017] The present invention further provides a method of treating a disorder, for example, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), obesity, narcolepsy, appetite suppression, depression, anxiety and wakefulness, comprising administering to the patient in need thereof a therapeutically effective amount for the appropriate indication or indications of a compound of Formula I according to the invention or a composition comprising the compound of Formula I.

[00018] The present invention further provides a method of treating a disorder, for example, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), obesity, narcolepsy, appetite suppression, depression, anxiety and wakefulness, comprising administering to the patient in need thereof a therapeutically effective amount for the appropriate indication or indications of a crystalline form of a compound of Formula I of the invention or a composition comprising the crystalline form.

[00019] The present invention further provides a method of treating or preventing fatigue, cognitive dysfunction, and/or inattentiveness, comprising administering to the patient in need thereof a therapeutically effective amount for the appropriate indication or indications of a compound of Formula I according to the invention or a composition comprising the compound of the invention.

[00020] The present invention further provides a method of treating or preventing fatigue, cognitive dysfunction, and/or inattentiveness, comprising administering to the patient in need thereof a therapeutically effective amount for the appropriate indication or indications of a crystalline form of a compound of Formula I of the invention or a composition comprising the crystalline form.

[00021] The present invention further provides a method of treating or preventing various conditions and disorders, such as chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis (ME); fatigue, cognitive dysfunction, and/or inattention in a patient suffering from CFS/ME; fatigue, cognitive dysfunction, and/or inattention in a patient suffering from fibromyalgia; fatigue, cognitive dysfunction, and/or inattention in a patient suffering from multiple sclerosis (MS); fatigue, cognitive dysfunction, and/or inattention in a patient suffering from major depressive disorder (MDD); fatigue, cognitive dysfunction, and/or inattention in a patient suffering from traumatic brain injury; fatigue, cognitive dysfunction, and/or inattention in a menopausal patient; fatigue, cognitive dysfunction, and/or inattention in a patient suffering from the negative symptoms of schizophrenia; post-cancer therapy fatigue, cognitive dysfunction, and/or inattention; fatigue in cancer patients caused by chemotherapy, radiation therapy, surgery, or a combination thereof; cognitive dysfunction in cancer patients caused by chemotherapy, radiation therapy, surgery, or a combination thereof; inattention in cancer patients caused by chemotherapy, radiation therapy, surgery, or a combination thereof; wakefulness disorder such as narcolepsy; wakefulness disorder as a result of chemotherapy or radiation therapy; hyperactivity and/or impulsivity associated with alcohol addiction, smoking, and symptoms of the Fragile X Syndrome; and fatigue, cognitive dysfunction, and/or inattention in a patient suffering from a metabolic disorder, e.g., obesity, appetite related symptoms of the Prader Willi Syndrome, and Type 1 and Type 2 diabetes mellitus, comprising administering to the patient in need thereof a therapeutically effective amount for the appropriate indication or indications of a compound of the invention and/or a crystalline form of the compound of the invention, or a composition comprising the compound of the invention and/or the crystalline form.

[00022] In one aspect, the present invention provides a method of treating or preventing fatigue which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I according to the invention and/or its crystalline form or a composition comprising the compound of Formula I according to the invention and/or its crystalline form for the treatment of fatigue. These amounts may be the same or different for different indications, combinations of indications, or patient populations. [00023] In one embodiment, the fatigue is in patients suffering from or diagnosed with ME/CFS. In another embodiment, the fatigue is in patients suffering from or diagnosed with fibromyalgia. In another embodiment, the fatigue is in patients suffering from or diagnosed with MS. In another embodiment, the fatigue is in patients suffering from or diagnosed with MDD. In another embodiment, the fatigue is in patients suffering from or diagnosed with menopause. In another embodiment, the fatigue is in patients suffering from or diagnosed with traumatic brain injury. In another embodiment, the fatigue is in patients suffering from or diagnosed with negative symptoms of schizophrenia. In another embodiment, the fatigue is in patients suffering from or diagnosed with narcolepsy. In another embodiment, the fatigue is in patients suffering from or diagnosed with cancer. In one embodiment, the fatigue is in cancer patients caused by chemotherapy, radiation therapy, surgery, or a combination thereof.

[00024] The present invention provides a method of treating or preventing cognitive dysfunction in a patient which comprises administering a therapeutically effective amount of a compound of Formula I according to the invention and/or its crystalline form or a composition comprising the compound of Formula I according to the invention and/or its crystalline form to the patient for the treatment of cognitive dysfunction. These amounts may be the same or different for different indications, combinations of indications, or patient populations.

[00025] In another embodiment, the cognitive dysfunction is in patients suffering from or diagnosed with ME/CFS. In another embodiment, the cognitive dysfunction is in patients suffering from or diagnosed with fibromyalgia. In another embodiment, the cognitive dysfunction is in patients suffering from or diagnosed with MS. In another embodiment, the cognitive dysfunction is in patients suffering from or diagnosed with MDD. In another embodiment, the cognitive dysfunction is in patients suffering from or diagnosed with menopause. In another embodiment, the cognitive dysfunction is in patients suffering from or diagnosed with traumatic brain injury. In another embodiment, the cognitive dysfunction is in patients suffering from or diagnosed with negative symptoms of schizophrenia. In another embodiment, the cognitive dysfunction is in patients suffering from or diagnosed with narcolepsy. In another embodiment, the cognitive dysfunction is in patients suffering from or diagnosed with cancer. In one embodiment, the cognitive dysfunction is in cancer patients caused by chemotherapy, radiation therapy, surgery, or a combination thereof. [00026] In one aspect, the present invention provides a method of treating or preventing inattention which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I according to the invention and/or its crystalline form of the invention or a composition comprising the compound of Formula I according to the invention and/or its crystalline form for the treatment of inattention. These amounts may be the same or different for different indications, combinations of indications, or patient populations.

[00027] In another embodiment, the inattention is in patients suffering from or diagnosed with ME/CFS. In another embodiment, the inattention is in patients suffering from or diagnosed with fibromyalgia. In another embodiment, the inattention is in patients suffering from or diagnosed with MS. In another embodiment, the inattention is in patients suffering from or diagnosed with MDD. In another embodiment, the inattention is in patients suffering from or diagnosed with menopause. In another embodiment, the inattention is in patients suffering from or diagnosed with traumatic brain injury. In another embodiment, the inattention is in patients suffering from or diagnosed with negative symptoms of schizophrenia. In another embodiment, the inattention is in patients suffering from or diagnosed with narcolepsy. In another embodiment, the inattention is in patients suffering from or diagnosed with cancer. In one embodiment, the inattention is in cancer patients caused by chemotherapy, radiation therapy, surgery, or a combination thereof.

[00028] In one aspect, the present invention provides a method for the treatment of symptoms related to fatigue and cognitive impairment in patients with chronic fatigue syndrome, also known as myalgic encephalomyelitis (ME/CSF), which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I according to the invention and/or its crystalline form or a composition comprising the compound of Formula I according to the invention and/or its crystalline form. In certain embodiments, the present invention provides a method for the treatment of at least one symptom related to fatigue and cognitive dysfunction in chronic fatigue syndrome, also known as myalgic encephalomyelitis (ME/CSF), which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I according to the invention and/or its crystalline form or a composition comprising the compound of Formula I according to the invention and/or its crystalline form for the treatment of at least one symptom. In certain embodiments, the present invention provides a method for the treatment of at least one symptom related to fatigue and cognitive dysfunction in chronic fatigue syndrome, also known as myalgic encephalomyelitis (ME/CSF), which comprises administering to an adult patient in need thereof a therapeutically effective amount of a compound of Formula I according to the invention and/or its crystalline form or a composition comprising compound of Formula I according to the invention and/or its the crystalline form for the treatment of at least one symptom.

[00029] In one aspect, the present invention provides a method to improve symptoms of fatigue (physical symptoms and cognitive symptoms) in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I according to the invention and/or its crystalline form or a composition comprising the compound of Formula I according to the invention and/or its crystalline form. In certain embodiments, the present invention provides a method to improve symptoms of fatigue (physical symptoms and cognitive symptoms) in adult patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I according to the invention and/or its crystalline form or a composition comprising the compound of Formula I according to the invention and/or its crystalline form. In certain embodiments, the present invention provides a method to improve at least one symptom of fatigue (physical symptoms and/or cognitive symptoms) associated with chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis (ME), which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I according to the invention and/or its crystalline form or a composition comprising the compound of Formula I according to the invention and/or its crystalline form for the improvement of at least one symptom. In certain embodiments, the present invention provides a method to improve at least one symptom of fatigue (physical symptoms and/or cognitive symptoms) associated with chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis (ME), which comprises administering to an adult patient in need thereof a therapeutically effective amount of a compound of Formula I according to the invention and/or its crystalline form or a composition comprising the compound of Formula I according to the invention and/or its crystalline form for the improvement of at least one symptom.

[00030] In another aspect, the present invention provides a method of treating or preventing symptoms associated with chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis (ME), which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I according to the invention and/or its crystalline form or a composition comprising the compound of Formula I according to the invention and/or its crystalline form. In one embodiment, the present invention provides a method of treating or preventing fatigue, cognitive dysfunction, and/or inattention in a patient with ME/CFS which comprises administering to a patient in need thereof a therapeutically effective amount for the appropriate indication or indications of a compound of Formula I according to the invention and/or its crystalline form or a composition comprising the compound of Formula I according to the invention and/or its crystalline form. In one embodiment, the present invention provides a method of treating or preventing fatigue in a patient with ME/CFS which comprises administering to a patient in need thereof a therapeutically effective amount for the treatment of fatigue of a compound of Formula I according to the invention and/or its crystalline form or a composition comprising the compound of Formula I according to the invention and/or its crystalline form. In one embodiment, the present invention provides a method of treating or preventing inattention in a patient with ME/CFS which comprises administering to a patient in need thereof a therapeutically effective amount for the treatment of inattention of a compound of Formula I according to the invention and/or its crystalline form or a composition comprising the compound of Formula I according to the invention and/or its crystalline form. In one embodiment, the present invention provides a method of treating or preventing cognitive dysfunction in a patient with ME/CFS which comprises administering to a patient in need thereof a therapeutically effective amount for the treatment of cognitive dysfunction of a compound of Formula I according to the invention and/or its crystalline form or a composition comprising the compound of Formula I according to the invention and/or its crystalline form. These amounts may be the same or different for different indications, combinations of indications, or patient populations.

[00031] In another aspect, the present invention provides a method of treating or preventing fatigue, cognitive dysfunction and/or inattention in a patient suffering from or diagnosed with fibromyalgia, which comprises administering to a patient in need thereof a therapeutically effective amount for the appropriate indication or indications of a compound of Formula I according to the invention and/or its crystalline form or a composition comprising the compound of Formula I according to the invention and/or its crystalline form. In one embodiment, the present invention provides a method of treating or preventing fatigue associated with fibromyalgia which comprises administering to a patient in need thereof a therapeutically effective amount for the treatment of fatigue of a compound of Formula I according to the invention and/or its crystalline form or a composition comprising the compound of Formula I according to the invention and/or its crystalline form. In another embodiment, the present invention provides a method of treating or preventing inattention associated with fibromyalgia which comprises administering to a patient in need thereof a therapeutically effective amount for the treatment of inattention of a compound of Formula I according to the invention and/or its crystalline form or a composition comprising the compound of Formula I according to the invention and/or its crystalline form. In another embodiment, the present invention provides a method of treating or preventing cognitive dysfunction associated with fibromyalgia which comprises administering to a patient in need thereof a therapeutically effective amount for the treatment of cognitive dysfunction of a compound of Formula I according to the invention and/or its crystalline form or a composition comprising the compound of Formula I according to the invention and/or its crystalline form. These amounts may be the same or different for different indications, combinations of indications, or patient populations.

[00032] In another aspect, the present invention provides a method of treating or preventing fatigue, cognitive dysfunction and/or inattention in a patient suffering from or diagnosed with multiple sclerosis (MS), which comprises administering to a patient in need thereof a therapeutically effective amount for the appropriate indication or indications of a compound of Formula I according to the invention and/or its crystalline form or a composition comprising the compound of Formula I according to the invention and/or its crystalline form. In one embodiment, the present invention provides a method of treating or preventing fatigue in a patient suffering from or diagnosed with MS, which comprises administering to a patient in need thereof a therapeutically effective amount for the treatment of fatigue of a compound of Formula I according to the invention and/or its crystalline form or a composition comprising the compound of Formula I according to the invention and/or its crystalline form. In another embodiment, the present invention provides a method of treating or preventing cognitive dysfunction in a patient suffering from or diagnosed with MS which comprises administering to a patient in need thereof a therapeutically effective amount for the treatment of cognitive dysfunction of a compound of Formula I according to the invention and/or its crystalline form or a composition comprising the compound of Formula I according to the invention and/or its crystalline form. In another embodiment, the present invention provides a method of treating or preventing inattention in a patient suffering from or diagnosed with MS which comprises administering to a patient in need thereof a therapeutically effective amount for the treatment of inattention of a compound of Formula I according to the invention and/or its crystalline form or a composition comprising the compound of Formula I according to the invention and/or its crystalline form. These amounts may be the same or different for different indications, combinations of indications, or patient populations.

[00033] In another aspect, the present invention provides a method of treating or preventing fatigue, cognitive dysfunction and/or inattention in a patient suffering from or diagnosed with major depressive disorder (MDD), which comprises administering to a patient in need thereof a therapeutically effective amount for the appropriate indication or indications of a compound of Formula I according to the invention and/or its crystalline form or a composition comprising the compound of Formula I according to the invention and/or its crystalline form. In one embodiment, the present invention provides a method of treating or preventing fatigue in a patient suffering from or diagnosed with MDD, which comprises administering to a patient in need thereof a therapeutically effective amount for the treatment of fatigue of a compound of Formula I according to the invention and/or its crystalline form or a composition comprising the compound of Formula I according to the invention and/or its crystalline form. In another embodiment, the present invention provides a method of treating or preventing cognitive dysfunction in a patient suffering from or diagnosed with MDD, which comprises administering to a patient in need thereof a therapeutically effective amount for the treatment of cognitive dysfunction of a compound of Formula I according to the invention and/or its crystalline form or a composition comprising the compound of Formula I according to the invention and/or its crystalline form. In another embodiment, the present invention provides a method of treating or preventing inattention in a patient suffering from or diagnosed with MDD, which comprises administering to a patient in need thereof a therapeutically effective amount for the treatment of inattention of a compound of Formula I according to the invention and/or its crystalline form or a composition comprising the compound of Formula I according to the invention and/or its crystalline form. These amounts may be the same or different for different indications, combinations of indications, or patient populations. [00034] In one aspect, the present invention provides a method of treating or preventing post-cancer therapy fatigue which comprises administering to a patient in need thereof a therapeutically effective amount for the treatment of fatigue of a compound of Formula I according to the invention and/or its crystalline form or a composition comprising the compound of Formula I according to the invention and/or its crystalline form. The amount may be the same or different for different indications, combinations of indications, or patient populations. In various embodiments of the invention, the cancer therapy is chemotherapy, radiation therapy, surgery, or a combination thereof. In one embodiment, the cancer therapy is a combination of at least two of the following: chemotherapy, radiation therapy, and surgery. In various embodiments, the compound of Formula I according to the invention and/or its crystalline form or a composition comprising the compound of Formula I according to the invention and/or its crystalline form is initially administered prior to the cancer therapy, after cancer therapy and before the patient is diagnosed with post-cancer therapy fatigue, or after cancer therapy and after the patient is diagnosed with post-cancer therapy fatigue.

[00035] In one aspect, the present invention provides a method of treating or preventing post-cancer therapy cognitive dysfunction which comprises administering to a patient in need thereof a therapeutically effective amount for the treatment of cognitive dysfunction of a compound of Formula I according to the invention and/or its crystalline form or a composition comprising the compound of Formula I according to the invention and/or its crystalline form. The amount may be the same or different for different indications, combinations of indications, or patient populations. In various embodiments of the invention, the cancer therapy is chemotherapy, radiation therapy, surgery, or a combination thereof. In one embodiment, the cancer therapy is a combination of at least two of the following: chemotherapy, radiation therapy, and surgery. In various embodiments, the compound of Formula I according to the invention and/or its crystalline form or a composition comprising the compound of Formula I according to the invention and/or its crystalline form is initially administered prior to the cancer therapy, after cancer therapy and before the patient is diagnosed with post-cancer therapy cognitive dysfunction, or after cancer therapy and after the patient is diagnosed with post-cancer therapy cognitive dysfunction.

[00036] In another aspect, the present invention provides a method of treating or preventing post-cancer therapy inattention which comprises administering to a patient in need thereof a therapeutically effective amount for the treatment of inattention of a compound of Formula I according to the invention and/or its crystalline form or a composition comprising the compound of Formula I according to the invention and/or its crystalline form. The amount may be the same or different for different indications, combinations of indications, or patient populations. In various embodiments of the invention, the cancer therapy is chemotherapy, radiation therapy, surgery, or a combination thereof. In one embodiment, the cancer therapy is a combination of at least two of the following: chemotherapy, radiation therapy, and surgery. In various embodiments, the compound of Formula I according to the invention and/or its crystalline form or a composition comprising the compound of Formula I according to the invention and/or its crystalline form is initially administered prior to the cancer therapy, after cancer therapy and before the patient is diagnosed with post-cancer therapy inattention, or after cancer therapy and after the patient is diagnosed with post-cancer therapy inattention.

[00037] In one aspect, the present invention provides a method of treating or preventing a wakefulness disorder which comprises administering to a patient in need thereof a therapeutically effective amount for the treatment of a wakefulness disorder of a compound of Formula I according to the invention and/or its crystalline form or a composition comprising the compound of Formula I according to the invention and/or its crystalline form. The amount may be the same or different for different indications, combinations of indications, or patient populations. In one embodiment of the invention, the wakefulness disorder is narcolepsy. In another embodiment, wakefulness disorder is as a result of chemotherapy, surgery, and/or radiation therapy.

[00038] In one aspect, the present invention provides a method of treating or preventing hyperactivity and/or impulsivity which comprises administering to a patient in need thereof a therapeutically effective amount for the appropriate indication or indications of a compound of Formula I according to the invention and/or its crystalline form or a composition comprising the compound of Formula I according to the invention and/or its crystalline form. The amount may be the same or different for different indications, combinations of indications, or patient populations. In various embodiments of the invention, the hyperactivity and/or impulsivity may be associated with one or more of alcohol addiction, smoking, and/or symptoms of the Fragile X syndrome. [00039] In one aspect, the present invention provides a method of treating or preventing fatigue, inattention, and/or cognitive dysfunction associated with metabolic disorders which comprises administering to a patient in need thereof a therapeutically effective amount for the appropriate indication or indications of a compound of Formula I according to the invention and/or its crystalline form or a composition comprising the compound of Formula I according to the invention and/or its crystalline form. The amount may be the same or different for different indications, combinations of indications, or patient populations. In various embodiments of the invention, the metabolic disorders may be one or more of obesity, appetite related symptoms of the Prader Willi Syndrome, and Type 1 and Type 2 diabetes mellitus.

[00040] In one embodiment of the present invention, the compound of Formula I according to the invention and/or its crystalline form or a composition comprising the compound of Formula I according to the invention and/or its crystalline form of the amphetamine- homoarginine conjugate is initially administered prior to the chemotherapy or radiation therapy.

[00041] In an alternative embodiment, the compound of Formula I according to the invention and/or its crystalline form or a composition comprising the compound of Formula I according to the invention and/or its crystalline form is initially administered after chemotherapy, radiation therapy, or surgery and before the patient is diagnosed with fatigue caused by chemotherapy, radiation therapy, or surgery.

[00042] In an alternative embodiment, the compound of Formula I according to the invention and/or its crystalline form or a composition comprising the compound of Formula I according to the invention and/or its crystalline form is initially administered after chemotherapy, radiation therapy, or surgery and before the patient is diagnosed with a sleep and/or wakefulness disorder caused by chemotherapy, radiation therapy, or surgery.

[00043] In a further embodiment, the compound of Formula I according to the invention and/or its crystalline form or a composition comprising the compound of Formula I according to the invention and/or its crystalline form is initially administered after chemotherapy, radiation therapy, or surgery and after the patient is diagnosed with fatigue caused by chemotherapy, radiation therapy, or surgery.

[00044] In an alternative embodiment, the compound of Formula I according to the invention and/or its crystalline form or a composition comprising the compound of Formula I according to the invention and/or its crystalline form is initially administered after chemotherapy, radiation therapy, or surgery and after the patient is diagnosed with a wakefulness disorder caused by chemotherapy, radiation therapy, or surgery.

[00045] In an alternative embodiment, the compound of Formula I according to the invention and/or its crystalline form or a composition comprising the compound of Formula I according to the invention and/or its crystalline form is initially administered after cancer therapy and before the patient is diagnosed with post-cancer therapy inattention.

[00046] In a further embodiment, the compound of Formula I according to the invention and/or its crystalline form or a composition comprising the compound of Formula I according to the invention and/or its crystalline form is initially administered after cancer therapy and after the patient is diagnosed with post-cancer therapy inattention.

[00047] In one aspect, the present invention provides a method of treating a cognitive dysfunction in a patient suffering from or diagnosed with a cancer comprising administering a therapeutically effective amount for cognitive dysfunction of a compound of Formula I according to the invention and/or its crystalline form or a composition comprising the compound of Formula I according to the invention and/or its crystalline form to a patient in need thereof, [00048] wherein the cognitive dysfunction is selected from the group consisting of: a short-term memory problem, an attention problem, a concentration problem, a planning problem, and a combination thereof; and

[00049] wherein the cognitive dysfunction appears before the patient receives chemotherapy.

[00050] In one aspect, the present invention provides a method of treating a cognitive dysfunction in a patient suffering from or diagnosed with a cancer comprising administering a therapeutically effective amount for cognitive dysfunction of a compound of Formula I according to the invention and/or its crystalline form of or a composition comprising the compound of Formula I according to the invention and/or its crystalline form to a patient in need thereof,

[00051] wherein the cognitive dysfunction is selected from the group consisting of: a short-term memory problem, an attention problem, a concentration problem, a planning problem, and a combination thereof; and

[00052] wherein the cognitive dysfunction arises during chemotherapy or after the patient receives chemotherapy. [00053] In one aspect, the present invention further provides a method of treating a cognitive dysfunction in a patient suffering from or diagnosed with a cancer comprising administering a therapeutically effective amount for cognitive dysfunction of a compound of Formula I according to the invention and/or its crystalline form of the invention or a composition comprising the compound of Formula I according to the invention and/or its crystalline form to a patient in need thereof, wherein the cognitive dysfunction is selected from the group consisting of: a short-term memory problem, an attention problem, a concentration problem, a planning problem, and a combination thereof; wherein the cognitive dysfunction arises during chemotherapy or after the patient receives chemotherapy.

[00054] In one aspect, the present invention further provides a method of treating fatigue, cognitive dysfunction and/or inattention in a patient suffering from or diagnosed with traumatic brain injury which comprises administering a therapeutically effective amount for the appropriate indication or indications of a compound of Formula I according to the invention and/or its crystalline form or a composition comprising the compound of Formula I according to the invention and/or its crystalline form to a patient in need thereof.

[00055] In one aspect, the present invention provides a method of treating fatigue, cognitive dysfunction and/or inattention in an elderly patient suffering from or diagnosed with major depressive disorder, which comprises administering a therapeutically effective amount for the appropriate indication or indications of a compound of Formula I according to the invention and/or its crystalline form or a composition comprising the compound of Formula I according to the invention and/or its crystalline form to a patient in need thereof.

[00056] In one aspect, the present invention encompasses a method of treating fatigue, cognitive dysfunction and/or inattention in a menopausal patient, which comprises administering a therapeutically effective amount for the appropriate indication or indications of a compound of Formula I according to the invention and/or its crystalline form or a composition comprising the compound of Formula I according to the invention and/or its crystalline form to a patient in need thereof.

[00057] In one aspect according to the present invention, a method is provided for treating fatigue, cognitive dysfunction and/or inattention in a patient suffering from or diagnosed with the negative symptoms of schizophrenia, which comprises administering a therapeutically effective amount for the appropriate indication or indications of a compound of Formula I according to the invention and/or its crystalline form or a composition comprising the compound of Formula I according to the invention and/or its crystalline form to a patient in need thereof.

[00058] In certain embodiments, the compound of Formula I according to the invention and/or its crystalline form is administered once daily.

[00059] These and other aspects of the present invention will become apparent to those skilled in the art after a reading of the following detailed description of the invention, including the appended claims

BRIEF DESCRIPTION OF THE DRAWINGS

[00060] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[00061] Figure 1 shows a magnified depiction of the crystals of an embodiment of Form I (50X magnification in oil).

[00062] Figure 2 shows a PXRD pattern for an embodiment of Form I.

[00063] Figure 3 shows results of a DSC and TGA-IR experiments for an embodiment of

Form I.

[00064] Figure 4 shows a magnified depiction of the crystals of another embodiment of Form I (10X magnification in oil).

[00065] Figure 5 shows a PXRD pattern for another embodiment of Form I.

[00066] Figure 6 shows results of a DSC and TGA-IR experiments for another embodiment of Form I.

[00067] Figure 7 shows an overlay of PXRD patterns for two different embodimetns of Form I.

[00068] Figure 8 shows an overlay of DSC results for two different embodiments of Form I.

[00069] Figure 9 shows a magnified depiction of the transformation of the crystals of Form I upon grinding (10X/20X magnification in oil).

[00070] Figure 10 shows an overlay of PXRD patterns for Form I and ground Form I.

[00071] Figure 11 shows Ion Chromatography (IC) report for l-homoarginine-d- amphetamine carbamate. [00072] Figure 12A shows a 1H NMR spectrum for l-homoarginine-d-amphetamine carbamate, with expansion of the aliphatic region (inset); Figure 12B shows a 13C NMR spectrum for l-homoarginine-d-amphetamine carbamate; Figure 12C shows a 2D COSY spectrum for l-homoarginine-d-amphetamine carbamate; Figure 12D shows a 2D HSQC spectrum for l-homoarginine-d-amphetamine carbamate; Figure 12E shows a 2D HMBC spectrum for l-homoarginine-d-amphetamine carbamate; Figure 12F shows 2D ROESY spectrum for l-homoarginine-d-amphetamine carbamate.

[00073] Figure 13A is a liquid chromatography (LC) trace for l-homoarginine-d- amphetamine carbamate of the invention; Figure 13B shows the peak times, relative heights and % area for the LC chromatography trace of Figure 13 A.

[00074] Figure 14A shows the structure of l-homoarginine-d-amphetamine carbamate of the invention as determined by single crystal x-ray diffraction; Figure 14B shows a crystal packing diagram of l-homoarginine-d-amphetamine carbamate of the invention as determined by single crystal x-ray diffraction.

DETAILED DESCRIPTION

[00075] Detailed embodiments of the present invention are disclosed herein; however, it is to be understood that the disclosed embodiments are merely illustrative of the invention that may be embodied in various forms. In addition, each of the examples given in connection with the various embodiments of the invention is intended to be illustrative, and not restrictive. Therefore, specific structural and functional details disclosed herein are not to be interpreted as limiting, but merely as a representative basis for teaching one skilled in the art to variously employ the present invention.

[00076] ETnless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[00077] 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. Thus, for example, a reference to“a method” includes one or more methods, and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure. [00078] The terms“treat” or“treatment” of a state, disorder or condition include: (1) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof or at least one clinical or sub-clinical symptom thereof or (2) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or sub-clinical symptoms. The benefit to a subject to be treated is either statistically significant or at least perceptible to the patient or to the physician.

[00079] The terms “prevent” or“preventing” a state, disorder or condition include: preventing, delaying, or reducing the incidence and/or likelihood of the appearance of at least one clinical or sub-clinical symptom of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition.

[00080] The terms“improve” or“improvement” as used herein, for example, refers to the improvement of a symptom associated with a disease, disorder, or condition, and can refer to an improvement in at least one parameter measuring or quantitating the symptom. Accordingly, the term encompasses an improvement of about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% in such parameter.

[00081] A“subject” or“patient” or“individual” or“animal”, as used herein, refers to humans, veterinary animals (e.g., cats, dogs, cows, horses, sheep, pigs, etc.) and experimental animal models of diseases (e.g., mice, rats). In an aspect of the invention, a subject according to the present invention is an adult patient.“Adult” as used herein refers to a patient age 18 years or greater. In a further aspect of the invention, a patient is a pediatric patient. In certain embodiments, a pediatric subject can be a human subject from ages of about 6 to about 12. In a further aspect of the invention, a patient is an adolescent. In certain embodiments, an adolescent subject can be a human subject from ages of about 13 to about 17. In a further aspect of the invention, a patient is an elderly patient. “Elderly” as used herein refers to a patient age 65 years or greater. In a preferred embodiment, the subject is a human.

[00082] As used herein the term“effective” applied to dose or amount refers to that quantity of a compound or pharmaceutical composition that is sufficient to result in a desired activity upon administration to a subject in need thereof. By way of example, and not limitation, the desired activity could be the treatment, prevention, and/or improvement of at least one disease, disorder, and/or condition and/or at least one symptom thereof. Note that when a combination of active ingredients is administered, the effective amount of the combination may or may not include amounts of each ingredient that would have been effective if administered individually. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the condition being treated, the particular drug or drugs employed, the mode of administration, and the like.

[00083] The phrase “pharmaceutically acceptable”, as used in connection with compositions of the invention, refers to molecular entities and other ingredients of such compositions that are physiologically tolerable and do not typically produce untoward reactions when administered to a mammal (e.g., a human). Preferably, as used herein, the term "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals, and more particularly in humans.

[00084] The present invention relates to, inter alia, an amphetamine prodrug which is an amphetamine-homoarginine conjugate carbamate l-homoarginine-d-amphetamine ((S)-6- guanidino-l-oxo-l-(((S)-l-phenylpropan-2-yl)amino)hexan-2-yl)carbamic acid according to Formula I,

[00085] which are useful for treatment of various conditions and disorders, and symptoms associated therewith.

[00086] The present invention further relates to crystalline forms of an amphetamine- homoarginine conjugate carbamate l-homoarginine-d-amphetamine ((S)-6-guanidino-l-oxo-l- (((S)-l-phenylpropan-2-yl)amino)hexan-2-yl)carbamic acid according to Formula I,

[00087] which are useful for treatment of various conditions and disorders, and symptoms associated therewith.

[00088] Chemically, l-homoarginine-d-amphetamine carbamate is a prodrug of d- amphetamine and l-homoarginine in which the C terminus of l-homoarginine is covalently bonded via an amide linkage to the primary amine of d-amphetamine and the amino N-terminus comprises a carbamic acid moiety. As such, l-homoarginine-d-amphetamine carbamate is a pro- drug of l-homoarginine-d-amphetamine, the chemical formula of which is depicted in the Background of the Invention, which itself is a prodrug of d-amphetamine.

[00089] The synthesis of l-homoarginine-d-amphetamine carbamate is carried out by the coupling of dextroamphetamine with a suitable protected homoarginine analog to form the amide bond. The homoarginine fragment can be synthesized through various approaches. In one method, N-protected L-homoarginine, e.g. Boc-Nco-(nitro)-L-homoarginine or Nw-, Nw-'- tris(tert-butoxycarbonyl)-L-homoarginine is coupled with dextroamphetamine. The intermediate is deprotected to provide the l-homoarginine-d-amphetamine as a salt (e.g. a hydrochloride salt), or as a free base. The carbamate target compound may be obtained by treating a l-homoarginine- d-amphetamine salt, e.g. l-homoarginine-d-amphetamine hydrochloride, with an aqueous carbonate solution (e.g. K₂CO₃, Na₂CC)₃). In another approach, the guanidine functionality is introduced in L-lysine, and the intermediate is reacted with dextroamphetamine, and finally deprotected to furnish the l-homoarginine-d-amphetamine salt or free base. The carbamate target compound may then be obtained in a similar manner, i.e, by treating the l-homoarginine-d- amphetamine salt, e.g. l-homoarginine-d-amphetamine hydrochloride, with an aqueous carbonate solution (e.g. K2CO3, Na2CC>3).

[00090] The present application also includes pharmaceutically acceptable salts of the compounds described herein. The“pharmaceutically acceptable salts” include a subset of the

“salts” described above which are conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, l7th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977). The phrase“pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

[00091] Inner salts of l-homoarginine-d-amphetamine carbamate, wherein the carboxyl group is deprotonated and the guanidine is protonated, as shown in the structural formula below, are also included in the present application.

[00092] Preparation of compounds can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Wuts and Greene, Greene Protective Groups in Organic Synthesis , 4th Ed., John Wiley & Sons: New York, 2006.

[00093] Typically, different crystalline forms of the same substance have different bulk properties relating to, for example, hygroscopicity, solubility, stability, and the like. Forms with high melting points often have good thermodynamic stability which is advantageous in prolonging shelf-life drug formulations containing the solid form. Forms with lower melting points often are less thermodynamically stable, but are advantageous in that they have increased water solubility, translating to increased drug bioavailability. Forms that are weakly hygroscopic are desirable for their stability to heat and humidity and are resistant to degradation during long storage. Anhydrous forms are often desirable because they can be consistently made without concern for variation in weight or composition due to varying solvent or water content. On the other hand, hydrated or solvated forms can be advantageous in that they are less likely to be hygroscopic and may show improved stability to humidity under storage conditions. [00094] As used herein, "crystalline form" is meant to refer to a certain lattice configuration of a crystalline substance. Different crystalline forms of the same substance typically have different crystalline lattices (e.g., unit cells) which are attributed to different physical properties that are characteristic of each of the crystalline forms. In some instances, different lattice configurations have different water or solvent content. The different crystalline lattices can be identified by solid state characterization methods such as by X-ray powder diffraction (PXRD). Other characterization methods such as differential scanning calorimetry (DSC), therm ogravimetric analysis (TGA), dynamic vapor sorption (DVS), solid state NMR, and the like further help identify the crystalline form as well as help determine stability and sol vent/ water content.

[00095] Crystalline forms of a substance include both solvated (e.g., hydrated) and non- solvated (e.g., anhydrous) forms. A hydrated form is a crystalline form that includes water in the crystalline lattice. Hydrated forms can be stoichiometric hydrates, where the water is present in the lattice in a certain water/molecule ratio such as for hemihydrates, monohydrates, dihydrates, etc. Hydrated forms can also be non-stoichiometric, where the water content is variable and dependent on external conditions such as humidity.

[00096] Crystalline forms are most commonly characterized by PXRD. A PXRD pattern of reflections (peaks) is typically considered a fingerprint of a particular crystalline form. It is well known that the relative intensities of the PXRD peaks can widely vary depending on, inter alia, the sample preparation technique, crystal size distribution, filters, the sample mounting procedure, and the particular instrument employed. In some instances, new peaks may be observed or existing peaks may disappear, depending on the type of instrument or the settings (for example, whether a Ni filter is used or not). As used herein, the term "peak" refers to a reflection having a relative height/intensity of at least about 4% of the maximum peak height/intensity. Moreover, instrument variation and other factors can affect the 2-theta values. Thus, peak assignments, such as those reported herein, can vary by plus or minus about 0.2° (2- theta), and the term "substantially" as used in the context of PXRD herein is meant to encompass the above-mentioned variations.

[00097] In the same way, temperature readings in connection with DSC, TGA, or other thermal experiments can vary about ±4 °C depending on the instrument, particular settings, sample preparation, etc. For example, with DSC it is known that the temperatures observed will depend on the rate of the temperature change as well as the sample preparation technique and the particular instrument employed. Thus, the values reported herein related to DSC thermograms can vary, as indicated above, by ±4 0 C. Accordingly, a crystalline form reported herein having a DSC thermogram "substantially" as shown in any of the Figures is understood to accommodate such variation.

[00098] The amphetamine-homoarginine conjugate l-homoarginine-d-amphetamine carbamate according to Formula I can be isolated in various crystalline forms, including crystalline forms which are anhydrous, hydrated, non-solvated, solvated, or as co-crystals. Example hydrates include hemihydrates, monohydrates, dihydrates, and the like. In some embodiments, the crystalline forms of l-homoarginine-d-amphetamine carbamate are anhydrous and non-solvated. By "anhydrous" is meant that the crystalline form of l-homoarginine-d- amphetamine carbamate contains essentially no bound water in the crystal lattice structure, i.e., the compound does not form a crystalline hydrate. In other embodiments, the crystalline forms of l-homoarginine-d-amphetamine carbamate are solvated, i.e. the crystalline form of 1- homoarginine-d-amphetamine carbamate contains at least some bound solvent molecules in the crystal lattice structure, i.e., the compound forms a crystalline solvate. In some embodiments, the crystalline forms of l-homoarginine-d-amphetamine carbamate are hydrated, i.e. the crystalline form of l-homoarginine-d-amphetamine carbamate contains at least some bound water molecules in the crystal lattice structure, i.e., the compound forms a crystalline hydrate.

[00099] In some embodiments, the compound of Formula I according to the invention and/or its crystalline forms are substantially isolated. By "substantially isolated" is meant that a particular compound and/or crystalline form of l-homoarginine-d-amphetamine carbamate is at least partially isolated from impurities. For example, in some embodiments a compound of Formula I according to the invention and/or its crystalline form comprises less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 2.5%, less than about 1%, or less than about 0.5% of impurities. Impurities generally include anything that is not the substantially isolated compound of Formula I according to the invention and/or its crystalline form including, for example, other crystalline forms and other substances.

[000100] In some embodiments, a crystalline form of l-homoarginine-d-amphetamine carbamate is substantially free of other crystalline forms. The phrase "substantially free of other crystalline forms" means that a particular crystalline form of the compound of Formula I comprises greater than about 80%, greater than about 90%, greater than about 95%, greater than about 98%, greater than about 99% or greater than about 99.5% by weight of the particular crystalline form.

Crystalline Form I

[000101] In some embodiments, the crystalline form of l-homoarginine-d-amphetamine carbamate is Form I.

[000102] Crystalline Form I can be identified by unique signatures with respect to, for example, powder X-ray powder diffraction (PXRD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). In some embodiments, crystalline Form I is characterized by an PXRD pattern substantially as shown in Figure 2. In some embodiments, crystalline Form I is characterized by a PXRD pattern substantially as shown in Figure 5.

[000103] In some embodiments, Form I is characterized by a DSC thermogram comprising a broad endothermic peak with an onset of about 121.1 °C having a maximum at about 134 °C. In some embodiments, crystalline Form I has a DSC thermogram substantially as shown in Figure 3. In some embodiments, Form I is characterized by a TGA-IR trace showing a 7.3% loss of water when Form I is heated from room temperature to 150 °C. In some embodiments, crystalline Form I has a TGA trace substantially as shown in Figure 3.

[000104] In some embodiments, Form I is characterized by a DSC thermogram comprising a broad decomposition endotherm with an onset at about 140.7 °C having a maximum at about 160.5 °C. In some embodiments, crystalline Form I has a DSC thermogram substantially as shown in Figure 6. In some embodiments, Form I is characterized by a TGA-IR trace showing a 8.8% loss of water and C0₂ when Form I is heated from room temperature to 165 °C. In some embodiments, crystalline Form I has a TGA trace substantially as shown in Figure 6.

Methods

[000105] The amphetamine-homoarginine conjugate carbamate of Formula I and/or crystalline forms thereof according to the invention can be administered to treat attention deficit hyperactivity disorder as well as the other disorders described herein. For example, one embodiment is a method of treating attention deficit hyperactivity disorder in a patient (e.g., a child or adult) in need thereof by administering an effective amount of l-homoarginine-d- amphetamine carbamate according to Formula I. In certain embodiments, the amphetamine- homoarginine conjugate l-homoarginine-d-amphetamine carbamate is administered orally. In one embodiment, a pharmaceutical composition consisting essentially of the l-homoarginine-d- amphetamine carbamate of Formula I is administered.

[000106] In yet another aspect of the invention, a method for preparing a l-homoarginine-d- amphetamine carbamate Form I is provided.

[000107] Another embodiment of the invention is directed to a method of reducing patient to patient variability of amphetamine levels among a group of patients. The method entails daily (preferably once daily) oral administration to each patient in the group of an l-homoarginine-d- amphetamine carbamate Form I. In one preferred embodiment, a pharmaceutical composition comprising an l-homoarginine-d-amphetamine carbamate Form I is administered. In one preferred embodiment, a pharmaceutical composition consisting essentially of an 1- homoarginine-d-amphetamine carbamate Form I is administered.

[000108] Yet another embodiment of the invention is a method of treating or preventing fatigue, cognitive dysfunction, and/or inattentiveness, in a patient in need thereof by administering an effective amount of l-homoarginine-d-amphetamine carbamate and/or its crystalline form Form I or a pharmaceutical composition containing it. According to one embodiment, the amphetamine-homoarginine conjugate carbamate is l-homoarginine-d- amphetamine carbamate Form I, and it is orally administered once daily.

[000109] Yet another embodiment of the invention is a method of treating or preventing various conditions and disorders, such as chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis (ME); fatigue, cognitive dysfunction, and/or inattention in a patient suffering from CFS/ME; fatigue, cognitive dysfunction, and/or inattention in a patient suffering from fibromyalgia; fatigue, cognitive dysfunction, and/or inattention in a patient suffering from multiple sclerosis (MS); fatigue, cognitive dysfunction, and/or inattention in a patient suffering from major depressive disorder (MDD); fatigue, cognitive dysfunction, and/or inattention in a patient suffering from traumatic brain injury; fatigue, cognitive dysfunction, and/or inattention in a menopausal patient; fatigue, cognitive dysfunction, and/or inattention in a patient suffering from the negative symptoms of schizophrenia; post-cancer therapy fatigue, cognitive dysfunction, and/or inattention; fatigue in cancer patients caused by chemotherapy, radiation therapy, surgery, or a combination thereof; cognitive dysfunction in cancer patients caused by chemotherapy, radiation therapy, surgery, or a combination thereof; inattention in cancer patients caused by chemotherapy, radiation therapy, surgery, or a combination thereof; wakefulness disorder such as narcolepsy; wakefulness disorder as a result of chemotherapy or radiation therapy; hyperactivity and/or impulsivity associated with alcohol addiction, smoking, and symptoms of the Fragile X Syndrome; and fatigue, cognitive dysfunction, and/or inattention in a patient suffering from a metabolic disorder, e.g., obesity, appetite related symptoms of the Prader Willi Syndrome, and Type 1 and Type 2 diabetes mellitus, in a patient in need thereof by administering an effective amount of the aforementioned l-homoarginine-d-amphetamine carbamate Form I or a pharmaceutical composition containing it. According to one embodiment, the amphetamine-homoarginine conjugate is l-homoarginine-d-amphetamine carbamate Form I, and it is orally administered once daily.

Indications

[000110] The invention also provides methods comprising providing, administering, prescribing, or consuming an amphetamine-homoarginine conjugate carbamate and/or its crystalline form Form I. The invention also provides pharmaceutical compositions comprising an amphetamine-homoarginine conjugate carbamate and/or its crystalline form Form I. The formulation of such a pharmaceutical composition can optionally enhance or achieve the desired release profile.

[000111] In one embodiment, the invention provides methods for treating a patient comprising administering a therapeutically effective amount of an amphetamine-homoarginine conjugate carbamate and/or its crystalline form Form I, i.e., an amount sufficient to prevent, ameliorate, and/or eliminate the symptoms of a disease. These methods can be used to treat any disease that may benefit from amphetamine-type drugs including, but not limited to: attention deficit disorders, e.g., ADD and ADHD, and other learning disabilities.

[000112] Fatigue can be described as the lack of energy and motivation (both physical and cognitive). As fatigue can be a symptom of an underlying condition, the treatment may depend upon the condition that is causing the fatigue, regardless of whether it is physical, psychological, or a combination of the two.

[000113] Cognitive dysfunction (also known as cognitive impairment) can be described as associated with an impairment in cognition, including memory [visual memory, verbal memory, short- and long-term memory]), attention (sustained, selective and divided), concentration, comprehension, decision making (logic and reasoning), planning, executive functions, information processing (including auditory, visual, simple, complex, and speed/ reaction times, and/or learning. Cognitive dysfunction is not caused by any one disease or condition, nor is it limited to a specific age group, and the treatment may depend upon the condition causing the cognitive dysfunction.

[000114] Chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis (ME), post-viral fatigue syndrome (PVFS), chronic fatigue immune dysfunction syndrome (CFIDS), and systemic exertion intolerance disease (SEID) is a complicated disorder characterized by extreme fatigue that cannot be explained by an underlying medical condition. The fatigue may worsen with physical or mental activity, but does not improve with rest. Cognitive symptoms (cognitive dysfunctions) in ME/CFS may include difficulty with: memory (including visual memory and verbal memory), attention, information processing, reaction times, and concentration is characterized by extreme physical or mental fatigue not relieved by rest. Patients with ME/CFS can also suffer from inattention.

[000115] The terms chronic fatigue syndrome (CFS), myalgic encephalomyelitis (ME), and systemic exertion intolerance disease (SEID) describe medical condition that manifests with a debilitating phenotype of unknown etiology and for which no clear treatment is available. Both diagnosis and treatment of ME/CFS are symptomatic. The 3 core symptoms necessary for diagnosis include disabling fatigue that persists for at least 6 months and results in a greatly diminished ability to perform activities that were easily accomplished before the illness, a worsening of symptoms after physical or mental activity that would not have been problematic before the illness (post-exertional malaise), and unrefreshing sleep. In addition to profound fatigue, sufferers have cognitive dysfunction, autoimmune manifestations, pain not caused by injury, and other symptoms that are worsened upon exertion. Tender lymph nodes, sore throat, digestive issues, orthostatic intolerance, chills and night sweats, and allergies/sensitivities to food, color, chemicals, or noise can also occur.

[000116] Cognitive dysfunction is a key symptom of ME/CFS and affects the gamut of cognitive abilities (e.g., memory, attention, and information processing). Cognitive dysfunction in ME/CFS has a significant impact on patients and interferes with work and role functioning. Patient-reported cognitive function was selected for assessment because of the prevalence, severity, and impact of cognitive dysfunction reported by patients with ME/CFS. A review of cognitive impairment in ME/CFS (Shanks et al., 2013) notes that research has highlighted the negative impact of ME/CFS on memory (visual memory, verbal memory, short- and long-term memory), concentration, attention, and simple and complex information processing. Problems with cognitive function have been reported by 85% to 95% of patients with ME/CFS (Komaroff and Buchwald, 1991; Grafman, 1993). For the majority of these patients, cognitive problems significantly interfere with daily functioning, particularly work and school functioning (Shanks et ak, 2013).

[000117] In addition to profound fatigue and cognitive dysfunction, sufferers have inattentiveness, autoimmune manifestations, pain not caused by injury, and other symptoms that are worsened upon exertion. Tender lymph nodes, sore throat, digestive issues, orthostatic intolerance, chills and night sweats, and allergies/sensitivities to food, color, chemicals, or noise can also occur.

[000118] No cure or treatment has been approved for ME/CFS, and the FDA recognizes the disease as serious with an unmet medical need for treatment (Guidance for Industry, ME/CFS 2014). According to the Institute of Medicine (IOM) committee report, approximately 836,000 to 2.5 million Americans are affected by ME/CFS. It is also noted in the report that approximately 90% of people with ME/CFS have yet to be diagnosed, so the true prevalence is unknown. Although ME/CFS can affect either gender, women are more frequently diagnosed than men. The average age of onset is 33 years; however, cases have been reported in patients younger than 10 years and older than 70 years (IOM). Approximately 25% of patients with ME/CFS are bed- or house-bound, leading to an annual 17 to 24 billion dollar economic burden from loss of productivity and high medical costs.

[000119] Fatigue and cognitive dysfunction are also a characteristic symptoms of fibromyalgia. Fibromyalgia is a medical condition characterized by chronic widespread pain and a heightened pain response to pressure. Other symptoms include fatigue to a degree that normal activities are affected, sleep problems, and troubles with memory. Some people also report restless legs syndrome, bowel or bladder problems, numbness and tingling, and sensitivity to noise, lights or temperature. Fibromyalgia is frequently associated with depression, anxiety, and posttraumatic stress disorder. Other types of chronic pain are also frequently present.

[000120] Fatigue is often a symptom of fibromyalgia. Patients of fibromyalgia often awaken tired, even though they report sleeping for long periods of time. Sleep is often disrupted by pain, and many patients with fibromyalgia have other sleep disorders, such as restless legs syndrome and sleep apnea. Patients with fibromyalgia may also experience cognitive dysfunction and/or inattention.

[000121] Narcolepsy is characterized by chronic excessive daytime sleepiness, often with sudden loss of muscle tone (cataplexy). Other symptoms include sleep paralysis and hypnagogic and hypnopompic hallucinations. Diagnosis may be performed, for example, by polysomnography and multiple sleep latency testing. Patients with Narcolepsy may also experience cognitive dysfunction and/or inattention.

[000122] Multiple Sclerosis (MS) according to the present invention includes relapsing- remitting, primary progressive, progressive-relapsing, and secondary progressive MS. Fatigue is a common, and often disabling, symptom of MS. Cognitive dysfunctions and/or inattention may also occur in patients with MS.

[000123] Major depressive disorder (MDD) according to the present invention may be diagnosed in a patient by a physician according to, for example, the criteria disclosed in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Patients with MDD may also experience cognitive dysfunction and/or inattention.

[000124] Medications for MDD include selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, paroxetine, sertraline, citalopram and escitalopram (Lexapro); serotonin- norepinephrine reuptake inhibitors (SNRJs) such as duloxetine, venlafaxine, desvenlafaxine and levomilnacipran; norepinephrine-dopamine reuptake inhibitors (NDRIs) such as bupropion; atypical antidepressants such as trazodone, mirtazapine, vortioxetine and vilazodone; tricyclic antidepressants such as imipramine, nortriptyline, amitriptyline, doxepin, trimipramine, desipramine and protriptyline; and monoamine oxidase inhibitors (MAOIs) such as tranylcypromine, phenelzine and isocarboxazid, and selegiline.

[000125] An amphetamine-homoarginine conjugate carbamate and/or its crystalline form Form I according to the present invention may be administered as monotherapy for fatigue and/or inattention in a patient suffering from MDD, or in combination with one or more of the above listed medications for MDD. In one embodiment, the patient suffering from MDD may be concurrently receiving treatment with a selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, paroxetine, sertraline, citalopram and escitalopram (Lexapro); serotonin- norepinephrine reuptake inhibitors (SNRJs) such as duloxetine, venlafaxine, desvenlafaxine and levomilnacipran; norepinephrine-dopamine reuptake inhibitors (NDRIs) such as bupropion; atypical antidepressants such as trazodone, mirtazapine, vortioxetine and vilazodone; tricyclic antidepressants such as imipramine, nortriptyline, amitriptyline, doxepin, trimipramine, desipramine and protriptyline; and monoamine oxidase inhibitors (MAOIs) such as tranylcypromine, phenelzine and isocarboxazid, and selegiline.

[000126] In an aspect of the invention, an amphetamine-homoarginine conjugate carbamate and/or its crystalline form Form I is administered to treat fatigue and/or inattention in a patient whose major depressive disorder was inadequately treated by one or more of the above listed medications for MDD. In one embodiment, the patient’s MDD may have been inadequately treated with a selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, paroxetine, sertraline, citalopram and escitalopram (Lexapro); serotonin-norepinephrine reuptake inhibitors (SNRIs) such as duloxetine, venlafaxine, desvenlafaxine and levomilnacipran; norepinephrine- dopamine reuptake inhibitors (NDRIs) such as bupropion; atypical antidepressants such as trazodone, mirtazapine, vortioxetine and vilazodone; tricyclic antidepressants such as imipramine, nortriptyline, amitriptyline, doxepin, trimipramine, desipramine and protriptyline; and monoamine oxidase inhibitors (MAOIs) such as tranylcypromine, phenelzine and isocarboxazid, and selegiline.

[000127] In a further aspect of the invention, an amphetamine-homoarginine conjugate carbamate and/or its crystalline form Form I of the present invention is administered to a patient with MDD in whom cognition (e.g., attention, fatigue) is not improved with a MDD medication. In one embodiment, the patient’s MDD symptoms may have not improved upon treatment with a selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, paroxetine, sertraline, citalopram and escitalopram (Lexapro); serotonin-norepinephrine reuptake inhibitors (SNRIs) such as duloxetine, venlafaxine, desvenlafaxine and levomilnacipran; norepinephrine-dopamine reuptake inhibitors (NDRIs) such as bupropion; atypical antidepressants such as trazodone, mirtazapine, vortioxetine and vilazodone; tricyclic antidepressants such as imipramine, nortriptyline, amitriptyline, doxepin, trimipramine, desipramine and protriptyline; and monoamine oxidase inhibitors (MAOIs) such as tranylcypromine, phenelzine and isocarboxazid, and selegiline.

[000128] In one aspect, the present invention provides a method of treating or preventing cancer associated fatigue, cognitive dysfunction, and/or inattention which comprises administering to a patient in need thereof a therapeutically effective amount of an amphetamine- homoarginine conjugate carbamate and/or its crystalline form Form I.

[000129] The terms “cancer” and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More particular examples of such cancers include squamous cell cancer (e.g. epithelial squamous cell cancer), lung cancer including small-cell lung cancer, non small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, cancer of the urinary tract, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, melanoma, multiple myeloma and B-cell lymphoma, brain, as well as head and neck cancer, and associated metastases. Additional examples of cancer can be found in The Merck Manual of Diagnosis and Therapy, l9th Edition, § on Hematology and Oncology, published by Merck Sharp & Dohme Corp., 2011 (ISBN 978-0-911910-19-3); The Merck Manual of Diagnosis and Therapy, 20th Edition, § on Hematology and Oncology, published by Merck Sharp & Dohme Corp., 2018 (ISBN 978-0-911-91042-1) (2018 digital online edition at internet website of Merck Manuals); and SEER Program Coding and Staging Manual 2016, each of which is incorporated by reference in their entirety for all purposes.

[000130] In one aspect, the present invention provides a method of treating or preventing post-cancer therapy fatigue, cognitive dysfunction, and/or inattention which comprises administering to a patient in need thereof a therapeutically effective amount of an amphetamine- homoarginine conjugate carbamate and/or its crystalline form Form I. In various embodiments of the invention, the cancer therapy is chemotherapy, radiation therapy, surgery, or a combination thereof. In one embodiment, the cancer therapy is a combination of at least two of the following: chemotherapy, radiation therapy, and surgery. In various embodiments, the amphetamine- homoarginine conjugate carbamate and/or its crystalline form Form I is initially administered prior to the cancer therapy, after cancer therapy and before the patient is diagnosed with post cancer therapy fatigue, cognitive dysfunction, and/or inattention, or after cancer therapy and after the patient is diagnosed with post-cancer therapy fatigue, cognitive dysfunction, and/or inattention.

[000131] The cancer therapy may be chemotherapy, radiation therapy, surgery, or any combination of these therapies. In some embodiments, the chemotherapy is methotrexate, cytarabine, vincristine, a steroid (e.g., dexamethasone, hydrocortisone, prednisone) or a combination thereof. According to the present invention, the chemotherapy may have been delivered directly to the central nervous system and/or systemic chemotherapy. In an aspect of the present invention, the radiation therapy is cranial radiation therapy. In a further aspect, the surgery is cranial surgery.

[000132] In non-limiting examples, the patient received chemo or radiation therapy for acute lymphoblastic leukemia, breast cancer, or a malignant brain cancer. The malignant brain cancer may be, for example, a glioma, astrocytoma, medulloblastoma, ependymoma, or brain stem glioma.

[000133] As used herein, “a post-cancer therapy condition” (e.g., post-cancer therapy fatigue or post-cancer therapy inattention) means a condition that occurs after a patient has undergone therapy for a cancer. Cancer therapy includes chemotherapy, radiation therapy (for example, cranial radiation therapy), surgery (for example, cranial surgery), and combinations thereof.

[000134] As used herein,“post-cancer therapy” and“post-cancer treatment” mean that a patient has undergone cancer therapy, which may include chemotherapy, radiation therapy (for example, cranial radiation therapy), surgery (for example, cranial surgery), and combinations thereof. Non-limiting examples of chemotherapy include glucocorticoids, methotrexate, 5- fluorouracil, doxorubicin, taxanes (e.g., docetaxel, paclitaxel), cisplatin, cyclophosphamide, capecitabine, and combinations thereof.

[000135] Fatigue caused by chemotherapy or radiation therapy may not end even when therapy is complete. Any chemotherapy drug may result in fatigue. To some people fatigue lasts only a couple of days. To others, fatigue persists through and beyond completion of treatment. Drugs such as vincristine, vinblastine, and cisplatin often cause fatigue. Radiation therapy can cause cumulative fatigue (fatigue that increases over time). This can occur regardless of treatment site. Fatigue usually lasts from 3-4 weeks after treatment stops but can continue for up to 2-3 months. [000136] In an aspect of the present invention, the patient suffering from MDD has primary inattentive symptoms. In a further aspect, the patient suffering from MDD is elderly.

[000137] In addition to the disorders and conditions listed above, the methods for treating fatigue, cognitive dysfunction, and/or inattentiveness comprising administering an amphetamine- homoarginine conjugate carbamate and/or its crystalline form Form I according to the present invention are suitable for treating fatigue, cognitive dysfunction, and/or inattentiveness associated with traumatic brain injury, menopause, negative symptoms of schizophrenia, and diabetes (Types I and II).

[000138] The methods of treatment include combination therapies which further comprise administering one or more therapeutic agents in addition to administering an amphetamine prodrug carbamate and/or its crystalline form Form I. In these embodiments, the therapeutic agents can be administered serially or together.

[000139] In one embodiment, the amphetamine-homoarginine conjugate carbamate and/or its crystalline form Form I are used in combination with another antidepressant for adjunctive antidepressant therapy.

[000140] The active ingredients can be formulated into a single dosage form, or they can be formulated together or separately among multiple dosage forms. The active ingredients can be administered simultaneously or sequentially in any order.

[000141] The amphetamine-homoarginine conjugate carbamate and/or its crystalline form Form I can be administered in combination with an antidepressant to treat depression or a depressive disorder, such as major depressive disorder. The amphetamine-homoarginine conjugate carbamate and/or its crystalline form Form I and antidepressant can be can be administered serially (in any order) or together (simultaneously). The active ingredients can be formulated into a single dosage form, or they can be formulated together or separately among multiple dosage forms.

[000142] In the adjunctive antidepressant therapy embodiment, the prodrugs of the present invention, and specifically the preferred prodrug salt (l)-homoarginine-(d)-amphetamine, can be paired with various antidepressants for co-therapy, including, but not limited to, serotonin norepinephrine reuptake inhibitors (SNRIs), selective serotonin reuptake inhibitors (SSRIs), and tertiary amine tricyclic norepinephrine reuptake inhibitors. In yet another adjunctive antidepressant therapy embodiment, a prodrug of the present invention is administered with an atypical antidepressant. Monoamine oxidase inhibitors can also be used in combination with the prodrugs of the present invention for adjunctive antidepressant therapy.

Dosage Form

[000143] In an aspect of the present invention, the amphetamine-homoarginine conjugate carbamate and/or its crystalline form Form I dose provides the equivalent of about 5 mg to about 40 mg of amphetamine freebase. Alternatively, the dose may also be provided in an equivalent of about 9 mg to about 30 mg of amphetamine freebase. In a further aspect, the conjugates are present in the composition in an amount equivalent to amphetamine freebase in the range of about 5 mg to about 40 mg.

[000144] In aspects of the invention, a physician titrates the dosage of an amphetamine- homoarginine conjugate carbamate and/or its crystalline form Form I (i.e., adjusts the amount and/or dosage frequency) to achieve the desired effect (improvement in inattention) with acceptable or absent adverse effects. For example, a starting dose may be 30 mg once daily. If a dose increase is warranted in the judgment of the physician, the daily dose may be adjusted in increments of 10 mg or 20 mg at approximately weekly intervals.

[000145] The dose range for adult or pediatric human patients may depend on a number of factors including the age, weight, and condition of the patient. Suitable oral dosages of the prodrugs of the present invention can be the equivalents of the doses typically found in treatments using that drug. For example, typical dosages for amphetamine-homoarginine conjugate carbamate and/or its crystalline form Form I can range from about 1 mg to about 100 mg. Preferred doses of the prodrug are doses equimolar to amphetamine freebase in the range from about 5 mg to about 40 mg. Preferred doses of the prodrug are doses equimolar to amphetamine freebase in the range from about 9 mg to about 30 mg. For example, doses of a preferred amphetamine-homoarginine conjugate carbamate and/or its crystalline form Form I prodrug in the range of about 25 mg to about 75 mg would provide an amphetamine freebase content in the preferred range of about 9 mg to about 30 mg. Using the molecular weight of the prodrug of the present technology, the release percentage (% release) of amphetamine from the prodrug and desired dosage forms of the required amphetamine, the following equation can be generated:

grams of a prodrug needed = (dosage/molecular weight of amphetamine)(% release)(molecular weight of the prodrug) [000146] Tablets, capsules, and other forms of unit dosages may conveniently contain a daily dose, or an appropriate fraction thereof, of one or more of the prodrug compounds of the invention. For example, the units may contain from about 1 mg to about 1000 mg, alternatively from about 5 mg to about 500 mg, alternatively from about 5 mg to about 250 mg, alternatively from about 5 mg to about 150 mg, alternatively from about 10 mg to about 100 mg of one or more of the prodrug compounds of the presently described technology. Preferred units of the prodrug are dose units equimolar to amphetamine freebase in the range from about 9 mg to about 27 mg.

[000147] In one embodiment, the amphetamine-homoarginine conjugate carbamate and/or its crystalline form Form I prodrug itself exhibits a sustained release profile. Thus, the invention provides a pharmaceutical composition exhibiting a sustained release profile due to the amphetamine-homoarginine conjugate carbamate and/or its crystalline form Form I prodrug. For example, the dosage form may be, but is not limited to, an immediate release (IR) form, an IR- delayed form, IR-delayed pulsatile (DPR) form, IR-sustained release (IR-SR) form, IR-DPR-SR form, IR-SR-SR form. Additional non-limiting examples of the dosage forms can be found in 6322819; 6605300; RE41148; RE42096; 6913768 7105486; 722735; 7,662787; 7655630; 7659253; 7659254; 7662787; 7662788; 7671030; 7671031; 7674774; 7678770; 7678771; 7687466; 7687467; 7700561; 7713936; 7718619; 8846100; and 9173857, each of which are incorporated by reference herein in their entirety.

[000148] Non-limiting examples of dosage forms according to the present invention include chewable tablets, quick dissolve tablets, effervescent tablets, reconstitutable powders, elixirs, liquids, solutions, suspensions, emulsions, tablets, multi-layer tablets, bi-layer tablets, capsules, soft gelatin capsules, hard gelatin capsules, caplets, troches, lozenges, chewable lozenges, beads, powders, granules, particles, microparticles, dispersible granules, cachets, thin strips, oral films, transdermal patches, and combinations thereof.

[000149] A dosage form according to the present invention may combine forms of release known to persons of ordinary skill in the art. These conventional release forms include immediate release, extended release, pulse release, variable release, controlled release, timed release, sustained release, delayed release, long acting, and combinations thereof. The ability to combine immediate release, extended release, pulsed release, controlled release, timed release, sustained release, delayed release, and combinations thereof is known in the art. [000150] In another embodiment, a sustained release profile is enhanced or achieved by including a hydrophilic polymer in the pharmaceutical composition. Suitable hydrophilic polymers include, but are not limited to, natural or partially or totally synthetic hydrophilic gums such as acacia, gum tragacanth, locust bean gum, guar gum, and karaya gum; cellulose derivatives such as methyl cellulose, hydroxymethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, and carboxymethyl cellulose; proteinaceous substances such as agar, pectin, carrageen, and alginates; hydrophilic polymers such as carboxypolymethylene; gelatin; casein; zein; bentonite; magnesium aluminum silicate; polysaccharides; modified starch derivatives; and other hydrophilic polymers known in the art. Preferably, the hydrophilic polymer forms a gel that dissolves slowly in aqueous acidic media thereby allowing the amphetamine-homoarginine conjugate carbamate and/or its crystalline form Form I to diffuse from the gel in the stomach. Then when the gel reaches the higher pH medium of the intestines, the hydrophilic polymer dissolves in controlled quantities to allow further sustained release. Preferred hydrophilic polymers are hydroxypropyl methylcelluloses such as Methocel ethers, e.g., Methocel E10M® (Dow Chemical Company, Midland, Mich.). One of ordinary skill in the art would recognize a variety of structures, such as bead constructions and coatings, useful for achieving particular release profiles. See, e.g., U.S. Pat. No. 6,913,768.

[000151] In addition to the amphetamine-homoarginine conjugate carbamate and/or its crystalline form Form I, the pharmaceutical compositions of the invention further comprise one or more pharmaceutical additives. Pharmaceutical additives include a wide range of materials including, but not limited to diluents and bulking substances, binders and adhesives, lubricants, glidants, plasticizers, disintegrants, carrier solvents, buffers, colorants, flavorings, sweeteners, preservatives and stabilizers, and other pharmaceutical additives known in the art. For example, in a preferred embodiment, the pharmaceutical composition comprises magnesium stearate. In another preferred embodiment, the pharmaceutical composition comprises microcrystalline cellulose (e.g., Avicel® PH- 102), croscarmellose sodium, and magnesium stearate. See, e.g., Table 62.

[000152] Diluents increase the bulk of a dosage form and may make the dosage form easier to handle. Exemplary diluents include, but are not limited to, lactose, dextrose, saccharose, cellulose, starch, and calcium phosphate for solid dosage forms, e.g., tablets and capsules; olive oil and ethyl oleate for soft capsules; water and vegetable oil for liquid dosage forms, e.g., suspensions and emulsions. Additional suitable diluents include, but are not limited to, sucrose, dextrates, dextrin, maltodextrin, microcrystalline cellulose (e.g., Avicel®), microfme cellulose, powdered cellulose, pregelatinized starch (e.g., Starch 1500®), calcium phosphate dihydrate, soy polysaccharide (e.g., Emcosoy®), gelatin, silicon dioxide, calcium sulfate, calcium carbonate, magnesium carbonate, magnesium oxide, sorbitol, mannitol, kaolin, polymethacrylates (e.g., Eudragit®), potassium chloride, sodium chloride, and talc. A preferred diluent is microcrystalline cellulose (e.g., Avicel® PH-102). Preferred ranges for the amount of diluent by weight percent include about 40% to about 90%, about 50% to about 85%, about 55% to about 80%, about 50% to about 60%, and increments therein.

[000153] In embodiments where the pharmaceutical composition is compacted into a solid dosage form, e.g., a tablet, a binder can help the ingredients hold together. Binders include, but are not limited to, sugars such as sucrose, lactose, and glucose; com syrup; soy polysaccharide, gelatin; povidone (e.g., Kollidon®, Plasdone®); Pullulan; cellulose derivatives such as microcrystalline cellulose, hydroxypropylmethyl cellulose (e.g., Methocel®), hydroxypropyl cellulose (e.g., Klucel®), ethylcellulose, hydroxyethyl cellulose, carboxymethylcellulose sodium, and methylcellulose; acrylic and methacrylic acid co-polymers; carbomer (e.g., Carbopol®); polyvinylpolypyrrolidine, polyethylene glycol (Carbowax®); pharmaceutical glaze; alginates such as alginic acid and sodium alginate; gums such as acacia, guar gum, and arabic gums; tragacanth; dextrin and maltodextrin; milk derivatives such as whey; starches such as pregelatinized starch and starch paste; hydrogenated vegetable oil; and magnesium aluminum silicate.

[000154] For tablet dosage forms, the pharmaceutical composition is subjected to pressure from a punch and dye. Among other purposes, a lubricant can help prevent the composition from sticking to the punch and dye surfaces. A lubricant can also be used in the coating of a coated dosage form. Lubricants include, but are not limited to, magnesium stearate, calcium stearate, zinc stearate, powdered stearic acid, glyceryl monostearate, glyceryl palmitostearate, glyceryl behenate, silica, magnesium silicate, colloidal silicon dioxide, titanium dioxide, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, hydrogenated vegetable oil, talc, polyethylene glycol, and mineral oil. A preferred lubricant is magnesium stearate. The amount of lubricant by weight percent is preferably less than about 5%, more preferably 4%, 3%, 2%, 1.5%, 1%, or 0.5%, or increments therein. [000155] Glidants can improve the flowability of non-compacted solid dosage forms and can improve the accuracy of dosing. Glidants include, but are not limited to, colloidal silicon dioxide, fumed silicon dioxide, silica gel, talc, magnesium trisilicate, magnesium or calcium stearate, powdered cellulose, starch, and tribasic calcium phosphate.

[000156] Plasticizers include both hydrophobic and hydrophilic plasticizers such as, but not limited to, diethyl phthalate, butyl phthalate, diethyl sebacate, dibutyl sebacate, triethyl citrate, acetyltri ethyl citrate, acetyltributyl citrate, cronotic acid, propylene glycol, castor oil, triacetin, polyethylene glycol, propylene glycol, glycerin, and sorbitol. Plasticizers are particularly useful for pharmaceutical compositions containing a polymer and in soft capsules and film-coated tablets. In one embodiment, the plasticizer facilitates the release of the amphetamine- homoarginine conjugate carbamate and/or its crystalline form Form I from the dosage form.

[000157] Disintegrants can increase the dissolution rate of a pharmaceutical composition. Disintegrants include, but are not limited to, alginates such as alginic acid and sodium alginate, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g., Kollidon®, Polyplasdone®), polyvinylpolypyrrolidine (Plasone-XL®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, starch, pregelatinized starch, sodium starch glycolate (e.g., Explotab®, Primogel®). Preferred disintegrants include croscarmellose sodium and microcrystalline cellulose (e.g., Avicel® PH- 102). Preferred ranges for the amount of disintegrant by weight percent include about 1% to about 10%, about 1% to about 5%, about 2% to about 3%, and increments therein.

[000158] In embodiments where the pharmaceutical composition is formulated for a liquid dosage form, the pharmaceutical composition may include one or more solvents. Suitable solvents include, but are not limited to, water; alcohols such as ethanol and isopropyl alcohol; methylene chloride; vegetable oil; polyethylene glycol; propylene glycol; and glycerin.

[000159] The pharmaceutical composition can comprise a buffer. Buffers include, but are not limited to, lactic acid, citric acid, acetic acid, sodium lactate, sodium citrate, and sodium acetate.

[000160] Any pharmaceutically acceptable colorant can be used to improve appearance or to help identify the pharmaceutical composition. See 21 C.F.R., Part 74. Exemplary colorants include D&C Red No. 28, D&C Yellow No. 10, FD&C Blue No. 1, FD&C Red No. 40, FD&C Green #3, FD&C Yellow No. 6, and edible inks. Preferred colors for gelatin capsules include white, medium orange, and light blue.

[000161] Flavorings improve palatability and may be particularly useful for chewable tablet or liquid dosage forms. Flavorings include, but are not limited to maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid. Sweeteners include, but are not limited to, sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar.

[000162] The pharmaceutical compositions of the invention can also include one or more preservatives and/or stabilizers to improve storagability. These include, but are not limited to, alcohol, sodium benzoate, butylated hydroxy toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid.

[000163] Other pharmaceutical additives include gelling agents such as colloidal clays; thickening agents such as gum tragacanth and sodium alginate; wetting agents such as lecithin, polysorbates, and laurylsulphates; humectants; antioxidants such as vitamin E, caronene, and BHT; adsorbents; effervescing agents; emulsifying agents, viscosity enhancing agents; surface active agents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate, triethanolamine, polyoxyethylene sorbitan, poloxalkol, and quaternary ammonium salts; and other miscellaneous excipients such as lactose, mannitol, glucose, fructose, xylose, galactose, sucrose, maltose, xylitol, sorbitol, chloride, sulfate and phosphate salts of potassium, sodium, and magnesium.

[000164] The pharmaceutical compositions can be manufactured according to any method known to those of skill in the art of pharmaceutical manufacture such as, for example, wet granulation, dry granulation, encapsulation, direct compression, slugging, etc. For instance, a pharmaceutical composition can be prepared by mixing the amphetamine-homoarginine conjugate carbamate and/or its crystalline form Form I with one or more pharmaceutical additives with an aliquot of liquid, preferably water, to form a wet granulation. The wet granulation can be dried to obtain granules. The resulting granulation can be milled, screened, and blended with various pharmaceutical additives such as water-insoluble polymers and additional hydrophilic polymers. In one embodiment, an amphetamine-homoarginine conjugate carbamate and/or its crystalline form Form I is mixed with a hydrophilic polymer and an aliquot of water, then dried to obtain granules of amphetamine-homoarginine conjugate carbamate and/or its crystalline form Form I encapsulated by hydrophilic polymer. [000165] After granulation, the pharmaceutical composition is preferably encapsulated, e.g., in a gelatin capsule. The gelatin capsule can contain, for example, kosher gelatin, titanium dioxide, and optional colorants. Alternatively, the pharmaceutical composition can be tableted, e.g., compressed and optionally coated with a protective coating that dissolves or disperses in gastric juices.

[000166] The pharmaceutical compositions of the invention can be administered by a variety of dosage forms. Any biologically-acceptable dosage form known in the art, and combinations thereof, are contemplated. Examples of preferred dosage forms include, without limitation, tablets including chewable tablets, film-coated tablets, quick dissolve tablets, effervescent tablets, multi-layer tablets, and bi-layer tablets; caplets; powders including reconstitutable powders; granules; dispersible granules; particles; microparticles; capsules including soft and hard gelatin capsules; lozenges; chewable lozenges; cachets; beads; liquids; solutions; suspensions; emulsions; elixirs; and syrups.

[000167] The pharmaceutical composition is preferably administered orally. Oral administration permits the maximum release of amphetamine, provides sustained release of amphetamine, and maintains abuse resistance. Preferably, the amphetamine-homoarginine conjugate carbamate and/or its crystalline form Form I releases the amphetamine over a more extended period of time as compared to administering unbound amphetamine.

[000168] Oral dosage forms can be presented as discrete units, such as capsules, caplets, or tablets. In a preferred embodiment, the invention provides a solid oral dosage form comprising an amphetamine-homoarginine conjugate carbamate and/or its crystalline form Form I that is smaller in size compared to a solid oral dosage form containing a therapeutically equivalent amount of unbound amphetamine. In one embodiment, the oral dosage form comprises a gelatin capsule of size 2, size 3, or smaller (e.g., size 4). The smaller size of the amphetamine- homoarginine conjugate carbamate and/or its crystalline form Form I dosage forms promotes ease of swallowing.

[000169] Soft gel or soft gelatin capsules may be prepared, for example, by dispersing the formulation in an appropriate vehicle (e.g., vegetable oil) to form a high viscosity mixture. This mixture then is encapsulated with a gelatin based film. The industrial units so formed are then dried to a constant weight. [000170] Chewable tablets can be prepared by mixing the amphetamine-homoarginine conjugate carbamate and/or its crystalline form Form I with excipients designed to form a relatively soft, flavored tablet dosage form that is intended to be chewed. Conventional tablet machinery and procedures (e.g., direct compression, granulation, and slugging) can be utilized.

[000171] Film-coated tablets can be prepared by coating tablets using techniques such as rotating pan coating methods, sprinkling of beads, and air suspension methods to deposit a contiguous film layer on a tablet.

[000172] Compressed tablets can be prepared by mixing the amphetamine-homoarginine conjugate carbamate and/or its crystalline form Form I with excipients that add binding qualities. The mixture can be directly compressed, or it can be granulated and then compressed.

[000173] The pharmaceutical compositions of the invention can alternatively be formulated into a liquid dosage form, such as a solution or suspension in an aqueous or non-aqueous liquid. The liquid dosage form can be an emulsion, such as an oil-in-water liquid emulsion or a water- in-oil liquid emulsion. The oils can be administered by adding the purified and sterilized liquids to a prepared enteral formula, which then is placed in the feeding tube of a patient who is unable to swallow.

[000174] For oral administration, fine powders or granules containing diluting, dispersing, and/or surface-active agents can be presented in a draught, in water or a syrup, in capsules or sachets in the dry state, in a non-aqueous suspension wherein suspending agents may be included, or in a suspension in water or a syrup. Liquid dispersions for oral administration can be syrups, emulsions, or suspensions. The syrups, emulsions, or suspensions can contain a carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, saccharose, saccharose with glycerol, mannitol, sorbitol, and polyvinyl alcohol.

[000175] In one aspect, a composition or unit dosage form according to the invention is formulated for sublingual administration, wherein the unit dosage form is a film including one or more disintegrants (e.g., materials that favor disintegration or fast dissolution by virtue of their solubility in water, such as hydrolyzed starches, sugars, and glycerin, which may play a dual role as a plasticizer and disintegrant) and a plasticizing agent, the film having a first portion including amphetamine-homoarginine conjugate carbamate and/or its crystalline form Form I, and a second portion including pH neutralizing agent, wherein the unit dosage form includes from 0.5 to 5 mg, from 4 to 10 mg, or from 8 to 20 mg of amphetamine-homoarginine conjugate carbamate and/or its crystalline form Form I and the pH neutralizing agent is present in an amount sufficient to produce a solution having a pH of between 3.0 and 6.0, preferably between 4.5 and 6.5, (e.g., a pH of between 2.5 and 4.5, 3.0 and 6.0, 3.5 and 6.5, 4.5 and 6.5, or 5.0 and 6.0) when the unit dosage form is placed in unbuffered water at pH 7 (e.g., the pH observed within 5 minutes of placing the unit dosage form in 1, 5, or 10 mL of unbuffered water). The film can include from 1 to 50% (w/w) (e.g., l±0.75%, 2±1.5%, 3±0.5%, 5±2%, 7.5±2.5%, l0±2%, l4±3%, 18±4%, 22±5%, 25±5%, 30±5%, 35±5%, 40±5%, 45±5%, or 50±5% (w/w)) of the one or more disintegrants. In certain embodiments, the unit dosage form further includes a high molecular weight polymer having a weight average molecular weight of greater than 60 KDa selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose. In other embodiments, the unit dosage form further includes a low molecular weight polymer having a weight average molecular weight of from 5 KDa to 50 KDa selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose. The pH neutralizing agent can be an organic base (e.g., pyridoxine, meglumine, or any organic base described herein) or an inorganic base (e.g., magnesium hydroxide, sodium bicarbonate, or an inorganic base described herein). Suitable film for oral administration of the compositions according to the invention is disclosed in, e.g., U.S. Pat. No. 8,846,074.

[000176] In some embodiments, the compounds or compositions described herein are administered intranasally. As used herein,“nasal delivery-enhancing agents” include agents which enhance the release or solubility (e.g., from a formulation delivery vehicle), diffusion rate, penetration capacity and timing, uptake, residence time, stability, effective half-life, peak or sustained concentration levels, clearance and other desired nasal delivery characteristics (e.g., as measured at the site of delivery, or at a selected target site of activity such as the brain) of the compounds or compositions of the invention. Enhancement of mucosal delivery can thus occur by any of a variety of mechanisms, for example by increasing the diffusion, transport, persistence or stability of the compounds or compositions of the invention, enzyme inhibition, increasing membrane fluidity, modulating the availability or action of calcium and other ions that regulate intracellular or paracellular permeation, solubilizing mucosal membrane components (e.g., lipids), changing non-protein and protein sulfhydryl levels in mucosal tissues, increasing water flux across the mucosal surface, modulating epithelial junctional physiology, reducing the viscosity of mucus overlying the mucosal epithelium, reducing mucociliary clearance rates, increasing nasal blood flow and other mechanisms. Suitable mucosal delivery enhancing agents will be clear to a person skilled in the art of pharmacology and are further described hereafter.

[000177] Compositions of the invention can be simple aqueous (e.g., saline) solutions. Alternatively, they can contain various additional ingredients which enhance stability and/or nasal delivery of the compounds of the invention. Such additional ingredients are well known in the art. Non-limiting examples of useful additional ingredients for enhancing nasal delivery include, e.g., (a) aggregation inhibitory agents (e.g., polyethylene glycol, dextran, diethylaminoethyl dextran, and carboxymethyl cellulose), (b) charge modifying agents, (c) pH control agents, (d) degradative enzyme inhibitors (e.g., amastatin and bestatin [see, e.g., O'Hagan et ah, Pharm. Res. 1990, 7: 772-776 and WO 05/120551]; (e) mucolytic or mucus clearing agents (e.g., n-acetyl-cysteine, propyl gallate and cysteine methionine dimers, chaotropes [see, e.g., WO 04/093917]), (f) ciliostatic agents; (g) membrane penetration enhancing agents, (h) modulatory agents of epithelial junction physiology, such as nitric oxide (NO) stimulators, chitosan, and chitosan derivatives; (i) vasodilator agents, (j) selective transport-enhancing agents, and (k) stabilizing delivery vehicles, carriers, supports or complex-forming agents. See, e.g., EP 037943, EP 094157, EP 173990, EP 214898, EP 215697, EP 327756, EP 490806, U.S. Pat. No. 4,476,116, U.S. Pat. No. 5,759,565, WO 04/093917 and WO 05/120551.

[000178] Non-limiting examples of membrane penetration-enhancing agents useful in the compositions of the invention include, e.g., (i) a surfactant (e.g., Tween 80, Poloxamer 188, polysorbates; see also EP 490806, U.S. Pat. No. 5,759,565, and W004/093917), (ii) a bile salt or bile salt derivative (e.g., unsaturated cyclic ureas and Transcutol), (iii) a phospholipid or fatty acid additive, mixed micelle, liposome, or carrier, (iv) an alcohol, (v) an enamine, (vi) a nitric oxide donor compound (e.g., S-nitroso-N-acetyl-DL-penicillamine, NOR1, NOR4, which are preferably co-administered with an NO scavenger such as carboxy-PITO or doclofenac sodium), (vii) a long-chain amphipathic molecule (e.g., deacylmethyl sulfoxide, azone, sodium lauryl sulfate, oleic acid) (viii) a small hydrophobic penetration enhancer, (ix) sodium salicylate or a salicylic acid derivative (e.g., acetyl salicylate, choline salicylate, salicylamide, etc.), (x) a glycerol ester of acetoacetic acid, (xi) a cyclodextrin or betacyclodextrin derivative, (xii) a medium-chain fatty acid including mono- and diglycerides (e.g., sodium caprate - extracts of coconut oil, Capmul), (xiii) a chelating agent (e.g., citric acid, salicylates), (xiv) an amino acid or salt thereof (e.g. monoaminocarboxlic acids such as glycine, alanine, phenylalanine, proline, hydroxyproline, etc.; hydroxyamino acids such as serine; acidic amino acids such as aspartic acid, glutamic acid, etc; and basic amino acids such as lysine etc., inclusive of their alkali metal or alkaline earth metal salts), (xv) an N-acetylamino acid or salt thereof, (xvi) an enzyme degradative to a selected membrane component, (xvii) an inhibitor of fatty acid synthesis, (xviii) an inhibitor of cholesterol synthesis, (xix) cationic polymers, or any combination thereof. The membrane penetration-enhancing agent can be also selected from small hydrophilic molecules, including but not limited to, dimethyl sulfoxide (DMSO), dimethylformamide, ethanol, propylene glycol, and the 2-pyrrolidones. Additional membrane penetration enhancers include emulsifiers (e.g. sodium oleyl phosphate, sodium lauryl phosphate, sodium lauryl sulfate, sodium myristyl sulfate, polyoxyethylene alkyl ethers, polyoxyethylene alkyl esters, etc.), caproic acid, lactic acid, malic acid and citric acid and alkali metal salts thereof, pyrrolidonecarboxylic acids, alkylpyrrolidonecarboxylic acid esters, N-alkylpyrrolidones, proline acyl esters, and the like; mixed micelles; glycerol esters of acetoacetic acid (e.g., glyceryl- 1, 3 -diacetoacetate or 1,2- isopropylideneglycerine-3-acetoacetate), and triglycerides (e.g., amylodextrin, Estaram 299, Miglyol 810); cyclodextrins and b-cyclodextrin derivatives (e.g., 2-hydroxypropyl-P- cyclodextrin and heptakis (2,6-di -O-m ethyl -b-cycl odextri n ) which can be optionally conjugated with Peptide and further optionally formulated in an oleaginous base; and N-acetylamino acids (N-acetylalanine, N-acetylphenylalanine, Nacetylserine, N-acetylglycine, N-acetyllysine, N- acetylglutamic acid, N-acetylproline, Nacetylhydroxyproline, etc.) and their salts (alkali metal salts and alkaline earth metal salts), as well as other penetration-promoting agents that are physiologically compatible for intranasal delivery. See, e.g., WO 04/093917, WO 05/120551 and Davis and Ilium (Clin. Pharmacokinet 2003, 42: 1107-1128).

[000179] Non-limiting examples of useful absorption enhancers include, e.g., surfactants, glycosides, cyclodextrin and glycols. Non-limiting examples of useful bioadhesive agents include, e.g., carbopol, cellulose agents, starch, dextran, and chitosan.

[000180] In various embodiments of the invention, a compound of the invention is combined with one or more of the nasal delivery-enhancing agents recited above. These nasal delivery-enhancing agents may be admixed, alone or together, with the nasal carrier and with the compound of the invention, or otherwise combined therewith in a pharmaceutically acceptable formulation or delivery vehicle. For nasal delivery-enhancing agents to be of value within the invention, it is generally desired that any significant changes in permeability of the mucosa be reversible within a time frame appropriate to the desired duration of drug delivery.

[000181] Furthermore, there should be no substantial, cumulative toxicity, nor any permanent deleterious changes induced in the barrier properties of the nasal mucosa with long term use.

[000182] In addition to the compound of the invention, the nasal carrier and, optionally, one or more further additives and/or agents, the composition of the invention may further comprise one or more additional therapeutic ingredients (or active substances). These therapeutic ingredients can be any compound that elicits a desired activity or therapeutic or biological response in the subject. Non-limiting examples of useful additional therapeutic ingredients is provided in the Combination Treatments section, below.

[000183] The proportion of each further component in the nasal composition of the invention may vary depending on the components used. For example, but without being limiting, the amount of nasal carrier may be in the range of from 0.1 to 99.9% by weight of the total weight or volume of the composition. When present, the amount surfactant may be in the range from about 0.01 to about 10% or higher and preferably about 0.05 to about 1.0% by weight of the total volume or weight of the composition, the amount depending on the specific surfactant used. The amount is generally kept as low as possible since above a certain level no further enhancement of absorption can be achieved and also too high of a surfactant level may cause irritation of the nasal mucosa. The amount of delivery enhancing agents may be at least 0.1%, suitably in the range from about 0.5 to 10% of the total weight of the composition. Where the composition is liquid, the enhancing agent may suitably be present in an amount of from 0.1 to 5% w/v of the total composition. Preserving agents may be present in an amount of from about 0.002 to 0.02% by weight of the total weight or volume of the composition.

[000184] The useful delivery volume of the pharmaceutical compositions of the invention is limited by the size of the nasal cavity. Suitable delivery volumes will be clear to a person skilled in the art of pharmacology. Preferably, the total composition quantity administered at each nasal application comprises from about 0.02 to 0.5 ml, preferably about 0.07 to 0.3 ml, typically about 0.09-0.1 ml. [000185] The liquid compositions of the invention may be prepared by bringing into intimate admixture a compound the invention in the liquid carrier optionally together with the further ingredients, additives and/or agents. The solid nasal composition of the invention may be prepared in conventional manner. A compound of the invention may be admixed with the carrier particles, e.g. a polymer base or cellulose product in conventional manner, optionally with further ingredients, additives and/or agents as indicated above e.g. a mucosal delivery enhancing agent or surfactant such as disclosed. A compound of the invention may be in solution e.g. an aqueous or alcoholic solution when being mixed with the carrier particles and the solvent evaporated, e.g. under freeze-drying or spray drying. Such drying may be effected under the conventional conditions. Alternatively, the mixture may be compacted or granulated and then be pulverized and/or sieved. If desired the particles may be coated. In one embodiment of the invention, the nasal composition is prepared by lyophilisation. A homogeneous solution, preferably aqueous, containing a compound of the invention and optionally containing further ingredients, additives and/or agents as discussed above, is prepared and then submitted to lyophilisation in analogy with known lyophilisation procedures, and to subsequent drying. The resulting powder may then be dissolved in a liquid excipient or nasal carrier before administration, e.g. to reconstitute nasal drops, gel or spray. Alternatively, it may be administered as such in the form of lyophilized powder or it may be mixed with further ingredients, additives and/or agents as discussed above. For example, a lyophilized powder comprising a compound of the invention but free of any nasal carrier may be prepared and then admixed with the desired nasal carrier or mixture of nasal carriers.

[000186] The present invention encompasses any delivery device that is suitable for nasal administration of the compositions of the invention. Preferably, such means administers a metered dosage of the composition. The composition of the present invention may be packed in any appropriate form or container as long as a means is provided to deliver the composition to the nasal mucosa. Non-limiting examples of useful intranasal delivery devices include, e.g., instillation catheters, droppers, unit-dose containers, squeeze bottles pump sprays, airless and preservative-fee sprays, compressed air nebulizers, metered-dose inhalers, insufflators and pressurized metered dose inhalers. [000187] For administration of a liquid in drop form, compositions of the invention can be placed in a container provided with a conventional dropper/closure device, e.g. comprising a pipette or the like, preferably delivering a substantially fixed volume of composition/drop.

[000188] For administration of an aqueous solution as a nasal spray, the aqueous solution may be dispensed in spray form by a variety of methods known to those skilled in the art. For example, such compositions will be put up in an appropriate atomising device, e.g. in a pump- atomiser, or the like. The atomising device will be provided with appropriate means, such as a spray adaptor for delivery of the aqueous spray to the naris. Preferably it will be provided with means ensuring delivery of a substantially fixed volume of composition/actuation (i.e. per spray- unit). Examples of nasal sprays include nasal actuators produced by Ing. Erich Pfeiffer GmbH, Radolfzell, Germany (see U.S. Pat. No. 4,511,069, U.S. Pat. No. 4,778,810, U.S. Pat. No. 5,203,840, U.S. Pat. No. 5,860,567, U.S. Pat. No. 5,893,484, U.S. Pat. No. 6,227,415, and U.S. Pat. No. 6,364,166. Additional aerosol delivery forms may include, e.g., compressed air-, jet-, ultrasonic-, and piezoelectric nebulizers.

[000189] Alternatively, the spray may be bottled under pressure in an aerosol device. The propellant may be a gas or a liquid (e.g. a fluorinated and/or chlorinated hydrocarbon). The spray composition may be suspended or dissolved in a liquid propellant. Stabilizing and/or suspending agents and/or co-solvents may be present.

[000190] A dry powder may be readily dispersed in an inhalation device as described in U.S. Pat. No. 6,514,496 and Garcia-Arieta et ak, Biol. Pharm. Bull. 2001; 24: 1411-1416.

[000191] If desired a powder or liquid may be filled into a soft or hard capsule or in a single dose device adapted for nasal administration. The powder may be sieved before filled into the capsules such as gelatine capsules. The delivery device may have means to break open the capsule. The powdery nasal composition can be directly used as a powder for a unit dosage form. The contents of the capsule or single dose device may be administered using e.g. an insufflator. Preferably it will be provided with means ensuring dosing of a substantially fixed amount of composition.

[000192] In another embodiment, the composition of the invention can be provided as a nasal insert having the compound of the invention dispersed therein. The insert may be retained in the naris, but flushed by the nasal mucus, and may be designed to release the compound of the invention at the same place in the naris. Suitable nasal insert types include nasal plugs, tampons and the like. Further examples of nasal inserts, their characteristics and preparation are described in EP 490806.

[000193] The dose range of the amphetamine-homoarginine conjugate carbamate and/or its crystalline form Form I for humans will depend on a number of factors including the age, weight, and condition of the patient. Tablets and other dosage forms provided in discrete units can contain a daily dose, or an appropriate fraction thereof, of one or more amphetamine- homoarginine conjugate carbamate and/or its crystalline form Form I. The dosage form can contain a dose of about 2.5 mg to about 500 mg, about 10 mg to about 250 mg, about 10 mg to about 100 mg, about 25 mg to about 75 mg, or increments therein of one or more of the amphetamine-homoarginine conjugate carbamate and/or its crystalline form Form I. In one embodiment, the dosage form contains 30 mg, 50 mg, or 70 mg of an amphetamine- homoarginine conjugate carbamate and/or its crystalline form Form I.

[000194] The dosage form can utilize any one or any combination of known release profiles including, but not limited to immediate release, extended release, pulse release, variable release, controlled release, timed release, sustained release, delayed release, and long acting.

[000195] The pharmaceutical compositions of the invention can be administered in a partial, i.e., fractional dose, one or more times during a 24 hour period. Fractional, single, double, or other multiple doses can be taken simultaneously or at different times during a 24 hour period. The doses can be uneven doses with regard to one another or with regard to the individual components at different administration times. Preferably, a single dose is administered once daily. The dose can be administered in a fed or fasted state.

[000196] The dosage units of the pharmaceutical composition can be packaged according to market need, for example, as unit doses, rolls, bulk bottles, blister packs, and so forth. The pharmaceutical package, e.g., blister pack, can further include or be accompanied by indicia allowing individuals to identify the identity of the pharmaceutical composition, the prescribed indication (e.g., ADHD), and/or the time periods (e.g., time of day, day of the week, etc.) for administration. The blister pack or other pharmaceutical package can also include a second pharmaceutical product for combination therapy.

[000197] It will be appreciated that the pharmacological activity of the compositions of the invention can be demonstrated using standard pharmacological models that are known in the art. Furthermore, it will be appreciated that the inventive compositions can be incorporated or encapsulated in a suitable polymer matrix or membrane for site-specific delivery, or can be functionalized with specific targeting agents capable of effecting site specific delivery. These techniques, as well as other drug delivery techniques, are well known in the art.

[000198] Any feature of the above-describe embodiments can be used in combination with any other feature of the above-described embodiments.

EXAMPLES

[000199] The following examples illustrate specific aspects of the instant description. The examples should not be construed as limiting, as the examples merely provide specific understanding and practice of the embodiments and their various aspects.

[000200] X-ray powder diffraction (XRPD) Analyses

[000201] XRPD diffractograms were acquired on PANalytical X’Pert Pro diffractometer using Ni-filtered Cu Ka (45 kV/40 mA) radiation with an X'celeratorTM RTMS (Real Time Multi-Strip) detector. Configuration on the incidental beam side: fixed divergence slit (0.25o), 0.04 rad Soller slits, anti-scatter slit (0.25o), and lOmm beam mask. Configuration on the diffracted beam side: fixed divergence slit (0.25o) and 0.04 rad Soller slit. Samples were mounted flat on zero-background Si wafers. Reference pattern was obtained at a scan rate 1° 20/min from 2 to 50° 20.

[000202] DSC Analyses

[000203] DSC was conducted with a TA Instruments Q100 of Q2000 differential scanning calorimeter equipped with an autosampler and a refrigerated cooling system under 40 mL/min N2 purge. DSC thermograms were obtained at lOoC/min in crimped Al pans.

[000204] Proton Nuclear Magnetic Resonance (TH NMR) Analyses

[000205] The 'H NMR spectra were collected using a Bruker 300 MHz spectrometer with TMS as reference. Samples were dissolved in D₂0 or CD₃OD.

[000206] TGA Analyses

[000207] TGA thermograms were obtained with a TA Instruments Q500 thermogravimetric analyzer under 40 mL/min N2 purge at lOoC/min in Pt or Al pans.

[000208] EXAMPLE 1 : Synthesis of l-homoarginine-d-amphetamine dihydrochloride

[000209] Synthesis of l-homoarginine-d-amphetamine dihydrochloride can be accomplished in three steps as shown in Scheme 1 below. In the first step, an N-protected homoarginine (e.g., Boc-homoarginine (NO2)) is coupled with d-amphetamine using EDCI. NHS is added to form an in-situ activated ester with DIPEA used as a co-base. The product is then subjected to hydrogenation under acidic conditions followed by deprotection with hydrochloric acid which forms the corresponding dihydrochloride salt.

[000210] SCHEME 1

Step 3

[000211] Step 1 :

[000212] To a suspension of Boc-hArgNCE-OH (Compound A, 26.0 g) in EtOAc (182 mL) was added MeCN (195 mL) under N₂ atmosphere at ambient temperature. D-Amphetamine (Compound B, 13.40 g, 1.3 equiv) was slowly added in portions to the mixture, followed by addition of Et₃N (32 mL, 3.0 equiv). The mixture was cooled in an ice-bath and T3P (94.8 g, 1.9 equiv), dissolved in EtOAC, was added over 45 minutes, maintaining the internal temperature below 10 °C. After HPLC analysis indicated reaction completion, the reaction was quenched by addition into a stirred mixture of EtOAc (260 mL) and H₂0 (172 mL). After end of addition, the phases were separated and the organic layer was subsequently washed with H₂0 (1 x 172 mL) and brine (1 x 100 mL) at ambient temperature. The organic layer was concentrated to about 240 mL in vacuo at 35 °C and then cooled in an ice bath. The solids were filtered off and the filter cake was washed with a small portion of cold EtOAc (25 mL). The product was dried under vacuum to provide 30.0 g (85% yield) of compound C as a white solid with an HPLC purity of

98.9% AUC .

[000213] Step 2: [000214] Compound C (100.0 g) was suspended in anhydrous MeOH (1.0 L, 10 vol) and the mixture was cooled to 0-5 °C under a N₂ atmosphere. AcCl (63.1 mL, 4.0 equiv) was slowly added to the reaction slurry over the course of about 20 minutes, maintaining the internal temperature of the exothermic reaction below 20 °C. During the course of the AcCl addition, the solids dissolved and a solution was formed. After completion of the addition, the reaction was heated to 50 °C for 1.5 h. After HPLC analysis indicated reaction completion, the reaction was cooled to room temperature. The solvents were exchanged under vacuum and the mixture was swapped into MTBE. The precipitated white product was filtered off and then dried in a vacuum oven at 30-35 °C for 17 h to afford Compound E (89.4 g, 88.7% w/w, 92% corrected yield) with an HPLC purity of 98.9% AUC. Chloride titration: 14.7% chloride (9.16% theory).

[000215] Step 3:

[000216] To a suspension of Compound E (5.00 g) in MeOH (75 mL) was charged 10% Pd/C (2.50 g; 50% wet) and 36% HC1 (1.8 mL, 2.0 equiv) at ambient temperature and under a nitrogen atmosphere. The vessel was purged with hydrogen (3x) and the mixture was hydrogenated (1 atm of hydrogen). After HPLC analysis indicated reaction completion, the reaction mixture was filtered through a pad of Celite (18 g). The Celite cake was rinsed with MeOH (75 mL). The combined clear yellow filtrates were concentrated in vacuo and the mixture was swapped into MTBE. The precipitated white product was filtered off and then dried in a vacuum oven at 30-35 °C to afford Compound D 5.08 g (103% mass yield) an off- white solid containing about 10 wt% of NH₄CL side-product.

[000217] EXAMPLE 2: Recrystallization of the l-homoarginine-d-amphetamine carbamate

[000218] To a solution of 2.00 g of l-homoarginine-d-amphetamine dihydrochloride in H₂0 (4 mL) at ambient temperature was added aqueous Na₂C0₃ (10 mL, saturated) over three minutes with stirring under N₂ atmosphere; final pH = 11. A couple of grains of seed material was added and did not dissolve at ambient temperature. Seed crystals were obtained after standing of the mixture (-homoarginine-d-amphetamine dihydrochloride and Na₂C0₃ solution) in the refrigerator over several days. These seeds were used for the first experiments. Going forward, some prepared carbamate crystals were kept as seeds for the next experiments.

[000219] The reaction mixture was slowly stirred using magnetic stirring. After approximately 20 minutes the reaction mixture had an oily appearance and additional H₂0 (1 mL) was charged. The second portion of H₂0 clarified the emulsion and the seed material remained undissolved. The formation of solids (crystallization) was observed after 30 minutes from the initial aqueous Na₂C0₃ charge. The slurry was stored cold (no stirring) for 16.5 h. The slurry was filtered cold and the white filtered solid was rinsed with cold H₂0 (2 x 2 mL) and dried under suction followed by further drying under vacuum at 40 °C. The first crop of material provided 1.01 g (63% yield) of white solid l-homoarginine-d-amphetamine carbamate with HPLC purity of 99.3% AUC, shown in Figure 13(A-B).

[000220] A second crop was obtained by allowing the filtrate to stand at ambient temperature for about 1.5 h. The white solid was filtered at ambient temperature, washed with H₂0 (2 X 2 mL), and dried to yield 0.36 g (22% yield) of freebase SRD006811 with HPLC purity 99.1% AUC.

[000221] An alternative synthesis of l-homoarginine-d-amphetamine carbamate is provided as follows. Crude l-homoarginine-d-amphetamine dihydrochloride (16.43 g) was dissolved in H₂0 (40 mL) and polish filtered using a 0.45 pm syringe filter. This aqueous solution was treated at 20 °C with a saturated aqueous solution of Na?CCh (80 mL) over two minutes (endotherm (19.6 °C 17.9 °C) was observed) with stirring. The mixture was stirred at 20 °C for 0.5 h and then seeded (17 mg, 0.10% wt/wt loading). The mixture was aged at 20 °C for several minutes upon which time the reaction mixture became cloudy. The mixture was cooled to 10 °C and aged for 1 h. A thick slurry resulted, and the mixture was cooled to 5 °C and aged for 15 h. The beige colored reaction slurry was filtered and dried. 12.39 g (96% yield) of 1- homoarginine-d-amphetamine carbamate was obtained with 99.16% HPLC purity, 0.468% ROI, 1.36% chloride by titration, and contained 5.06% H₂0 (KF).

[000222] It is noted that other salts of l-homoarginine-d-amphetamine may be successfully used instead of the dihydrochloride salt to prepare the carbamate compound according to the above-described process. It is further noted that other carbonate bases, such as K₂C0₃, CaC0₃ may be used instead of Na₂CCh to prepare the carbamate compound of the instant invention according to the above-described process.

[000223] EXAMPLE 3 : Characterization and Loss of C0₂ Evaluation

[000224] The final l-homoarginine-d-amphetamine carbamate was characterized by 1D and 2D NMR. In addition, the compound was evaluated by NMR and MS for the loss of C0₂ after treatment with water and acid. Spectra are shown in Figures 12A-F.

[000225] Reagents:

[000226] Deuterated dimethyl sulfoxide-d₆ (DMSO-d₆) with tetramethylsilane (TMS);

99.96% D + 0.03% v/v TMS; Cambridge Isotope Laboratories, Inc.; Deuterium oxide (D₂0); 99.96% D; Cambridge Isotope Laboratories, Inc.; Deuterated trifluoroacetic acid-d (TFA); 99.5% D; Cambridge Isotope Laboratories, Inc.; Methanol, Fisher Optima.; Formic Acid, Fisher Optima LC/MS.

[000227] 500 MHz Agilent DirectDrive2 (DD2) NMR spectrometer equipped with a 5 mm inverse probe and Xevo G2-XS mass spectrometer were used for the experiments.

[000228] For mass spectrometry, the mass scale was calibrated using Sodium Iodide / Cesium Iodide calibration mix. All data were acquired and processed with MassLynx Version 4.1 software. The mass spectrometer was equipped with an ESI source. A Waters Acquity Ultra High Performance Liquid Chromatograph equipped with a quaternary gradient pump, autosampler, column heater, and diode array detector served as the inlet to the mass spectrometer.

[000229] A solution of the sample for initial 2D NMR characterization was prepared by weighing samples in a tared glass vial. 45.63 mg was weighed and put into solution by adding two ampoules (approximately 0.75 mL) of 99.96% deuterated dimethyl sulfoxide (DMSO-d6) containing 0.03% v/v tetramethylsilane (TMS). The solution was transferred to a new 5-mm NMR tube.

[000230] Preparation of the sample in the presence of deuterated water (D₂0) and trifluoroacetic acid (TFA) was done by first weighing 8.890 mg of the sample which was put into solution by adding an ampoule (approximately 0.75 mL) of 99.96% deuterated dimethyl sulfoxide (DMSO-d₆) containing 0.03% v/v tetramethylsilane (TMS). Approximately 4 drops of D20 and 3 drops of TFA were added to the sample. The solution was transferred to a new 5-mm NMR tube. [000231] For MS analysis an initial solution (dilution A) was prepared by transferring approximately 0.1 mg of sample to an HPLC vial and adding— 1 mL of diluent (0.2% formic acid in methanol). Approximately 3 drops of dilution A were added to a new HPLC vial containing— 1 mL of diluent and mixed well (dilution B). Approximately 3 drops of dilution B were then added to a new HPLC vial containing— 1 mL of diluent to create dilution C (the injected sample solution).

[000232] Summary of NMR assignments for l-homoarginine-d-amphetamine carbamate is shown in Table 1, below:

[000233] Table 1: NMR assignments for l-homoarginine-d-amphetamine carbamate

[000234] Summary of MS data for l-homoarginine-d-amphetamine carbamate after removal of the C0₂ moiety is shown in Table 2, below: [000235] Table 2: Mass Spectrometry data for l-homoarginine-d-amphetamine carbamate after removal of the C0₂ moiety

[000236] All data acquired indicate that the sample is consistent with the purported structure of l-homoarginine-d-amphetamine carbamate. In addition, the NMR and MS data, respectively, of the water/acid treated sample indicated that it is consistent with the purported structure without the C0₂ moiety, i.e. after the loss of the carbamate moiety.

[000237] Homoarginine is different from other standard and non-standard amino acids in that it requires a separate step of deprotection to remove the nitro group from the side chain. Failure to do so correctly can lead to undesirable products that do not perform in vivo with respect to the desired therapeutic outcomes discussed herein.

* * *

[000238] As various changes can be made in the above-described subject matter without departing from the scope and spirit of the present invention, it is intended that all subject matter contained in the above description, or defined in the appended claims, be interpreted as descriptive and illustrative of the present invention. Many modifications and variations of the present invention are possible in light of the above teachings. Accordingly, the present description is intended to embrace all such alternatives, modifications, and variances which fall within the scope of the appended claims.

[000239] All patents, applications, publications, test methods, literature, and other materials cited herein are hereby incorporated by reference in their entirety as if physically present in this specification.

Embodiments:

1. A method of treating fatigue in a patient which comprises administering a therapeutically effective amount of an amphetamine-homoarginine conjugate carbamate to a patient in need thereof. 2 The method of embodiment 1, wherein the fatigue is in a patient diagnosed with chronic fatigue syndrome.

3. The method of embodiment 1, wherein the fatigue is in a patient diagnosed with myalgic encephalomyelitis.

4. The method of embodiment 1, wherein the fatigue is in a patient diagnosed with fibromyalgia.

5. The method of embodiment 1, wherein the fatigue is in a patient diagnosed with multiple sclerosis.

6 The method of embodiment 1, wherein the fatigue is in a patient diagnosed with major depressive disorder.

7. The method of embodiment 1, wherein the fatigue is in a patient diagnosed with a metabolic disorder.

8. The method of embodiment 7, wherein the metabolic disorder is obesity, appetite related symptoms of the Prader Willi Syndrome, Type 1 diabetes mellitus, Type 2 diabetes mellitus, or a combination thereof.

9. The method of embodiment 1, wherein the fatigue is post-cancer therapy fatigue caused by cancer therapy, wherein the cancer therapy is chemotherapy, radiation therapy, surgery, or combinations thereof.

10. The method of embodiment 9, wherein the chemotherapy is selected from the group consisting of methotrexate, cytarabine, vincristine, dexamethasone, hydrocortisone, and prednisone.

11. The method of embodiment 9, wherein the chemotherapy is for acute

lymphoblastic leukemia, breast cancer, or a malignant brain cancer.

12. The method of embodiment 11, wherein the malignant brain cancer is a glioma, astrocytoma, medulloblastoma, ependymoma, or brain stem glioma. 13. A method of treating fatigue in a patient diagnosed with chronic fatigue syndrome, which comprises administering a therapeutically effective amount of an

amphetamine-homoarginine conjugate carbamate to a patient in need thereof.

14. A method of treating fatigue in a patient diagnosed with myalgic

encephalomyelitis, which comprises administering a therapeutically effective amount of an amphetamine-homoarginine conjugate carbamate to a patient in need thereof.

15. A method of treating fatigue in a patient suffering from fibromyalgia, which comprises administering a therapeutically effective amount of an amphetamine-homoarginine conjugate carbamate to a patient in need thereof.

16. A method of treating fatigue in a patient suffering from multiple sclerosis which comprises administering a therapeutically effective amount of an amphetamine-homoarginine conjugate carbamate to a patient in need thereof.

17. A method of treating fatigue in a patient suffering from major depressive disorder which comprises administering a therapeutically effective amount of an amphetamine- homoarginine conjugate carbamate to a patient in need thereof.

18. The method of embodiment 17, wherein the patient is receiving concurrent treatment with a selective serotonin reuptake inhibitor, a serotonin norepinephrine reuptake inhibitor, a norepinephrine dopamine reuptake inhibitor, an atypical antidepressant, a tricyclic antidepressant, and/or a monoamine oxidase inhibitor.

19. The method of embodiment 17 or 18, wherein the patient’s fatigue was inadequately treated with a selective serotonin reuptake inhibitor, a serotonin norepinephrine reuptake inhibitor, a norepinephrine dopamine reuptake inhibitor, an atypical antidepressant, a tricyclic antidepressant, and/or a monoamine oxidase inhibitor.

20. A method of treating fatigue in a cancer patient caused by chemotherapy, radiation therapy, surgery, or a combination thereof, which comprises administering a therapeutically effective amount of an amphetamine-homoarginine conjugate carbamate to a patient in need thereof. 21. The method of any of embodiments 1-20, further comprising treating cognitive dysfunction.

22. The method of any of embodiments 1-21, further comprising treating inattention.

23. A method of treating cognitive dysfunction which comprises administering a therapeutically effective amount of an amphetamine-homoarginine conjugate carbamate to a patient in need thereof.

24. The method of embodiment 23, wherein the cognitive dysfunction is in a patient diagnosed with chronic fatigue syndrome.

25. The method of embodiment 23, wherein the cognitive dysfunction is in a patient diagnosed with myalgic encephalomyelitis.

26. The method of embodiment 23, wherein the cognitive dysfunction is in a patient diagnosed with fibromyalgia.

27. The method of embodiment 23, wherein the cognitive dysfunction is in a patient diagnosed with multiple sclerosis.

28. The method of embodiment 23, wherein the cognitive dysfunction is in a patient diagnosed with major depressive disorder.

29. The method of embodiment 23, wherein the cognitive dysfunction is in a patient diagnosed with a metabolic disorder.

30. The method of embodiment 29, wherein the metabolic disorder is obesity, appetite related symptoms of the Prader Willi Syndrome, Type 1 diabetes mellitus, Type 2 diabetes mellitus, or a combination thereof.

31. The method of embodiment 23, wherein the cognitive dysfunction is post-cancer therapy cognitive dysfunction caused by cancer therapy, wherein the cancer therapy is chemotherapy, radiation therapy, surgery, or combinations thereof. 32. The method of embodiment 31, wherein the chemotherapy is selected from the group consisting of methotrexate, cytarabine, vincristine, dexamethasone, hydrocortisone, and prednisone.

33. The method of embodiment 31, wherein the chemotherapy is for acute lymphoblastic leukemia, breast cancer, or a malignant brain cancer.

34. The method of embodiment 33, wherein the malignant brain cancer is a glioma, astrocytoma, medulloblastoma, ependymoma, or brain stem glioma.

35. A method of treating cognitive dysfunction in a patient diagnosed with chronic fatigue syndrome, which comprises administering a therapeutically effective amount of an amphetamine-homoarginine conjugate carbamate to a patient in need thereof.

36. A method of treating cognitive dysfunction in a patient diagnosed with myalgic encephalomyelitis, which comprises administering a therapeutically effective amount of an amphetamine-homoarginine conjugate carbamate to a patient in need thereof.

37. A method of treating cognitive dysfunction in a patient suffering from fibromyalgia, which comprises administering a therapeutically effective amount of an amphetamine-homoarginine conjugate carbamate to a patient in need thereof.

38. A method of treating cognitive dysfunction in a patient suffering from multiple sclerosis which comprises administering a therapeutically effective amount of an amphetamine- homoarginine conjugate carbamate to a patient in need thereof.

39. A method of treating cognitive dysfunction in a patient suffering from major depressive disorder which comprises administering a therapeutically effective amount of an amphetamine-homoarginine conjugate carbamate to a patient in need thereof.

40. The method of embodiment 39, wherein the patient is receiving concurrent treatment with a selective serotonin reuptake inhibitor, a serotonin norepinephrine reuptake inhibitor, a norepinephrine dopamine reuptake inhibitor, an atypical antidepressant, a tricyclic antidepressant, and/or a monoamine oxidase inhibitor. 41. The method of embodiment 39 or 40, wherein the patient’s cognitive dysfunction was inadequately treated with a selective serotonin reuptake inhibitor, a serotonin norepinephrine reuptake inhibitor, a norepinephrine dopamine reuptake inhibitor, an atypical antidepressant, a tricyclic antidepressant, and/or a monoamine oxidase inhibitor.

42. A method of treating cognitive dysfunction in a cancer patient caused by chemotherapy, radiation therapy, surgery, or a combination thereof, which comprises

administering a therapeutically effective amount of an amphetamine-homoarginine conjugate carbamate to a patient in need thereof.

43. The method of any of embodiments 23-42, further comprising treating fatigue.

44. The method of any of embodiments 23-43, further comprising treating inattention.

45. The method of any of embodiments 23-44, wherein the cognitive dysfunction is a short-term memory problem, an attention problem, a concentration problem, a planning problem, or a combination thereof.

46. A method of treating inattention which comprises administering a therapeutically effective amount of an amphetamine-homoarginine conjugate carbamate to a patient in need thereof.

47. The method of embodiment 46, wherein the inattention is in a patient diagnosed with chronic fatigue syndrome.

48. The method of embodiment 46, wherein the inattention is in a patient diagnosed with myalgic encephalomyelitis.

49 The method of embodiment 46, wherein the inattention is in a patient diagnosed with fibromyalgia.

50. The method of embodiment 46, wherein the inattention is in a patient diagnosed with multiple sclerosis. 51. The method of embodiment 46, wherein the inattention is in a patient diagnosed with major depressive disorder.

52. The method of embodiment 46, wherein the inattention is in a patient diagnosed with a metabolic disorder.

53. The method of embodiment 52, wherein the metabolic disorder is obesity, appetite related symptoms of the Prader Willi Syndrome, Type 1 diabetes mellitus, Type 2 diabetes mellitus, or a combination thereof.

54. The method of embodiment 46, wherein the inattention is post-cancer therapy inattention caused by cancer therapy, wherein the cancer therapy is chemotherapy, radiation therapy, surgery, or combinations thereof.

55. The method of embodiment 54, wherein the chemotherapy is selected from the group consisting of methotrexate, cytarabine, vincristine, dexamethasone, hydrocortisone, and prednisone.

56. The method of embodiment 45, wherein the chemotherapy is for acute lymphoblastic leukemia, breast cancer, or a malignant brain cancer.

57. The method of embodiment 56, wherein the malignant brain cancer is a glioma, astrocytoma, medulloblastoma, ependymoma, or brain stem glioma.

58. A method of treating inattention in a patient diagnosed with chronic fatigue syndrome, which comprises administering a therapeutically effective amount of an

amphetamine-homoarginine conjugate carbamate to a patient in need thereof.

59. A method of treating inattention in a patient diagnosed with myalgic encephalomyelitis, which comprises administering a therapeutically effective amount of an amphetamine-homoarginine conjugate carbamate to a patient in need thereof.

60. A method of treating inattention in a patient suffering from fibromyalgia, which comprises administering a therapeutically effective amount of an amphetamine-homoarginine conjugate carbamate to a patient in need thereof. 61. A method of treating inattention in a patient suffering from multiple sclerosis which comprises administering a therapeutically effective amount of an amphetamine- homoarginine conjugate carbamate to a patient in need thereof.

62. A method of treating inattention in a patient suffering from major depressive disorder which comprises administering a therapeutically effective amount of an amphetamine- homoarginine conjugate carbamate to a patient in need thereof.

63. The method of embodiment 62, wherein the patient is receiving concurrent treatment with a selective serotonin reuptake inhibitor, a serotonin norepinephrine reuptake inhibitor, a norepinephrine dopamine reuptake inhibitor, an atypical antidepressant, a tricyclic antidepressant, and/or a monoamine oxidase inhibitor.

64. The method of embodiment 62 or 63, wherein the patient’s inattention was inadequately treated with a selective serotonin reuptake inhibitor, a serotonin norepinephrine reuptake inhibitor, a norepinephrine dopamine reuptake inhibitor, an atypical antidepressant, a tricyclic antidepressant, and/or a monoamine oxidase inhibitor.

65. A method of treating inattention in a cancer patient caused by chemotherapy, radiation therapy, surgery, or a combination thereof, which comprises administering a therapeutically effective amount of an amphetamine-homoarginine conjugate carbamate to a patient in need thereof.

66. The method of any of embodiments 46-65, further comprising treating cognitive dysfunction.

67. The method of any of embodiments 46-66, further comprising treating fatigue.

68. The method of any of embodiment 9-12, 20-22, 31-34, 42-45, 54-57, or 65-67 wherein the amphetamine-homoarginine conjugate carbamate is administered to a patient in need thereof.

69. The method of any of embodiment 9-12, 20-22, 31-34, 42-45, 54-57, or 65-67, wherein the amphetamine-homoarginine conjugate carbamate is initially administered after cancer therapy and before the patient is diagnosed with fatigue caused by chemotherapy or radiation therapy.

70. The method of any of embodiment 9-12, 20-22, 31-34, 42-45, 54-57, or 65-67, wherein the amphetamine-homoarginine conjugate is initially administered after cancer therapy and after the patient is diagnosed with fatigue caused by chemotherapy or radiation therapy.

71. The method of any of embodiment 9-12, 20-22, 31-34, 42-45, 54-57, or 65-67, wherein the patient received chemotherapy that was delivered directly to the central nervous system.

72. The method of any of embodiment 9-12, 20-22, 31-34, 42-45, 54-57, or 65-67, wherein the patient received systemic chemotherapy.

73. The method of any of embodiment 9-12, 20-22, 31-34, 42-45, 54-57, or 65-67, wherein the cancer therapy is radiation therapy.

74. The method of embodiment 73, wherein the radiation therapy is cranial radiation therapy.

75. The method of any of embodiment 9-12, 20-22, 31-34, 42-45, 54-57, or 65-67, wherein the cancer therapy is surgery.

76. The method of embodiment 75, wherein the surgery is cranial surgery.

77. The method of any of embodiment 9-12, 20-22, 31-34, 42-45, 54-57, or 65-67, wherein the cancer therapy is a combination of chemotherapy and radiation therapy.

78. The method of any of embodiment 9-12, 20-22, 31-34, 42-45, 54-57, or 65-67, wherein the cancer therapy is a combination of at least two of the following: chemotherapy, radiation therapy, or surgery.

79. The method of any of embodiment 6, 17-19, 21, 22, 28, 39-41, 43-45, 51, 62-64, 66 or 67, wherein the patient is elderly. 80. The method of any of embodiment 6, 17-19, 21, 22, 28, 39-41, 43-45, 51, 62-64, 66, 67, or 79 wherein the patient is receiving concurrent treatment with a selective serotonin reuptake inhibitor, a serotonin norepinephrine reuptake inhibitor, a norepinephrine dopamine reuptake inhibitor, an atypical antidepressant, a tricyclic antidepressant, and/or a monoamine oxidase inhibitor.

81. The method of any of embodiment 6, 17-19, 21, 22, 28, 39-41, 43-45, 51, 62-64, 66, 67, 79, or 80 wherein the patient’s inattention was inadequately treated with a selective serotonin reuptake inhibitor, a serotonin norepinephrine reuptake inhibitor, a norepinephrine dopamine reuptake inhibitor, an atypical antidepressant, a tricyclic antidepressant, and/or a monoamine oxidase inhibitor.

82. A method of treating fatigue, cognitive dysfunction, and/or inattention in a patient suffering from traumatic brain injury which comprises administering a therapeutically effective amount of an amphetamine-homoarginine conjugate carbamate to a patient in need thereof.

83. A method of treating fatigue, cognitive dysfunction, and/or inattention in a menopausal patient, which comprises administering a therapeutically effective amount of an amphetamine-homoarginine conjugate carbamate to a patient in need thereof.

84. A method of treating fatigue, cognitive dysfunction, and/or inattention in a patient suffering from the negative symptoms of schizophrenia, which comprises administering a therapeutically effective amount of an amphetamine-homoarginine conjugate carbamate to a patient in need thereof.

85. A method of treating fatigue, cognitive dysfunction, and/or inattention in a patient suffering from diabetes mellitus type I or type II, which comprises administering a

therapeutically effective amount of an amphetamine-homoarginine conjugate carbamate to a patient in need thereof.

86. A method of treating cognitive dysfunction in a patient suffering from a cancer comprising administering a therapeutically effective amount of an amphetamine-homoarginine conjugate carbamate to a patient in need thereof, wherein the cognitive dysfunction is selected from the group consisting of: a short-term memory problem, an attention problem, a concentration problem, a planning problem, and a combination thereof; and

wherein the cognitive dysfunction appears before the patient receives chemotherapy.

87. A method of treating a cognitive dysfunction in a patient suffering from a cancer comprising administering a therapeutically effective amount of an amphetamine-homoarginine conjugate carbamate to a patient in need thereof,

wherein the cognitive dysfunction is selected from the group consisting of: a short-term memory problem, an attention problem, a concentration problem, a planning problem, and a combination thereof; and

wherein the cognitive dysfunction arises during chemotherapy or after the patient receives chemotherapy.

88. A method of treating a wakefulness disorder which comprises administering a therapeutically effective amount of an amphetamine-homoarginine conjugate carbamate to a patient in need thereof.

89. A method of treating narcolepsy in a patient which comprises administering a therapeutically effective amount of an amphetamine-homoarginine conjugate carbamate to a patient in need thereof.

90. The method of embodiment 89, wherein the patient is a child patient or an adult patient.

91. A method of treating a wakefulness disorder caused by chemotherapy or radiation therapy which comprises administering a therapeutically effective amount of an amphetamine- homoarginine conjugate carbamate to a patient in need thereof.

92. A method of treating a behavior caused by hyperactivity and impulsivity in a patient which comprises administering a therapeutically effective amount of an amphetamine- homoarginine conjugate carbamate to a patient in need thereof. 93. A method of treating alcohol addiction in a patient which comprises administering a therapeutically effective amount of an amphetamine-homoarginine conjugate carbamate to a patient in need thereof.

94. A method of treating smoking addiction in a patient which comprises

95. A method of treating symptoms of Fragile X syndrome in a patient which comprises administering a therapeutically effective amount of an amphetamine-homoarginine conjugate carbamate to a patient in need thereof.

96. A method of treating a metabolic disorder in a patient which comprises administering a therapeutically effective amount of an amphetamine-homoarginine conjugate carbamate to a patient in need thereof.

97. A method of treating obesity in a patient which comprises administering a therapeutically effective amount of an amphetamine-homoarginine conjugate carbamate to a patient in need thereof.

98. A method of treating an appetite related symptom of the Prader Willi Syndrome in a patient which comprises administering a therapeutically effective amount of an

amphetamine-homoarginine conjugate carbamate to a patient in need thereof.

99. A method of treating Type 1 diabetes mellitus in a patient which comprises administering a therapeutically effective amount of an amphetamine-homoarginine conjugate carbamate to a patient in need thereof.

100. A method of treating Type 2 diabetes mellitus in a patient which comprises administering a therapeutically effective amount of an amphetamine-homoarginine conjugate carbamate to a patient in need thereof.

101. The method according to any one of embodiments 1-100 wherein the

amphetamine-homoarginine conjugate carbamate is as described in any of claims 1-12 below. 103. The method according to any one of embodiments 1-102, wherein the amphetamine-homoarginine conjugate carbamate is in an amount of from about 1 mg to about 500 mg.

104. The method according to any one of embodiments 1-103, wherein the amphetamine-homoarginine conjugate carbamate is in an amount of from about 5 mg to about 250 mg.

105. The method according to any one of embodiments 1-104, wherein the amphetamine-homoarginine conjugate carbamate is in an amount of from about 10 mg to about 100 mg.

Claims

WHAT IS CLAIMED IS:

1. A compound l-homoarginine-d-amphetamine carbamate having the structure according to Formula I:

or a pharmaceutically acceptable salt thereof.

2. A crystalline form of the compound l-homoarginine-d-amphetamine carbamate having the structure according to Formula I:

3. The crystalline form of claim 2 which is solvated.

4. The crystalline form of claim 2 which is hydrated.

5. The crystalline form of claim 2 which is Form I.

6. The crystalline form of claim 2 having a powder X-ray diffraction pattern substantially as shown in Figure 2.

7. The crystalline form of claim 2 having a powder X-ray diffraction pattern substantially as shown in Figure 5.

8. The crystalline form of claim 2 having a differential scanning calorimetry thermogram (DSC) substantially as shown in Figure 3.

9. The crystalline form of claim 2 having a differential scanning calorimetry thermogram (DSC) substantially as shown in Figure 6.

10. The crystalline form of claim 2 having a thermogravimetric analysis (TGA) substantially as shown in Figure 3.

11. The crystalline form of claim 2 having a thermogravimetric analysis (TGA) substantially as shown in Figure 6.

12. The crystalline form of any of claims 2-12 which is substantially isolated.

13. A pharmaceutical composition comprising the compound of claim 1 or the crystalline form of any one of claims 2-13.

14. The pharmaceutical composition of claim 14, wherein said composition comprises at least one pharmaceutically acceptable carrier.

15. A process for preparing the compound of claim 1 or the crystalline form of any one of claims 2-l3Formula I.

16. A method of treating attention deficit hyperactivity disorder in a patient in need thereof, comprising the step of orally administering the compound of claim 1 or the crystalline form of any one of claims 2-13 or the pharmaceutical composition of claim 14 or 15 to the patient.

17. The method of claim 16, wherein the patient is 6-12 years of age.

18. A method of reducing patient to patient variability of amphetamine levels among a group of patients comprising once daily oral administration to each patient in the group of the compound of claim 1 or the crystalline form of any one of claims 2-13 or the pharmaceutical composition of claim 14 or 15.

19. The method of claim 18, wherein all of the patients are 6-12 years of age.

20. The method of any of claims 16-19, wherein daily dose of the compound of claim 1 or the crystalline form of any one of claims 2-13 ranges from about 20 to about 70 mg.

21. The method of claim 16, wherein the patient is an adult.

22. The method of claim 18, wherein all of the patients are adults.

23. The method of claims 16, 18, 21 or 22, wherein daily dose of the compound of claim 1 or the crystalline form of any one of claims 2-13 ranges from about 50 to about 250 mg.

24. The method of claim 23, wherein daily dose of the compound of claim 1 or the crystalline form of any one of claims 2-13 ranges from about 100 to about 250 mg.

25. The method of claim 23, wherein daily dose of the compound of claim 1 or the crystalline form of any one of claims 2-13 ranges from about 150 to about 250 mg.

26. The method of any one of claims 16-25, wherein the compound of claim 1 or the crystalline form of any one of claims 2-13 is administered in the form of a tablet or capsule.