USOO81 01661 B2

(12) United States Patent (10) Patent No.: US 8,101,661 B2 Mickle (45) Date of Patent: *Jan. 24, 2012

(54) POLAR HYDROPHILIC PRODRUGS AND W 388-39. 358. NON-STANDARDAMNO ACID CONUGATES OF AMPHETAMINE AND WO 2008/098151 8, 2008 OTHER STIMULANTS AND PROCESSES FOR OTHER PUBLICATIONS MAKING AND USING THE SAME European Patent Office, Communication dated Jun. 8, 2010, in EP Application No. 07869 098.9. (75) Inventor: Travis C. Mickle, Coralville, IA (US) Amy Sorter, Understanding ADHD Stimulant Abuse, Publication, Vitality Drug Free Work, 2002. (http://12.42.224.168/HealthyLiv (73) Assignee: KemPharm, Inc., North Libery, IA (US) ing family homeljan04 family homestimulantabuse.htm). International Preliminary Report on Patentability for PCT Interna (*) Notice: Subject to any disclaimer, the term of this tional Application No. PCT/US08/53363, dated Nov. 6, 2008. Davankova et al., “Synthesis and Pharmacological Properties of N patent is extended or adjusted under 35 Aminoacyl Derivatives of Beta Phenyl ISO Propylamine.” Pharma U.S.C. 154(b) by 0 days. ceutical Chemistry Journal, vol. 9, No. 3, 1975. G.C. Barrett, D.T. Elmore; Methods for Peptide Bonds Amino Acids This patent is Subject to a terminal dis and Peptides; 1st Edition, Cambridge University Press, UK, 1998, pp. claimer. 151-156. International Search Report and Written Opinion corresponding to (21) Appl. No.: 12/843,169 International Application Serial No. PCT/US08/53363, mailed Nov. 6, 2008, 19 pages. (22) Filed: Jul. 26, 2010 J. Jones; Amino Acid and Peptide Synthesis; 2nd Edition, Oxford University Press, UK, 2002, pp. 25-41. Musshoff, "Illegal or legitimate use? Precursor compounds to (65) Prior Publication Data amphetamine and methamphetamine.” Drug Metabolism Reviews US 2010/O2.92336A1 Nov. 18, 2010 2000 US, vol. 32, No. 1, pp. 15-44. Office Action in U.S. Appl. No. 11/953,668, dated Dec. 16, 2009. Office Action in U.S. Appl. No. 11/953,668, dated Jun. 5, 2009. Related U.S. Application Data Office Action in U.S. Appl. No. 11/953,668, dated Mar. 19, 2009. Office Action in U.S. Appl. No. 12/028, 152, dated Feb. 16, 2010. (63) Continuation of application No. 11/953,668, filed on Office Action in U.S. Appl. No. 12/028, 152, dated Feb. 23, 2010. Dec. 10, 2007, now Pat. No. 7,776,917, application Office Action in U.S. Appl. No. 12/028, 152, dated Mar, 20, 2009. No. 12/843,169, which is a continuation of application Office Action in U.S. Appl. No. 12/028, 152, dated Nov. 12, 2008. No. 12/028,152, filed on Feb. 8, 2008, now Pat. No. Office Action in U.S. Appl. No. 12/028, 152, dated Nov. 13, 2009. 7,772,222. The Drug Enforcement Administration Office of Diversion Control and Office of Congressional and Public Affairs Demand Reduction (60) Provisional application No. 60/888,870, filed on Feb. Section, Stimulant Abuse by School Age Children: A Guide for 8, 2007, provisional application No. 60/869,375, filed School Officials; Publication, Developed and Published by The Drug on Dec. 11, 2006. Enforcement Administration Office of Diversion Control and Office of Congressional and Public Affairs Demand Reduction Section; Jun. Int. C. 2001. (http://www.deadiversion.usdoj.gov/pubs/brochures/stimu (51) lant? stimulant abuse.htm). A6 IK3I/96 (2006.01) European Search Report for European Patent Application No. A6 IK3I/6 (2006.01) 07869098.9-2112, dated Dec. 10, 2009. A6IP 25/00 (2006.01) Notice of Allowance in U.S. Appl. No. 1 1/953,668, dated Apr. 7, (52) U.S. Cl...... 514/561; 514/613 2010. Notice of Allowance in U.S. Appl. No. 12/028, 152, dated Apr. 12, (58) Field of Classification Search ...... 514/561, 2010. 514f613 Berge et al., Pharmaceutical Salts, J. Pharm. Sci., 66(1):1-19 (1977). See application file for complete search history. Office Action in U.S. Appl. No. 12/473,903, dated Apr. 13, 2011. Office Action in U.S. Appl. No. 12/473.903, dated Aug. 4, 2010. (56) References Cited Office Action in U.S. Appl. No. 12/473,903, dated Sep. 15, 2010. Office Action in U.S. Appl. No. 12/477,616, dated Jun. 28, 2011. U.S. PATENT DOCUMENTS Structure-Activity Relationship and Drug Design, Remington's Pharmaceutical Sciences (Sixteenth Edition). Mack Publishing, 2,881,113 A 4, 1959 Millman 1980. pp. 420-425. 2,892,753. A 6, 1959 Schmidt 6,417, 184 B1 7, 2002 Ockert 6,475,494 B2 11/2002 Kaiko et al. Primary Examiner — Sreeni Padmanabhan 6,503.950 B1 1/2003 Ockert Assistant Examiner — Sahar Javanmard 6,525,062 B2 2/2003 Levine (74) Attorney, Agent, or Firm — McAndrews, Held & 6,696,066 B2 2, 2004 Kaiko et al. Malloy, Ltd. 7,105,486 B2 9, 2006 Mickle et al. 7,223,735 B2 5, 2007 Mickle et al. 7,772,222 B2 8, 2010 Mickle (57) ABSTRACT 7,776,917 B2 8, 2010 Mickle Disclosed are polar, hydrophilic stimulant prodrug composi 2005, OO38121 A1 2/2005 Mickle et al. 2005.0054561 A1 3/2005 Mickle et al. tions comprising at least one stimulant chemically attached to 2006/0177892 A1 8, 2006 De Frees a polar hydrophilic ligand, a salt thereof, a derivative thereof, or a combination thereof. Also disclosed are non-standard FOREIGN PATENT DOCUMENTS amino acid conjugates of amphetamine. Methods of making CN 1816346. A 8, 2006 and using the same are also disclosed. FR 1421130 3, 1966 WO O3,O72046 9, 2003 16 Claims, 5 Drawing Sheets U.S. Patent Jan. 24, 2012 Sheet 1 of 5 US 8,101,661 B2

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Figure 2 U.S. Patent Jan. 24, 2012 Sheet 2 of 5 US 8,101,661 B2

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U.S. Patent Jan. 24, 2012 Sheet 3 of 5 US 8,101,661 B2

Lys-Amp vs. harg-Amp

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U.S. Patent Jan. 24, 2012 Sheet 5 of 5 US 8,101,661 B2

intravenous d-Amp, Lys-Amp and harg-Amp

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Figure 9 US 8,101,661 B2 1. 2 POLAR HYDROPHILIC PRODRUGS AND Initial drug therapy for ADHD was limited to fast acting NON-STANDARDAMNOACD immediate release formulations of stimulants (e.g., CONUGATES OF AMPHETAMINE AND Dexedrine(R), pure dextroamphetamine Sulfate, commercially OTHER STIMULANTS AND PROCESSES FOR available from SmithKline and French located in the United MAKING AND USING THE SAME Kingdom) which triggered an array of potentially undesirable side effects including, for example, fast wear-off of the thera RELATED APPLICATIONS peutic effect of the stimulant active ingredient causing rebound symptoms, cardiovascular stress/disorders (e.g., This application is a continuation of U.S. patent applica increased heart rate, hypertension, cardiomyopathy), other 10 side effects (e.g., insomnia, euphoria, psychotic episodes), tion Ser. No. 11/953,668, filed on Dec. 10, 2007 now U.S. Pat. addiction and abuse. No. 7,776,917, which claims priority to and benefit of U.S. Behavioral deterioration (rebound/"crashing) is observed provisional patent application No. 60/869,375, filed on Dec. in a significant portion of children with ADHD as the medi 11, 2006; and a continuation of U.S. patent application Ser. cation wears off, typically in the afternoon or early evening. No. 12/028, 152, filed on Feb. 8, 2008 now U.S. Pat. No. 15 Rebound symptoms include, for example, irritability, cranki 7,772,222, which claims priority to and benefit of U.S. pro ness, hyperactivity worse than in the unmedicated State, sad visional patent application No. 60/888,870, filed on Feb. 8, ness, crying and in rare cases psychotic episodes. The Symp 2007. toms may subside quickly or last several hours. Some patients may experience rebound/crashing so severe that treatment BACKGROUND OF THE INVENTION must be discontinued. Rebound/crashing effects can also give rise to addictive behavior by enticing patients to administer The present technology describes, in general, novel pro additional doses of stimulant with the intent to prevent antici drugs/compositions of the stimulant amphetamine (i.e., pated rebound/crashing negative outcomes and side effects. 1-phenylpropan-2-amine). The present technology also Stimulants, such as methylphenidate and amphetamine, describes polar hydrophilic conjugates of amphetamine, Salts 25 have shown to exhibit noradrenergic and dopaminergic thereof, other derivatives thereof, and combinations thereof, effects that can lead to cardiovascular events comprising, for as well as non-standard amino acid conjugates of amphet example, increased heart rate, hypertension, palpitations, amine, salts thereof, other derivatives thereof, and combina tachycardia and in isolated cases cardiomyopathy, stroke, tions thereof. Additionally, the presently described technol myocardial infarction and Sudden death. Consequently, cur ogy also relates generally to the methods of making and using 30 rently available stimulants expose patients with pre-existing these new prodrugs/compositions. structural cardiac abnormalities or other severe cardiac indi The presently described technology in at least one aspect is cations to even greater health risks and are frequently not used focused on a slow/Sustained controlled release composition or used with caution in this population. It is notable, however of amphetamine, in prodrug form, that allows slow/Sustained/ that the cardiovascular effects of stimulants, for example on controlled delivery of the stimulant into the blood system of a 35 heart rate and blood pressure, is dependent on the adminis human or animal within a safe therapeutic window upon oral tered dose. As a result, a treatment which maintains the lowest administration. At least Some compositions/formulation of effective stimulant blood concentrations for a therapeutically the current technology can lessen the rebound effect, cardio beneficial duration is believed to demonstrate fewer cardio vascular stress, addiction/abuse potential and/or other com vascular risks/side effects. mon stimulant side effects associated with amphetamine and 40 Amphetamine and many of its derivatives (e.g., metham similar compounds. Such compositions may also increase the phetamine, 3.4-methylenedioxy-methamphetamine?"Ec duration of therapeutic efficacy, ease of application, patient stasy) are widely abused for various purposes Such as eupho compliance and/or any combination of these characteristics ria, extended periods of alertness/wakefulness, or rapid when administered, in particular, orally. weight loss or by actual ADHD patients who developed Stimulants, including amphetamine and its derivatives, 45 excessive self-dosing habits to prevent rebound symptoms enhance the activity of the sympathetic nervous system and/ from manifesting, for example, in anxiety or depression. The or central nervous system (CNS) and are prescribed for the effects desired by potential abusers originated from the stimu treatment of a range of conditions and disorders predomi lation of the central nervous system and prompted a Schedule nantly encompassing, for example, attention deficit hyperac II or even Schedule I classification for amphetamine (d-and tivity disorder (ADHD), attention deficit disorder (ADD), 50 1-amphetamine individually and any combination of both are obesity, narcolepsy, appetite Suppression, depression, anxiety Schedule II) and certain derivatives thereof after passage of and wakefulness. the Controlled Substance Act (CSA) in 1970. Both classifi Attention deficit hyperactivity disorder (ADHD) in chil cations are defined by the high propensity for abuse. Schedule dren has been treated with stimulants for many years. How II drugs have an accepted medical use while Schedule I sub ever, more recently, the increase in the number of prescrip 55 stances do not pursuant to the CSA. So far, all amphetamine tions for ADHD therapy in an adult population has, at times, products, including compositions with Sustained release for outperformed the growth of the pediatric market. Although mulations and prodrugs thereof, are obligated to include a there are various drugs currently in use for the treatment of blackbox warning on the drug label to inform patients about ADHD, such as methylphenidate (commercially available the potential for amphetamine abuse and dependence. from, for example, Novartis International AG (located in 60 It has been observed in the conventional art that most side Basel, Switzerland) under the trademark Ritalin R) and non effects of amphetamines are caused by a large initial spike in stimulant atomoxetine (commercially from Eli Lilly and blood concentration of the stimulant which quickly erodes to Company (located in Indianapolis, Ind.) as StratteraR), levels below therapeutic effectiveness (typically within 4-6 amphetamine has been the forerunner in ADHD therapy. hours). As a consequence, the high potency of dextroamphet Moreover during classroom trials, non-stimulants have 65 amine (d-amphetamine) was Subsequently modulated by a shown to be less effective in improving behavior and attention series of new drugs with increasingly sustained release pro of ADHD afflicted children than amphetamine derivatives. files achieved by delivering amphetamine more slowly into US 8,101,661 B2 3 4 the blood stream with the goal to create safer and less abus describes that using any amino acid other than 1-lysine (Table able treatment outcomes and regimens. The methods and 46) will not give rise to the same in vivo properties demon technologies for generating Smaller spikes in drug blood con strated by 1-lysine-d-amphetamine (Lys-Amp, VyvanseTM). centrations include, for example, use of mixed salts and iso Additionally, since lysine is a natural and standard amino mer compositions (i.e., different salts of d- and less potent acid, the breakdown of the new prodrug occurs faster than 1-amphetamine), extended/controlled/sustained release for desired to reduce the side effect profile. Thus, quick release of mulations (e.g., Adderall XRR) commercially available from amphetamine from Such standard amino acid conjugate com Shire U.S., Inc. located in Wayne, Pa.) and, most recently, positions may cause an increase in blood pressure and heart prodrugs of amphetamine (VyvanseTM also commercially rate found in other conventional stimulant treatments. As a available from Shire). The ideal drug treatment option should 10 produce stimulant blood concentrations within a narrow result, there still exists a need within the art for a safer dosage therapeutic window for an extended time duration followed form of amphetamine, and treatment regimen that is thera by a prolonged fade-out period in order to minimize cardio peutically effective and can provide Sustained release and vascular stress and behavioral deterioration, and would also sustained therapeutic effect. exhibit anti-abuse properties. 15 Besides immediate release formulations, newer Sustained BRIEF SUMMARY OF THE INVENTION release formulations have been developed with the objective to provide a therapeutic treatment option that offers the con The presently described technology provides, in part, com Venience of a single daily dosing regimen versus multiple positions comprising at least one amphetamine conjugated quotidian administrations. Such formulations also have the with a non-standard amino acid, or a salt thereof, which can objective of imparting or rendering a euphoric response. Sus diminish or eliminate pharmacological activity of the tained release formulations commonly consist of drug par amphetamine until released in vivo. The non-standard amino ticles coated with a polymer or polymer blend that delays and acid conjugate(s) of the present technology is amphetamine extends the absorption of the active drug substance by the in a prodrug form, and can be converted into its active form in gastrointestinal tract for a relatively defined period of time. 25 the body by normal metabolic processes. Although not want Such formulations frequently embed the therapeutic agent/ ing to be bound by any particular theory, one or more non active ingredient/drug within a hydrophilic hydrocolloid gel standard amino acid conjugates of the present technology are ling polymer matrix (e.g., hydroxypropyl methylcellulose, believed to be safer than other sustained release forms of hydroxypropyl cellulose or pullulan). This dosage formula amphetamine by providing controlled blood levels for a pro tion in turn becomes a gel upon entering an acidic medium, as 30 longed period of time, thus preventing the rebound effect, found in the stomach of humans and animals, thereupon cardiovascular stress and euphoria associated with conven slowly effusing the therapeutic agent/active ingredient/drug. tional stimulant treatment options. However, the dosage formulation dissolves in an alkaline The presently described technology further provides meth medium, as found in the intestines of humans and animals, ods of controlled therapeutic delivery of amphetamine com concurrently liberating the drug more quickly in an uncon 35 positions by oral administration. Release of amphetamine trolled manner. Some formulations, such as acrylic resins, following oral administration of the non-standard amino acid acrylic latex dispersions, cellulose acetate phthalate, and conjugates of the present technology can occur gradually over hydroxypropyl methylcellulose phthalate, offer improved an extended period of time thereby eliminating unintended Sustained release in the intestines by being resistant to acidic elevations (e.g., blood level concentration spikes) of drug environments and dispensing the active ingredient only at 40 levels in the bloodstream of a human or animal patient. Again elevated pH via a diffusion-erosion mechanism, either by not wanting to be bound by any particular theory, it is also themselves or mixed with hydrophilic polymers. believed that such spikes in blood levels can lead to a euphoric Sustained release formulations have been moderately drug “high” and cardiovascular effects like increased blood effective in providing an improved and extended dosage form pressure and heart rate. Additionally, sustained blood levels over immediate release tablets. Nonetheless, such formula 45 are achieved within an effective therapeutic range for a longer tions are potentially Subject to inconsistent, erratic or prema duration than other conventional therapies, thereby prevent ture release of the therapeutic agent due to failure of the ing a rebound effect. polymer material, and they also usually allow easy extraction At least Some compositions comprising the amphetamine of the active ingredient utilizing a simple physical procedure. prodrugs of the present technology are resistant to abuse by Since single daily dose formulations contain a greater amount 50 parenteral routes of administration, Such as intravenous of amphetamine than immediate release formulations, they 'shooting intranasal "snorting.” or inhalation "Smoking.” are more attractive to potential abusers, consequently making that are often employed during illicit use. The present tech the extractability of drug substance an additional undesirable nology thus provides a stimulant based treatment modality property. It is also, at least in part, a reason for increased drug and dosage form for certain disorders requiring the stimula diversion, especially evident by selling or trading of medica 55 tion of the CNS such as ADHD, ADD, obesity, narcolepsy, tion by school children who are ADHD patients and in pos appetite Suppressant, depression, anxiety, and wakefulness session of Sustained release amphetamine capsules. The with reduced or prevented abuse potential. Although not obtained stimulants are then abused by classmates without wanting to be bound by any particular theory, it is believed the disorder by either ingesting high doses or Snorting the that the treatment of such CNS conditions as noted above with drug material after crushing it. 60 compositions of the present technology results in Substan U.S. Pat. No. 7,105,486 (to assignee New River Pharma tially decreased abuse liability as compared to existing stimu ceuticals, hereinafter the "486 patent) appears to describe lant treatment modalities and dosage forms. compounds comprising a chemical moiety (namely l-lysine) At least Some compositions comprising the amphetamine covalently attached to amphetamine, compositions thereof, prodrugs of the present technology can also be used for treat and methods of using the same. Allegedly, these compounds 65 ing stimulant (cocaine, methamphetamine) abuse and addic and their compositions are useful for reducing or preventing tion, for improving battle field alertness, and/or for combat abuse and overdose of amphetamine. The 486 patent also ing fatigue. US 8,101,661 B2 5 6 In a first aspect, the presently described technology pro disorder or condition requiring the stimulation of the patients vides a composition comprising at least one non-standard CNS, comprising orally administering to the patient in need a amino acid conjugate of amphetamine, a salt thereof, a composition formulated for oral dosage comprising at least derivative thereof, or a combination thereof. Preferably, the one non-standard amino acid conjugate of amphetamine, non-standard amino acid is covalently attached to amphet wherein the blood levels of amphetamine in the patients amine through the C-terminus of the non-standard amino body can maintain a therapeutically effect level, but do not acid. The N-terminus or the side chain amino group of the result in an euphoric effect (such as that observed with abuse non-standard amino acid may be in a free and unprotected of amphetamines). state, or in the form of a salt thereof. The non-standard amino In a further aspect, the presently described technology acid moiety can be derived from a non-standard amino acid 10 provides a method for delivering amphetamine, comprising that is either a dextro- (d-) or levo- (1-) form amino acid, providing a human or animal patient with a therapeutically racemic amino acid, or a mixture thereof. effective amount of at least one non-standard amino acid In accordance with some embodiments, non-standard conjugate of amphetamine, which can provide a therapeuti amino acids are used. Examples of preferred non-standard cally bioequivalent area under the curve (AUC) when com amino acids to be conjugated with the amphetamine include, 15 pared to free amphetamine, but does not provide a maximum but are not limited to, homoarginine, selenomethionine, cit plasma concentration (C) which results in an increased rulline, and homocitrulline. Homoarginine is most preferred heart rate, increased blood pressure or drug related euphoria for at least some embodiments of the present technology. when taken orally. The compositions of the present technology preferably In another aspect, the presently described technology pro have no or a Substantially decreased pharmacological activity vides a composition for treating a human or animal patient when administered through injection or intranasal routes of having attention deficit disorder or attention deficit hyperac administration. However, they remain orally bioavailable. tivity disorder, comprising amphetamine chemically attached The bioavailability can be a result of the hydrolysis of the to a polar hydrophilic ligand, a salt thereof, or a combination covalent linkage following oral administration. Hydrolysis is thereof. time-dependent, thereby allowing amphetamine and other 25 In an additional aspect, the presently described technology metabolites Such as p-hydroxyamphetamine and p-hydrox provides a composition for treating a human or animal patient yephedrine to become available in its active form over an having attention deficit disorder or attention deficit hyperac extended period of time. In at least one further embodiment, tivity disorder, comprising amphetamine chemically attached release of amphetamine is diminished or eliminated when the to a polar hydrophilic ligand, a salt thereof, or a combination composition of the present technology is delivered by 30 thereof, wherein the polar hydrophilic ligand is homoargin parenteral routes. ine. For example, in one embodiment, the composition of the In a further aspect, the presently described technology present technology maintains its effectiveness and abuse provides a composition for treating a human or animal patient resistance following the crushing of the tablet, capsule or having attention deficit disorder or attention deficit hyperac other oral dosage form utilized to deliver the therapeutic 35 tivity disorder, comprising amphetamine chemically attached component (i.e., active ingredient/drug) due to the inherent to a polar hydrophilic ligand, a salt thereof, or a combination controlled release components being a property of the com thereof, wherein the polar hydrophilic ligand is 1-homoargi position not formulation. In contrast, conventional extended nine. release formulations used to control the release of amphet In another aspect, the presently described technology pro amine are Subject to release of up to the entire amphetamine 40 vides a composition for treating a human or animal patient content immediately following crushing. When the content of having attention deficit disorder or attention deficit hyperac the crushed tablet is injected or snorted, the large dose of tivity disorder, comprising amphetamine chemically attached amphetamine produces the “rush’ effect sought by addicts. to a polar hydrophilic ligand, a salt thereof, or a combination In another aspect, the presently described technology pro thereof, wherein the amphetamine is d-amphetamine. vides a method for treating a human or animal patient with a 45 In an additional aspect, the presently described technology disorder or condition requiring the stimulation of the patients provides a composition for treating a human or animal patient CNS (Central Nervous System), comprising the step of orally having attention deficit disorder or attention deficit hyperac administering to the patient in need a composition formulated tivity disorder, comprising amphetamine chemically attached for oral dosage comprising at least one non-standard amino to a polar hydrophilic ligand, a salt thereof, or a combination acid conjugate of amphetamine of the present technology, 50 thereof, wherein the salt thereof is an acefyllinate, 4-aceta wherein the blood levels of amphetamine in the patients midobenzoate, acetate, aceturate, adipate, aminosalicylate, body can maintain a therapeutically effect level throughout a ammonium, ascorbate, 1-aspartate, benzoate, besylate, bicar given day, and do not lead to behavioral deterioration or the bonate, borate, butyrate, calcium, camphocarbonate, cam rebound effect. phorate, d-camsylate, 1-camsylate, camsylate, carbonate, In another aspect, the presently described technology pro 55 cholate, citrate, cypionate, decanoate, dichloroacetate, eden vides a method for treating a human or animal patient with a tate, edisylate, estolate, esylate, ethyl Sulfate, fumarate, disorder or condition requiring the stimulation of the patients furate, fusidate, galactarate (mucate), galacturonate, gallate, CNS (Central Nervous System), comprising the step of orally gentisate, gluceptate, gluconate, glucuronate, glutamate, glu administering to the patient in need a composition formulated tarate, glycerophosphate, glycolate, heptanoate (enanthate), for oral dosage comprising at least one non-standard amino 60 hexanoate, hippurate, hybenzate, hydrobromide/bromide, acid conjugate of amphetamine of the present technology, hydrochloride/chloride, hydroxide, hydroxybenzoate, wherein the blood levels of amphetamine in the patients iodide, isethionate, d-lactate, 1-lactate, d.l-lactate, lactobion body are not unnecessarily elevated (i.e., blood level spikes) ate, laurate, lithium, magnesium, malate, d.l-malate, maleate, thus preventing additional cardiovascular stress through, for malonate, mandelate, meso-tartrate, meSylate, methane example, increased blood pressure and/or heart rate. 65 Sulfonate, methylsulfate, myristate, napadisilate, 2-napsy In another aspect, the presently described technology pro late, nicotinate, nitrate, octanoate, oleate, orotate, oxalate, vides a method for treating a human or animal patient with a palmitate, pamoate, phenylpropionate, phosphate, picrate, US 8,101,661 B2 7 8 pivalate, potassium, propionate, pyrophosphate, Salicylate, etate, edentate, edisylate, estolate, esylate, ethyl sulfate, salicylsulfate, Sodium, Stearate. Succinate, Sulfate, Sulfosali fumarate, furate, fusidate, galactarate (mucate), galactur cylate, tannate, d-tartrate, 1-tartrate, d.l-tartrate, terephthalate, onate, gallate, gentisate, gluceptate, gluconate, glucuronate, thiocyanate, thiosalicylate, tosylate, tribrophenate, triflate, glutamate, glutarate, glycerophosphate, glycolate, hep undecylenate, Valerate, Valproate, Xinafoate, Zinc, and mix tanoate (enanthate), hexanoate, hippurate, hybenzate, hydro tures thereof. bromide/bromide, hydrochloride/chloride, hydroxide, In a further aspect, the presently described technology hydroxybenzoate, iodide, isethionate, d-lactate, l-lactate, d.l- provides a composition for treating a human or animal patient lactate, lactobionate, laurate, lithium, magnesium, malate, having attention deficit disorder or attention deficit hyperac d.l-malate, maleate, malonate, mandelate, meso-tartrate, tivity disorder, comprising amphetamine chemically attached 10 to a polar hydrophilic ligand, a salt thereof, or a combination mesylate, methanesulfonate, methylsulfate, myristate, napa thereof, wherein the salt thereof is a mesylate, a hydrochlo disilate, 2-napsylate, nicotinate, nitrate, octanoate, oleate, ride salt, a Sulfate, an oxalate, a triflate, a citrate, a malate, a orotate, oxalate, palmitate, pamoate, phenylpropionate, phos tartrate, a phosphate, a nitrate, a benzoate, or a mixture phate, picrate, pivalate, potassium, propionate, pyrophos thereof. 15 phate, Salicylate, Salicylsulfate, sodium, Stearate. Succinate, Another aspect of the present technology provides a com Sulfate, Sulfosalicylate, tannate, d-tartrate, kartrate, d.l-tar position for treating a human or animal patient having atten trate, terephthalate, thiocyanate, thiosalicylate, tosylate, tri tion deficit disorder or attention deficit hyperactivity disorder, brophenate, triflate, undecylenate, Valerate, valproate, Xin comprising a derivative of amphetamine chemically attached afoate, Zinc, and mixtures thereof. to a polar hydrophilic ligand, a salt thereof, or a combination In an additional aspect, the present technology provides a thereof. composition for treating a human or animal patient having In an additional aspect, the present technology provides a attention deficit disorder or attention deficit hyperactivity composition for treating a human or animal patient having disorder, comprising a derivative of amphetamine chemically attention deficit disorder or attention deficit hyperactivity attached to a polar hydrophilic ligand, a salt thereof, or a disorder, comprising a derivative of amphetamine chemically 25 combination thereof wherein the salt thereof is mesylate, a attached to a polar hydrophilic ligand, a salt thereof, or a hydrochloride salt, a Sulfate, an oxalate, a triflate, a citrate, a combination thereof wherein the polar hydrophilic ligand is malate, a tartrate, a phosphate, a nitrate, a benzoate, or a homoarginine. mixture thereof. In a further aspect, the present technology provides a com Another aspect of the present technology provides a com position for treating a human or animal patient having atten 30 position for treating a human or animal patient having atten tion deficit disorder or attention deficit hyperactivity disorder, tion deficit disorder or attention deficit hyperactivity disorder, comprising a derivative of amphetamine chemically attached comprising at least one conjugate, a salt of the conjugate, or a to a polar hydrophilic ligand, a salt thereof, or a combination combination thereof, wherein the conjugate comprises thereof wherein the polar hydrophilic ligand is 1-homoargin amphetamine or a derivative thereof and homoarginine. ine. 35 In a further aspect, the present technology provides a com In another aspect, the present technology provides a com position for treating a human or animal patient having atten position for treating a human or animal patient having atten tion deficit disorder or attention deficit hyperactivity disorder, tion deficit disorder or attention deficit hyperactivity disorder, comprising at least one conjugate, a salt of the conjugate, or a comprising a derivative of amphetamine chemically attached combination thereof, wherein the composition has a reduced to a polar hydrophilic ligand, a salt thereof, or a combination 40 pharmacological activity when administered by parenteral thereof wherein the derivative of amphetamine is 1-amphet rOuteS. amine, methamphetamine, p-methoxyamphetamine, 3.4-me In an additional aspect, the present technology provides a thylenedioxyamphetamine, 2.3-methylenedioxyamphet composition for treating a human or animal patient having amine, 3.4-methylenedioxymethamphetamine, 2.5- attention deficit disorder or attention deficit hyperactivity dimethoxy-4-methylamphetamine, 3,4,5- 45 disorder, comprising at least one conjugate, a salt of the trimethoxyamphetamine, 2,4,5-trimethoxyamphetamine, conjugate, or a combination thereof, wherein the composition 2,3,4-trimethoxyamphetamine, 2,3,5-trimethoxyamphet is in the form of a tablet, a capsule, a caplet, a troche, a amine, 2.3.6-trimethoxyamphetamine, or 2,4,6-tri lozenge, an oral powder, a solution, a oral film, a thin strip, or methoxyamphetamine. a Suspension. In a further aspect, the present technology provides a com 50 In a further aspect, the present technology provides a com position for treating a human or animal patient having atten position for treating a human or animal patient having atten tion deficit disorder or attention deficit hyperactivity disorder, tion deficit disorder or attention deficit hyperactivity disorder, comprising a derivative of amphetamine chemically attached comprising at least one conjugate, a salt of the conjugate, or a to a polar hydrophilic ligand, a salt thereof, or a combination combination thereof, wherein the composition is in the form thereof wherein the derivative of amphetamine is 1-amphet 55 or a chewable tablet, chewable troche, or chewable lozenge. amine. In another aspect, the present technology provides a com In an additional aspect, the present technology provides a position for treating a human or animal patient having atten composition for treating a human or animal patient having tion deficit disorder or attention deficit hyperactivity disorder, attention deficit disorder or attention deficit hyperactivity comprising at least one conjugate, a salt of the conjugate, or a disorder, comprising a derivative of amphetamine chemically 60 combination thereof, wherein the conjugate, the salt of the attached to a polar hydrophilic ligand, a salt thereof, or a conjugate, or the combination thereof is present in the amount combination thereof wherein the salt thereof is an acefylli of from about 1 mg to about 500 mg. nate, 4-acetamidobenzoate, acetate, aceturate, adipate, ami In an additional aspect, the present technology provides a nosalicylate, ammonium, ascorbate, l-aspartate, benzoate, composition for treating a human or animal patient having besylate, bicarbonate, borate, butyrate, calcium, camphocar 65 attention deficit disorder or attention deficit hyperactivity bonate, camphorate, d-camsylate, 1-camsylate, camsylate, disorder, comprising at least one conjugate, a salt of the carbonate, cholate, citrate, cypionate, decanoate, dichloroac conjugate, or a combination thereof, wherein the conjugate, US 8,101,661 B2 10 the salt of the conjugate, or the combination thereof is present DETAILED DESCRIPTION OF THE INVENTION in the amount of from about 5 mg to about 250 mg. In another aspect, the present technology provides a com The presently described technology relates to novel pro position for treating a human or animal patient having atten drugs/compositions of stimulants, including stimulants tion deficit disorder or attention deficit hyperactivity disorder, chemically attached to polar hydrophilic ligands, salts comprising at least one conjugate, a salt of the conjugate, or a thereof, derivatives thereof, or combinations thereof. More combination thereof, wherein the conjugate, the salt of the specifically, the presently described technology is related, in conjugate, or the combination thereof is present in the amount Some embodiments, to compositions comprising non-stan of from about 10 mg to about 100 mg. dard amino acid conjugates of amphetamine, salts thereof, In a further aspect, the present technology provides a com 10 derivatives thereof, or combinations thereof. Methods of position for treating a human or animal patient having atten making and using the prodrugs/compositions of the present tion deficit disorder or attention deficit hyperactivity disorder, technology are also disclosed. comprising at least one conjugate, a salt of the conjugate, or a Polar hydrophilic ligands suitable for the presently combination thereof, wherein the conjugate, the salt of the described technology can take a number of forms. These conjugate, or the combination thereof is in an amount Suffi 15 forms can be divided into several categories including non cient to provide a therapeutically bioequivalent AUC when standard amino acids, amino acid derivatives, amino acid compared to amphetamine alone, but does not provide a C, precursors, amino alcohols, synthetic amino acid derivatives, spike. natural Substrates, and other hydrophilic groups or ligands. In another aspect, the present technology provides a com They can be in d-, 1- or racemic form, or a mixture thereof position for treating a human or animal patient having atten along with a number of other possible enantiomeric? diaste tion deficit disorder or attention deficit hyperactivity disorder, reomeric forms depending on the ligands. For example, the comprising at least one conjugate, a salt of the conjugate, or a non-standard amino acid used to produce the stimulant pro combination thereof, wherein the conjugate, the salt of the drug of the present technology can be either d- or 1-form conjugate, or the combination thereof is in an amount Suffi amino acid, racemic amino acid, or a mixture thereof. cient to provide a therapeutically bioequivalent AUC when 25 As used herein, a “non-standard amino acid refers to an compared to amphetamine alone, but does not provide an amino acid that is not one of the “standard' twenty amino equivalent C. acids. Non-standard amino acids may be derived from either Another aspect of the present technology provides a natural or synthetic sources. Non-standard amino acids are method of treating a human oranimal patient having attention non-essential and are not readily incorporated into proteins of deficit disorder or attention deficit hyperactivity disorder, 30 natural origin. With the exception of selenocysteine and pyr comprising the step of orally administering to the patient a rolysine, there are no known human genetic codons that are pharmaceutically effective amount of a composition compris translated into non-standard amino acids. Non-standard ing amphetamine chemically attached to a polar hydrophilic amino acids may be metabolites of other amino acids or ligand, a salt thereof, or a combination thereof. precursors in various metabolic pathways. Other objects, advantages and embodiments of the inven 35 As used herein, an “amino acid derivative' is a chemically tion are described below and will be obvious from this modified version of a naturally occurring amino acid (stan description and practice of the invention. dard or non-standard). As used herein, an "amino acid pre cursor refers to a molecule that can either chemically or BRIEF DESCRIPTION OF SEVERAL VIEWS OF metabolically breakdown into a naturally occurring amino THE DRAWINGS 40 acid (standard or non-standard). As used herein, a “synthetic amino acid is an amino acid that is not naturally occurring. FIG. 1 compares mean plasma concentrations released As used herein, an "amino alcohol refers to a derivative of an from rats orally administered 1-homoarginine-d-amphet amino acid (standard or non-standard, natural or synthetic) amine or 1-lysine-d-amphetamine. wherein the carboxylic acid group has been reduced to an FIG. 2 compares the relative blood levels of d-amphet 45 alcohol. amine released from 1-homoarginine-d-amphetamine and As used herein, “amphetamine' shall mean any of the 1-lysine-d-amphetamine. sympathomimetic phenethylamine derivatives which have FIGS. 3 and 4 illustrate the difference in blood levels central nervous system stimulant activity, Such as but not obtained from the study results shown in FIG. 2. limited to, amphetamine (C.-methyl-phenethylamine), levo FIG. 5 compares average plasma concentrations from four 50 amphetamine, methamphetamine, p-methoxyamphetamine (4) oral Studies of rats administered 1-homoarginine-d-am (PMA), methylenedioxyamphetamine, 3.4-methylene phetamine or 1-lysine-d-amphetamine. dioxyamphetamine (MDA), 2.3-methylenedioxyamphet FIG. 6 compares mean plasma concentrations released amine, 2,5-dimethoxy-4-methylamphetamine (DOM), 3,4- from rats orally administered 1-citrulline-d-amphetamine or methylenedioxy-methamphetamine (MDMA), 3,4,5- 1-lysine-d-amphetamine. 55 trimethoxyamphetamine (TMA), 2,4,5- FIG. 7 compares the mean plasma concentrations of d-am trimethoxyamphetamine (TMA-2), 2,3,4- phetamine released from rats orally administered 1-homoc trimethoxyamphetamine (TMA-3), 2,3,5- itrulline-d-amphetamine, 1-homoarginine(NO)-d-amphet trimethoxyamphetamine (TMA-4), 2,3,6- amine or 1-lysine-d-amphetamine. trimethoxyamphetamine (TMA-5), 2.4.6- FIG. 8 compares the mean plasma concentrations of d-am 60 trimethoxyamphetamine (TMA-6), and methylphenidate. phetamine released from rats intranasally administered d-am Please note that although the present technology some phetamine, 1-homoarginine-d-amphetamine or 1-lysine-d- times may be described with a reference to amphetamine amphetamine. only, amphetamine is merely used as an example. It should be FIG. 9 compares the mean plasma concentrations of d-am understood that any method or composition of the presently phetamine released from rats intravenously administered 65 described technology is not limited to amphetamine. d-amphetamine, 1-homoargine-d-amphetamine or 1-lysine-d- As used herein, “in a manner inconsistent with the manu amphetamine. facturers instructions' or similar expression is meant to US 8,101,661 B2 11 12 include, but is not limited to, consuming amounts greater than linate, 4-acetamidobenzoate, acetate, aceturate, adipate, ami amounts described on the label or ordered by a licensed nosalicylate, ammonium, ascorbate, 1-aspartate, benzoate, physician, and/or altering by any means (e.g., crushing, besylate, bicarbonate, borate, butyrate, calcium, camphocar breaking, melting, separating etc.) the dosage formulation bonate, camphorate, d-camsylate, 1-camsylate, camsylate, Such that the composition may be injected, inhaled or carbonate, cholate, citrate, cypionate, decanoate, dichloroac Smoked. etate, edentate, edisylate, estolate, esylate, ethyl sulfate, As used herein, the phrases such as "decreased.” fumarate, furate, fusidate, galactarate (mucate), galactur “reduced,” “diminished' or “lowered' is meant to include at onate, gallate, gentisate, gluceptate, gluconate, glucuronate, least a 10% change in pharmacological activity with greater glutamate, glutarate, glycerophosphate, glycolate, hep percentage changes being preferred for reduction in abuse 10 potential and overdose potential. For instance, the change tanoate (enanthate), hexanoate, hippurate, hybenzate, hydro may also be greater than 25%, 35%, 45%, 55%, 65%, 75%, bromide/bromide, hydrochloride/chloride, hydroxide, 85%, 95%, 96%, 97%, 98%, 99%, or increments therein. hydroxybenzoate, iodide, isethionate, d-lactate, l-lactate, d.l- Some abbreviations that may be used in the present appli lactate, lactobionate, laurate, lithium, magnesium, malate, cation include: DCC-dicyclohexylcarbodiimide, NHS-N- 15 d.l-malate, maleate, malonate, mandelate, meso-tartrate, hydroxySuccinimide, EtOAc-ethyl acetate, mesylate, methanesulfonate, methylsulfate, myristate, napa MsOH-methanesulfonic acid, EDCI=1-ethyl-3-(3-dimethy disilate, 2-napsylate, nicotinate, nitrate, octanoate, oleate, laminopropyl)carbodiimide, PyBrOP-bromo-tris-pyrroli orotate, oxalate, palmitate, pamoate, phenylpropionate, phos dino phosphoniumhexafluorophosphate, NMM-N-methyl phate, picrate, pivalate, potassium, propionate, pyrophos morpholine or 4-methylmorpholine, TEA=triethylamine, phate, Salicylate, Salicylsulfate, sodium, Stearate. Succinate, CDI-carbonyl diimidazole, IPAc-isopropyl acetate, Sulfate, Sulfosalicylate, tannate, d-tartrate, 1-tartrate, d.l-tar DEA diethylamine, BOP=(benzotriazol-1-yloxy)tris(dim trate, terephthalate, thiocyanate, thiosalicylate, tosylate, tri ethylamino)phosphonium hexafluorophosphate. brophenate, triflate, undecylenate, Valerate, valproate, Xin In accordance with some embodiments, the present tech afoate, Zinc, and mixtures thereof. nology provides stimulants such as amphetamine in a prodrug 25 form. More specifically, the stimulant prodrug comprises at Examples of amphetamine derivatives of the present technol least one stimulant chemically attached to a polar hydrophilic ogy to which non-standard amino acids, including but not ligand, a salt thereof, a derivative thereof, or a combination limited to homoarginine, can be chemically conjugated to are thereof. shown below in Tables 1 and 2. In accordance with other embodiments, the amphetamine 30 prodrug of the present technology comprises at least one TABLE 1 non-standard amino acid covalently bonded or attached to amphetamine, which includes different forms or modified Amphetamine Derivatives forms of sympathomimetic phenethylamine derivatives. The Structure Chemical Name 35

amino acid can be either the dextro-(d-) or levo- (1-) form of the amino acid, a racemic mixture of the amino acid, or a (R) NH2 levoamphetamine mixture thereof. According to the presently described technology, polar hydrophilic molecules or ligands can be chemically (prefer ably covalently) attached to amphetamine (d-, 1-, or racemic 40 methamphetamine form or a mixture thereof) to produce novel polar, hydrophilic prodrugs of amphetamine. Other stimulants (including stimu N lant or stimulant-like drugs) can also be modified with these ligands. Some examples of other stimulants include adrafinil, modafinil, aminorex, benzylpiperazine, cathinone, chlor 45 phentermine, chlobenzorex, cyclopentamine, diethylpro NH2 p-methoxyamphetamine (PMA) pion, ephedrine, fenfluramine, 4-methyl-aminorex, methy lone, methylphenidate, pemoline, phentermine, phenylephrine, propylhexadrine, pseudoephedrine, and Syn No ephrine. Metabolites and derivatives of these and other stimu 50 lants could also be modified with the same potential benefit. O NH 3.4-methylenedioxyamphetamine Examples of metabolites of amphetamine include p-hy { (MDA) droxyamphetamine and p-hydroxyephedrine. In accordance with some embodiments of the presently O described technology, the non-standard amino acid is 55 /- O 2,3-methylenedioxyamphetamine attached to amphetamine to make the non-standard amino acid conjugate of amphetamine or salts thereof. Preferably, O NH2 the non-standard amino acid is covalently attached to amphet amine through the C-terminus of the amino acid. The N-ter minus or, when it is present, the side chain amino group of the 60 amino acid may be in a free and unprotected State, or in the form of a salt thereof. Alternatively, in some embodiments, 3,4-methylenedioxymethampheta the non-standard amino acid can be attached to amphetamine mine (MDMA) through the N-terminus. Examples of salts of non-standard amino acid conjugates of amphetamine that can be formed 65 Crs and administered to patients in accordance with the presently described technology include, but are not limited to, acefyl US 8,101,661 B2 13 14 TABLE 1-continued Examples of non-standard amino acids that are contem plated for the presently described technology include, but are Amphetamine Derivatives not limited to: homoarginine, pyrrolysine, lanthionine, 2-aminoisobutyric acid, dehydroalanine, homocysteine, Structure Chemical Name 2-oxoarginine, Y-aminobutyric acid (GABA), 4-amino NH 2,5-dimethoxy-4-methylampheta butanoic acid, 1.1-2,6-diaminopimelic acid, 1-2-aminoadipate mine (DOM) 6-semialdehyde, d-threo-2,4-diaminopentanoate, 2-amino 4-oxopentanoic acid, 1-erythro-3,5-diaminohexanoic acid, we-OY (S)-5-amino-3-oxohexanoic acid, N'-hydroxy-l-lysine, 10 N-acyl-l-lysine, 5-aminovaleric acid, N-methyl-l-lysine, N,N-dimethyl-l-lysine, N.N.N-trimethyl-l-lysine, 3-hy droxy-N,N',N'-trimethyl-l-lysine, 4-trimethylammoniobu tanoic acid, 5-hydroxy-l-lysine, 1-citrulline, 2-oxo-4-hy TABLE 2 droxy-5-aminovalerate, pyrrole-2-carboxylate, 1-erythro-4- Trimethoxyamphetamine derivatives. 15 hydroxyglutamic acid, trans-4-hydroxy-l-proline, 4-oxoproline, 3-sulfino-l-alanine, O-acetyl-l-serine, sele Structure Chemical Name nomethionine, selenocysteine, Se-methyl selenomethionine, 3,4,5-trimethoxyamphetamine Se-methyl selenocysteine, selenocyStathionine, selenocys NH2 (TMA)TMA teine selenate, and cyStathione. In accordance with at least some embodiments, the polar hydrophilic ligands Suitable for the present technology con tain at least one of the following functional groups: hydroxyl, NoO carboxylic acid, amine (primary or secondary), ketone or aldehyde, acetylhalide, phosphate, phosphonate, Sulfate, Sul 25 fonate, sulfonyl, sulfonamide, and thiol. These functional groups can be chemically attached to amphetamine, for NH 2,4,5-trimethoxyamphetamine example, through the primary amine of amphetamine to form (TMA-2) the following chemical linkages: carbamate, thiocarbamate, amide, urea, phosphoramidate, phosphonamidate, phos No10 30 phoramide, Sulfamate, Sulfonamide, or thiourea. The final prodrug products of the present technology may be in a num ber of derivative forms such as salt forms depending on other 2,3,4-trimethoxyamphetamine functionality of the attached ligands and any deprotection O (TMA-3) steps that may or may not be necessary. 35 Salts of the stimulant chemically attached to the polar hydrophilic ligand that can be formed and utilized include, but are not limited to, acefyllinate, 4-acetamidobenzoate, O10 acetate, aceturate, adipate, aminosalicylate, ammonium, ascorbate, l-aspartate, benzoate, besylate, bicarbonate, 40 borate, butyrate, calcium, camphocarbonate, camphorate, 2,3,5-trimethoxyamphetamine d-camsylate, 1-camsylate, camsylate, carbonate, cholate, cit O (TMA-4) rate, cypionate, decanoate, dichloroacetate, edentate, edisy late, estolate, esylate, ethylsulfate, fumarate, furate, fusidate, galactarate (mucate), galacturonate, gallate, gentisate, glu 45 ceptate, gluconate, glucuronate, glutamate, glutarate, glyc erophosphate, glycolate, heptanoate (enanthate), hexanoate, hippurate, hybenzate, hydrobromide/bromide, hydrochlo rerO ride/chloride, hydroxide, hydroxybenzoate, iodide, isethion ate, d-lactate, 1-lactate, d.l-lactate, lactobionate, laurate, 2,3,6-trimethoxyamphetamine 50 lithium, magnesium, malate, d.l-malate, maleate, malonate, C. (TMA-5) mandelate, meso-tartrate, mesylate, methanesulfonate, meth ylsulfate, myristate, napadisilate, 2-napsylate, nicotinate, nitrate, octanoate, oleate, orotate, oxalate, palmitate, pamo ate, phenylpropionate, phosphate, picrate, pivalate, potas sium, propionate, pyrophosphate, Salicylate, salicylsulfate, 55 Sodium, Stearate. Succinate, Sulfate, Sulfosalicylate, tannate, d-tartrate, 1-tartrate, d.l-tartrate, terephthalate, thiocyanate, thiosalicylate, tosylate, tribrophenate, triflate, undecylenate, 2,4,6-trimethoxyamphetamine Valerate, valproate, Xinafoate, Zinc, and mixtures thereof. Fur No (TMA-6) ther, in accordance with some embodiments, the salts may be 60 required in multiple forms (e.g., di-, tri-, or tetra-). Other NH2 derivative forms such as free base, free acid, or neutral forms may also be prepared depending on the polar hydrophilic ligand used. Cor Examples of non-standard amino acids Suitable for the 65 presently described technology include homoarginine, citrul line, homocitrulline, hydroxyproline, 2-hydroxy-4-(meth ylthio)butanoic acid (HMB), Y-aminobutyric acid, taurine, US 8,101,661 B2 15 16 glutathione, statine, homocysteine, selenomethionine, and combinations thereof. Structures of some non-standard O O O amino acids are shown below. | HO NH2 HO i - OH 5 O OH NH2 O H N NH2 isoserine cysteic acid HO r O NH2 NH N homoarginine 10 --~~ N O NH2 H N NH2 N-e, e-dimethyl-lysine O HO r 15 NH2 O HO OH homocitrulline O NH2 C-methylserine SH 2O HO Examples of synthetic amino acids suitable for use in the presently described technology include 2-amino-3-guanidi homocysteine nopropionic acid, 2-amino-3-ureidopropioninc acid, 4-ni O O 25 troanthranillic acid, and combinations thereof. Structures of Some synthetic amino acids for use in the practice of the present technology are provided below. HO--~~ NH 1s NH2 citrulline 30 O O O

H HO NH2 35 2-amino-3-ureidopropionic acid O NH OH hydroxyproline O OH H 40 NH2 2-amino-3-guanidinopropionic acid HO1 NH2 statine Examples of amino alcohols suitable for use in the pres O 45 ently described technology include alaminol, indano, norephedrine, asparaginol, aspartimol, glutamol, leucinol, methioninol, phenylalaminol, prolinol, tryptophanol, Valinol, HO YOH isoleucinol, argininol, serinol, tyrosinol, threoninol, cys NH2 teinol, lysinol, histidinol, and combinations thereof. Struc 50 tures of some amino alcohols for use in the practice of the N'-hydroxy-lysine present technology are provided below. O

Se HO n 55 NH2 HO Selenomethionine in-l NH2 HO NH2 Examples of amino acids derivatives or precursors Suitable 60 alaninol HO in the presently described technology include isoserine, N-(D- serinol nitro-arginine, N-e.e-dimethyl-lysine, buthionine, cysteic NH2 acid, ethionine, (2-amino ethyl)cysteine, cystathionine, lysinol 2-amino-3-ethyoxybutanoic acid, methylserine, O-ethyl threonine, and combinations thereof. Structures of some 65 Other polar hydrophilic ligands that can be used to produce amino acids derivatives or precursors for use in the practice of stimulant prodrugs of the present technology include natural the present technology are provided below. Substrates, and other hydrophilic groups. As used herein, US 8,101,661 B2 17 18 “natural substrates' refer to polar molecules that are readily give the corresponding salt form. Salt forms may also be found in humans and can include essential or non-essential Switched by first free basing the product and then adding any nutrients and biological components. Other hydrophilic acid. Neutral, free base or anionic salts may also be formed. groups or ligands include examples of compounds that occur Additional deprotection may be necessary in the case of some in natural or are regarded as non-toxic and could not be polar hydrophilic ligands such as homoarginine and any pro readily classified in the other groupings. tected urea derivative. These deprotections usually occur Examples of some natural substrates suitable for use in the under hydrogenation conditions. presently described technology include carnitine, tartaric For another example, coupling of carnitine (d-, 1-, or race acid, biotin, pantothenic acid and salts, choline, cystine mic) to amphetamine may require protection of the hydroxyl dimer, lactic acid, niacin, riboflavin, and combinations 10 group prior to coupling. In accordance with some embodi thereof. Structures of some preferred natural substrates for ments, use of a silyl or benzoyl group to protect the hydroxyl use in the practice of the present technology are provided group would be preferred. Deprotection of the silyl can occur below. in water or slightly acidic media. On the other hand, depro tection of benzoyl usually requires strong basic conditions 15 such as in the presence of NaOMe. O More specifically, using a non-standard amino acid and amphetamine as an example, the non-standard amino acid can be attached to amphetamine to make an amino acid conjugate of amphetamine or salts thereof in accordance with the pres ---OH ently described technology. Preferably, the amino acid is carnitine covalently attached to amphetamine through the C-terminus of the amino acid. The N-terminus or the side chain amino - group of the amino acid may be in a free and unprotected 1. N1 No state, or in the form of a salt thereof. Alternatively, in some choline 25 embodiments, the amino acid can be attached to amphet amine through the N-terminus. Examples of salts of amino Examples of other hydrophilic groups suitable for use in acid conjugates of amphetamine that can be formed and the presently described technology include t-butylated administrated to patients in accordance with the presently hydroxyanisole (BHA), propionic acid, Sorbic acid, erythor described technology include, but are not limited to, acefyl bic acid, methyl paraben, propyl gallate, propyl paraben, thio 30 linate, 4-acetamidobenzoate, acetate, aceturate, adipate, ami dipropionic acid, propylene glycol, pyridoxine, adipic acid, nosalicylate, ammonium, ascorbate, 1-aspartate, benzoate, malic acid, acetoin, N-butyric acid, Vanillin, geraniol, methyl besylate, bicarbonate, borate, butyrate, calcium, camphocar anthranilate, benzoin, benzyl alcohol, and combinations bonate, camphorate, d-camsylate, 1-camsylate, camsylate, thereof. Structures of two representative hydrophilic groups carbonate, cholate, citrate, cypionate, decanoate, dichloroac for use in the practice of the present technology are provided 35 etate, edentate, edisylate, estolate, esylate, ethyl sulfate, fumarate, furate, fusidate, galactarate (mucate), galactur below. onate, gallate, gentisate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycerophosphate, glycolate, hep O H tanoate (enanthate), hexanoate, hippurate, hybenzate, hydro 40 bromide/bromide, hydrochloride/chloride, hydroxide, hydroxybenzoate, iodide, isethionate, d-lactate, l-lactate, d.l- O lactate, lactobionate, laurate, lithium, magnesium, malate, d.l-malate, maleate, malonate, mandelate, meso-tartrate, -N-N-OH 1. mesylate, methanesulfonate, methylsulfate, myristate, napa Sorbic acid O 45 disilate, 2-napsylate, nicotinate, nitrate, octanoate, oleate, orotate, oxalate, palmitate, pamoate, phenylpropionate, phos OH phate, picrate, pivalate, potassium, propionate, pyrophos vanillin phate, Salicylate, Salicylsulfate, sodium, Stearate. Succinate, Sulfate, Sulfosalicylate, tannate, d-tartrate, kartrate, d.l-tar Generally, to produce a stimulant prodrug of the present 50 trate, terephthalate, thiocyanate, thiosalicylate, tosylate, tri technology, a selected polar hydrophilic ligand (e.g., a com brophenate, triflate, undecylenate, Valerate, valproate, Xin mercially available non-standard amino acid or amino acid afoate, Zinc, and mixtures thereof. derivative) can be added to the stimulant (e.g. amphetamine) To conjugate an amino acid of the present technology, in dextro, levo or racemic forms. Depending on the polar including non-standard amino-acids, with amphetamine, the hydrophilic ligand selected, one or more functional groups on 55 one or more amino groups are preferably protected using the polar hydrophilic ligand may or may not need to be agents described above before the amino acid is reacted with protected prior to coupling the ligand with the stimulant. amphetamine. The amino acid whose amino groups are pro For example, to conjugate an amino acid with amphet tected can be referred to as an N-protected amino acid. One amine, the one or more amino groups are preferably protected can either protect the amino groups in situ during the produc before the amino acid is reacted with amphetamine. Agents 60 tion process, or use commercially available N-protected and methods for protecting amino groups in a reactant are amino acids directly. Preferably, the carboxylic acid group in known in the art. Examples of protecting groups that may be the N-protected amino acid is activated by an acid activating used to protect the amino groups include, but are not limited agent (sometimes also called coupling reagent) to help the to, fluorenylmethoxycarbonyl (Fmoc), t-butylcarbonate reaction of the N-protected amino acid with amphetamine. (Boc), trifluoroacetate (TFA), acetate (Ac) and benzyloxycar 65 General information about the reaction of amino acids to bonyl (Z). After coupling with any standard coupling proce form peptide bonds can be found in, for example, G.C. Barett, dure, deprotection can occur with a variety of strong acids to D. T. Elmare, Amino Acids and Peptides, page 151-156, US 8,101,661 B2 19 20 Cambridge University Press, UK (1st edition, 1998); Jones, -continued J., Amino Acid and Peptide Synthesis, pages 25-41, Oxford HN University Press, UK (2nd edition, 2002), which are incorpo NO rated herein by reference in their entirety. One category of acid activating agents (coupling reagents) NH well known in the art are carbodiimides. Examples of carbo diimide acid activating agents include, but are not limited to, dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3'-dimethy laminopropyl)-carbodiimide (EDCI), and diisopropylcarbo 10 diimide (DIPCDI). Examples of other coupling reagents that could be used include bromo-tris-pyrrolidino phosphonium O l hexafluorophosphate, (benzotriazol-1-yloxy)-tris-(dimethy N lamino)-phosphonium hexafluorophosphate, PCls/PhH. O SOCl, NH 1-ethoxycarbonyl-2-ethoxy-1,2-dihydro 15 HN quinoline, other phosphonium reagents, and uronium N n NO reagents. The use of appropriate acyl halide or anhydride is 1. H2, Pd/C, also contemplated. NH MeOHA HCI The N-protected amino acid conjugate of amphetamine -- 2. HCI in resulting from the reaction of the N-protected amino acid and dioxane amphetamine as described above can then be de- or un-pro tected with a strong acid to produce the corresponding final O salt form of the amino acid conjugate of amphetamine. N > O us N H Scheme 1 below outlines an exemplary route for the syn 25 H thesis of a derivative of amphetamine chemically attached to O homoarginine in accordance with the presently described technology. In this exemplary reaction scheme, a dihydro N NH, HCI chloride Salt form of homoarginine-amphetamine is pro duced. The procedure uses tert-butyloxycarbonyl (Boc) and 30 NH nitro protected homoarginine (Boc-homoarginine(NO)) as the starting material. In this exemplary reaction scheme, the coupling agent EDCI is added to Boc-homoarginine(NO) in dimethylformamide (DMF). N-hydroxysuccinamide (NHS) 35 is then added to the reaction mixture. A stable, yet still acti H vated. Succinimidyl ester of Boc-homoarginine(NO) is N formed. Amphetamine is then added to the resulting Succin HCI HN imidyl ester of Boc-homoarginine(NO) to make the corre sponding protected prodrug, Boc-homoarginine(NO)-am 40 phetamine. This protected prodrug can be de- or un-protected using hydrogenation followed by a strong acid such as meth The preparation of hArg-Amp required extensive modifi anesulfonic acid (MSOH) or hydrochloric acid to produce the cations to previously published methods and syntheses. First, prodrug of amphetamine, which is a dihydrochloride Salt of Boc-harg(NO)—OH required use of DMF to solubilize the material prior to reaction. Second, formation of the free base homoarginine-amphetamine in this exemplary reaction 45 of amphetamine was performed in situ and was not isolated. scheme. Also, the formation of the activated ester was performed in situ with the addition reaction following in the same reaction vessel. Homoarginine is different from many other standard Scheme 1 and non-standard amino acids in that it requires a separate 50 step of deprotection to remove the nitro group from the side HN chain. Failure to adequately protect homoarginine can lead to n SNO, undesirable products that do not perform in vivo with respect to the desired therapeutic outcomes discussed herein. NH Examples of other solvents that can be used in the presently 55 described technology include, but are not limited to, isopro pyl acetate (IPAc), acetone, and dichloromethane (DCM), dimethylformamide (DMF), ethyl acetate, chloroform, dim ethyl sulfoxide, dioxane, diethyl ether, methyl t-butyl ether, hexanes, heptane, methanol, ethanol, isopropanol, and 60 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. Example of suitable co-bases include, but are not limited to NHS, EDCI, DIPEA Her 4-methylmorpholine (NMM), triethylamine (TEA), ammo DMF 65 nia or any tertiary amine base. NH2 The amphetamine to be chemically attached to polar hydrophilic ligands of the presently described technology can US 8,101,661 B2 21 22 be in d-form, 1-form, or racemic form, or can be a mixture -continued thereof. In accordance with some embodiments of the pres ently described technology, d-amphetamine (dextroamphet amine) and a non-standard amino acid with a know toxicity profile are preferably used to make an amphetamine prodrug. Other preferred polar hydrophilic ligands to form d-amphet amine prodrugs include, for example, 1-carnitine, 1-lysinol, or choline. In accordance with Some other embodiments, the prodrugs of d-amphetamine can be used in combination with a prodrug of 1-amphetamine or 1-amphetamine itself. 10 Scheme 2 below outlines an exemplary route for the syn sulfate salt thesis of a derivative of amphetamine chemically attached to Scheme 3 below outlines an exemplary route for the syn selenomethionine in accordance with the presently described thesis of a derivative of amphetamine chemically attached to technology. The amphetamine prodrug produced here is in a 15 statine in accordance with the presently described technol sulfate salt form. ogy. The amphetamine prodrug produced here is in an HCl salt form. Scheme 2

Y CH3 Se 1. EDCI, amphetamine Her 2. HCI O DCC, NHS Hess us OH EtOAc 25 O N H O 1 CH3 Se 30

O HC Salt O > O ul N YN O Scheme 4 below outlines an exemplary route for the syn H 35 thesis of a derivative of amphetamine chemically attached to O isoserine in accordance with the presently described technol O ogy. The amphetamine prodrug produced here is in an MSOH 1 CH3 Se salt form.

40 O Scheme 4 O > O us N NN O -- H DCC, NHS O --- O 45 > -----. EtOAc EtOAc --- NH2

1 CH 3 Se 50

O O N O > O ul N H 55 H O

1. CH 3 O Se O O 60 N >ulO N o1 -- H O

65 US 8,101,661 B2 23 24 -continued O-ethyl-threonine in accordance with the presently described technology. The amphetamine prodrug produced here is in an EtOAc He- HCl Salt form. NH2 5

O N N O 10 O O 1. EDCI, amphetamine Her OH 2. HCI O N H O O 1. anhydrous 15 O l acid (HCl in O N N dioxane) H H 2. MSOH O O

-N 2O NH O HN O HN N HC Salt H 25 OH MSOHSalt Scheme 7 below outlines an exemplary route for the syn thesis of a derivative of amphetamine chemically attached to 2-amino-3-guanidinopropionic acid in accordance with the Scheme 5 below outlines an exemplary route for the Syn- 30 presently described technology. The amphetamine prodrug thesis of a derivative of amphetamine chemically attached to produced here is in an MsCH salt form. cystathionine in accordance with the presently described technology. The amphetamine prodrug produced here is in an HCl Salt form. Scheme 7 35 HN Scheme 5 N n NO O NH DCC, NHS o, O -- 40 EtOAc

>rryronO 1. EDC1, >ulO N OH S amphetamine H Ho O H O 2. HCI 45 HN NS

Orls N OH n NO H NH O

O HN O 50 > O l N NN O R H O O S HN 55 N YNO, NH R O

O -- HN > l n O O 60 O NH N HC Salt O R = OH or amphetamine O R = OH or amphetamine EtOAc 65 NH2 -e- Scheme 6 below outlines an exemplary route for the syn thesis of a derivative of amphetamine chemically attached to US 8,101,661 B2 26 -continued -continued HNN YNO, NH O 1. amphetamine N -e- > O l N H O fs 2. HCI H O > O l O N.Na N

HN N n NO NH O 1. H2/Pd, 15 H EtOAc N He O N 2. MSOH O HNn NH2 NH

H 25 N HN O Scheme 9 below outlines an exemplary route for the syn thesis of a derivative of amphetamine chemically attached to MSOHSalt 30 lysinol-urea in accordance with the presently described tech nology.

Scheme 9 Scheme 8 below outlines an exemplary route for the syn 35 thesis of a derivative of amphetamine chemically attached to NH2 lysinol-carbamate in accordance with the presently described technology. The amphetamine prodrug produced here is in an HCl Salt form. CDI, IPAc 40 He

Fmoc O n N n BZ H O 45 1. N1\ N S. CD1, IPAc -as 50 O

>ulO N OH Fmoc O H n N n BZ 55 H O HN ls N1\ N

60 N/ -as1. amphetamine 2. DEA, NaOMe

Fmoc O n N n BZ H US 8,101,661 B2 27 -continued Scheme 12

O O l s NH2

DCC, NHS THF OH

OH HN 15 O Scheme 10 below outlines an exemplary route for the syn thesis of a derivative of amphetamine chemically attached to 1. carnitine in accordance with the presently described technol Ogy. O N NN 25 Scheme 10 >ul f3 O

-- 1. DCC, TEA 1. 2. d-amphetamine 30 OTMS 3. water

35 N O JuC

> OH 40 Scheme 11 below outlines an exemplary route for the syn thesis of a derivative of amphetamine chemically attached to THF -e- choline in accordance with the presently described technol NH2 Ogy. 45 O Scheme 11

-- OH 1. CD s NH2 N1a 50 1. 2. d-amphetamine O H N O N 55 H O

O In some other preferred embodiments of the present tech s NH2 nology, 1-citrulline-d-amphetamine hydrochloride (Cit 60 HCI Amp) can be synthesized as shown in reaction Scheme 12 in below in three overall steps. The first step involves the acti H dioxane vation of Boc-Cit-OH to form an activated ester using DCC N and NHS followed by the addition of d-amphetamine to pro 65 duce the protected Boc-Cit-Amp. Deprotection using 4NHCl in dioxane gives the corresponding hydrochloride salt. US 8,101,661 B2 30 -continued -continued O NH

s NH2 HN l NH2 5

H N CIHN O 10 HN Another example of the preparation of homoarginine con O jugates of amphetamine derivatives of the present technology o1 is shown in the general pathway of Scheme 13. 15 Scheme 15 provides an exemplary route for the synthesis ofa methylenedioxyamphetamine derivative (example shows 3.4-methylenedioxyamphetamine) chemically attached to Scheme 13 2O homoarginine. NO Scheme 15 NO N Y 2 ins, 25 1. NHS, EDCI, NMM, DMF, 1. Activating agent ins, O NH2 2. Amphetamine

O derivative (PEA) HeOrr Her 3. Deprotection 30 O 3. H., Pd/C, HCl, EtOH, HO OH O N OH 4. HCl, dioxane H O NH 35 HN l NH2 HN NH2

40

H N O

PEA HN X HN 45 O O O Scheme 16 provides an exemplary route for the synthesis Scheme 14 provides an exemplary route for the synthesis of 2,5-dimethoxy-4-methylamphetamine (DOM) chemically of p-methoxyamphetamine (PMA) chemically attached to attached to homoarginine. homoarginine.

Scheme 16

Scheme 14 55 N Y NO 1. NHS, DCC, 2-MeTHF No. 1. NHS, DCC, THF l 2. l. 3. HN NH, NH HN NH NH2 1 COrO 22 No Orr O O > -- OH NMM > l OH 3. H2, Pd/C, HCI, MeOH H Her O N O 3. H2, Pd/C, HCl, IPA, H2O H O 4. HCI, MeOH 65 4. HCI, IPA US 8,101,661 B2 31 -continued -continued NH NH

HN l NH2 HN ls NH2

10 H O N HN HN

15 At least Some compounds of the present technology, Scheme 17 provides an exemplary route for the synthesis including polar, hydrophilic stimulant prodrugs, have no or a of a trimethoxyamphetamine derivative (example shows 3.4. Substantially decreased pharmacological activity when 5-trimethoxyamphetamine) chemically attached to administered through alternative routes of administration homoarginine. including, but not limited to, injection or intranasal. However, they remain orally bioavailable. The bioavailability can be a result of the hydrolysis of the covalent linkage following oral Scheme 17 administration. Hydrolysis of a chemical linkage is time dependent, thereby allowing amphetamine and other metabo NO 1. NHS, EDCI, NMM, DMSO, 25 lites Such as p-hydroxyamphetamine and p-hydroxyephe drine or another stimulant to become available in its active form over an extended period of time. Therefore, the prodrug compounds of the present technol 30 ogy can release amphetamine or another stimulant over an extended period and provide a therapeutically area under the 3. H., Pd/C, HCI, MeOH curve (AUC) when compared to free amphetamine or another OH stimulant (including other controlled release forms of 4. HCI, MeOH amphetamine such as Adderall XRR) or VyvanseTM), with NH 35 little or no spike in maximum plasma concentration (C) or equivalent C. Not wanting to be bound by any particular ls theory, it is believed that since non-standard amino acids and HN NH2 the other suitable polar hydrophilic ligands are used to pro duce the prodrugs, the in vivo breakdown of the prodrugs by 40 enzymes would occurata slower rate than, for example, when a standard amino acid is used to conjugate the stimulants. This will allow the prodrugs of the present technology to release amphetamine or other stimulants slowly and, preferably, only O under in vivo conditions. HN 45 As a person of ordinary skill in the art will understand, drug products are considered pharmaceutical equivalents if they contain the same active ingredient(s), are of the same dosage form, route of administration and are identical in strength or 19 concentration. Pharmaceutically equivalent drug products are 50 formulated to contain the same amount of active ingredient in the same dosage form and to meet the same or compendial or Scheme 18 provides an exemplary route for the synthesis other applicable standards (i.e., strength, quality, purity, and of levoamphetamine chemically attached to homoarginine. identity), but they may differ in characteristics such as shape, scoring configuration, release mechanisms, packaging, 55 excipients (including colors, flavors, preservatives), expira Scheme 18 tion time, and, with certain limits, labeling. Drug products are NO2 considered to be therapeutic equivalents only if they are phar N 1. NHS, EDCI, DIPEA, DMSO, maceutical equivalents and if they can be expected to have the l same clinical effect and safety profile when administered to 60 patients under the conditions specified in the labeling. The HN NH2 Orr NH2 term “bioequivalent on the other hand, describes pharma His ceutical equivalent or pharmaceutical alternative products O 3. H2, Pd/C, HCl, MeOH, H2O that display comparable bioavailability when studied under similar experimental conditions. > Orl N OH 4. HCI, MeOH H 65 Standard amino acids such as lysine or glutamic acid are O not contemplated for the presently described technology. Because standard amino acids are essential parts of all dietary US 8,101,661 B2 33 34 requirements, it would be expected that the prodrug of the abuse. Also, with a full day therapy, the risk of re-dosing is present technology conjugated with a standard amino acid lowered, thus preventing additional toxicities or drug abuse would be released at a faster rate. By using non-standard issues. amino acids, synthetic amino acids, amino acid derivatives or The polar, hydrophilic prodrugs of stimulants, including, precursors, or other polar hydrophilic ligands of the presently but not limited to, amphetamine prodrugs, of the presently described technology, the release rate of amphetamine or described technology could be used for any condition requir another stimulant will be reduced due to the difference in ing the stimulation of the central nervous system (CNS). overall digestion rate of the stimulant prodrug. These conditions include, for example, attention deficit Once produced, the prodrug of amphetamine (or another hyperactivity disorder (ADHD), attention deficit disorder stimulant) of the present technology can be administered 10 (ADD), obesity, narcolepsy, appetite Suppressant, depres through oral routes of delivery and once administered will Sion, anxiety, withdrawals (e.g., alcohol withdrawals or drug release the stimulant under digestive conditions. Due to the withdrawals), and wakefulness. Some stimulants such as hydrophilic and polar nature of the prodrug and the slow rate amphetamine have also demonstrated usefulness in treating of hydrolysis of the chemical linkage as described above, stimulant (e.g., cocaine, methamphetamine) abuse and addic should high levels of drug be administered either accidentally 15 tion. Amphetamine stimulants have also been used exten or intentionally, the prodrug will be cleared by metabolic sively to improve battlefield alertness and to combat fatigue. and/or excretory pathways prior to releasing large amounts of Therefore, in accordance with some embodiments, the the stimulant. Also, release of amphetamine (or another presently described technology provides stimulant composi stimulant) over an extended period should alleviate or dimin tions comprising at least one polar, hydrophilic stimulant ish drug induced side-effects that can limit or terminate prodrug of the present technology. amphetamine therapy. These side effects include increase in In accordance with Some other embodiments, the presently the heart and respiration rates, increased blood pressure, dila described technology provides amphetamine compositions tion of the pupils of the eyes, and decreased appetite. Other comprising at least one amphetamine prodrug of the present side effects include anxiety, blurred vision, sleeplessness, and technology. dizziness. Also, amphetamines and other stimulants are 25 One embodiment is a composition that can prevent behav power psychoStimulants and are prone to Substance abuse. ioral deterioration of amphetamine dosing comprising at least Substance abuse of stimulants is often characterized by an one polar hydrophilic conjugate of amphetamine. escalation of events. First, a substantial “rush” or high may be Another embodiment is a composition that can prevent obtained from increasing oral dosages. Due to the properties behavioral deterioration of amphetamine dosing comprising of these polar, hydrophilic prodrugs, these potential routes for 30 at least one non-standard amino acid conjugate of amphet abuse can be mitigated via the polar nature of the prodrug. amine. That is, once administered at higher than therapeutic levels, Another embodiment is a composition for safely delivering the body will excrete any remaining prodrug withoutbreak a stimulant, comprising a therapeutically effective amount of down into amphetamine. After oral amounts exceed an attain at least one polar, hydrophilic prodrug of the stimulant of the able amount, other routes can be explored including Smoking, 35 present technology wherein the polar hydrophilic moiety can Snorting, or injection. In accordance with the presently reduce the rate of absorption of the stimulant as compared to described technology, release of amphetamine or another delivering the unconjugated stimulant or the stimulant con stimulant would only occur under desired physiological con jugated to a standard amino acid, for example. ditions. Preferably, non-oral routes of administration (e.g., Another embodiment is a composition for safely delivering intranasal or intravenous) do not break the prodrug down to 40 amphetamine, comprising a therapeutically effective amount any appreciable extent. Also preferably, external means of at least one non-standard amino acid conjugate of amphet (chemical, enzymatic or other) will not break the prodrug amine wherein the non-standard amino acid moiety can downto any appreciable extent either. The breakdown ratio of reduce the rate of absorption of the amphetamine as com the prodrug that can be achieved through external means is pared to delivering the unconjugated amphetamine or preferably less than about 50%, alternatively less than about 45 amphetamine conjugated to a standard amino acid. 25%, alternatively less than about 20%, alternatively less than Another embodiment of the present technology is a com about 10%. position that can reduce amphetamine toxicity, comprising at The presently described technology utilizes covalent least one polar hydrophilic prodrug of amphetamine wherein modification of amphetamine by a non-standard amino acid, the non-standard amino acid moiety can release amphetamine an amino acid derivative or any polar hydrophilic group to 50 over the entire course of a day providing a limited behavioral decrease its potential for causing behavioral deterioration or deterioration effect. the rebound effect. It is believed that since the amphetamine Another embodiment of the present technology is a com is covalently modified to form the polar hydrophilic conju position that can reduce amphetamine toxicity, comprising at gate of the present technology and releases slowly over the least one non-standard amino acid conjugate of amphetamine entire length of the day, little or no rebound effect can occur 55 wherein the non-standard amino acid moiety can release due to the slow continuous release of the active ingredient/ amphetamine over the entire course of a day providing a drug/therapeutic component. limited behavioral deterioration effect. Compounds, compositions and methods of the presently Another embodiment of the present technology is a com described technology are also believed to provide reduced position that can reduce amphetamine toxicity, comprising at potential for rebound, reduced potential for abuse or addic 60 least one polar, hydrophilic prodrug of amphetamine of the tion, and/or improve amphetamine's stimulant related toxici present technology wherein the polar hydrophilic moiety can ties. By limiting the blood level spike, doses are kept at levels provide a plasma release curve which does not increase above required for a clinically significant effect without the unnec amphetamine's toxicity level when given at doses exceeding essary levels administered with other therapies. It is widely those within the therapeutic range of amphetamine. held that these spikes in blood levels can lead to cardiovas 65 Another embodiment of the present technology is a com cular toxicity in the form of higher blood pressure and rapid position that can reduce amphetamine toxicity, comprising at heart rate in addition to the euphoria encountered in drug least one non-standard amino acid conjugate of amphetamine US 8,101,661 B2 35 36 wherein the non-standard amino acid moiety can provide a compositions of the present technology can reduce or elimi plasma release curve which does not increase above amphet nate the possibility of overdose by intranasal administration. amines therapeutic level and does not cause blood level In one or more embodiments, the stimulant compositions of spiking. the present technology can reduce or eliminate the possibility Another embodiment of the present technology is a com of overdose by injection. In one or more embodiments, the position that can reduce bioavailability of amphetamine, stimulant compositions of the present technology can reduce comprising at least one polar, hydrophilic prodrug of amphet or eliminate the possibility of overdose by inhalation. amine of the present technology wherein the amphetamine In one or more embodiments, the polar, hydrophilic pro prodrug can maintain a steady-state plasma release curve drugs of stimulants, such as non-standard amino acid conju which can provide a therapeutically effective bioavailability 10 gates of amphetamine, of the present technology may further but prevent spiking or increased plasma concentrations com pared to unconjugated amphetamine or amphetamine conju comprise a polymer blend which comprises a hydrophilic gated with a standard amino acid when given at doses exceed polymer and/or a water-insoluble polymer. The polymers ing those within the therapeutic range of amphetamine. may be used according to industry standards to further Another embodiment of the present technology is a com 15 enhance the Sustained release/abuse resistant properties of the position that can reduce bioavailability of amphetamine or stimulant prodrug of the present technology without reducing prevent a toxic release profile in a patient, comprising at least the abuse resistance. For instance, a composition might one non-standard amino acid conjugate of amphetamine include: about 70% to about 100% stimulant prodrug of the wherein the non-standard amino acid conjugate of amphet present technology by weight, from about 0.01% to about amine can maintain a steady-state plasma release curve which 10% of a hydrophilic polymer (e.g. hydroxypropyl methyl can provide a therapeutically effective bioavailability but pre cellulose), from about 0.01% to about 2.5% of a water-in vent spiking or increased plasma concentrations compared to soluble polymer (e.g. acrylic resin), from about 0.01% to unconjugated amphetamine oramphetamine conjugated with about 1.5% of additives (e.g. magnesium Stearate), and from a standard amino acid. about 0.01% to about 1% colorant by weight. Another embodiment of the present technology is a com 25 Hydrophilic polymers suitable for use in the sustained position comprising at least one polar, hydrophilic prodrug of release formulations include one or more natural or partially amphetamine of the present technology that can prevent a or totally synthetic hydrophilic gums such as acacia, gum C, or equivalent C spike for amphetamine when taken tragacanth, locust bean gum, guar gum, or karayagum, modi by means other than orally while still providing a therapeu fied cellulosic Substances such as methylcellulose, tically effective bioavailability curve if taken orally. 30 hydroxymethylcellulose, hydroxypropyl methylcellulose, Another embodiment of the present technology is a com hydroxypropyl cellulose, hydroxyethylcellulose, carboxym position comprising at least one non-standard amino acid conjugate of amphetamine that can prevent a C or equiva ethylcellulose; proteinaceous Substances such as agar, pectin, lent C spike for amphetamine. carrageen, and alginates; and other hydrophilic polymers Another embodiment of the present technology is a com 35 Such as carboxypolymethylene, gelatin, casein, Zein, bento position comprising at least one non-standard amino acid nite, magnesium aluminum silicate, polysaccharides, modi conjugate of amphetamine that can prevent a C or equiva fied starch derivatives, and other hydrophilic polymers lent C. Spike for amphetamine when taken by means other known to those of skill in the art, or a combination of such than orally while still providing a therapeutically effective polymers. These hydrophilic polymers gel and would dis bioavailability curve if taken orally. 40 Solve slowly in aqueous acidic media thereby allowing the Another embodiment of the present technology is a com stimulant prodrug to diffuse from the gel in the stomach. position that can prevent a toxic release profile in a patient When the gel reaches the intestines it would dissolve in con comprising at least one polar, hydrophilic prodrug of amphet trolled quantities in the higher pH medium to allow further amine of the present technology wherein the amphetamine sustained release. Preferred hydrophilic polymers are the prodrug can maintain a steady-state plasma release curve 45 hydroxypropyl methylcelluloses Such as those manufactured which provides a therapeutically effective bioavailability but by The Dow Chemical Company and known as Methocel prevents spiking or increased plasma concentrations com ethers, such as Methocel E1 OM. pared to unconjugated amphetamine or amphetamine conju Otherformulations according to one or more embodiments gated with a naturally occurring and standard amino acid. of the present technology may further comprise pharmaceu One or more embodiments of the present technology pro 50 tical additives including, but not limited to, lubricants such as vide stimulant Such as amphetamine compositions which magnesium Stearate, calcium Stearate, Zinc Stearate, pow allow the stimulant to be therapeutically effective when deliv dered Stearic acid, hydrogenated vegetable oils, talc, polyeth ered at the proper dosage but reduces the rate of absorption or ylene glycol, and mineral oil; colorants such as Emerald extent of bioavailability of the stimulant when given at doses Green Lake, FD&C Red No. 40, FD&C Yellow No. 6, D&C exceeding those within the therapeutic range of the stimulant. 55 Yellow No. 10, or FD&C Blue No. 1 and other various certi One or more embodiments of the present technology also fied color additives (See 21 CFR, Part 74); binders such as provide stimulant compositions wherein the polar hydro Sucrose, lactose, gelatin, starch paste, acacia, tragacanth, philic moiety increases the rate of clearance of the stimulant poVidone, polyethylene glycol, Pullulan and corn Syrup; when given at doses exceeding those within the therapeutic glidants such as colloidal silicon dioxide and talc; Surface range of the stimulant. 60 active agents such as sodium lauryl Sulfate, dioctyl Sodium In one or more embodiments, the stimulant compositions SulfoSuccinate, triethanolamine, polyoxyethylene Sorbitan, of the present technology have substantially lower toxicity poloxalkol, and quaternary ammonium salts; preservatives compared to unconjugated Stimulant or the stimulant conju and Stabilizers; excipients such as lactose, mannitol, glucose, gated with a standard amino acid. In one or more embodi fructose, Xylose, galactose, Sucrose, maltose, Xylitol, Sorbitol, ments, the stimulant compositions of the present technology 65 chloride, Sulfate and phosphate salts of potassium, Sodium, can reduce or eliminate the possibility of overdose by oral and magnesium; and/or any other pharmaceutical additives administration. In one or more embodiments, the stimulant known to those of skill in the art. In one preferred embodi US 8,101,661 B2 37 38 ment, a Sustained release formulation of the present technol about 5% by weight of a disintegrant Such as croScarmellose ogy further comprises magnesium Stearate and Emerald sodium, from about 0.5% to about 2.5% of a lubricant such as Green Lake. magnesium Stearate or other fatty acid salts. The carrier can The stimulant compositions, such as amphetamine compo be eitherhard gelatin capsules, and preferably use the Smaller sitions, of the present technology, which comprises at least sized ones such as #3 or #4 hard gelatin capsules. one polar, hydrophilic stimulant prodrug of the present tech Soft gel or soft gelatin capsules may be prepared, for nology, can be furtherformulated with excipients, and may be example, by dispersing the formulation of the present tech manufactured according to any appropriate method known to nology in an appropriate vehicle (vegetable oils are com those of skill in the art of pharmaceutical manufacture. For monly used) to form a high viscosity mixture. This mixture instance, the stimulant prodrug and a hydrophilic polymer 10 can then be encapsulated with a gelatin based film using may be mixed in a mixer with analiquot of water to form a wet technology and machinery known to those in the soft gel granulation. The granulation may be dried to obtain hydro industry. The individual units so formed are then dried to philic polymer encapsulated granules of the stimulant pro constant weight. drug. The resulting granulation may be milled, screened, then Chewable tablets, for example, may be prepared by mixing blended with various pharmaceutical additives such as, for 15 the formulations of the present technology with excipients example, water insoluble polymers, and/or additional hydro designed to form a relatively soft, flavored, tablet dosage form philic polymers. The formulation may then be tableted and that is intended to be chewed rather than swallowed. Conven may further be film coated with a protective coating which tional tablet machinery and procedures, that is both direct rapidly dissolves or disperses in gastric juices. compression and granulation, i.e., or slugging, before com It should be noted that the above additives are not required pression, can be utilized. Those individuals involved in phar for the stimulant composition of the present technology to maceutical Solid dosage form production are versed in the have Sustained release and abuse resistance properties. The processes and the machinery used as the chewable dosage stimulant prodrug of the present technology itself can control form is a very common dosage form in the pharmaceutical the release of the stimulant into the digestive tract over an industry. extended period of time resulting in animproved profile when 25 Film-coated tablets, for example, may be prepared by coat compared to immediate release combinations and prevention ing tablets using techniques such as rotating pan coating of abuse without the addition of the above additives. In one or methods or air Suspension methods to deposit a contiguous more embodiments of the present technology, no further Sus film layer on a tablet. tained release additives are required to achieve a blunted or Compressed tablets, for example, may be prepared by mix reduced pharmacokinetic curve (e.g., reduced euphoric 30 ing the formulation of the present technology with excipients effect) while achieving therapeutically effective amounts of intended to add binding qualities to disintegration qualities. stimulant release when taken orally. The mixture can be either directly compressed or granulated The compounds and compositions of the presently then compressed using methods and machinery known to described technology can be formulated into and adminis those in the industry. The resultant compressed tablet dosage tered by a variety of dosage forms, preferably, through any 35 units are then packaged according to market need, i.e., unit oral routes of delivery. Once administered, the prodrugs will dose, rolls, bulk bottles, blister packs, etc. release amphetamine or another stimulant under digestive One preferred formulation of the polar hydrophilic pro conditions. Any biologically-acceptable dosage form known drugs, such as non-standard amino acid conjugates of to persons of ordinary skill in the art, now or in the future, and amphetamine, of the present technology is a fast dissolving combinations thereof, are contemplated for use with the 40 oral film or thin strip. Methods and other ingredients needed present technology. Examples of preferred dosage forms to make oral films or thin strips are known in the art. Potential include, without limitation, chewable tablets, quick dissolve film forming agents include pullulan, hydroxypropylmethyl tablets, effervescent tablets, reconstitutable powders, elixirs, cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, liquids, Solutions, Suspensions, emulsions, tablets, multi polyvinyl alcohol, Sodium alginate, polyethylene glycol, Xan layer tablets, bi-layer tablets, capsules, soft gelatin capsules, 45 than gum, tragacanth gum, guar gum, acacia gum, Arabic hard gelatin capsules, caplets, troches, lozenges, chewable gum, polyacrylic acid, amylase, starch, dextrin, pectin, chitin, lozenges, beads, powders, granules, particles, microparticles, chitosin, levan, elsinan, collagen, gelatin, Zein, gluten, Soy dispersible granules, cachets, thin Strips, oral films, transder protein isolate, whey protein isolate, casein, and mixtures mal patches, and combinations thereof. Preferred dosage thereof. forms include, but are not limited to, capsules, thin Strips, fast 50 Also, saliva stimulating agents, plasticizing agents, cool dissolving oral films and solution formulations. ing agents, Surfactants, emulsifying agents, thickening Formulations of the present technology suitable for oral agents, binding agents, Sweeteners, flavoring, coloring administration can be presented as discrete units, such as agents, preservatives, or taste masking resins may be capsules, caplets or tablets. These oral formulations also can employed in the oral films or thin strips. Preferred agents comprise a solution or a suspension in an aqueous liquid or a 55 include: pullulan, triethanolamine Stearate, methyl cellulose, non-aqueous liquid. The formulation can be an emulsion, starch, triacetin, polysorbate 80, Xanthan gum, maltitol, Sor Such as an oil-in-water liquid emulsion or a water-in-oil liquid bitol and glycerol. emulsion. The oils can be administered by adding the purified The presently described technology also contemplates the and sterilized liquids to a prepared enteral formula, which can use of biologically-acceptable carriers which may be pre then be placed in the feeding tube of a patient who is unable 60 pared from a wide range of materials. Without being limited to Swallow. thereto. Such materials include diluents, binders and adhe If the capsule form is chosen, for example, excipients used sives, lubricants, plasticizers, disintegrants, colorants, bulk in the capsule formulation could be broken up into four sepa ing Substances, flavorings, Sweeteners and miscellaneous rate groups: bulk agent/binder, disintergrant, lubricant and materials such as buffers and adsorbents in order to prepare a carrier. A preferred capsule formulation comprises from 65 particular medicated composition. about 50% to about 90% by weight of a bulk agent such as Binders may be selected from a wide range of materials various types of microcrystalline cellulose, from about 1% to Such as hydroxypropylmethylcellulose, ethylcellulose, or US 8,101,661 B2 39 40 other suitable cellulose derivatives, povidone, acrylic and salts can range from about 1 mg to about 100 mg, although methacrylic acid co-polymers, pharmaceutical glaze, gums, higher dosages may be approved at later dates. Using the milk derivatives, such as whey, starches, and derivatives, as molecular weight of the prodrug of the present technology, well as other conventional binders known to persons skilled in the release percentage (% release) of amphetamine from the the art. Exemplary non-limiting solvents are water, ethanol, prodrug and desired dosage forms of the required amphet isopropyl alcohol, methylene chloride or mixtures and com amine, the following equation can be generated: binations thereof. Exemplary non-limiting bulking Sub stances include Sugar, lactose, gelatin, starch, and silicon grams of a prodrug needed (dosage/molecular weight dioxide. of amphetamine)(% release) (molecular weight of the prodrug) Preferred plasticizers may be selected from the group con 10 sisting of diethyl phthalate, diethyl sebacate, triethyl citrate, Tablets, capsules, and otherforms of presentation provided cronotic acid, propylene glycol, butyl phthalate, dibutyl seba in discrete units conveniently contain a daily dose, or an cate, castor oil and mixtures thereof, without limitation. As is appropriate fraction thereof, of one or more of the prodrug evident, the plasticizers may be hydrophobic as well as hydro compounds of the invention. For example, the units may philic in nature. Water-insoluble hydrophobic substances, 15 contain from about 1 mg to about 1000 mg, alternatively from Such as diethyl phthalate, diethyl sebacate and castor oil are about 5 mg to about 500 mg, alternatively from about 5 mg to used to delay the release of water-soluble vitamins, such as about 250 mg, alternatively from about 10 mg to about 100 Vitamin B and vitamin C. In contrast, hydrophilic plasticiz mg of one or more of the prodrug compounds of the presently ers are used when water-insoluble vitamins are employed described technology. which aid in dissolving the encapsulated film, making chan It is also possible for the dosage form of the present tech nels in the Surface, which aid in nutritional composition nology to combine any forms of release known to persons of release. ordinary skill in the art. These conventional release forms It should be understood that in addition to the ingredients include immediate release, extended release, pulse release, particularly mentioned above, the formulations of the present variable release, controlled release, timed release, Sustained technology can include other Suitable agents such as flavoring 25 release, delayed release, long acting, and combinations agents, preservatives and antioxidants. Such antioxidants thereof. The ability to obtain immediate release, extended would be food acceptable and could include, for example, release, pulse release, variable release, controlled release, vitamin E, carotene, BHT or other antioxidants known to timed release, Sustained release, delayed release, long acting those of skill in the art. characteristics and combinations thereof is known in the art. Other compounds which may be included are, for example, 30 Compositions of the present technology may be adminis medically inertingredients, e.g., Solid and liquid diluent, Such tered in a partial, i.e., fractional dose, one or more times as lactose, dextrose, saccharose, cellulose, starch or calcium during a 24 hour period, a single dose during a 24 hour period phosphate for tablets or capsules, olive oil or ethyl oleate for of time, a double dose during a 24 hour period of time, or more Soft capsules and water or vegetable oil for Suspensions or thana double dose during a 24hour period of time. Fractional, emulsions; lubricating agents such as silica, talc, Stearic acid, 35 double or other multiple doses may be taken simultaneously magnesium or calcium Stearate and/or polyethylene glycols; or at different times during the 24 hour period. The doses may gelling agents such as colloidal clays; thickening agents such be uneven doses with regard to one another or with regard to as gum tragacanth or Sodium alginate, binding agents such as the individual components at different administration times. starches, arabic gums, gelatin, methylcellulose, carboxym Likewise, the compositions of the present technology may ethylcellulose or polyvinylpyrrolidone; disintegrating agents 40 be provided in a blister pack or other such pharmaceutical Such as starch, alginic acid, alginates or Sodium starch gly package. Further, the compositions of the present technology colate; effervescing mixtures; dyestuff Sweeteners; wetting may further include or be accompanied by indicia allowing agents such as lecithin, polysorbates or laurylsulphates; and individuals to identify the compositions as products for a other therapeutically acceptable accessory ingredients, such prescribed treatment. The indicia may additionally include an as humectants, preservatives, buffers and antioxidants, which 45 indication of the above specified time periods for administer are known additives for such formulations. ing the compositions. For example, the indicia may be time For oral administration, fine powders or granules contain indicia indicating a specific or general time of day for admin ing diluting, dispersing and/or Surface-active agents may be istration of the composition, or the indicia may be a day presented in a draught, in water or a syrup, in capsules or indicia indicating a day of the week for administration of the Sachets in the dry state, in a non-aqueous Suspension wherein 50 composition. The blister pack or other combination package Suspending agents may be included, or in a Suspension in may also include a second pharmaceutical product. water or a syrup. Where desirable or necessary, flavoring, It will be appreciated that the pharmacological activity of preserving, Suspending, thickening or emulsifying agents can the compositions of the present technology can be demon be included. strated using standard pharmacological models that are Liquid dispersions for oral administration may be syrups, 55 known in the art. Furthermore, it will be appreciated that the emulsions or Suspensions. The syrups may contain as a car compositions of the present technology can be incorporated rier, for example, saccharose or saccharose with glycerol or encapsulated in a suitable polymer matrix or membrane for and/or mannitol and/or Sorbitol. The Suspensions and the site-specific delivery, or can be functionalized with specific emulsions may contain a carrier, for example a natural gum, targeting agents capable of effecting site specific delivery. agar, Sodium alginate, pectin, methylcellulose, carboxymeth 60 These techniques, as well as other drug delivery techniques, ylcellulose or polyvinyl alcohol. are well known in the art. The dose range for adult or pediatric human beings will In one or more embodiments of the present technology, the depend on a number of factors including the age, weight and solubility and dissolution rate of the composition can be condition of the patient. Suitable oral dosages of the prodrugs Substantially changed under different physiological condi of one stimulant of the presently described technology can be 65 tions encountered, for example, in the intestine, at mucosal the equivalents of those typically found in treatments using Surfaces, or in the bloodstream. In one or more embodiments that stimulant. For example, typical dosages for amphetamine of the present technology, the solubility and dissolution rate US 8,101,661 B2 41 42 of the composition can Substantially decrease the bioavail Another embodiment provides a method for reducing ability of the amphetamine, particularly at doses above those amphetamine cardiovascular toxicity comprising providing a intended for therapy. In one embodiment of the present tech patient with at least one non-standard amino acid conjugate of nology, the decrease in bioavailability occurs upon intranasal amphetamine, wherein the amino acid moiety can decrease administration. In another embodiment, the decrease in bio- 5 the rate of release of amphetamine within the first a few hours availability occurs upon intravenous administration. of administration. For each of the described embodiments of the present Another embodiment provides a method for reducing technology, one or more of the following characteristics can amphetamine cardiovascular toxicity comprising providing a be realized: The cardiovascular toxicity of the amphetamine patient with at least one non-standard amino acid conjugate of prodrug is Substantially lower than that of the unconjugated 10 amphetamine, wherein the amino acid moiety can provide a amphetamine and amphetamine conjugated with a standard plasma release curve which does not increase above the amino acid. The covalently bound polar hydrophilic moiety, amphetamine's cardiovascular toxicity level. Such as a non-standard amino acid moiety, reduces or elimi Another embodiment provides a method for reducing bio nates the possibility of behavioral deterioration or the availability of stimulant a comprising providing at least one rebound effect. The covalently bound polar hydrophilic moi- 15 polar, hydrophilic stimulant prodrug of the present technol ety reduces or eliminates the possibility of abuse by intranasal ogy, wherein the stimulant prodrug can maintain a steady administration. The covalently bound polar hydrophilic moi state plasma release curve which provides a therapeutically ety reduces the possibility of abuse by injection. effective bioavailability but prevents spiking or increased The presently described technology further provides meth plasma concentrations compared to unconjugated stimulant ods for altering and/or delivering amphetamines and other 20 when given at doses exceeding those within the therapeutic stimulants in a manner that can decrease their potential for range for the unconjugated Stimulant or the stimulant conju abuse. Methods of the present technology provide various gated with a standard diamino acid, for example. ways to regulate pharmaceutical dosage through conjugating Another embodiment provides a method for reducing bio stimulants such as amphetamine with polar hydrophilic availability of amphetamine or for preventing a toxic release ligands. Such as non-standard amino acids, of the present 25 profile of amphetamine in a patient, comprising providing at technology. least one non-standard amino acid conjugate of amphet One embodiment provides a method for preventing behav amine, wherein the conjugated amphetamine can maintain a ioral deterioration or the rebound effect by administering to a steady-state plasma release curve which provides a therapeu patient in need an amphetamine prodrug composition of the tically effective bioavailability but prevents spiking or present technology, which comprises at least one polar hydro- 30 increased plasma concentrations compared to amphetamine philic conjugate of amphetamine. conjugated with a standard amino acid. Another embodiment provides a method for preventing Another embodiment provides a method for preventing a behavioral deterioration or the rebound effect by administer C, or equivalent C spike for amphetamine or another ing to a patient in need an amphetamine prodrug composition stimulant while still providing a therapeutically effective bio of the present technology, which comprises at least one non- 35 availability curve comprising the step of administering to a standard amino acid conjugate of amphetamine. patient at least one polar, hydrophilic prodrug of amphet Another embodiment provides a method for safely deliv amine or another stimulant of the present technology. ering amphetamine or another stimulant comprising provid Another embodiment provides a method for preventing a ing a therapeutically effective amount of at least one polar, C, or equivalent C. Spike for amphetamine while still hydrophilic prodrug of stimulant of the present technology 40 providing a therapeutically effective bioavailability curve wherein the polar hydrophilic moiety can reduce the rate of comprising the step of administering to a patient at least one absorption of amphetamine or another stimulantas compared non-standard amino acid conjugate of amphetamine. to delivering the unconjugated Stimulant or the stimulant Another embodiment provides a method for preventing a conjugated with a standard amino acid, for example. toxic release profile in a patient comprising administering to Another embodiment provides a method for safely deliv- 45 a patient at least one polar, hydrophilic stimulant prodrug of ering amphetamine comprising providing a therapeutically the present technology, wherein the stimulant prodrug can effective amount of at least one non-standard amino acid maintain a steady-state plasma release curve which provides conjugate of amphetamine wherein the non-standard amino a therapeutically effective bioavailability but prevents spik acid moiety can reduce the rate of absorption of amphetamine ing or increased plasma concentrations compared to uncon as compared to delivering the unconjugated amphetamine or 50 jugated Stimulant or the stimulant conjugated to a standard amphetamine conjugated with a standard amino acid. amino acid, particularly when taken at doses above pre Another embodiment provides a method for reducing scribed amounts. stimulant toxicity comprising providing a patient with at least Another embodiment of the present technology is a method one polar, hydrophilic prodrug of the stimulant of the present for reducing or preventing abuse of a stimulant comprising technology, wherein the polar hydrophilic moiety can 55 providing, administering, or prescribing a composition to a increase the rate of clearance of pharmacologically active patient in need thereof, wherein said composition comprises stimulant (i.e., released stimulant such as amphetamine) at least one polar, hydrophilic stimulant prodrug of the when given at doses exceeding those within the therapeutic present technology Such that the pharmacological activity of range of the stimulant. the stimulant is decreased when the composition is used in a Another embodiment provides a method for reducing 60 manner inconsistent with the manufacturers instructions. stimulant toxicity comprising providing a patient with at least Another embodiment of the present technology is a method one polar, hydrophilic stimulant prodrug of the present tech for reducing or preventing abuse of a stimulant such as nology, wherein the polar hydrophilic moiety can provide a amphetamine comprising consuming at least one polar, plasma release curve which does not increase above the hydrophilic prodrug of the stimulant of the present technol stimulants toxicity level when given at doses exceeding 65 ogy, wherein said prodrug comprises the stimulant covalently those within the therapeutic range for the unconjugated attached to a polar hydrophilic ligand Such that the pharma stimulant. cological activity of the stimulant is substantially decreased US 8,101,661 B2 43 44 when the composition is used in a manner inconsistent with amphetamine prodrug is resistant to release amphetamine the manufacturers instructions. from the non-standard amino acid moiety when the compo Another embodiment of the present technology is a method sition is administered parenterally, such as intranasally or for reducing or preventing abuse of amphetamine comprising intravenously. Preferably, amphetamine may be released providing, administering, consuming, or prescribing a com from the non-standard amino acid moiety in the presence of position to a patient in need thereof, wherein said composi the intestinal tract. Optionally, the amphetamine composition tion comprises at least one non-standard amino acid conju used may be in the form of a tablet, capsule, oral film, oral gate of amphetamine Such that the pharmacological activity Solution, oral Suspension, or other oral dosage form discussed of amphetamine is decreased when the composition is used in herein. a manner inconsistent with the manufacturers instructions. 10 Another embodiment of the present technology is a method For one or more of the recited methods, the composition of of preventing behavioral deterioration or the rebound effect of the present technology used may yield a therapeutic effect amphetamine or stimulant treatment comprising providing, without substantial euphoria. Preferably, the stimulant, such administering, or prescribing an amphetamine composition as amphetamine, composition of the present technology can of the presently described technology to a patient in need 15 provide a therapeutically equivalent AUC when compared to thereof, wherein said composition comprises at least one the stimulant alone but does not provide a C, which results polar hydrophilic prodrug of amphetamine that can decrease in euphoria or an equivalent C. the potential of behavioral deterioration or the rebound effect Another embodiment of the present technology is a method from amphetamine or stimulant treatment. for reducing or preventing abuse of stimulants such as Another embodiment of the present technology is a method amphetamine comprising orally administering a stimulant of preventing behavioral deterioration or the rebound effect of prodrug composition of the present technology to a patient, amphetamine or stimulant treatment comprising providing, wherein said composition comprises at least one polar, hydro administering, consuming, or prescribing an amphetamine philic stimulant prodrug of the present technology that can composition of the presently described technology to a decrease the pharmacological activity of the stimulant when patient in need thereof, wherein said composition comprises 25 the composition is used in a manner inconsistent with the at least one non-standard amino acid conjugate of amphet manufacturers instructions. amine that can decrease the potential of behavioral deterio Another embodiment is a method for reducing or prevent ration or the rebound effect from amphetamine or stimulant ing the euphoric effect of a stimulant comprising orally treatment. administering a stimulant prodrug composition of the present Another embodiment of the present technology is a method 30 technology to a patient in need thereof, wherein said compo for reducing or preventing the euphoric effect of a stimulant sition comprises at least one polar, hydrophilic prodrug of the comprising providing, administering, or prescribing to a stimulant of the present technology that can decrease the human oranimal in need thereof, a composition comprising at pharmacological activity of the stimulant when the composi least one polar, hydrophilic stimulant prodrug of the present tion is used in a manner inconsistent with the manufacturers technology that can decrease the pharmacological activity of 35 instructions. the stimulant when the composition is used in a manner For one or more of the recited methods of the present inconsistent with the manufacturers instructions. technology, the following properties may be achieved Another embodiment of the present technology is a method through conjugating amphetamine to a polar hydrophilic for reducing or preventing the euphoric effect of amphet group or to a non-standard amino acid. In one embodiment, amine comprising providing, administering, or prescribing to 40 the cardiovascular toxicity or stress of the polar hydrophilic a human in need thereof, or consuming a composition com prodrug of, or non-standard amino acid conjugate of amphet prising at least one non-standard amino acid conjugate of amine of the present technology may be lower than that of the amphetamine that can decrease the pharmacological activity amphetamine when the amphetamine is delivered in its of amphetamine when the composition is used in a manner unconjugated State, as a compound conjugated to a standard inconsistent with the manufacturers instructions. 45 amino acid, or as a salt thereof. In another embodiment, the Another embodiment of the present technology is a method possibility of behavioral deterioration is reduced or elimi for reducing or preventing the euphoric effect of a stimulant, nated. In another embodiment, the possibility of abuse by comprising consuming a composition comprising at least one intranasal administration is reduced or eliminated. In another polar, hydrophilic stimulant prodrug of the present technol embodiment, the possibility of abuse by intravenous admin ogy that can decrease the pharmacological activity of the 50 istration is reduced or eliminated. stimulant when the composition is used in a manner incon Another embodiment of the present technology provides sistent with the manufacturers instructions. methods of treating various diseases or conditions requiring Another embodiment of the present technology is any of the stimulation of the central nervous system (CNS) compris the preceding methods wherein the stimulant composition ing administering compounds or compositions of the present used is adapted for oral administration, and wherein the 55 technology which, optionally, further comprise commonly stimulant prodrug is resistant to release the stimulant from the prescribed active agents for the respective illness or disease. polar hydrophilic moiety when the composition is adminis For instance, one embodiment of the invention comprises a tered parenterally, such as intranasally or intravenously. Pref method of treating attention deficit hyperactivity disorder erably, the stimulant may be released from the polar hydro (ADHD) comprising administering to a patient at least one philic moiety in the presence of acid and/or enzymes present 60 polar, hydrophilic prodrug of amphetamine of the present in the stomach, intestinal tract, or blood serum. Optionally, technology. Another embodiment of the invention comprises the stimulant composition used may be in the form of a tablet, a method of treating attention deficit hyperactivity disorder capsule, oral Solution, oral Suspension, thin Strip or other oral (ADHD) comprising administering to a patient at least one dosage form discussed herein. non-standard amino acid conjugate of amphetamine. Another Another embodiment of the present technology is any of 65 embodiment provides a method of treating attention deficit the preceding methods wherein the amphetamine composi disorder (ADD) comprising administering to a patient com tion used is adapted for oral administration, and wherein the pounds or compositions of the invention. US 8,101,661 B2 45 46 Another embodiment of the invention provides a method of EXAMPLE 2 treating narcolepsy comprising administering to a patient compounds or compositions of the presently described tech Preparation of Boc-harg(NO)-Amp nology. The presently described technology and its advantages will Boc-harg(NO)—OH (2.667g, 8 mmol) was dissolved in be better understood by reference to the following examples. DMF (25 mL). EDCI (2.30 g, 12 mmol), NHS (1.012 g, 8.8 These examples are provided to describe specific embodi mmol), d-amphetamine (1.269 g, 9.6 mmol) and DIEA (1.138 ments of the present technology. By providing these specific g, 8.8 mmol) were then added sequentially. The clear reaction mixture was stirred at room temperature for 16 hrs. The examples, the applicants do not limit the scope and spirit of reaction mixture was quenched with pH 3 water (150 mL), the present technology. It will be understood by those skilled 10 and the product was extracted with EtOAc (3x50 mL). The in the art that the full scope of the presently described tech combined extracts were washed with pH 3 water followed by nology encompasses the Subject matter defined by the claims saturated NaCl. The EtOAc layer was dried over anhydrous appending this specification, and any alterations, modifica MgSO. The product was recrystallized from EtOAc/hexane tions, or equivalents of those claims. two times to give 2.36 g of desired protected product. 15 The product was analyzed using H NMR (DMSO-d) 8. EXAMPLE1 The result shows 0.9-1.1 (m, 3H, Amp CH), 1.1-1.2 (m. 2H, hArg Y CH), 1.2-1.5 (m, 13H, Boc CH, hArg (3, Ó CH), Comparative Study of Pharmacokinetic Parameters 2.55-2.75 (m,2H, Amp BCH), 3.1 (m,2H, hArge CH), 3.75 of Released D-Amphetamine Following (m. 1H, Amp C. CH), 3.95 (m. 1H, hArg C. CH), 6.65 (t, 1H, Administration of a Polar Hydrophilic Prodrug of the hargguanidino NH), 7.1-7.3 (m, 5H, Amp Ar—H), 7.6-8.2 Non-Standard Amino Acid Type (harg-Amp) and a (brm, 2H, hargguanidine NH and amide NH), 8.5 (brs, 1H, Standard Amino Acid Conjugate (VyvanseTM, hArg NH NO). These results are consistent with the pro Lys-Amp) posed structure.

The pharmacokinetic parameters of d-amphetamine fol 25 EXAMPLE 3 lowing oral administration in rats of a non-standard amino acid conjugate of the present technology and a standard Preparation of hArg-Amp-2 HCl amino acid conjugate, VyvanseM (Lys-Amp), commercially (1-homoarginine-d-amphetamine dihydrochloride) available from Shire, Incorporated of Wayne, Pa. are studied in this example. The non-standard amino acid conjugate used 30 Boc-harg(NO)-Amp (1.5 g) was dissolved in HPLC in this example is the hydrochloride salt of hArg-Amp. The grade MeCH (120 mL) and to the clear solution was added the results are recorded in Table 3 below: Pd/C catalyst (10%, Aldrich). A small stir bar was placed in the flask and the reaction mixture was stirred under a slow TABLE 3 stream of hydrogen overnight after incorporating the 5-6 N 35 Non-standard amino HCl in 2-propanol solution (1.5 mL). After the overnight Parameter Acid% amp' Vyvanse TM% total Amp? reaction, the solution was filtered and the solvent evaporated. The white crystalline product was dried under vacuum to give AUCo. 8, 94% 100% 1.61 g of the Boc-harg-Amp intermediate product. AUCo. 4, 770, 100% 95% 100% The product (1.6 g) was dissolved in 80 mL of HPLC grade AUC 40 ex 76% 100% MeOH, and 5-6N HCl in 2-propanol (3.2 mL) was added to 400% 100% ex the solution. The reaction mixture was stirred overnight, Sol vent removed and re-dissolved in minimum amount of Percent amphetamine released relative to Vyvanse TM (at an equimolar concentration of amphetamine contained in the non-standard amino acid prodrug compared to the total MeOH. The final product was crashed out with MTBE, and amphetamine contained in Vyvanse TM) *Percent amphetamine relative to 50 mg Vyvanse TM dose dried under vacuum at 30°C. for about 20 hours to yield 1.12 45 g of a white powder. The study shows that the C of a prodrug of the preset The white powder was analyzed using "H NMR (DMSO technology is significantly lower than that of VyvanseTM, a d) 8. The result shows 0.9-1.1 (m, 3H, Amp CH), 1.1-1.2 standard amino acid conjugate of d-amphetamine, which can (m. 2H, hargy CH), 1.35 (m. 2H, harg BCH), 1.55 (m. 2H, lead to lower cardiovascular effects (blood pressure, heart harg 8 CH), 2.75 (d. 2H, Amp B CH), 3.0 (m. 2H, harge rate). Quick release (higher C) of amphetamine has 50 CH), 3.75 (m. 1H, Amp C. CH), 4.05 (m. 1H, harg C. CH), already demonstrated significant increases in blood pressure 7.1-7.2 (m, 5H, Amp Ar H), 7.2-7.8 (brm, 3H, amide NH, and heart rate. In certain patient populations, these cardiovas HCl), 8.0 (t, 1H, hargguanidino NH), 8.2 (brs, 2H, amide or cular side effects can be dose limiting or can cause the termi guanidino NH), 8.75 (d. 1H, amide NH); 'CNMR (DMSO nation of stimulant therapy. d) & 21.08 (Amp CH), 21.36 (hargy), 28.23 (hArgö),32.28 The pharmacokinetic parameters of d-amphetamine fol 55 (harg B), 40.18 (Amp B), 42.19 (harge), 46.88 (Amp C.), lowing parental administration of hArg-Amp and d-amphet 52.23 (harg C.), 126.54 (p-Ar), 128.52 (m-Ar), 129.60 (o-Ar), amine are also studied. The study shows that little release of 139.34 (Ar), 157.61 (C=O), 167.95 (guanidino C): amphetamine (intranasal: <40% of AUC and <20% of C. M+1=306. These results are consistent with the proposed intravenous: <50% of AUC and <40% of C, when com Structure. pared to d-amphetamine Sulfate) happens when harg-Amp is 60 taken through parental routes (intranasal, intravenous) due to EXAMPLE 4 differences in enzymes encountered in the gut versus other routes. When Adderall XRR) or other controlled release for Preparation of Cit-Amp. Hel mulations of amphetamine are injected or Snorted, the phar (1-citrulline-d-amphetamine hydrochloride) macokinetic parameters of the amphetamine are significantly 65 altered and an individual can use these changes to produce Boc-Cit-OH (0.500 g, 1.82 mmol) was dissolved in anhy euphoria. drous THF. To this solution was added NHS (0.209 g, 1.82 US 8,101,661 B2 47 48 mmol) followed by DCC (0.376 g, 1.82 mmol). Resulting was kept overnight at ambient temperature. White crystals slurry was stirred at ambient temperature overnight. In a formed which were filtered off, rinsed with water and dried in separate flask, d-amphetamine sulfate (0.306 g. 0.83 mmol) high vacuum to yield 877 mg (2.00 mmol) of Z-1-hyPro(tBu)- was suspended in THF (10 mL) and NMM (0.34 mL, 3.64 d-Amp. mmol) was added. The activated ester was filtered directly Fully protected Z-l-hyPro(t-Bu)-d-Amp (500 mg, 1.14 into the amphetamine Suspension and the resulting Suspen mmol) was dissolved in 10 mL of MeOH. Pd/C (10 w.t.-% Pd, sion was stirred overnight. The reaction was quenched with 250 mg) was added and the mixture stirred overnight in 5% NaHCO and IPAc for 45 min. Organic solvent was then hydrogen atmosphere at ambient temperature. The Suspen removed. The aqueous layer was then extracted 3 times with sion was filtered through Celite(R) and solvent was evaporated IPAc and the combined organics were washed with 5% acetic 10 to dryness. Crude product was purified via column chroma acid, 5% NaHCO and 5% NaCl. The organic layer was then tography (0-2.5% MeOH/DCM) to give 96 mg (0.32 mmol) dried over NaSO and solvent was removed. Crude product of 1-hyPro(t-Bu)-d-Amp. was re-crystallized using IPAc/heptane to yield 200 mg of a Hydroxyl-protected 1-hyPro(t-Bu)-d-Amp (96 mg, 0.32 white solid. HPLC: column: YMC ODS-AQ, 5um, 120 A, 4.6x250 mm; mobile phase: A=0.1% TFA/HO, B=0.1% 15 mmol) was cooled in an ice-bath and 5 mL of chilled TFA TFA/MeCN; method: 0-15 min.: 85/15->60/40, 15-25 min.: were added. The ice-bath was removed and the mixture was 60/40->0/100; flow rate: 1 mL/min. UV detection: 230 nm, stirred overnight. The solvent was evaporated and the remain retention time: 8.06 min. ing residue was dissolved in 4 NHCl/dioxane. This process 10 mL of 4N HCl in dioxane were added to the 200 mg was repeated three times. The product was dried in high (0.200 g) Boc-Cit-Amp. The mixture was stirred at room vacuum to yield 90 mg (0.32 mmol) of 1-hyPro-d-Amp.HC1. temperature for 6 hours and solvent was removed. HPLC: column: YMCODS-AQ, 5um, 120 A, 4.6x250 mm: mobile phase: A=0.1 TFA/HO, B=0.1% TFA/MeCN: EXAMPLE 5 method: 0-15 min.: 85/15->60/40, 15-25 min.: 60/40->0/ 100; flow rate: 1 mL/min. UV detection: 230 nm, retention Preparation of hCit-Amp.HCl 25 time: 9.61 min. (1-homocitrulline-d-amphetamine hydrochloride) EXAMPLE 7 Procedure as described for citrulline. However, 1,4-diox ane was used during amino acid activation and coupling reac Preparation of Lys-ol-Co-Amp tion instead of THF. Crude product was purified via column 30 (1-Lysinol-Co-D-Amphetamine) chromatography (0-6.5% MeOH/DCM) to give 201 mg (0.49 mmol) of Boc-l-hCit-d-amphetamine (based on 500 mg of Boc-1-Lys(Z)-ol (500 mg, 1.36 mmol) was dissolved in 10 Boc-1-hCit-OH). mL of anhydrous dioxane. CDI was added and the mixture The Boc-protected Boc-l-hCit-d-Amp (110 mg, 0.27 stirred overnight at ambient temperature. Solvent was evapo mmol) was cooled in an ice-bath and 10 mL of chilled 4 N 35 HCl/dioxane were added. The mixture was stirred for 4 hand rated to dryness and the remaining oily residue was dissolved solvent was evaporated to dryness yielding 92 mg (0.27 in 15 mL of anhydrous THF. Amphetamine sulfate (277 mg, mmol) of 1-hCit-d-Amp.HC1. HPLC: column: YMC ODS 0.75 mmol) and EtN (0.40 mL, 2.86 mmol) were added and AQ, 5um, 120 A, 4.6x250mm; mobile phase: A-0.1%TFA/ the mixture was stirred overnight at 50° C. The reaction was HO, B=0.1% TFA/MeCN; method: 0-15 min.: 85/15->60/ 40 quenched with water and the aqueous layer extracted with 40, 15-25 min.: 60/40->0/100; flow rate: 1 mL/min. UV IPAc (3x75 mL). The combined organics were washed with detection: 230 nm, retention time: 8.92 min. 5%HOAc, sat. NaHCO, sat. NaCl and 5% NaCl solution and dried over NaSO. Solvents were evaporated to dryness EXAMPLE 6 yielding Boc-1-Lys(Z)-ol-CO-d-Amp as a white foam. 45 HPLC: column: YMCODS-AQ, 5um, 120 A, 4.6x250 mm: Preparation of hyPro-Amp.HCl mobile phase: A=0.1% TFA/HO, B=0.1% TFA/MeCN: (2-hydroxyproline-d-amphetamine hydrochloride) method: 0-15 min.: 85/15->60/40, 15-25 min.: 60/40->0/ 100; flow rate: 1 mL/min. UV detection: 230 nm, retention Z-l-hyPro(t-Bu)-OH (1.000 g, 3.11 mmol) was dissolved time: 20.59 min. in 15 mL of anhydrous THF. NHS (0.358 g., 3.11 mmol) was 50 added and the solution was stirred for 5 min. DCC (0.642 g, EXAMPLE 8 3.11 mmol) was then added and the mixture stirred overnight at ambient temperature. In a separate flask, d-amphetamine Preparation of Carn-Amp sulfate (0.521 g, 1.41 mmol) was suspended in 15 mL of (O-acetyl-l-carnitine-d-amphetamine) anhydrous THF and NMM (0.68 mL, 6.22 mmol) was added. 55 The mixture was stirred for 10 min. Subsequently, the prior O-Acetyl-l-carnitine.C1 (1.000 g, 4.17 mmol) was dis prepared Succinimidyl ester was charged to the Suspension solved in 12.5 mL of a mixture of DMF/dioxane?water (2:2: through a sintered funnel and the mixture was stirred over 1). NHS (0.528g, 4.59 mmol) and DCC (0.947g, 4.59 mmol) night. The reaction was quenched with 5% NaHCO solution were added and the mixture was stirred overnight at ambient (75 mL). IPAc (25 mL) was added and the solution stirred for 60 temperature. Solvents were evaporated and the remaining 45 min. The mixture was concentrated by evaporating most of residue was dried overnight in high vacuum. The crude Suc the organic solvents. The aqueous layer was extracted with cinimidyl ester intermediate was dissolved in 20 mL of anhy IPAc (3x100 mL). The combined organics were washed with drous DMF, Amphetamine sulfate (0.700 g, 1.90 mmol) and 5% HOAc (1x100 mL), 5 NaHCO, (1x100 mL) and 5% NaCl NMM (0.92 mL, 8.34 mmol) were added and the mixture solution (2x100 mL), dried over NaSO and evaporated to 65 stirred overnight. Solvent was evaporated to dryness and the dryness. Crude product was dissolved in 10 mL of AcO at remaining residue was leached with IPA. Solvent was evapo 60° C. and 10 mL water were added while hot. The mixture rated to yield Carn-d-Amp. US 8,101,661 B2 49 50 EXAMPLE 9 TABLE 5 Average Results of 6 Oral Studies (n = 30 per compound Pharmacokinetic Study of hArg-Amp Vs. Lys-Amp Vehicle % AUC T 96 T 96 C 96 AUCo. 4, Male Sprague-Dawley rats were fasted overnight and Lys-Amp 100% 1 100% 100% 100% dosed by oral gavage with either 1-homoarginine-d-amphet hArg-Amp 81% 2-4h 200-400%. 69% 67% amine (harg-Amp) or 1-lysine-d-amphetamine (VyvanseTM, Lys-Amp). Water was provided ad libitum. Doses were cal culated at an equivalent 1.5 mg/kg freebase equivalent of 10 EXAMPLE 10 d-amphetamine. Plasma concentrations of d-amphetamine Comparative Biological Study of Lys-Amp and were measured using ELISA (Neogen Corp. Lexington, Ky.). Cit-Amp Mean plasma concentration curves (n=5) of d-amphet amine released by 1-homoarginine-d-amphetamine or 15 To compare the amount of release of d-amphetamine 1-lysine-d-amphetamine are shown in FIG.1. Pharmacokinet among various polar hydrophilic prodrugs, 1-citruline-d-am ic(PK) parameters of this study are listed in Table 4. phetamine (Cit-Amp) was dosed with Lys-Amp in another oral pharmacokinetic study. Mean plasma concentration TABLE 4 curves (n=5) of d-amphetamine released by Cit-Amp and 2O Lys-Ampare shown in FIG. 6. Pharmacokinetic parameters Pharmacokinetic Properties of hArg-Amp and Lys-Amp of this study are listed in Table 6. Vehicle % AUC T C % Tax % Cmax Direct comparison of polar hydrophilic prodrugs espe ex ex cially non-standard amino acid conjugates of amphetamine Lys-Amp 100% 44 ng/mL 100% 100% hArg-Amp 99% 44 ng/mL 1.33% 100% (Cit and harg) demonstrate the significant ability to shift or 25 change the pharmacokinetic properties versus the standard amino acids. All non-standard amino acids studied released This pharmacokinetic (PK) study clearly demonstrates a amphetamine in an amount greater than 50%. Homoarginine shift in the T for the polar hydrophilic prodrug of the showed Clevels far below that of lysine and homoarginine non-standard amino acid type (harg-Amp) compared to the and citrulline significantly shifted the T compared to Lys 30 Amp. These changes to the pharmacokinetic properties of standard amino acid (Lys-Amp). This shift may be due to a amphetamine when conjugated to non-standard amino acids reduction in the rate of enzymatic hydrolysis of the amide represent clinically significant changes not described or dem bond of the non-standard amino acid attached to amphet onstrated by Lys-Amp nor described or demonstrated by amine vs. the standard amino acid attached to amphetamine. other standard amino acids. FIGS. 2-4 represent different ways to view the data 35 reflected in FIG. 1 and Table 4. As further discussed below, TABLE 6 these figures highlight the differences of hArg-Amp over Lys-Amp during the first several hours. Oral Properties of Lys-Amp and Cit-Amp FIG. 2 demonstrates the relative blood levels of d-amphet Vehicle % AUC Tmax Cmax % Tax % Cna. 40 amine released from both Lys-Amp and harg-Amp. The Lys-Amp 100% 1 h 59ng/mL 100% 100% graph shows that equivalent blood levels do not occur until Cit-Amp 95% 15 min. 129 ng/mL 25%. 21.9% later time points and that blood levels do not appear to spike or have a more significant C than Lys-Amp. The amount of d-amphetamine released from hArg-Amp is gradual and as EXAMPLE 11 maintains a more steady concentration over the duration of the study than did Lys-Amp. In contrast, Lys-Amp blood Pharmacokinetic Study of Lys-Amp, hCit-Amp and levels of released d-amphetamine "spiked at 3 hours and harg(NO)-Amp cleared more quickly than the blood levels obtained from To compare the amount of release of d-amphetamine hArg-Amp. 50 among various polar hydrophilic prodrugs, 1-homocitrulline FIGS. 3 and 4 show the difference in blood levels obtained d-amphetamine (hCit-Amp) and 1-homoarginine(NO)-d- from the study described in FIG. 2. As is shown, the initial amphetamine (harg(NO)-Amp) were dosed with Lys-Amp blood levels for both conjugates (Lys-Amp and harg-Amp) in another oral pharmacokinetic study. Mean plasma concen are very different, with hArg-Amp releasing amphetamine at tration curves (n=5) of d-amphetamine released by the a more gradual rate. These differences in blood levels become 55 amphetamine prodrugs are shown in FIGS. 7 and 8. Pharma less during the more critical duration of action for stimulant cokinetic parameters of this study are listed in Table 7 treatments and more importantly, the differences are greater again at later time points suggesting that harg-Amp main TABLE 7 tains a more consistent dose of amphetamine when compared Oral Properties of Lys-Amp, h0lit to Lys-Amp. The longer duration of release for harg-Amp 60 Amp, Sar-Amp and hArg(NO2)-Amp would suggest a much lower opportunity for behavioral dete rioration to occur. Vehicle % AUC T. Cmax % Tax % Cna. Lys-Amp 100% 1 h 54 ng/mL 100% 100% Other oral studies have been conducted in a similar fashion hCit-Amp 78% 1 h 57 ng/mL NA 105% and are summarized in Table 5 below. The average PK results 65 hArg(NO-)-Amp 69% 1 h 59ng/mL NA 109% for four (4) oral studies (n=30 per vehicle) are recorded in FIG.S: US 8,101,661 B2 51 52 EXAMPLE 12 changing AUC significantly. In addition, the slope of uptake of hArg-Amp vs. Lys-Amp appears to be more gradual thus Intranasal Study of AMP. Lys-Amp and harg-Amp leading to a slower onset which could further alleviate side effects. Male Sprague-Dawley rats were fasted overnight and 5 The amphetamine conjugates listed above of the present dosed by intranasal administration with either harg-Amp, technology demonstrate that by using polar hydrophilic pro Lys-Amp or d-amphetamine. Doses were calculated at an drugs, a shift in the T occurs while still retaining AUC and equivalent 1.5 mg/kg freebase equivalent of d-amphetamine. potential clinical effect. By using polar hydrophilic prodrugs, Plasma concentrations of d-amphetamine were measured we are able to demonstrate that harg-Amp shows little using ELISA. Mean plasma concentration curves (n=5) of 10 release via the IN (intranasal) and IV (intravenous) route yet d-amphetamine released by harg-Amp or Lys-Amp are still maintain a similar AUC. shown in FIG. 8. Pharmacokinetic parameters of this study In addition, the amphetamine conjugate, harg-Amp, of the are listed in Table 8. No significant release (<50%) was present technology demonstrates that by using non-standard observed in either harg-Amp or Lys-Amp and less release amino acids, a shift in the T occurs while still retaining 15 AUC and potential clinical effect. was observed within the first hour of administration (<25%). For example, value ranges for the pharmacokinetic param Observed levels from Lys-Amp are significantly higher than eters of amphetamine derivatives conjugated to homoarginine previously published data. after oral administration when compared to the respective unconjugated amphetamine derivatives are provided in Table TABLE 8 2O 10. Intranasal Properties of d-Amp, hArg-Amp and Lys-Amp TABLE 10 0. Vehicle % AUC T ex C ex 96 Tmax %Cmax PK Parameter hArg-PEA' d-Amp 100% 5 min. 779 ng/mL 100% 100% hArg-Amp 42% O.S 71 ng/mL. 600% 99%. 25 AUCo-12, SO-200% Lys-Amp 36% 3 h 79 ng/mL 3600% 10% AUCs, SO-200% AUC SO-200% Cmax 50-500% Tmax 25-500% EXAMPLE 13 T1/2 SO-200% 30 PEA = derivative of amphetamine (phenethylamine analog) Intravenous Study of d-Amp, hArg-Amp, Lys-Amp PK Parameter for amphetamine derivative released from hArg-PEA conjugate expressed as percent of PK parameter for the unconjugated amphetamine derivative (both adminstered at equimolar doses) Male Sprague-Dawley rats were dosed by intravenous In no case shallC and T and T12 and any AUC value for any one harg-PEA conjugate administration through the tail vein with hArg-Amp, Lys all be within 80-125%. Amp or d-amphetamine. Doses were calculated at an equiva- 35 The polar, hydrophilic amphetamine prodrug, such as a lent 1.5 mg/kg freebase equivalent of d-amphetamine. Plasma non-standard amino acid amphetamine conjugate, of the concentrations of d-amphetamine were measured using present technology is chemically stable to in vitro hydrolysis ELISA. Mean plasma concentration curves (n=5) of d-am of the amide linkage to prevent tampering or removing the phetamine released by harg-Amp or Lys-Amp are shown in amphetamine prior to oral ingestion. Also, the controlled FIG.9. Pharmacokinetic parameters of this study are listed in 40 release of amphetamine through oral administration of the Table 9. No significant release (<15%) was observed in either polar, hydrophilic amphetamine prodrug, such as a non-stan hArg-Amp or Lys-Amp though hArg-Amp was significantly dard amino acid amphetamine conjugate, of the present tech less. Observed levels from Lys-Amp are significantly higher nology is an inherent property of the molecule, not related to than previously published data. The initial spike in d-amphet the formulation. Therefore, the prodrug of the present tech amine released from hArg-Amp cleared quickly. 45 nology can be easily formulated to different dosage forms. The invention is now described in such full, clear, concise TABLE 9 and exact terms as to enable any person skilled in the art to which it pertains, to practice the same. It is to be understood Intravenous Properties of d-Amp, harg-Amp and Lys-Amp that the foregoing describes preferred embodiments of the 50 Vehicle % AUC Tmax Cmax % Tax %Cna. invention and that modifications may be made therein without d-Amp 100% 5 min. 554 ng/mL 100% 100% departing from the spirit or scope of the invention as set forth hArg-Amp 8% 5 min. 68 ng/mL. 100% 12% in the appended claims. Lys-Amp 14% 15 min. 79 ng/mL 100% 14% What is claimed is: 55 1. A composition for treating a human or animal patient Results of the studies in above examples clearly show an having attention deficit disorder or attention deficit hyperac unexpected change in the oral pharmacokinetic properties tivity disorder, comprising at least one salt of a conjugate exhibited by polar hydrophilic prodrugs, including non-stan comprising amphetamine chemically attached to homoargi dard amino acid conjugates of amphetamine. By changing the nine, wherein the salt is selected from an acefyllinate, 4-ac polar hydrophilic group attached to amphetamine, the conju- 60 etamidobenzoate, acetate, aceturate, adipate, aminosalicy gates are able to shift T. (earlier or later), modify curve late, ammonium, ascorbate, 1-aspartate, besylate, shape, lower C, and raise C. In addition, the shift in bicarbonate, borate, butyrate, calcium, camphocarbonate, T for harg-Amp may be clinically significant in that many camphorate, d-camsylate, 1-camsylate, camsylate, carbonate, of the cardiovascular side effects and toxicity are related to cholate, cypionate, decanoate, dichloroacetate, edentate, edi T, and C. The results demonstrate that by using these 65 Sylate, estolate, esylate, ethyl sulfate, fumarate, furate, fusi polar hydrophilic groups, including non-standard amino date, galactarate (mucate), galacturonate, gallate, gentisate, acids, a shift in the T with a lower C. occurs without gluceptate, gluconate, glucuronate, glutamate, glutarate, US 8,101,661 B2 53 54 glycerophosphate, glycolate, heptanoate (enanthate), hex heptanoate (enanthate), hexanoate, hippurate, hybenzate, anoate, hippurate, hybenzate, hydrobromide/bromide, hydrobromide/bromide, hydrochloride/chloride, hydroxide, hydroxide, hydroxybenzoate, iodide, isethionate, d-lactate, hydroxybenzoate, iodide, isethionate, d-lactate, l-lactate, d.l- 1-lactate, d.l-lactate, lactobionate, laurate, lithium, magne lactate, lactobionate, laurate, lithium, magnesium, malate, sium, maleate, malonate, mandelate, meso-tartrate, methane d.l-malate, maleate, malonate, mandelate, meso-tartrate, Sulfonate, methylsulfate, myristate, napadisilate, 2-napsy mesylate, methanesulfonate, methylsulfate, myristate, napa late, nicotinate, octanoate, oleate, orotate, palmitate, disilate, 2-napsylate, nicotinate, nitrate, octanoate, oleate, pamoate, phenylpropionate, picrate, pivalate, potassium, pro orotate, oxalate, palmitate, pamoate, phenylpropionate, phos pionate, pyrophosphate, Salicylate, salicylsulfate, Sodium, phate, picrate, pivalate, potassium, propionate, pyrophos Stearate. Succinate, Sulfosalicylate, tannate, terephthalate, 10 phate, Salicylate, Salicylsulfate, sodium, Stearate. Succinate, thiocyanate, thiosalicylate, tosylate, tribrophenate, unde Sulfate, Sulfosalicylate, tannate, d-tartrate, kartrate, d.l-tar cylenate, Valerate, valproate, Xinafoate, Zinc, and mixtures trate, terephthalate, thiocyanate, thiosalicylate, tosylate, tri thereof. brophenate, triflate, undecylenate, Valerate, valproate, Xin 2. The composition of claim 1, wherein the homoarginine afoate, Zinc, and mixtures thereof. is 1-homoarginine. 15 8. The composition of claim 1, wherein the conjugate is 3. The composition of claim 1, wherein the amphetamine is 1-homoarginine-d-amphetamine. d-amphetamine. 9. The composition of claim 1, wherein the composition 4. A composition for treating a human or animal patient has a reduced pharmacological activity when administered by having attention deficit disorder or attention deficit hyperac parenteral routes. tivity disorder, comprising a derivative of amphetamine 10. The composition of claim 1, wherein the composition is chemically attached to homoarginine, a salt thereof, or a in the form of a tablet, a capsule, a caplet, a troche, a lozenge, combination thereof, wherein the derivative of amphetamine an oral powder, a Solution, a oral film, a thin strip, or a is selected from 1-amphetamine, methamphetamine, p-meth Suspension. oxyamphetamine, 3.4-methylenedioxyamphetamine, 2.3- 11. The composition of claim 10, wherein the tablet, tro methylenedioxyamphetamine, 3.4-methylenedioxymetham 25 che, or lozenge is chewable. phetamine, 2,5-dimethoxy-4-methylamphetamine, 3,4,5- 12. The composition of claim 1, wherein the salt of the trimethoxyamphetamine, 2,4,5-trimethoxyamphetamine, conjugate is present in the amount of from about 1 mg to 2,3,4-trimethoxyamphetamine, 2,3,5-trimethoxyamphet about 500 mg. amine, 2.3.6-trimethoxyamphetamine, and 2,4,6-tri 13. The composition of claim 12, wherein the salt of the methoxyamphetamine. 30 conjugate is present in the amount of from about 5 mg to 5. The composition of claim 4, wherein the homoarginine about 250 mg. is 1-homoarginine. 14. The composition of claim 13, wherein the salt of the 6. The composition of claim 4, wherein the derivative of conjugate is present in the amount of from about 10 mg to amphetamine is 1-amphetamine. about 100 mg. 7. The composition of claim 4, wherein the salt thereofisan 35 15. The composition of claim 1, wherein the salt of the acefyllinate, 4-acetamidobenzoate, acetate, aceturate, adi conjugate is in an amount Sufficient to provide a therapeuti pate, aminosalicylate, ammonium, ascorbate, 1-aspartate, cally bioeduivalent AUC when compared to amphetamine benzoate, besylate, bicarbonate, borate, butyrate, calcium, alone, but does not provide a C. Spike. camphocarbonate, camphorate, d-camsylate, 1-camsylate, 16. The composition of claim 1, wherein the salt of the camsylate, carbonate, cholate, citrate, cypionate, decanoate, 40 conjugate is in an amount Sufficient to provide a therapeuti dichloroacetate, edentate, edisylate, estolate, esylate, ethyl cally bioeduivalent AUC when compared to amphetamine Sulfate, fumarate, furate, fusidate, galactarate (mucate), alone, but does not provide an equivalent C. galacturonate, gallate, gentisate, gluceptate, gluconate, glu curonate, glutamate, glutarate, glycerophosphate, glycolate, k k k k k