WO2019199724A1 - Salts of amphetamine-homoarginine conjugate prodrug - Google Patents

Abstract

Disclosed are improved amphetamine-homoarginine conjugate salts, including compositions thereof. These amphetamine-homoarginine conjugate salts and compositions are useful for treating certain disorders, such as attention deficit hyperactivity disorder (ADHD), ADD, as well as fatigue, cognitive dysfunction, and/or inattention associated with various disorders.

Description

SALTS OF AMPHETAMINE-HOMO ARGININE CONJUGATE PRODRUG

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 62/655,793, filed April 10, 2018, the disclosure of which is herein incorporated by reference in its entirety.

FIELD OF INVENTION

[0002] The present invention provides for salt forms of amphetamine-homoarginine conjugate with improved pharmaceutical properties. The invention also relates to pharmaceutical compositions comprising amphetamine-homoarginine conjugate salt forms, and to methods of manufacturing, delivering, and using the amphetamine-homoarginine conjugate salt forms. The invention further relates to a crystalline form of the amphetamine prodrug (l)-homoarginine-(d)- amphetamine dibenzoate and a crystalline form of the amphetamine prodrug (l)-homoarginine-(d)- amphetamine dinitrate.

BACKGROUND OF THE INVENTION

[0003] Amphetamines stimulate the central nervous system (CNS) and have been used medicinally to treat various disorders including attention deficit hyperactivity disorder (ADHD), obesity, and narcolepsy. In children with ADHD, potent CNS stimulants have been used for several decades as a drug treatment given either alone or as an adjunct to behavioral therapy. While methylphenidate (Ritalin®) has been the most frequently prescribed stimulant, the prototype of the class, amphetamine (alpha-methyl phenethylamine) has been used all along and increasingly so in recent years. (Bradley C, Bowen M,“Amphetamine (benzedrine) therapy of children’s behavior disorders.” American Journal of Orthopsychiatry 11 : 92-103 (1941).

[0004] Because of their stimulating effects, amphetamines, including amphetamine derivatives and analogs, are subject to abuse. A user can become dependent over time on these drugs and their physical and psychological effects, even when the drugs are used for legitimate therapeutic purposes. Legitimate amphetamine users that develop drug tolerances are especially susceptible to becoming accidental addicts as they increase dosing in order to counteract their increased tolerance of the prescribed drugs. Additionally, it is possible for individuals to inappropriately self-administer higher than prescribed quantities of the drug or to alter either the product or the route of administration (e.g., inhalation (snorting), injection, and smoking), potentially resulting in immediate release of the active drug in quantities larger than prescribed. When taken at higher than prescribed doses, amphetamines can cause temporary feelings of exhilaration and increased energy and mental alertness.

[0005] Recent developments in the abuse of prescription drug products increasingly raise concerns about the abuse of amphetamine prescribed for ADHD. The National Survey on Drug Use and Health (NSDUH), estimates that in 2003, 1.2 million Americans aged 12 and older abused stimulants, such as amphetamines. The high abuse potential has earned amphetamines Schedule II status according to the Controlled Substances Act (CSA). Schedule II classification is reserved for those drugs that have accepted medical use but have the highest potential for abuse.

[0006] Extended release formulations of amphetamines, e.g., Adderall XR®, have an increased abuse liability relative to the single dose tablets because each tablet of the sustained release formulation contains a higher concentration of amphetamine. It may be possible for substance abusers to obtain a high dose of amphetamine with rapid onset by crushing the tablets into powder and snorting it or by dissolving the powder in water and inj ecting it. Sustained release formulations may also provide uneven release.

[0007] Amphetamine-homoarginine conjugate and salts of the conjugate, and methods for synthesizing the conjugates and salts thereof, are disclosed in U.S. Patent Nos. 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. The hydrochloride salt, however, exhibits properties that make it more difficult to use in a pharmaceutical product. For example, it is 1) an amorphous solid, and non-crystallinity is not preferable for a pharmaceutical product 2) hygroscopic; and 3) deliquescent. These three points demonstrate that the hydrochloride salt is not ideal for draft product development. After a comprehensive salt screening with the hydrochloride salt, no crystalline form could be identified.

[0008] The need exists for amphetamine conjugates with improved pharmacokinetic and/or physiochemical properties. Further, the need exists for additional amphetamine conjugate compositions that provide sustained release and sustained therapeutic effect. SUMMARY OF THE INVENTION

[0009] The present invention provides salts of amphetamine-homoarginine conjugate. In certain embodiments, the amphetamine-homoarginine conjugate is (l)-homoarginine-(d)-amphetamine. In particular, the present invention provides, inter alia , salts selected from:

(l)-homoarginine-(d)-amphetamine dibenzoate ((A')-2-amino-6-guanidino-A-((A')-l- phenylpropan-2-ly)hexanamide dibenzoate)

(l)-homoarginine-(d)-amphetamine dinitrate ((A')-2-amino-6-guanidino-A-((A')-l- phenylpropan-2-ly)hexanamide dinitrate)

(l)-homoarginine-(d)-amphetamine diacetate ((A')-2-amino-6-guanidino-A^f-((A')-l- phenylpropan-2-ly)hexanamide diacetate)

(l)-homoarginine-(d)-amphetamine difumarate ((A')-2-amino-6-guanidino-A-((A')-l- phenylpropan-2-ly)hexanamide difumarate)

(l)-homoarginine-(d)-amphetamine diphosphate ((A')-2-amino-6-guanidino-A-((A')-l- phenylpropan-2-ly)hexanamide diphosphate)

[00010] A preferred amphetamine prodrug is (l)-homoarginine-(d)-amphetamine dibenzoate.

[00011] Another preferred amphetamine prodrug is (l)-homoarginine-(d)-amphetamine dinitrate.

[00012] The amphetamine-homoarginine conjugate salts can be in crystalline form.

[00013] One embodiment, the amphetamine-homoarginine conjugate salts is crystalline (1)- homoarginine-(d)-amphetamine dibenzoate, which exhibits an X-ray powder diffraction (XRPD) pattern having at least one peak in degrees 2Q ± 0.2° 2Q selected from 6.11, 12.27, 14.06, 15.57, 16.53, 16.85, 18.07, 18.29, 20.05, 20.75, 21.57, 22.21, 22.75, 22.96, and 25.35. In another embodiment, the crystalline (l)-homoarginine-(d)-amphetamine dibenzoate exhibits 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or all of the aforementioned peaks. The crystalline (l)-homoarginine- (d)-amphetamine dibenzoate can exhibit an XRPD substantially as shown in Figure 2.

[00014] One embodiment, the amphetamine-homoarginine conjugate salts is crystalline (1)- homoarginine-(d)-amphetamine dinitrate, which exhibits an X-ray powder diffraction (XRPD) pattern having at least one peak in degrees 2Q ± 0.2° 2Q selected from 8.39, 11.16, 11.37, 13.51, 14.68, 15.30, 15.47, 16.96, 19.89, 22.51, 23.66, 24.62, 25.38, 26.44, 26.91, and 30.74. In another embodiment, the crystalline (l)-homoarginine-(d)-amphetamine dinitrate exhibits 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or all of the aforementioned peaks. The crystalline (l)-homoarginine- (d)-amphetamine dinitrate can exhibit an XRPD substantially as shown in Figure 13.

[00015] The amphetamine-homoarginine conjugate salt 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 (ADHD) in a patient (e.g., a child or adult) in need thereof by administering an effective amount for the treatment of ADHD of an amphetamine-homoarginine conjugate salt. In certain embodiments, the amphetamine-homoarginine conjugate salt is administered orally. In one preferred embodiment, a pharmaceutical composition consisting essentially of the an (l)-homoarginine-(d)-amphetamine conjugate salt is administered. In certain embodiments, the prodrug is (l)-homoarginine-(d)- amphetamine dibenzoate. In certain embodiments, the prodrug is (l)-homoarginine-(d)- amphetamine dinitrate.

[00016] In yet another aspect of the invention, an improved method for preparing a (1)- homoarginine-(d)-amphetamine salt.

[00017] 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 amphetamine- homoarginine conjugate salt. In one preferred embodiment, a pharmaceutical composition comprising an (l)-homoarginine-(d)-amphetamine salt is administered. In certain embodiments, a pharmaceutical composition consisting essentially of an (l)-homoarginine-(d)-amphetamine salt is administered. In certain embodiments, the prodrug is (l)-homoarginine-(d)-amphetamine dibenzoate. In certain embodiments, the prodrug is (l)-homoarginine-(d)-amphetamine dinitrate.

[00018] 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 for the appropriate indication or indications of the aforementioned amphetamine-homoarginine conjugate salt or a pharmaceutical composition containing it. According to one preferred embodiment, the amphetamine-homoarginine conjugate salt is an (1)- homoarginine-(d)-amphetamine salt. In certain embodiments, it is orally administered once daily. In certain embodiments, the (l)-homoarginine-(d)-amphetamine dibenzoate is orally administered once daily. In other embodiments, the (l)-homoarginine-(d)-amphetamine dinitrate is orally administered once daily. A preferred (l)-homoarginine-(d)-amphetamine salt is (l)-homoarginine- (d)-amphetamine dibenzoate. Another preferred (l)-homoarginine-(d)-amphetamine salt is (1)- homoarginine-(d)-amphetamine dinitrate.

[00019] 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 or diagnosed with fibromyalgia; fatigue, cognitive dysfunction, and/or inattention in a patient suffering from or diagnosed with multiple sclerosis (MS); fatigue, cognitive dysfunction, and/or inattention in a patient suffering from or diagnosed with major depressive disorder (MDD); fatigue, cognitive dysfunction, and/or inattention in a patient suffering from or diagnosed with traumatic brain injury; fatigue, cognitive dysfunction, and/or inattention in a menopausal patient; fatigue, cognitive dysfunction, and/or inattention in a patient suffering from or diagnosed with 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 or diagnosed with a metabolic disorder, e g., obesity, appetite related symptoms of the Prader Willi Syndrome, and Type 1 and Type 2 diabetes me!litus, in a patient in need thereof by administering an effective amount of the aforementioned amphetamine-homoarginine conjugate salt or a pharmaceutical composition containing it. According to one preferred embodiment, the amphetamine- homoarginine conjugate is an (l)-homoarginine-(d)-amphetamine salt. In certain embodiments, it is orally administered once daily. According to another preferred embodiment, the (1)- homoarginine-(d)-amphetamine dibenzoate is orally administered once daily. In other preferred embodiments, the (l)-homoarginine-(d)-amphetamine dinitrate is orally administered once daily. A preferred (l)-homoarginine-(d)-amphetamine salt is (l)-homoarginine-(d)-amphetamine dibenzoate. In another preferred (l)-homoarginine-(d)-amphetamine salt is (l)-homoarginine-(d)- amphetamine dinitrate. [00020] 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 an amphetamine-homoarginine conjugate salt for the treatment of fatigue. These amounts may be the same or different for different indications, combinations of indications, or patient populations.

[00021] In one embodiment, the fatigue is in patients suffering from or diagnosed with CFS/ME. 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.

[00022] In another aspect, the present invention provides a method of treating or preventing cognitive dysfunction in a patient, which comprises administering a therapeutically effective amount of an amphetamine-homoarginine conjugate salt 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.

[00023] In one embodiment, the cognitive dysfunction is in patients suffering from or diagnosed with CFS/ME. 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.

[00024] In another 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 an amphetamine-homoarginine conjugate salt for the treatment of inattention. These amounts may be the same or different for different indications, combinations of indications, or patient populations.

[00025] In one embodiment, the inattention is in patients suffering from or diagnosed with CSF/ME. 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.

[00026] In another aspect, the present invention provides a method for the treatment of symptoms related to fatigue and cognitive impairment in patients with CSF/ME, which comprises administering to a patient in need thereof a therapeutically effective amount of an amphetamine- homoarginine conjugate salt. In certain embodiments, the present invention provides a method for the treatment of at least one symptom related to fatigue and cognitive dysfunction in CSF/ME, which comprises administering to a patient in need thereof a therapeutically effective amount of an amphetamine-homoarginine conjugate salt 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 CSF/ME, which comprises administering to an adult patient in need thereof a therapeutically effective amount of an amphetamine-homoarginine conjugate salt for the treatment of at least one symptom. [00027] In one aspect, the present invention provides a method to improve symptoms of fatigue (physical symptoms and cognitive symptoms) in patients with CSF/ME, which comprises administering to a patient in need thereof a therapeutically effective amount of an amphetamine- homoarginine conjugate salt. In certain embodiments, the present invention provides a method to improve symptoms of fatigue (physical symptoms and cognitive symptoms) in adult patients with CSF/ME, which comprises administering to a patient in need thereof a therapeutically effective amount of an amphetamine-homoarginine conjugate salt. In certain embodiments, the present invention provides at a method to improve at least one symptom of fatigue (physical symptoms and/or cognitive symptoms) associated with CSF/ME, which comprises administering to a patient in need thereof a therapeutically effective amount of an amphetamine-homoarginine conjugate salt for the improvement of at least one symptom. In certain embodiments, the present invention provides at a method to improve at least one symptom of fatigue (physical symptoms and/or cognitive symptoms) associated with CSF/ME, which comprises administering to an adult patient in need thereof a therapeutically effective amount of an amphetamine-homoarginine conjugate salt for the improvement of at least one symptom.

[00028] In another aspect, the present invention provides a method of treating or preventing symptoms associated with CSF/ME, which comprises administering to a patient in need thereof a therapeutically effective amount of an amphetamine-homoarginine conjugate salt. In one embodiment, the present invention provides a method of treating or preventing fatigue, cognitive dysfunction, and/or inattention in a patient with CSF/ME, which comprises administering to a patient in need thereof a therapeutically effective amount for the appropriate indication or indications of an amphetamine-homoarginine conjugate salt. In one embodiment, the present invention provides a method of treating or preventing fatigue in a patient with CSF/ME, which comprises administering to a patient in need thereof a therapeutically effective amount for the treatment of fatigue of an amphetamine-homoarginine conjugate salt. In one embodiment, the present invention provides a method of treating or preventing inattention in a patient with CSF/ME, which comprises administering to a patient in need thereof a therapeutically effective amount for the treatment of inattention of an amphetamine-homoarginine conjugate salt. In one embodiment, the present invention provides a method of treating or preventing cognitive dysfunction in a patient with CSF/ME, which comprises administering to a patient in need thereof a therapeutically effective amount for the treatment of cognitive dysfunction of an amphetamine-homoarginine conjugate salt. These amounts may be the same or different for different indications, combinations of indications, or patient populations.

[00029] 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 an amphetamine-homoarginine conjugate salt. 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 an amphetamine-homoarginine conjugate salt. 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 an amphetamine- homoarginine conjugate salt. 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 an amphetamine-homoarginine conjugate salt. These amounts may be the same or different for different indications, combinations of indications, or patient populations.

[00030] 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 an amphetamine- homoarginine conjugate salt. 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 an amphetamine-homoarginine conjugate salt. 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 an amphetamine- homoarginine conjugate salt. 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 an amphetamine-homoarginine conjugate salt. 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 major depressive disorder (MDD), which comprises administering to a patient in need thereof a therapeutically effective amount for the appropriate indication or indications of an amphetamine- homoarginine conjugate salt. 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 an amphetamine-homoarginine conjugate salt. 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 an amphetamine- homoarginine conjugate salt. 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 an amphetamine-homoarginine conjugate salt. These amounts may be the same or different for different indications, combinations of indications, or patient populations.

[00032] 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 an amphetamine-homoarginine conjugate salt. 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 amphetamine-homoarginine conjugate salt 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.

[00033] 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 an amphetamine-homoarginine conjugate salt. 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 amphetamine- homoarginine conjugate salt 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.

[00034] 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 an amphetamine-homoarginine conjugate salt. 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 amphetamine-homoarginine conjugate salt 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.

[00035] 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 an amphetamine-homoarginine conjugate salt. 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.

[00036] 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 an amphetamine- homoarginine conjugate salt. 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.

[00037] 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 an amphetamine-homoarginine conjugate salt. 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.

[00038] In one embodiment of the present invention, the amphetamine-homoarginine conjugate or a salt of the amphetamine-homoarginine conjugate is initially administered prior to the chemotherapy or radiation therapy.

[00039] In an alternative embodiment, the amphetamine-homoarginine conjugate or a salt of the amphetamine-homoarginine conjugate is initially administered after chemotherapy, radiation therapy, or surgery and before the patient is diagnosed with fatigue caused by chemotherapy, radiation therapy, or surgery.

[00040] In an alternative embodiment, the amphetamine-homoarginine conjugate or a salt of the amphetamine-homoarginine conjugate 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.

[00041] In a further embodiment, the amphetamine-homoarginine conjugate or a salt of the amphetamine-homoarginine conjugate is initially administered after chemotherapy, radiation therapy, or surgery and after the patient is diagnosed with fatigue caused by chemotherapy, radiation therapy, or surgery.

[00042] In an alternative embodiment, the amphetamine-homoarginine conjugate or a salt of the amphetamine-homoarginine conjugate 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. [00043] In an alternative embodiment, the amphetamine-homoarginine conjugate or a salt of the amphetamine-homoarginine conjugate is initially administered after cancer therapy and before the patient is diagnosed with post-cancer therapy inattention.

[00044] In a further embodiment, the amphetamine-homoarginine conjugate or a salt of the amphetamine-homoarginine conjugate is initially administered after cancer therapy and after the patient is diagnosed with post-cancer therapy inattention.

[00045] 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 an amphetamine-homoarginine conjugate or a salt of the amphetamine-homoarginine conjugate 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.

[00046] 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 an amphetamine-homoarginine conjugate or a salt of the amphetamine-homoarginine conjugate 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.

[00047] 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 an amphetamine- homoarginine conjugate or a salt of the amphetamine-homoarginine conjugate 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.

[00048] 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 an amphetamine-homoarginine conjugate or a salt of the amphetamine- homoarginine conjugate to a patient in need thereof.

[00049] 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 an amphetamine-homoarginine conjugate or a salt of the amphetamine-homoarginine conjugate to a patient in need thereof.

[00050] 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 an amphetamine- homoarginine conjugate or a salt of the amphetamine-homoarginine conjugate to a patient in need thereof.

[00051] 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 an amphetamine-homoarginine conjugate or a salt of the amphetamine-homoarginine conjugate to a patient in need thereof.

[00052] 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 DRAWINGS

[00053] 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.

[00054] Figure 1. Polarized-Light Microscopy (PLM) image of crystalline (1)- homoarginine-(d)-amphetamine dibenzoate salt. [00055] Figure 2. XRPD pattern of crystalline (l)-homoarginine-(d)-amphetamine dibenzoate salt.

[00056] Figure 3. TGA and DSC traces of crystalline (l)-homoarginine-(d)-amphetamine dibenzoate salt.

[00057] Figure 4. ¾ NMR pattern of crystalline (l)-homoarginine-(d)-amphetamine dibenzoate salt.

[00058] Figure 5. XRPD pattern overlay of crystalline (l)-homoarginine-(d)-amphetamine dibenzoate salt solid state stability samples.

[00059] Figure 6. HPLC Chromatographs of crystalline (l)-homoarginine-(d)-amphetamine dibenzoate salt solid state stability samples at 1 week.

[00060] Figure 7. HPLC Chromatographs of crystalline (l)-homoarginine-(d)-amphetamine dibenzoate salt solid state stability samples at 2 weeks.

[00061] Figures 8A-8F. XRPD pattern overlays of the crystalline (l)-homoarginine-(d)- amphetamine dibenzoate salt residues in solubility samples. Figure 8 A: residues in 0.1N HC1 at Day 7: XRD patterns were the same as benzoic acid. Figure 8B: residues in 0.1N HC1 and Britton- Robinson (BR) pH 2.5, 3,5, 4.5, 6.5, 7.5 and 8.5 at Day 5: XRD patterns were the same as input API except there was no peak at 16.3°2Q (which may be a phase impurity). Sample in 0.1N HC1 had a mixture of input API (but in a different salt form) and Benzoic acid. Figure 8C: residues in water and organic solvents at 25°C (Day 6): same XRD patterns as input materials except there was no peak at 16.3° 20 (1 of 2). Figure 8D: residues in organic solvents at 25°C (Day 6): same XRD patterns as input materials except there was no peak at 16.3° 20 (2 of 2). Figure 8E: residues in water and in solvents at 60°C (Day 7): same XRD patterns as input materials except there was no peak at 16.3° 20 (1 of 2). Figure 8F: residues in organic solvents at 60°C (Day 7): same XRD patterns as input materials except there was no peak at 16.3° 20 (2 of 2).

[00062] Figure 9. ¾ NMR spectrum in DMSO-d6of crystalline (l)-homoarginine-(d)- amphetamine dibenzoate salt.

[00063] Figure 10. TGA and DSC traces of crystalline (l)-homoarginine-(d)-amphetamine dibenzoate salt.

[00064] Figure 11. DVS traces of crystalline (l)-homoarginine-(d)-amphetamine dibenzoate salt. [00065] Figure 12. DVS traces of amorphous (l)-homoarginine-(d)-amphetamine dihydrochloride salt.

[00066] Figure 13. XRPD pattern of crystalline (l)-homoarginine-(d)-amphetamine dinitrate salt.

[00067] Figure 14. Polarized-Light Microscopy (PLM) image of crystalline (1)- homoarginine-(d)-amphetamine dinitrate salt.

[00068] Figure 15. TGA and DSC traces of crystalline (l)-homoarginine-(d)-amphetamine dinitrate salt.

[00069] Figure 16. DVS traces of crystalline (l)-homoarginine-(d)-amphetamine dinitrate salt.

[00070] Figure 17. ¾ NMR spectrum of crystalline (l)-homoarginine-(d)-amphetamine dibenzoate salt.

DETAILED DESCRIPTION OF THE INVENTION

[00071] The present invention provides, inter alia , salts of amphetamine-homoarginine conjugates. These amphetamine-homoarginine conjugates provide slow/sustained/controlled delivery of the amphetamine into the blood system of a human within a safe and therapeutic window upon oral administration. The salts of the amphetamine-homoarginine conjugates are selected from the benzoic, nitric, acetic, fumaric, and phosphoric acids. The amphetamine- homoarginine conjugate salt can be orally administered to treat attention deficit hyperactivity disorder as well as the other disorders described herein.

[00072] The salts of the invention have numerous advantageous properties over the free base form and other salt forms. In particular, the (l)-homoarginine-(d)-amphetamine dibenzoate and (l)-homoarginine-(d)-amphetamine dinitrate salts were highly crystalline, which would facilitate the preparation of pharmaceutical formulations and improve general handling, manipulation, and storage of the amphetamine-homoarginine conjugates. The salts of the invention also have low hygroscopicity, superior aqueous solubility, rate of dissolution, chemical stability (with a longer shelf life), compatibility with excipients, and reproducibility compared with the free base form or the amorphous (l)-homoarginine-(d)-amphetamine dihydrochloride salt.

[00073] In particular, (l)-homoarginine-(d)-amphetamine dibenzoate is not hygroscopic (e.g., showed moisture uptake of 0.5% from 40-75% RH with the largest moisture change observed during the final desorption cycle from 95-5% RH which showed a loss of 1.6%.). The homoarginine-(d)-amphetamine dibenzoate was also highly soluble. Thus, the dibenzoate salt exhibits a surprising and significant advantage for compound handling and stability.

[00074] The (l)-homoarginine-(d)-amphetamine dinitrate salt showed moisture uptake of 0.3% from 40-75% RH. The moisture uptake is <1% up to 80% RH and is fairly linear and reversible. The homoarginine-(d)-amphetamine dinitrate was also highly soluble. Thus, the dinitrate salt exhibits a surprising and significant advantage for compound handling and stability.

Definitions

[00075] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[00076] 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.

[00077] As used herein, “amphetamine” means any of the sympathomimetic phenethylamine derivatives which have central nervous system stimulant activity such as, but not limited to, amphetamine (alpha-methyl-phenethylamine), methamphetamine, p- methoxyamphetamine, methyl enedioxyamphetamine, 2, 5 -dimethoxy-4-methyl amphetamine, 2,4,5-trimethoxyamphetamine, and 3,4-methylenedioxy-methamphetamine. The amphetamine can be a metabolite of amphetamine, a salt thereof, a derivative thereof, or a mixture thereof. Amphetamine can be in the form of dextro- (d-), levo- (1-), or racemic. In an embodiment, the amphetamine is d-amphetamine. An amphetamine-homoarginine conjugate of the present invention includes pharmaceutically acceptable salts of an amphetamine-homoarginine conjugate.

[00078] As used herein,“prodrug” means a form of a drug that is not therapeutically active on its own until it is metabolized in the body and made active.

[00079] 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 (XRPD). Other characterization methods such as differential scanning calorimetry (DSC), thermogravimetric 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 solvent/water content.

[00080] Crystalline forms of a substance include both solvated (e.g., hydrated) and non- solvated (e.g., anhydrous) forms.

[00081] The term“hydrate” refers to a 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.

[00082] An“anhydrous crystalline form” lacks bound water molecules.

[00083] The term“polymorph” refers to crystallographically distinct forms of a substance.

[00084] Crystalline forms are most commonly characterized by XRPD. As XRPD pattern of reflections (peaks) is typically considered a fingerprint of a particular crystalline form. It is well known that the relative intensities of the XRPD 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 XRPD herein is meant to encompass the above-mentioned variations.

[00085] 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 instalment 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.

[00086] The term“amine” refers to a— NH2 group.

[00087] Salts of the homoarginine amphetamine prodrug that can be formed and utilized include, but are not limited to, aspartate, mesylate, hydrochloride, sulfate, oxalate, triflate, citrate, malate, tartrate, phosphate, nitrate, benzoate, acetate, carbonate, hydroxide, sodium, potassium, magnesium, calcium, zinc, saccharate, sulfate, and ammonium salts. Further, in accordance with some embodiments, the salts may be in multiple forms (e.g., di-, tri-, or tetra-). Other derivative forms such as free base, free acid, or neutral forms may also be prepared.

[00088] A“composition” refers broadly to any composition containing one or more amphetamine-homoarginine conjugate salt prodrugs. The composition can comprise a dry formulation, an aqueous solution, or a sterile composition. Compositions comprising the compounds described herein may be stored in freeze-dried form and may be associated with a stabilizing agent such as a carbohydrate. In use, the composition may be deployed in an aqueous solution containing salts, e.g., NaCl, detergents such as sodium dodecyl sulfate (SDS), and other components.

[00089] 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.

[00090] 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.

[00091] 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.

[00092] 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.

[00093] 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.

[00094] 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. [00095] As used herein in connection with a measured quantity, the term“about” refers to the normal variation in that measured quantity that would be expected by the skilled artisan making the measurement and exercising a level of care commensurate with the objective of the measurement and the precision of the measuring equipment used. Unless otherwise indicated, “about” refers to a variation of ±10% of the value provided.

[00096] Throughout this application, the term“increment” is used to define a numerical value in varying degrees of precision, e.g., to the nearest 10, 1, 0.1, 0.01, etc. The increment can be rounded to any measurable degree of precision. For example, the range 1 to 100 or increments therein includes ranges such as 20 to 80, 5 to 50, 0.4 to 98, and 0.04 to 98.05.

[00097] The term“bioavailability” refers to the rate and extent to which a drug is absorbed. One measurement of bioavailability is defined by the fraction (F) of the dose that reaches systemic circulation. Thus, in extreme cases, F=0 in drugs which are not absorbed at all in the GI tract while for drugs that are completely absorbed (and not metabolized by a first pass effect) F=l . The bioavailability can also be calculated from the area under the curve (AUC) of the serum level vs. time plot.

[00098] The coefficient of variation (CV) is typically used to express the variability in bioavailability. This value is obtained by expressing the standard deviation as a percentage of the arithmetic mean.

Synthesis of Amphetamine-Homoarginine Conjugate Salts

[00099] According to the presently described technology, homoarginine can be chemically attached to amphetamine (d-, 1-, or racemic form or a mixture thereof) to produce homoarginine amphetamine conjugates/prodrugs. Amphetamine-homoarginine conjugate and salts of the conjugate, and methods for synthesizing the conjugates and salts thereof, are disclosed in U.S. Patent Nos. 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. Metabolites and derivatives of amphetamine can also be so modified. Examples of metabolites of amphetamine include N-hydroxyamphetamine, 4-hydroxyamphetamine, a-hydroxyamphetamine, norephedrine, 4-hydroxynorephedrine, phenylacetone oxime, phenylacetone and l-phenyl-2-propanol.

[000100] Generally, to conjugate homoarginine with amphetamine, the amino group and guanidino group are preferably protected before homoarginine is reacted with amphetamine. Agents and methods for protecting amino groups and guanidino groups in a reactant are known in the art. Examples of protecting groups that may be used to protect the amino groups include, but are not limited to, fluorenylmethoxycarbonyl (Fmoc), t-butylcarbonate (Boc), trifluoroacetate (TFA), and benzyloxycarbonyl (Z). Additional protection of the guanidino group may be necessary. Examples of protecting groups that may be used to protect the guanidino group include, but are not limited to, t-butylcarbonate (Boc), benzyloxycarbonyl (Z) and nitro. After coupling with any standard coupling procedure, depending on protecting groups, for example, deprotection can occur via catalytic hydrogenation using a catalyst such as palladium-carbon in the presence of hydrogen gas or any other hydride donor molecule, and/or with a variety of strong acids, such as hydrochloric acid, sulfuric acid, hydrobromic acid, or methanesulfonic acid, to give the corresponding salt form. Examples of other catalysts that could be used in place of palladium- carbon include titanium trichloride (TiCB) tin dichloride (SnCl2), Raney nickel, platinum (IV) oxide (Pt02), samaribum diiodide (Sml2), ETshibara catalysts (for example, U-Ni- A, ET-Ni-B, U- Ni-BA, U-Ni-AA, U-N1-NH3, U-Co-A, U-Co-B, U-Fe(II); where A=acid, B-base, BA-base with aluminum, AA=acid with aluminum), and iron metal. Salt forms may also be switched by first free basing the product and then adding any acid. Neutral (i.e., free base) or anionic salts may also be formed.

[000101] The amino acid whose amino group and guanidino group are protected can be referred to as an N-protected amino acid. One can either protect the amino groups before the coupling reaction or use commercially available N-protected amino acids directly. Preferably, the carboxylic acid group in the N-protected amino acid is activated by an acid activating agent (sometimes also called coupling reagent) to help the reaction of the N-protected amino acid with amphetamine. General information about the reaction of amino acids to form peptide bonds can be found in, for example, G.C. Barett, D.T. Elmare, Amino Acids and Peptides, page 151-156, Cambridge ETniversity Press, ETC (lst edition, 1998); Jones, J., Amino Acid and Peptide Synthesis, pages 25-41, Oxford University Press, ETC (2nd edition, 2002), each of which are incorporated herein by reference in their entirety for all purposes.

[000102] Salts of the invention also include all isotopes of atoms occurring in the salts. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. [000103] Salts of the invention can be prepared using known techniques. Conventionally, a salt form is prepared by combining in solution the free base compound and an acid containing the anion of the salt form desired, and then isolating the solid salt product from the reaction solution (e.g., by crystallization, precipitation, evaporation, etc.). Other salt-forming techniques can be employed.

[000104] Examples of solvents that can be used in the presently described technology include, but are not limited to, isopropyl acetate (IP AC), acetone, and dichloromethane (DCM), dimethylformamide (DMF), 2-methyltetrahydrofuran (2-MeTHF), ethyl acetate, chloroform, dimethyl sulfoxide, dioxane, diethyl ether, methyl t-butyl ether, hexanes, heptane, methanol, ethanol, isopropanol, and butanol. A mixture of different solvents can also be used. Co-bases such as tertiary amines may or may not be added in the coupling reaction of the presently described technology. Examples of suitable co-bases include, but are not limited to, l-methylmorpholine (NMM), 4-methylmorpholine, triethylamine (TEA), ammonia or any tertiary amine base.

[000105] Particular salts may be less hygroscopic thereby facilitating handling. In a preferred embodiment, amphetamine-homoarginine conjugate salt has a water content (Karl Fischer analysis) of about 0% to about 5%, about 0.1% to about 3%, about 0.25% to about 2%, or increments therein. When the amphetamine-homoarginine conjugate salt is formulated into a pharmaceutical composition, the pharmaceutical composition preferably has a water content of about 1% to about 10%, about 1% to about 8%, about 2% to about 7%, or increments therein.

[000106] In one embodiment, the purity of the amphetamine-homoarginine conjugate salt prodrug is at least about 95%, more preferably at least about 96%, 97%, 98%, 98.5%, 99%, 99.5%, 99.9%, or increments therein.

[000107] In certain embodiments, the amphetamine-homoarginine conjugate salt exhibits an unbound amphetamine oral bioavailability of at least about 60% AUC (area under the curve), more preferably at least about 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or other increments greater than 60%. Preferably, the amphetamine prodrug exhibits an unbound amphetamine parenteral, e.g., intranasal, bioavailability of less than about 70% AUC, more preferably less than about 50%, 30%, 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1%, or other increments less than 70%.

[000108] In another embodiment, the toxicity of the amphetamine-homoarginine conjugate salt is substantially lower than that of the unbound amphetamine. For example, in a preferred embodiment, the acute toxicity is l-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9- fold, lO-fold less, or increments therein less lethal than oral administration of unbound amphetamine.

[000109] In certain embodiments, the amphetamine-homoarginine conjugate salt provides a serum release curve that does not increase above amphetamine’s toxicity level when administered at higher than therapeutic doses. The amphetamine-homoarginine conjugate salt prodrug may exhibit a reduced rate of amphetamine absorption and/or an increased rate of clearance compared to the free amphetamine. The amphetamine-homoarginine conjugate salt prodrug may also exhibit a steady-state serum release curve. In certain embodiments, the amphetamine-homoarginine conjugate salt prodrug provides bioavailability but prevents Cmax spiking or increased blood serum concentrations.

[000110] The amphetamine-homoarginine conjugate salt may exhibit delayed and/or sustained release characteristics. Delayed release prevents rapid onset of pharmacological effects, and sustained release is a desirable feature for particular dosing regimens, e.g., once a day regimen. The amphetamine-homoarginine conjugate salt prodrug may achieve the release profile independently. Alternatively, the amphetamine-homoarginine conjugate salt prodrug may be pharmaceutically formulated to enhance or achieve such a release profile. It may be desirable to reduce the amount of time until onset of pharmacological effect, e.g., by formulation with an immediate release product.

[000111] In one aspect, the amphetamine-homoarginine conjugate is l-homoarginine-d- amphetamine dibenzoate (fV)-2-amino-6-guanidino-A-(fV)-l -phenyl propan-2-1 yjhexanamide dibenzoate):

Chemical formula: C30H39N5O5

Exact Mass: 549.30

Molecular Weight: 549.67 [000112] Chemically, l-homoarginine-d-amphetamine dibenzoate 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. The synthesis is carried out by the coupling of dextroamphetamine with a homoarginine analog to form the amide bond. The homoarginine fragment can be synthesized through various approaches. In one method, L- homoarginine or nitro homoarginine thereof protected at the amine functionality is coupled with dextroamphetamine. The intermediate is deprotected to provide the desired target compound. In another approach, the guanidine functionality is introduced in L-lysine, and the intermediate is reacted with dextroamphetamine, and finally deprotected to furnish the desired compound.

[000113] Scheme 1 below outlining exemplary routes for the synthesis of l-homoarginine-d- amphetamine dibenzoate in accordance with the presently described technology.

[000114] In one aspect, the amphetamine-homoarginine conjugate is l-homoarginine-d- amphetamine dinitrate (fV)-2-ami no-6-guanidino-A^f-(0V)-l -phenyl propan-2-1 yjhexanamide dinitrate):

Chemical formula: C16H27N7O7

Molecular Weight: 429.43 [000115] The amphetamine-homoarginine conjugate can be synthesized as discussed above. Scheme 2 below outlining exemplary routes for the synthesis of l-homoarginine-d-amphetamine dinitrate in accordance with the presently described technology.

Indications

[000116] The invention also provides methods comprising providing, administering, prescribing, or consuming an amphetamine-homoarginine conjugate salt. The invention also provides pharmaceutical compositions comprising an amphetamine-homoarginine conjugate salt. The formulation of such a pharmaceutical composition can optionally enhance or achieve the desired release profile.

[000117] In one embodiment, the invention provides methods for treating a patient comprising administering a therapeutically effective amount of an amphetamine-homoarginine conjugate salt, 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.

[000118] 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.

[000119] 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.

[000120] 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 CFS/ME 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 CFS/ME can also suffer from inattention.

[000121] 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 CFS/ME 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.

[000122] Cognitive dysfunction is a key symptom of CFS/ME and affects the gamut of cognitive abilities ( e.g ., memory, attention, and information processing). Cognitive dysfunction in CFS/ME 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 CFS/ME. A review of cognitive impairment in CFS/ME (Shanks et al., 2013) notes that research has highlighted the negative impact of CFS/ME 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 CFS/ME (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).

[000123] 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.

[000124] No cure or treatment has been approved for CFS/ME, and the FDA recognizes the disease as serious with an unmet medical need for treatment (Guidance for Industry, CFS/ME 2014). According to the Institute of Medicine (IOM) committee report, approximately 836,000 to 2.5 million Americans are affected by CFS/ME. It is also noted in the report that approximately 90% of people with CFS/ME have yet to be diagnosed, so the true prevalence is unknown. Although CFS/ME 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 CFS/ME are bed- or house-bound, leading to an annual 17 to 24 billion dollar economic burden from loss of productivity and high medical costs.

[000125] Fatigue and cognitive dysfunction are also a characteristic symptom 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.

[000126] 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. [000127] 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.

[000128] 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.

[000129] 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.

[000130] 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.

[000131] A homoarginine-amphetamine conjugate according to the present invention may be administered as monotherapy for fatigue and/or inattention in a patient suffering from or diagnosed with MDD, or in combination with one or more of the above listed medications for MDD. In one embodiment, the patient suffering from or diagnosed with 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 (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.

[000132] In an aspect of the invention, a homoarginine-amphetamine conjugate is administered to treat fatigue, cognitive dysfunction, 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.

[000133] In a further aspect of the invention, a homoarginine- amphetamine conjugate 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.

[000134] 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 salt.

[000135] 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 are incorporated by reference in their entirety for all purposes.

[000136] 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 salt. 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 salt 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.

[000137] 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.

[000138] In non-limiting examples, the patient received chemotherapy or radiation therapy for ALL, breast cancer, or a malignant brain cancer. The malignant brain cancer may be, for example, a glioma, astrocytoma, medulloblastoma, ependymoma, or brain stem glioma.

[000139] 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.

[000140] 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.

[000141] 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.

[000142] In an aspect of the present invention, the patient suffering from or diagnosed with MDD has primary inattentive symptoms. In a further aspect, the patient suffering from or diagnosed with MDD is elderly.

[000143] 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 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). [000144] The symptoms of cognitive dysfunction, which can be used interchangeably with cognitive impairment, can include by way of example and not limitation, 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.

Dosage Form

[000145] In an aspect of the present invention, the amphetamine-homoarginine conjugate salt 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 or salts thereof are present in the composition in an amount equivalent to amphetamine freebase in the range of about 5 mg to about 40 mg.

[000146] In aspects of the invention, a physician titrates the dosage of an amphetamine- homoarginine conjugate salt (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.

[000147] 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 salts 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 homoarginine amphetamine dichloride 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)

[000148] 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.

[000149] In one embodiment, the amphetamine-homoarginine conjugate salt 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 salt 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 U.S. Patents NOs.: 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.

[000150] 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.

[000151] 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.

[000152] 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 salt 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.

[000153] In addition to the amphetamine-homoarginine conjugate salt, 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.

[000154] 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.

[000155] 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.

[000156] 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.

[000157] 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.

[000158] 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 salt from the dosage form.

[000159] 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.

[000160] 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.

[000161] 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.

[000162] 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.

[000163] 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.

[000164] 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.

[000165] 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.

[000166] 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 salt 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 salt is mixed with a hydrophilic polymer and an aliquot of water, then dried to obtain granules of amphetamine-homoarginine conjugate salt encapsulated by hydrophilic polymer. [000167] 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.

[000168] 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 salt releases the amphetamine over a more extended period of time as compared to administering unbound amphetamine.

[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 salt 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 and sprinklings (e.g., capsules or packers containing beads) can be prepared by coating tablets using techniques such as rotating pan coating methods and air suspension methods to deposit a contiguous film layer on a tablet. Examples of film-coating can be found in Felton et ak, Expert Opinion on Drug Delivery. 10 (4): 421-35, which is incorporated by reference in its entirety.

[000172] Compressed tablets can be prepared by mixing the amphetamine-homoarginine conjugate salt 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 salt, 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 salt 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±l .5%, 3±0.5%, 5±2%, 7.5±2.5%, 10±2%, 14±3%, l8±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, ET.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-l,3-diacetoacetate or l,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 -0-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 al., 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 salt 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 salt. 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 salt. In a preferred embodiment, the dosage form contains 30 mg, 50 mg, or 70 mg of an amphetamine-homoarginine conjugate salt.

[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] X-ray powder diffraction (XRPD) Analyses

[000200] 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 (0.25°), 0.04 rad Soller slits, anti-scatter slit (0.25°), and lOmm beam mask. Configuration on the diffracted beam side: fixed divergence slit (0.25°) 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.

[000201] DSC Analyses

[000202] 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 l0°C/min in crimped Al pans.

[000203] TGA Analyses [000204] TGA thermograms were obtained with a TA Instruments Q500 thermogravimetric analyzer under 40 mL/min N₂ purge at lO°C/min in Pt or Al pans.

[000205] High-Performance Liquid Chromatography

[000206] HPLC analyses were conducted with an Agilent 1260 Infinity system equipped with a G1311B Quad pump, G1329B Autosampler, G4212B diode array detector, and Agilent 1290, model G1330B autosampler thermostat. The solubility assessment involved the methods below.

[000207] Proton Nuclear Magnetic Resonance t'H NMR)

[000208] The 'H NMR spectra were collected using Agilent DD2 500 MHz spectrometer with TMS reference. Samples were dissolved in DMSO-d6, DMSO-d6 with 5 drops of D₂0, or CD₃OD.

[000209] Polarized-Light Microscopy (PLM)

[000210] The photomicrographs were collected using Olympus BX60 polarized-light microscope equipped with Olympus DP70 camera.

[000211 ] Gravimetric Vapor Sorption (GVS)

[000212] GVS experiments were conducted on a Surface Measurement Systems DVS- Advantage (SN: P22F00054). The experiments were performed at 25 °C. The instrument was operated in step mode and the relative humidity was increased in 10% RH increments from 40% RH to 75% RH, then decreased from 75% RH to 5% RH, then increased a second time from 5% RH to 95% RH, then decreased from 95% RH to 5% RH. The mass equilibrium criterion was set at 0.003% change in mass over time (dm/dt). A minimum step time of 20 minutes and a maximum step time of 240 minutes were specified.

[000213] Ion Chromatography (IC)

[000214] Ion chromatography was performed on a Dionex ICS-3000. Column: Dionex IonPac AS12A 4x200mm; Detection: Suppressed conductivity, ASRS 300 with suppressor current at 22 mA; Eluent (2.7 mM Na₂CO₃/0.3 mM NaHCCh) at 1.5 mL/min.

Example 1. Synthesis of (l)-Homoarginine-(d)-Amphetamine Salts

[000215] Salts were formed and crystalline forms were obtained as indicated below.

1. Dispensed 500 pL of solvents into 2-mL HPLC vials containing the free base (20 mg). 2. Added stoichiometric amount of either the benzoic acid (2 eq) or nitric acid (2 eq) to the vial.

3. Stirred the solutions and amorphous suspensions/gums/oils while cycling the temperature between 40°C and 5°C at a rate of 0.5°C /min for two days (TC1).

4. Evaporated solutions and amorphous suspensions/gums/oils rapidly under reduced

pressure by Genevac.

5. Added original solvent to the solids (300 pL).

6. Stirred the solutions and amorphous suspensions/gums/oils while cycling the temperature between 40°C and 5°C at a rate of 0.5°C /min for two days (TC2).

7. Stirred solutions and amorphous suspensions/gums/oils at 40°C for an hour, and then cooled slowly at a rate of 0.l°C/min to 5°C and maintained at 5°C for two days (CC).

8. To increase solubility and encourage crystallization, added methanol (50-200 pL) to

amorphous suspensions/gums/oils. Repeated step 7 (CC).

9. Evaporated remaining solutions at ambient conditions for up to 7 days (EV).

Table 1 shows the results. Salt hits were produced from phosphoric, acetic, nitric, benzoic, and fumaric acids. These salt hits range from poorly to highly crystalline. The remaining experiments yielded gums or oils.

Table 1.

Example 2. Synthesis of (1 )-Homoargi nine-id)- Amphetamine Dibenzoate

[000216] (l)-homoarginine-(d)-amphetamine dibenzoate was synthesized by the following method.

[000217] The (l)-homoarginine-(d)-amphetamine freebase (351 mg; l . l5mmol) was dissolved in 2-propanol (lOvol; 3.5 lmL) at 40°C. Solid benzoic acid (2.0eq; 28lg) and seed crystals of the dibenzoate salt were added. The slurry was heated at 40°C for 1 hr, then slowly cooled to RT at 0.1 °C/min. The mixture was stirred at RT overnight. The solids were isolated by filtration under vacuum. The material was dried in a vacuum oven with nitrogen bleed at 40°C for 3 hours. The yield was 76.1% (48lmg; 0.875mmol) of the dibenzoate salt.

Example 3. Synthesis of n)-Hornoarginine-(d)-Amphetamine Dibenzoate

[000218] (l)-homoarginine-(d)-amphetamine dibenzoate was synthesized by the following method.

[000219] The (l)-homoarginine-(d)-amphetamine freebase (5.63g; l8.4mmol) was dissolved in 2-propanol (7vol; 39mL) at 50°C. Solid benzoic acid (2.0eq; 4.53g) and seed crystals of the dibenzoate salt were added. The slurry was heated at 50°C, and poor stirring was observed for the thick mixture. Additional 2-propanol (~3vol; l6mL) was added to improve stirring. The mixture was stirred at 50°C for 1 hr, then heat was turned off. The mixture was stirred at RT overnight. The solids were isolated by filtration under vacuum. The material was dried in a vacuum oven with nitrogen bleed at 40°C overnight (-18 hrs). The yield was 83.9% (8.5 lg; l5.5mmol) of the dibenzoate salt. Example 4. Characterization of Crystalline (D-Homoarginine-(d)- Amphetamine Dibenzoate

[000220] The crystalline (l)-homoarginine-(d)-amphetamine dibenzoate prepared according to Example 3 is an off-white crystalline powder consisting of small irregularly shaped particles (Figure 1). The batch showed diffraction peaks between 2 - 50° 20 consistent with a crystalline material (Figure 2 and Table 2). DSC analysis showed an endothermic event at 155.3°C (DH = 126.4 J/g) (Figure 3). TGA showed a gradual weight loss of 0.7% up to 100 °C (Figure 3). Figure 4 shows the ¾ NMR results.

[000221] The XRPD spectra of a sample of the dibenzoate salt is shown in Figure 2. Peak locations (in degrees 2Q ± 0.2, 0.1, 0.05, or 0.01° C) for the XRPD pattern in Figure 2 are provided in Table 2, below.

Table 2. XRPD Peaks of (l)-Homoarginine-(d)-Amphetamine Dibenzoate

Example 5. Solid-State Stability Assessment

[000222] Stability assessment was performed to evaluate the solid-state stability of the crystalline dibenzoate salt prepared according to Example 3. [000223] Solid-state stability of crystalline dibenzoate salt was assessed at an initial time point and after storage at 50°C/ambient RH (closed and opened) for one and two weeks by HPLC and XRPD (Figures 5-7).

[000224] Results of the stability assessments are summarized in Table 3, below.

250504.000681

Table 3 Summary of Solid-State Stability Assessment

NA: Not Applicable; NT: Not Tested

Note: only impurity peaks with %AUC at least 0.05% were listed in this table; impurity value <0.05% was listed for the trend purpose

[000225] An overlay of the XRPD data for the stability samples is presented in Figure 5. No significant changes were observed in the physical appearance, and chemical assays by HPLC (LC conditions shown in Table 4, below) for samples at all exposure conditions for up to two weeks. At both one and two-week timepoints, XRPD analysis of the stability samples at 50C (closed) showed no change in the XRPD patterns. Though XRPD analysis of the stability samples at 50°C (opened) were generally consistent with the input batch.

Table 4. HPLC Method for Stability Assessment

Example 6. Solubility Assessment in Aqueous Britton-Robinson Buffers

[000226] Solubility assessment was performed to evaluate the solid-state stability of the crystalline dibenzoate salt prepared according to Example 3.

[000227] Solubility of the dibenzoate salt was conducted in 0.1N HC1 (pH 1.42), pH 2.5, 3.5, 4.5, 6.5, 7.5 and 8.5 Britton-Robinson (BR) buffers at room temperature. Initial solubility assessment was performed with maximum loading of 5 mg/mL (freebase equivalent) to minimize shifts in the pH of the buffer. Results indicated solubility in excess of 5 mg/mL at all pHs tested (Table 5, below). With the 0.1 N HC1 buffer, a salt exchange occurs (HC1 for benzoic acid). The free benzoic acid then precipitates from water (due to low solubility) while the HC1 asalt of the (1)- homoarginine-(d)- amphetamine remains in solution. Excess solids were observed inO. l N HC1 but XRPD indicated the solids were consistent with benzoic acid and not of the salt, thus suggesting higher solubility for the salt (Figure 8).

Table 5. Solubility of the Dibenzoate Salt in pH 1 (0.1N HC1) and BR Buffers at RT

* Solubility was assayed and it was at least 8.8 mg/mL (FB equiv); the residues were consistent with benzoic acid. FB: Freebase; NA: Not Applicable

[000228] Solubility of the dibenzoate salt in the same aqueous media above was re-assessed at room temperature with the samples prepared with maximum concentration of 300 mg/mL (freebase equivalent). Assay indicated high solubility values (33 - 53 mg/mL freebase equivalent) for all samples (Table 6). Due to the high concentration of the salt in the supernatant, significant shift between the initial and final values of media pH were noted. XRPD patterns of excess solids from pH-solubility experiments for all samples were generally consistent with the solid form of the input dibenzoate salt. XRPD analysis of the excess solids in 0.1N HC1 was consistent with a mixture of the input the dibenzoate salt and benzoic acid (Figure 8).

[000229] Results of the stability assessments are summarized in Table 6, below. 250504.000681

Table 6. Solubility of the Dibenzoate Salt in 0.1N HC1 and BR Buffers at RT with API Loading at 300mg/ml (Freebase Equivalent)

250504.000681

FB: Free base

Example 7. Solubility in Solvents

[000230] The solubility of the crystalline dibenzoate salt prepared according to Example 3 was assessed in 12 solvents at 25°C and 60°C.

[000231] The solubility was visually estimated at room temperature (RT; ~23°C) by dosing small aliquots of solvent into a fixed amount of solid (~36 mg) until the dissolution point or a maximum volume of 0.6 mL was reached. Solubility in methanol was visually determined, and it was in excess of 500 mg/mL (salt equivalent). Samples that contained undissolved solids at RT were stirred at 25°C for several days and the samples were assayed by HPLC (Table 7).

Table 7. HPLC Method for Solubility Assessment

[000232] The solubility samples at 60°C were prepared in the same manner as samples at 25°C. No solubility in methanol was carried out at this temperature. Sample in acetone was done at 50°C and assayed at 4h timepoint due to the potential degradation in acetone at elevated temperatures.

[000233] The solubility in most solvents at 50°C and 60°C were higher than at 25°C except in ethyl acetate whose solubility was slightly similar at both tested temperatures (28.3 mg/mL at 25°C vs 29.1 mg/mL at 60°C). Solubility in heptane was low (< 0.01 mg/mL at 25°C; 0.01 mg/mL at 60°C) as well as in methyl t-butyl ether and toluene (<0.01 mg/mL at both 25°C and 60°C). [000234] The undissolved materials which remained following solubility measurements in solvents were analyzed by XRPD to confirm the solid-state form. Excess solids from solubility experiments for all samples were consistent with the crystalline input solid form except there was no peak at 16.3o2q (Figure 8). Summary of solubility in 12 solvents are shown in Table 8.

Table 8. Solubility of the Dibenzoate Salt in Solvents at 25°C and 50-60°C

a: visual solubility

b: solubility analyzed at 4h

NT: Not Tested

Example 8. Characterization of Crystalline (D-Homoarginine-(d)- Amphetamine Dibenzoate

[000235] The crystalline (l)-homoarginine-(d)-amphetamine dibenzoate prepared according to Example 2 was compared to the (l)-homoarginine-(d)-amphetamine dihydrochloride salt.

[000236] The dibenzoate salt was determined to have a 2: 1 ratio of benzoic acid to freebase by ¾ NMR. (Figure 9). The crystalline (l)-homoarginine-(d)-amphetamine dibenzoate salt showed a sharp endotherm at l56°C and 0.6% weight loss up to l00°C (Figure 10). DVS data showed it is slightly hygroscopic (1.6% total moisture update) from 5-95% RH (Figure 11). This demonstrates that the crystalline dibenzoate is less hygroscopic than the amorphous free base material and handled better as compared to the amorphous dihydrochloride salt, which is deliquescent. Example 9. Bioavailabilitv of (1 )-Homoarui nine-id)- Amphetamine Dibenzoate

[000237] Male Sprague-Dawley rats and male beagle dogs were provided water ad libitum, fasted overnight, and dosed by oral gavage or IV (l)-homoarginine-(d)-amphetamine dibenzoate or (l)-homoarginine-(d)-amphetamine dihydrochloride.

Table 9. Dosing

* equivalent of freebase

[000238] In all studies, doses contained equivalent amounts of d-amphetamine base. Plasma d-amphetamine concentrations were measured by ELISA (Amphetamine ETltra, 109319, Neogen, Corporation, Lexington, Ky.). The assay is specific for d-amphetamine with only minimal reactivity (0.6%) of the major d-amphetamine metabolite (para-hydroxy-d-amphetamine) occurring.

[000239] Mean plasma concentration curves of d-amphetamine for the dibenzoate and dihydrochloride salts are shown for rats in Figure 9 and dogs in Figure 10. Extended release was observed for all dosed animals.

[000240] A summary of the pharmacokinetic results for the orally administrated amphetamine-homoarginine conjugate salts is presented in Table 10. A summary of the pharmacokinetic results for the IV administrated amphetamine-homoarginine conjugate salts is presented in Tables 11 and 12.

Table 10. Oral PK Summary of d-Amphetamine Following Administration of HC1 and Benzoate Salt Forms of (l)-Homoarginine-(d)-Amphetamine

Table 11. Rat IV PK Summary of d- Amphetamine vs Prodrug

Table 12. Dog IV PK Summary of d-Amphetamine vs Prodrug

Example 10. Synthesis of (D-Homoarginine-id)- Amphetamine Dinitrate

[000241] (l)-homoarginine-(d)-amphetamine dinitrate was synthesized by the following method.

[000242] The (l)-homoarginine-(d)-amphetamine freebase (5 l8mg; l .70mmol) was dissolved in 2-propanol (lOvol; 5. l8mL) and aqueous nitric acid was added (2.0eq; 6M; 566 pL). The solution was concentrated in vacuo to remove solvent and water. 2-Propanol (lOvol; 5. l8mL) was added to the mixture along with seed crystals of the dinitrate salt, and heated to 40°C for 1 hr. A significant amount of sticky, non-crystalline material was present after 1 hr and was broken up with a spatula to promote better homogeneity. The mixture continued heating at 40°C for 2 hrs, then was slowly cooled at 0. l°C/min to 5°C and held at 5°C over the weekend. The solids were isolated by filtration under vacuum. The material was dried in a vacuum oven with nitrogen bleed at 40°C for 3 hours. The yield was 59.6% (436mg; l .Olmmol) of the dinitrate salt.

Example 11. Characterization of Crystalline (O-Homoarginine-(d)- Amphetamine Dinitrate

[000243] The crystalline (l)-homoarginine-(d)-amphetamine dinitrate prepared according to Example 10 was characterized.

[000244] The dinitrate salt was crystalline by XRPD and showed no changes upon drying (Figure 13), and the material was birefringent with small irregular particles by PLM (Figure 14). Thermal analysis showed one endotherm at H2°C and weight loss of 0.2% up to l00°C (Figure 15). The dinitrate salt was a 2: 1 nitrate salt by ion chromatography. DVS showed moisture uptake of 0.3% from 40-75% RH (Figure 16). The moisture uptake is <1% up to 80% RH and is fairly linear and reversible, but above 80% RH the sample is extremely hygroscopic and partially deliquesced. The solids post-DVS were observed to have congealed and to be damp during preparation for XRPD analysis. However, XRPD analysis of the dinitrate post-DVS showed no change in crystalline form.

[000245] Peak locations (in degrees 2Q ± 0.2, 0.1, 0.05, or 0.01° C) for the XRPD pattern in Figure 13 are provided in Table 13, below.

Table 13. XRPD Peaks of (l)-Homoarginine-(d)-Amphetamine Dinitrate

* * *

[000246] It will be understood that the specific embodiments of the invention shown and described herein are exemplary only. Numerous variations, changes, substitutions and equivalents will occur to those skilled in the art without departing from the spirit and scope of the invention. In particular, the terms used in this application should be read broadly in light of similar terms used in the related applications. Accordingly, it is intended that all subject matter described herein and shown in the accompanying drawings be regarded as illustrative only and not in a limiting sense and that the scope of the invention be solely determined by the appended claims.

[000247] 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 salt 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 salt 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 salt 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 salt 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 salt 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 salt 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 salt 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 salt 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 salt 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 salt 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 salt 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 salt 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 salt 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 salt 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 salt 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 I diabetes mei!itus, 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 salt 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 salt 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 salt 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 salt 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 salt 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 salt 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 salt 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 salt 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 salt 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 salt 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 salt 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 salt 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 salt 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 salt 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 salt 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 salt 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 salt 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 salt 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 salt to a patient in need thereof f.

93. A method of treating alcohol addiction in a patient which comprises administering a therapeutically effective amount of an amphetamine-homoarginine conjugate salt to a patient in need thereof.

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

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

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 salt 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 salt 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 salt 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 salt 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 salt 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 salt to a patient in need thereof.

101. The method according to any one of embodiments 1-100 wherein the salt of the conjugate is the crystalline salt as described in any of claims 1-24 below.

103. The method according to any one of embodiments 1-102, wherein the salt of the conjugate 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 salt of the conjugate 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 salt of the conjugate is in an amount of from about 10 mg to about 100 mg.

Claims

CLAIMS:

1. Crystalline (l)-homoarginine-(d)-amphetamine dibenzoate.

2. Crystalline (l)-homoarginine-(d)-amphetamine dibenzoate exhibiting an X-ray powder diffraction pattern substantially as shown in Figure 2.

3. Crystalline (l)-homoarginine-(d)-amphetamine dibenzoate exhibiting an X-ray powder diffraction pattern having at least one peak in degrees 2Q ± 0.2 2Q selected from 6.11, 12.27, 14.06, 15.57, 16.53, 16.85, 18.07, 18.29, 20.05, 20.75, 21.57, 22.21, 22.75, 22.96, and 25.35.

4. The crystalline (l)-homoarginine-(d)-amphetamine dibenzoate of claim 3, wherein the crystalline (l)-homoarginine-(d)-amphetamine dibenzoate exhibits an X-ray powder diffraction pattern having at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, or at least 14 peaks in degrees 2Q ± 0.2 2Q selected from 6.11, 12.27, 14.06, 15.57, 16.53, 16.85, 18.07, 18.29, 20.05, 20.75, 21.57, 22.21, 22.75, 22.96, and 25.35.

5. The crystalline (l)-homoarginine-(d)-amphetamine dibenzoate of claim 4, wherein the crystalline (l)-homoarginine-(d)-amphetamine dibenzoate exhibits an X-ray powder diffraction pattern having peaks in degrees 2Q ± 0.2 2Q at 6.11, 12.27, 14.06, 15.57, 16.53, 16.85, 18.07, 18.29, 20.05, 20.75, 21.57, 22.21, 22.75, 22.96, and 25.35.

6. The crystalline (l)-homoarginine-(d)-amphetamine dibenzoate of claim 2, wherein the crystalline (l)-homoarginine-(d)-amphetamine dibenzoate exhibits an X-ray powder diffraction pattern having at least one peak in degrees 2Q ± 0.2 2Q selected from 6.11, 12.27, 14.06, 15.57, 16.53, 16.85, 18.07, 18.29, 20.05, 20.75, 21.57, 22.21, 22.75, 22.96, and 25.35.

7. The crystalline (l)-homoarginine-(d)-amphetamine dibenzoate of claim 2, wherein the crystalline (l)-homoarginine-(d)-amphetamine dibenzoate exhibits an X-ray powder diffraction pattern having at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, or at least 14 peaks in degrees 2Q ± 0.2 2Q selected from 6.11, 12.27, 14.06, 15.57, 16.53, 16.85, 18.07, 18.29, 20.05, 20.75, 21.57, 22.21, 22.75, 22.96, and 25.35.

8. Crystalline (l)-homoarginine-(d)-amphetamine dibenzoate having a melting point onset as determined by differential scanning calorimetry at about 155.3°C.

9. The (l)-homoarginine-(d)-amphetamine dibenzoate of claim 1 having a differential scanning calorimetry thermogram (DSC) substantially as shown in Figure 3.

10. The (l)-homoarginine-(d)-amphetamine dibenzoate of claim 1 having a

thermogravimetric analysis (TGA) substantially as shown in Figure 3.

11. The crystalline (l)-homoarginine-(d)-amphetamine dibenzoate of any of claims 1-10 which is substantially isolated.

12. A pharmaceutical composition comprising (l)-homoarginine-(d)-amphetamine dibenzoate of any one of claims 1-11 and optionally a pharmaceutically acceptable additive.

13. The pharmaceutical composition of claim 12, wherein the pharmaceutical composition comprises at least about 95% by weight of the crystalline (l)-homoarginine-(d)-amphetamine dibenzoate of any of claims 1-11, based upon 100% total weight of (l)-homoarginine-(d)- amphetamine dibenzoate in the pharmaceutical composition.

14. Crystalline (l)-homoarginine-(d)-amphetamine dinitrate.

15. Crystalline (l)-homoarginine-(d)-amphetamine dinitrate exhibiting an X-ray powder diffraction pattern substantially as shown in Figure 13.

16. Crystalline (l)-homoarginine-(d)-amphetamine dinitrate exhibiting an X-ray powder diffraction pattern having at least one peak in degrees 2Q ± 0.2 2Q selected from 8.39, 11.16,

11.37, 13.51, 14.68, 15.30, 15.47, 16.96, 19.89, 22.51, 23.66, 24.62, 25.38, 26.44, 26.91, and 30.74.

17. The crystalline (l)-homoarginine-(d)-amphetamine dinitrate of claim 16, wherein the crystalline (l)-homoarginine-(d)-amphetamine dinitrate exhibits an X-ray powder diffraction pattern having at least two, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, or at least 15 peaks in degrees 2Q ± 0.2 2Q selected from 8.39, 11.16, 11.37, 13.51, 14.68, 15.30, 15.47, 16.96, 19.89, 22.51, 23.66, 24.62, 25.38, 26.44, 26.91, and 30.74.

18. The crystalline (l)-homoarginine-(d)-amphetamine dinitrate of claim 17, wherein the crystalline (l)-homoarginine-(d)-amphetamine dinitrate exhibits an X-ray powder diffraction pattern having peaks in degrees 2Q ± 0.2 2Q at 8.39, 11.16, 11.37, 13.51, 14.68, 15.30, 15.47, 16.96, 19.89, 22.51, 23.66, 24.62, 25.38, 26.44, 26.91, and 30.74.

19. The crystalline (l)-homoarginine-(d)-amphetamine dinitrate of claim 15, wherein the crystalline (l)-homoarginine-(d)-amphetamine dinitrate exhibits an X-ray powder diffraction pattern having at least one peaks in degrees 2Q ± 0.2 2Q selected from 8.39, 11.16, 11.37, 13.51, 14.68, 15.30, 15.47, 16.96, 19.89, 22.51, 23.66, 24.62, 25.38, 26.44, 26.91, and 30.74.

20. The crystalline (l)-homoarginine-(d)-amphetamine dinitrate of claim 15, wherein the crystalline (l)-homoarginine-(d)-amphetamine dinitrate exhibits an X-ray powder diffraction pattern having at least two, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, or at least 15 peaks in degrees 2Q ± 0.2 2Q selected from 8.39, 11.16, 11.37, 13.51, 14.68, 15.30, 15.47, 16.96, 19.89, 22.51, 23.66, 24.62, 25.38, 26.44, 26.91, and 30.74

21. Crystalline (l)-homoarginine-(d)-amphetamine dinitrate having a melting point onset as determined by differential scanning calorimetry at about 11 l .5°C.

22. The (l)-homoarginine-(d)-amphetamine dinitrate of claim 14 having a differential scanning calorimetry thermogram (DSC) substantially as shown in Figure 15.

23. The (l)-homoarginine-(d)-amphetamine dinitrate of claim 14 having a thermogravimetric analysis (TGA) substantially as shown in Figure 15.

24. The crystalline (l)-homoarginine-(d)-amphetamine dinitrate of any of claims 14-22 which is substantially isolated.

25. A pharmaceutical composition comprising (l)-homoarginine-(d)-amphetamine dinitrate of any one of claims 14-24 and optionally a pharmaceutically acceptable additive.

26. The pharmaceutical composition of claim 25, wherein the pharmaceutical composition comprises at least about 95% by weight of the crystalline (l)-homoarginine-(d)-amphetamine dinitrate of any of claims 14-24, based upon 100% total weight of (l)-homoarginine-(d)- amphetamine dinitrate in the pharmaceutical composition.

27. A process for preparing the crystalline form of any one of claims 1-13.

28. A process for preparing the crystalline form of any one of claims l4-24s.

29. A method of treating attention deficit hyperactivity disorder in a patient in need thereof, comprising the step of orally administering the crystalline (l)-homoarginine-(d)-amphetamine dibenzoate of any one of claims 1-11 or the pharmaceutical composition of claim 12 or 13 to the patient.

30. A method of treating attention deficit hyperactivity disorder in a patient in need thereof, comprising the step of orally administering the crystalline (l)-homoarginine-(d)-amphetamine dinitrate of any one of claims 14-24 or the pharmaceutical composition of claim 25 or 26 to the patient.

31. 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 a salt of (1)- homoarginine-(d)-amphetamine of any one of claims 1-14 or 17-24 or the pharmaceutical composition of claim 12, 13, 25, or 26.

32. 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 a

pharmaceutical composition consisting essentially of a salt of (l)-homoarginine-(d)-amphetamine of any one of claims 1-14 or 17-24 or the pharmaceutical composition of claim 12, 13, 25, or 26.

33. The method of claim 31 or 32, wherein the salt of (l)-homoarginine-(d)-amphetamine is (l)-homoarginine-(d)-amphetamine dibenzoate.

34. The method of claim 31 or 32, wherein the salt of (l)-homoarginine-(d)-amphetamine is (l)-homoarginine-(d)-amphetamine dinitrate.

35. The method of any one of claims 29-34, wherein all of the patients are 6-12 years of age.

36. The method of any one of claims 29-34, wherein all of the patients are 13-17 years of age.

37. The method of claim 35, wherein daily dose of (l)-homoarginine-(d)-amphetamine dibenzoate ranges from about 20 to about 70 mg.

38. The method of claim 35, wherein daily dose of (l)-homoarginine-(d)-amphetamine dinitrate ranges from about 20 to about 70 mg.

39. The method of any one of claims 29-34, wherein all of the patients are adults.

40. The method of claim 39, wherein daily dose of (l)-homoarginine-(d)-amphetamine dibenzoate ranges from about 50 to about 250 mg.

41. The method of claim 40, wherein daily dose of (l)-homoarginine-(d)-amphetamine dibenzoate ranges from about 100 to about 250 mg.

42. The method of claim 41, wherein daily dose of (l)-homoarginine-(d)-amphetamine dibenzoate ranges from about 150 to about 250 mg.

43. The method of claim 39, wherein daily dose of (l)-homoarginine-(d)-amphetamine dinitrate ranges from about 50 to about 250 mg.

44. The method of claim 40, wherein daily dose of (l)-homoarginine-(d)-amphetamine dinitrate ranges from about 100 to about 250 mg.

45. The method of claim 41, wherein daily dose of (l)-homoarginine-(d)-amphetamine dinitrate ranges from about 150 to about 250 mg.

46. The method of any one of claims 29-45, wherein the amphetamine prodrug is administered in the form of a tablet or capsule.