WO2018107131A1

WO2018107131A1 - Methylphenidate-prodrugs, processes of making and using the same

Info

Publication number: WO2018107131A1
Application number: PCT/US2017/065481
Authority: WO
Inventors: Travis Mickle; Sven M. GUENTHER; Gouchen Chi
Original assignee: Kempharm, Inc.
Priority date: 2016-12-11
Filing date: 2017-12-09
Publication date: 2018-06-14

Abstract

The present technology is directed to d-threo-methylphenidate conjugates and a composition comprising d-threo-methylphenidate conjugated to nicotinoyl-L-serine, or salt thereof. The present technology also relates to a composition comprising at least one conjugate of d-methylphenidate having at least two or more chiral centers. The composition is optically active. The present technology additionally relates to oral formulations and pharmaceutical kits comprising at least one d-threo-methylphenidate conjugate. The pharmaceutical kit may comprise a specified amount of individual doses in a package. Each individual dose in the package may contain a pharmaceutically effective amount of a conjugate of d-threo methylphenidate.

Description

METHYLPHENIDATE-PRODRUGS, PROCESSES OF MAKING AND USING THE

SAME

RELATED APPLICATIONS

[1 ] The present application claims priority to U.S. Provisional Patent Application

No. 62/432,675, filed on December 1 1 , 2016, and to U.S. Provisional Patent Application No. 62/519,629, filed June 14, 2017, each of which is incorporated by reference in its entirety.

FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[2] [Not Applicable]

BACKGROUND OF THE INVENTION

[3] Methylphenidate is a psychostimulant which is a chain substituted amphetamine derivative. Similar to amphetamine and cocaine, methylphenidate targets the central nervous system, specifically the dopamine transporter (DAT) and norepinephrine transporter (NET). Methylphenidate is thought to act by increasing the concentrations of dopamine and norepinephrine in the synaptic cleft, as methylphenidate has both dopamine transporter (DAT) and norepinephrine transporter (NET) binding capabilities. Although an amphetamine derivative, the pharmacology of methylphenidate and amphetamine differ, as amphetamine is a dopamine transport substrate whereas methylphenidate works as a dopamine transport blocker. As a norepinephrine and dopamine re-uptake inhibitor, methylphenidate thus blocks reuptake of dopamine and norepinephrine (noradrenaline) into presynaptic neurons (and possibly stimulates the release of dopamine from dopamine nerve terminals at high doses), thereby increasing the levels of dopamine and norepinephrine in the synapse. In some in vitro studies, methylphenidate has been shown to be more potent as an inhibitor of norepinephrine uptake/re-uptake when compared to dopamine. However, some in vivo studies have indicated that methylphenidate is more potent in potentiating extracellular dopamine concentrations than norepinephrine concentrations. Unlike amphetamine, it has been suggested in the scientific and/or clinical research community that methylphenidate does not seem to significantly facilitate the release of these two monoamine neurotransmitters at therapeutic doses.

[4] Four isomers of methylphenidate are known to exist: ά-erythro- methylphenidate, /-eryfftro-methylphenidate, d-fftreo-methylphenidate, and l-threo- methylphenidate. Originally, methylphenidate was marketed as a mixture of two racemates, d//-eryf/7ro-methylphenidate and d//-f/7reo-methylphenidate. Subsequent research showed that most of the desired pharmacological activity of the mixture is associated with the fftreo-isomer resulting in the marketing of the isolated threo- methylphenidate racemate. Later, the scientific community determined that the 6-threo- isomer is mostly responsible for the stimulant activity. Consequently, new products were developed containing only d-fftreo-methylphenidate (also known as "d-threo- MPH").

[5] Stimulants, including methylphenidate ("MPH"), are believed to enhance the activity of the sympathetic nervous system and/or central nervous system (CNS). Stimulants such as MPH and the various forms and derivatives thereof are used for the treatment of a range of conditions and disorders predominantly encompassing, for example, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), obesity, narcolepsy, appetite suppression, depression, anxiety and/or wakefulness.

[6] Methylphenidate is currently approved by the United States Food and Drug

Administration ("FDA") for the treatment of attention-deficit hyperactivity disorder and narcolepsy. Methylphenidate has also shown efficacy for some off-label indications that include depression, obesity and lethargy. In some embodiments, the prodrugs of the present technology may be administered for the treatment of attention-deficit hyperactivity disorder and narcolepsy, or any condition that requires the blocking of the norepinephrine and/or dopamine transporters.

[7] Attention deficit hyperactivity disorder (ADHD) in children has been treated with stimulants for many years. However, more recently, an increase in the number of prescriptions for ADHD therapy in the adult population has, at times, outperformed the growth of the pediatric market. Although there are various drugs currently in use for the treatment of ADHD, including some stimulants and some non-stimulant drugs, methylphenidate (commercially available from, for example, Novartis International AG (located in Basel, Switzerland) under the trademark Ritalin®) is commonly prescribed. Moreover, during classroom trials, non-stimulants have shown to be less effective in improving behavior and attention of ADHD afflicted children than amphetamine derivatives.

[8] Behavioral deterioration (rebound or "crashing") is observed in a significant portion of children with ADHD as the medication wears off, typically in the afternoon or early evening. Rebound symptoms include, for example, irritability, crankiness, hyperactivity worse than in the un-medicated state, sadness, crying, and in rare cases psychotic episodes. The symptoms may subside quickly or last several hours. Some patients may experience rebound/crashing so severe that treatment must be discontinued. Rebound/crashing effects can also give rise to addictive behavior by enticing patients to administer additional doses of stimulant with the intent to prevent anticipated rebound/crashing negative outcomes and side effects.

[9] Stimulants, such as methylphenidate and amphetamine, have been shown in the conventional art to exhibit noradrenergic and dopaminergic effects that can lead to cardiovascular events comprising, for example, increased heart rate, hypertension, palpitations, tachycardia and in isolated cases cardiomyopathy, stroke, myocardial infarction and/or sudden death. Consequently, currently available stimulants expose patients with pre-existing structural cardiac abnormalities or other severe cardiac indications to even greater health risks and are frequently not used or used with caution in this patient population.

[10] Methylphenidate, like other stimulants and amphetamine derivatives, can become addictive and is prone to substance abuse. Oral abuse has been reported, and euphoria can be achieved through intranasal and intravenous administration.

[1 1 ] Dependence on stimulants like cocaine can occur even after usage for a very short period of time due to their potent euphoric effects. For example, early signs of cocaine dependence include difficulty to abstain from cocaine use when it is present or available. Many stimulants including cocaine have a short elimination half-life and thus require frequent dosing to maintain the "high". Chronic use of supratherapeutic doses of such stimulants may result in numerous mental and/or physical problems. Effects on mood include anxiety, restlessness, feelings of superiority, euphoria, panic, irritation, and fearfulness. Behavioral symptoms include but are not limited to being extremely talkative, having increased energy, stealing or borrowing money, erratic or odd behavior, violence, lack of participation in activities that were once enjoyable, and reckless and risky behaviors. Examples of physical symptoms of stimulant dependence may include one or more of the following: decreased need to sleep, headaches, nosebleeds, hoarseness, increased heart rate, muscle twitches, malnutrition, increase in body temperature, nasal perforation, abnormal heart rhythms, chronic runny nose, constricting blood vessels, increased heart rate, increased blood pressure, sexual dysfunction, decreased appetite, dilated pupils, risks for contracting Human Immunodeficiency Virus (HIV), hepatitis C and other bloodborne diseases, gangrene of the bowel, cravings, and tremors. Examples of psychological symptoms of stimulant dependence may include one or more of the following: severe paranoia, violent mood swings, break from reality, lack of motivation, psychosis, hallucinations, inability to use sound judgment, and the rationalization of drug use. There is a variety of factors that can trigger or play a role in stimulant use disorder or stimulant dependence. Generally, these factors can be placed into three categories: genetic, biological, and environmental. Research has shown that individuals who have relatives with addiction problems are more likely to develop an addiction including cocaine dependence. The likelihood of becoming stimulant dependent is higher if the relative is a parent. Changes in brain function may be a biological factor that correlates with addiction problems. For example, low dopamine levels in the brain may result in an individual to abuse substances with the goal to attain pleasurable feelings. Environmental factors include but are not limited to unpredictable situations in the home lives of an individual; stressors, such as child abuse, the loss of a loved one, or other traumatic events.

[12] There is a need in the art for forms of methylphenidate that have a slow gradual increase in methylphenidate blood/brain concentrations until peak concentrations are achieved, or a slow gradual decrease of methylphenidate blood/brain concentrations after peak concentrations, or both. Not wishing to be bound by any particular theory, it is possible that slow onset of stimulant concentrations can decrease cardiovascular side effects, and slow elimination can decrease rebound effects. It has also been suggested that a larger increase in synaptic dopamine per time unit (i.e., higher rate of dopamine increase) results in more robust and intense euphoric effect. A slow increase in methylphenidate brain concentration produces a low rate of increase in synaptic dopamine and thus, may result in less rewarding and reinforcing effects. Without wishing to be bound by any particular theory, it has also been suggested that high occupancy of dopamine transporter receptors may decrease the rewarding and reinforcing effects of additional doses of stimulants like cocaine. This could be accomplished, for example, by repeated administration of large doses of a form of methylphenidate with a slow onset that does not result in euphoria.

[13] There is a need in the art for forms of methylphenidate that maintain the pharmacological benefit when administered, in particular via the oral route, but which preferably have no or a substantially decreased pharmacological activity when administered through injection or intranasal routes of administration. There is also a need in the art for forms of methylphenidate that can provide flexibility in dosing regimens. For example, a single daily dose form of methylphenidate that can provide an extended release PK profile would be highly desirable.

BRIEF SUMMARY OF THE INVENTION

[14] The present technology provides a particular d-fftreo-methylphenidate ("d-

MPH", "d-methylphenidate", "dexmethylphenidate") conjugate, or pharmaceutically acceptable salts thereof, to provide, for example, at least one single daily dose form of d-methylphenidate that can provide an extended release PK profile when compared to unconjugated d-methylphenidate. The release profile in some instances provides the ability of the prodrug or composition to be administered using dosing regimens that are not easily utilized with the unconjugated d-methylphenidate.

[15] In another aspect, the present technology provides a compound having a structure of Formula I:

or a pharmaceutically acceptable salt thereof.

[16] In another aspect, the present technology provides at least one composition comprising at least one conjugate, wherein the at least one conjugate is d-methylphenidate-CO₂CH₂-nicotinoyl-L-Ser (Formula I), or pharmaceutically acceptable salts thereof, and the composition does not contain unconjugated d- methylphenidate. Upon administration to a subject, the composition results in an extended release of d-methylphenidate in the subject compared to the release of d- methylphenidate upon administration of an equivalent molar amount of unconjugated d- methylphenidate.

[17] In another further aspect, the present technology provides an oral formulation. The oral formulation may comprise a therapeutic dose of d-threo- methylphenidate (s)-serine conjugate and/or its pharmaceutically acceptable salts, wherein the oral formulation does not contain unconjugated d-methylphenidate. Upon administration to a subject, the oral formulation may result in an extended release of d- methylphenidate in the subject compared to the release of d-methylphenidate upon administration of an equivalent molar amount of unconjugated d-methylphenidate.

In another aspect, the present technology provides an oral formulation that comprises a therapeutically effective dose of d-threo-methylphenidate conjugate having the following structure:

[18] wherein, the oral formulation does not contain unconjugated d- methylphenidate. [19] In yet another aspect, the present technology provides a method for chemically synthesizing a d-methylphenidate-CO₂CH2-nicotinoyl-L-Ser conjugate of the present technology by performing the appropriate steps to conjugate d-methylphenidate to the -CO₂CH₂-nicotinoyl-L-Ser ligand.

[20] In further aspects, some embodiments of the prodrug compositions of the present technology, upon administration, unexpectedly exhibit increased plasma concentrations of d-methylphenidate after T_max resulting in a controlled or extended- release profile as compared to an equimolar dose of unconjugated d-methylphenidate.

[21 ] In some embodiments, the conjugates or prodrugs of the present technology are provided in an amount sufficient to provide a surprisingly lowered C_max and a lower AUC but significantly increased partial AUCs for time periods after T_max (or later) as compared to unconjugated d-methylphenidate when administered orally at equimolar doses.

[22] In yet an alternative aspect, some embodiments of the conjugates or prodrugs of the present technology are believed to provide reduced side effects as compared to unconjugated d-methylphenidate when administered at equimolar doses, and are also contemplated in some alternative aspects to provide reduced abuse potential as compared to unconjugated d-methylphenidate.

[23] In addition, some embodiments of the conjugates or prodrugs of the present technology are also believed to unexpectedly provide an amount sufficient to provide an extended T_max when compared to unconjugated d-methylphenidate when administered at equimolar doses. [24] Moreover, the present technology provides at least one method of treating one or more subjects (human or animal) having at least one disease, disorder or condition mediated by controlling, preventing, limiting, or inhibiting neurotransmitter uptake/re-uptake or hormone uptake/re-uptake comprising orally administering to one or more subjects a pharmaceutically and/or therapeutically effective amount of at least one prodrug composition of the present technology.

[25] In still yet a further aspect, the present technology provides at least one method of treating a subject (human or animal) having at least one disorder or condition requiring stimulation of the central nervous system of the subject, comprising orally administering a pharmaceutically effective amount of at least one prodrug composition of the present technology, wherein the administration treats at least one disorder or condition requiring stimulation of the central nervous system of the subject.

[26] In still yet a further aspect, the present technology provides at least one method of treating a subject (human or animal) or patient (human or animal) having at least one disorder or condition requiring stimulation of the central nervous system of the subject, comprising orally administering a therapeutically effective amount of at least one prodrug composition of the present technology, wherein the administration treats at least one disorder or condition requiring stimulation of the central nervous system of the subject .

[27] In yet another aspect, the present technology provides one or more methods of administering at least one d-methylphenidate composition or prodrug of the present technology wherein the administration decreases the number and/or amount of metabolites produced when compared with unconjugated d-methylphenidate. In other aspects, the one or more methods of administering the one or more d-methylphenidate compositions or prodrugs of the present technology is believed to decrease the exposure of the subject to ritalinic acid when compared with unconjugated d-methylphenidate. In some embodiments, compositions of the present technology may reduce overall exposure to ritalinic acid by about 25% to about 75%.

[28] In yet a further embodiment, some embodiments of the compositions or prodrugs of the present technology are believed to provide an increased water solubility of the d-methylphenidate-based conjugate or prodrug compared to unconjugated d-methylphenidate. In another embodiment, the increased water solubility is believed to allow for the prodrug to be formed into certain dosage forms at higher concentrations, dosage strengths, or higher dose loading capacities than unconjugated d-methylphenidate. In some embodiments, such dosage forms include, for example, oral thin films or strips.

[29] In still yet a further embodiment, the administration of some embodiments of the d-methylphenidate-based compositions or prodrugs to a patient (human or animal) are believed to provide a reduced interpatient variability of d-methylphenidate plasma concentrations, and are believed to have an improved safety profile when compared to unconjugated d-methylphenidate.

[30] In yet another alternative embodiment, the present technology provides at least one method of treating attention-deficit hyperactivity disorder in a subject or patient comprising administering a pharmaceutically and/or therapeutically effective amount of at least one d-methylphenidate conjugate or prodrug composition of the present technology, wherein the administration treats attention-deficit hyperactivity disorder in a subject or patient.

[31 ] In yet another alternative embodiment, the present technology provides at least one method of treating eating disorder, binge eating disorder, obesity, narcolepsy, chronic fatigue, sleep disorder, excessive daytime sleepiness (EDS), cocaine dependence, or stimulant dependence in a subject or patient comprising administering a pharmaceutically and/or therapeutically effective amount of the d-methylphenidate conjugates or prodrug compositions of the present technology, wherein the administration treats an eating disorder, binge eating disorder, obesity, narcolepsy, chronic fatigue, sleep disorder, excessive daytime sleepiness (EDS), cocaine dependence, or stimulant dependence in a subject or patient.

[32] In another further embodiment, the present technology provides at least one d-methylphenidate prodrug composition for treating at least one subject or patient having a disorder or condition requiring stimulation of the central nervous system of the subject, wherein d-methylphenidate prodrug or composition has a reduced abuse potential when administered compared to unconjugated d-methylphenidate.

[33] In some embodiments, the one or more d-methylphenidate-based prodrug or conjugate compositions of the present technology are contemplated to exhibit reduced or prevented pharmacological activity when administered by parenteral routes, or reduced plasma or blood concentration of released d-methylphenidate when administered intranasally, intravenously, intramuscularly, subcutaneously or rectally as compared to free unconjugated d-methylphenidate when administered at equimolar amounts. [34] In some embodiments, d-methylphenidate-based conjugates of the present technology have an extended or controlled release profile as measured by plasma concentrations of released d-methylphenidate when compared to unconjugated d-methylphenidate when administered orally at equimolar doses. In some embodiments, the plasma concentration of d-methylphenidate released from the prodrug would increase more slowly and over a longer period of time after oral administration, resulting in a delay in peak plasma concentration of released d-methylphenidate and in a longer duration of action when compared to unconjugated d-methylphenidate.

[35] In another aspect, the present technology provides a pharmaceutical kit comprising a specified amount of individual doses in a package. Each dose comprises a pharmaceutically and/or therapeutically effective amount of d-methylphenidate composition or prodrug of the present technology, or a pharmaceutically or therapeutically acceptable salt thereof, and does not contain unconjugated d- methylphenidate. The pharmaceutical kit may also include instructions for use.

[36] In yet another aspect, the present technology provides a composition that comprises at least one conjugate of d-methylphenidate, and does not comprise unconjugated d-methylphenidate. The conjugate may have at least two or more chiral centers and may be optically active. The conjugate may have the following structure:

[38] In certain embodiments, compositions of the present technology comprise at least one conjugate of d-threo-methylphenidate, and do not contain unconjugated d- methylphenidate, and can be used in neonatal, pediatric, adolescent, adult and/or geriatric subjects with ADHD. For example, in some embodiments, the present compositions can be used for a once-daily dosing with extended release of d- methylphenidate. In an embodiment, the present composition can be used for once daily dosing with longer duration of action attributes that may benefit adult and/or geriatric subjects with ADHD.

BRIEF DESCRIPTION OF THE DRAWINGS

[39] Figure 1 . Oral PK curves comparing the bioavailability of d-MPH and l-MPH with unconjugated methylphenidate in rats.

[40] Figure 2. Oral PK curves comparing the d-MPH-CO₂CH₂-nicotinoyl-L-Thr conjugate with l-MPH-CO₂CH₂-nicotinoyl-L-Thr in rats.

[41 ] Figure 3. Oral PK curves comparing the d-MPH-CO₂CH₂-nicotinoyl-L-Ser conjugate with l-MPH-CO₂CH₂-nicotinoyl-L-Ser in rats.

[42] Figure 4. Oral PK curves comparing the d-MPH-CO₂CH₂-nicotinoyl-L-Ser with unconjugated d-methylphenidate in rats. [43] Figure 5. Intranasal PK curves comparing the d-MPH-CO₂CH₂- nicotinoyl-L-Ser with unconjugated d-methylphenidate in rats.

[44] Figure 6. Intravenous PK curves comparing the d-MPH-CO₂CH₂- nicotinoyl-L-Ser with unconjugated d-methylphenidate in rats.

[45] Figure 7. Oral PK curves comparing the d-threo-methylphenidate-CO₂CH₂- nicotinoyl-L-Ser (60 mg) in fasted and fed treatment regimens in humans.

[46] Figure 8. Oral PK curve of the mean plasma concentration-time profiles for intact d-threo-methylphenidate-CO₂CH₂-nicotinoyl-L-Ser after a single oral dose of 60 mg d-threo-methylphenidate-CO₂CH₂-nicotinoyl-L-Ser in a fasted treatment regimen in humans.

[47] Figure 9. Oral PK curve comparing the mean molar plasma concentration- time profiles for intact d-threo-methylphenidate-CO₂CH₂-nicotinoyl-L-Ser and for d-threo-methylphenidate released from the prodrug after a single oral dose of 60 mg d-threo-methylphenidate-CO₂CH₂-nicotinoyl-L-Ser (plasma concentrations presented in nM) in humans in the fasted state.

[48] Figure 10. Oral PK curves comparing the d-threo-methylphenidate-CO₂CH₂- nicotinoyl-L-Ser (60 mg) with Concerta^® (60.4 mg) in humans.

[49] Figure 1 1 . Oral PK curve of the mean plasma concentration-time profile of intact d-threo-methylphenidate-CO₂CH₂-nicotinoyl-L-Ser after a single oral dose of 32 mg d-threo-methylphenidate-CO₂CH₂-nicotinoyl-L-Ser liquid. DETAILED DESCRIPTION OF THE INVENTION

[50] The present technology provides a d-methylphenidate conjugated to a nicotinoyl-L-Serine moiety to form a prodrug having surprising beneficial properties as further described herein.

[51 ] The use of the term "methylphenidate" herein is meant to include any of the stereoisomer forms of methylphenidate, including the four stereoisomers: d-erythro- methylphenidate, /-eryfftro-methylphenidate, c/-f/7reo-methylphenidate and l-threo- methylphenidate and the salts and derivatives thereof. Methylphenidate is interchangeable with methyl phenyl(piperidin-2-yl)acetate. The term "methylphenidate" includes all salt forms. Methylphenidate is also known by its trade name Concerta^® (commercially available from Janssen Pharmaceuticals, Inc., Beerse, Belgium), Ritalin^®, Ritalin^® SR, Methylin^®, Methylin^® ER (all commercially available from Novartis International AG, of Basil, Switzerland). The methylphenidate used in the present technology can be any stereoisomer of methylphenidate, including, but not limited to, d-erythro- methylphenidate, /-eryfftro-methylphenidate, c/-f/7reo-methylphenidate and l-threo- methylphenidate. In a preferred embodiment, the conjugates contain a single d-threo- methylphenidate isomer. In another embodiment, the prodrug conjugates are optically active single isomers thereof.

[52] The use of the term "unconjugated methylphenidate" means methyl 2- phenyl-2-(piperidin-2-yl)acetate and salts thereof.

[53] The use of the term "d-methylphenidate" means methyl (R)-2-phenyl-2-((R)- piperidin-2-yl)acetate. [54] Stereoisomers, used hereinafter, means that two molecules are described as stereoisomers of each other if they are made of the same atoms, connected in the same sequence, but the atoms are positioned differently in space. The difference between two stereoisomers can only be seen when the three dimensional arrangement of the molecules is considered.

[55] Bioavailability, used hereinafter, means the proportion of a drug or other substance that enters the circulation over time when introduced into the body and so is able to have an active effect.

[56] Cmax, used hereinafter, is a term used in pharmacokinetics and refers to the maximum (or peak) plasma concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administered and before the administration of a second dose.

[57] T_max, used hereinafter, is the term used in pharmacokinetics to describe the time at which the C_max is observed. After an intravenous administration, C_max and T_max are closely dependent on the experimental protocol, since the concentrations are always decreasing after the dose.

[58] The use of the term "dose" means the total amount of a drug or active component taken each time by an individual subject.

[59] As used herein, the term "subject" means a human or animal, including but not limited to a human or animal patient.

[60] The term "patient" means a human or animal subject in need of treatment. [61 ] AUCiast is a term used in pharmacokinetics to describe the area under the curve in a plot of drug concentration in blood, serum, or plasma vs time from time=0 (or or predose) to the time of the last measurable drug concentration.

[62] AUCinf is a term used in pharmacokinetics to describe the area under the curve in a plot of drug concentration in blood, serum, or plasma vs time from time=0 (or or predose) to infinity.

[62] Molar equivalent as used hereinafter, means an equal number of moles of the substance as the number of moles in a certain mass (weight) or volume of the comparison substance, e.g. a dose of d-methylphenidate that is molar equivalent to a dose of about 0.1 mg d-methylphenidate hydrochloride per day would provide the same number of moles of d-methylphenidate as from 0.1 mg of d-methylphenidate hydrochloride.

[63] As used herein, the phrases such as "decreased," "reduced," "diminished" or "lowered" are meant to include at least about a 10% change in pharmacological activity, area under the curve (AUC) and/or peak plasma concentration (C_max) with greater percentage changes being preferred for reduction in abuse potential and overdose potential of the conjugates of the present technology as compared to unconjugated d-methylphenidate. For instance, the change may also be greater than about 10%, about 15%, about 20%, about 25%, about 35%, about 45%, about 55%, about 65%, about 75%, about 85%, about 95%, about 96%, about 97%, about 98%, about 99%, or increments therein.

[64] "Pharmaceutically effective amount" as used herein means an amount that has a pharmacological effect. A "pharmaceutically acceptable salt" as used herein is a salt of the d-methylphenidate conjugate which, when used in a pharmaceutically effective amount, has at least one pharmacological effect.

[65] "Therapeutically effective amount" as used herein means an amount effective for treating a disease or condition. A "therapeutically acceptable salt" as used herein is a pharmaceutically acceptable salt of the d-methylphenidate conjugate of the present technology, which, when used in a therapeutically effective amount, is effective for treating a disease, condition, or syndrome.

[66] As used herein, the term "attention deficit hyperactivity disorder" (ADHD) encompasses various sub-types of ADHD including, for example, subjects who do not show or only show weak symptoms of hyperactivity or impulsiveness, or for example, subjects who are predominately inattentive (formerly attention deficit disorder (ADD)).

[67] As used herein, the term "prodrug" refers to a substance that is inactive or has reduced pharmacological activity but is converted to an active drug by a chemical or biological reaction in the body. In the present technology, the prodrug is a conjugate of at least one drug, d-methylphenidate, a linker, and a nicotinoyl-L-Serine moiety. Thus, the conjugates of the present technology are prodrugs and the prodrugs of the present technology are conjugates.

[68] Prodrugs are often useful because, in some embodiments, they may be easier to administer or process than the parent drug. They may, for instance, be more bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in water and/or other solvents over the parent drug. An embodiment of a prodrug would be a d-methylphenidate conjugate that is metabolized to the active moiety. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically more active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound. To produce a prodrug, a pharmaceutically active compound is modified such that the active compound will be regenerated upon in vivo administration. The prodrug is designed to alter the metabolism or the transport characteristics of a drug— the changes typically varying with route of administration— in certain embodiments, to mask side-effects or toxicity, to improve bioavailability and/or water solubility, to improve the flavor of a drug or to alter other characteristics or properties of a drug in other discrete embodiments.

[69] The d-methylphenidate prodrug can be prepared so as to have a variety of different chemical forms including chemical derivatives or salts. Such d-methylphenidate prodrugs can also be prepared to have different physical forms. For example, the d-methylphenidate prodrug may be amorphous, may have different crystalline polymorphs, or may exist in different solvation or hydration states, such as semi- hydrates, monohydrates, hydrates (nH₂O, when n is 0.5, 1 , 2..). Such polymorphs can be produced by, e.g., using crystallization conditions to isolate a free-base and salt forms and/or by ball-milling such forms.

[70] By varying the form of the d-methylphenidate prodrug, it is possible to vary the physical properties thereof. For example, crystalline polymorphs typically have different solubilities from one another, such that a more thermodynamically stable polymorph is less soluble than a less thermodynamically stable polymorph. Pharmaceutical polymorphs can also differ in properties such as shelf-life, bioavailability, morphology, vapor pressure, density, color, and compressibility. Accordingly, variation of the crystalline state of the d-methylphenidate prodrug is one of many ways in which to modulate the physical properties thereof.

[71 ] A co-crystal is a multiple component crystal containing two or more non- identical molecules in which all components are solid under ambient conditions (i.e., 22°Celsius, 1 atmosphere of pressure) when in their pure form. The components comprise a target molecule (i.e., a d-methylphenidate prodrug) and a molecular co- crystal former that coexist in the co-crystal at the molecular level within a single crystal.

[72] Co-crystals that comprise two or more molecules (co-crystal formers)

(Jmarsson et al., 2004) that are solids under ambient conditions represent a long-known class of compounds (see Wohler, 1844). However, co-crystals remain relatively unexplored. A Cambridge Structural Database (CSD) (Allen et al., 1993) survey reveals that co-crystals represent less than 0.5% of published crystal structures. Nevertheless, their potential impact upon pharmaceutical (e.g., nutraceutical) formulation (Vishweshwar et al., 2006; Li et al., 2006; Remenar et al., 2003; and Childs et al., 2004) and green chemistry (Anastas et al., 1998) is of topical and growing interest. In particular, the fact that all co-crystal components are solids under ambient conditions has important practical considerations because synthesis of co-crystals can be achieved via solid-state techniques (mechanochemistry)(Shan et al., 2002), and chemists can execute a degree of control over the composition of a co-crystal since they can invoke molecular recognition, especially hydrogen bonding, during the selection of co-crystal formation. Those features distinguish co-crystals from solvates which are another broad and well-known group of multiple component compounds. Solvates are much more widely characterized than co-crystals (e.g., 1652 co-crystals are reported in the CSD versus 10,575 solvates; version 5.27 (May 2006) 3D coordinates, RO.075, no ions, organics only).

[73] It would be advantageous to have new forms of d-methylphenidate prodrugs that have improved properties. Specifically, it is desirable to identify improved forms of d-methylphenidate prodrugs that exhibit significantly improved properties including increased aqueous and/or solvent solubility and stability. Further, it is desirable to improve the processability, or preparation of pharmaceutical formulations. For example, needle-like crystal forms or habits of d-methylphenidate prodrugs can cause aggregation, even in compositions where the d-methylphenidate prodrug is mixed with other substances, such that a non-uniform mixture is obtained. It is also desirable to increase or decrease the solution rate of d-methylphenidate prodrug-containing pharmaceutical compositions in water or other solvents, increase or decrease the bioavailability of orally-administered compositions, and provide a more rapid or more delayed onset to therapeutic effect. It is also desirable to have a form of the d-methylphenidate prodrug which, when administered to a subject, reaches a peak plasma level faster or slower, has a longer lasting therapeutic plasma concentration, and higher or lower overall exposure when compared to equivalent amounts of the d-methylphenidate prodrug in its presently-known form. The improved properties discussed above can be altered in a way which is most beneficial to a specific d-methylphenidate prodrug for a specific therapeutic effect.

[74] The d-methylphenidate prodrug can be either a positively charged (cationic) molecule, or a pharmaceutically acceptable anionic or cationic salt form or salt mixtures with any ratio between positive and negative components. These anionic salt forms can include, but are not limited to, for example, acetate, /-aspartate, besylate, bicarbonate, carbonate, /-camsylate, /-camsylate, citrate, edisylate, formate, fumarate, gluconate, hydrobromide/bromide, hydrochloride/chloride, cZ-lactate, /-lactate, /,/-lactate, /,/-malate, /-malate, mesylate, pamoate, phosphate, succinate, sulfate, bisulfate, /-tartrate, /- tartrate, d, /-tartrate, meso-tartrate, benzoate, gluceptate, cZ-glucuronate, hybenzate, isethionate, malonate, methylsulfate, 2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate, thiocyanate, acefyllinate, aceturate, aminosalicylate, ascorbate, borate, butyrate, camphorate, camphocarbonate, decanoate, hexanoate, cholate, cypionate, dichloroacetate, edentate, ethyl sulfate, furate, fusidate, galactarate, galacturonate, gallate, gentisate, glutamate, glutarate, glycerophosphate, heptanoate, hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate, mandelate, methanesulfonate, myristate, napadisilate, oleate, oxalate, palmitate, picrate, pivalate, propionate, pyrophosphate, salicylate, salicylsulfate, subsalicylate, tannate, terephthalate, thiosalicylate, tribrophenate, valerate, valproate, adipate, 4-acetamidobenzoate, camsylate, octanoate, estolate, esylate, glycolate, thiocyanate, or undecylenate. In the preferred embodiments, the anionic salt form is selected from the group consisting of chloride, hydrogen carbonate (bicarbonate), iodide, bromide, citrate, acetate, formate, salicylate, hydrogen sulfate (bisulfate), hydroxide, nitrate, hydrogen sulfite (bisulfite), propionate, benzene sulfonate, hypophosphite, phosphate, bromate, iodate, chlorate, fluoride, nitrite.

[75] The cationic salt forms can include, but are not limited to, for example, sodium, potassium, calcium, magnesium, lithium, cholinate, lysinium, or ammonium. [76] Without wishing to be limited to the following theory, it is believed that the prodrugs/conjugates of the present technology undergo rate determining enzyme hydrolysis in vivo, which subsequently leads to a cascade reaction resulting in rapid formation of d-methylphenidate and the respective ligands, metabolites thereof and/or derivatives thereof. The prodrug conjugates of the present technology are non-toxic or have very low toxicity at the given dose levels and are preferably known drugs, natural products, metabolites, or GRAS (Generally Recognized As Safe) compounds (e.g., preservatives, dyes, flavors, etc.) or non-toxic mimetics or derivatives thereof.

General Structures and Definitions

[77] Abbreviations for the components of conjugates of the present technology include: MPH stands for methylphenidate; MPH HCI stands for methylphenidate hydrochloride; Ser stands for serine; Thr stands for threonine; tBu stands for tert-butyl; Et stands for ethyl.

[78] In some embodiments, the general structure of the conjugates of d-methylphenidate of the present technology can be represented by Formula I:

[79] In some embodiments, the conjugate has at least two or more chiral centers. In some embodiments the conjugate has three chiral centers, such as the three chiral centers shown in Formula I.

[80] In one embodiment, the conjugate can be an ionic salt, such as chloride, preferably d-MPH-CO₂CH2-nicotinoyl-L-Ser chloride having the following Formula II:

It will be appreciated by one of skill in the art that, in some embodiments, up to about 5% by weight of methylphenidate can be provided by sources other than the d- methylphenidate prodrug of the present technology, including but not limited to, other conjugates, un-conjugated methylphenidate, methylphenidate-like stimulants, amphetamines, and amphetamine-like stimulants. In some embodiments, the conjugate compositions and formulations of the present technology do not contain unconjugated methylphenidate prior to administration to a patient.

Administration, Formulation and Advantages

[81 ] The prodrugs or conjugate compositions of the present technology can be administered, for example, orally or rectally, and, upon administration, release the active d-methylphenidate, derivatives thereof or combinations thereof, after being hydrolyzed in the body. Not wishing to be bound by any particular theory, the nicotinoyl-L-Serine ligand that is conjugated to the d-methylphenidate of the present technology comprises niacin and serine, both naturally-occurring metabolites, pharmaceutically active compounds or mimetics thereof or derivatives thereof. It is believed that the prodrugs or conjugates of the present technology can be easily recognized by physiological systems resulting in hydrolysis and release of d-methylphenidate.

[82] The prodrugs of the present technology are believed to have no or limited pharmacological activity themselves and consequently may follow a metabolic pathway that differs from the parent drug (i.e., methylphenidate).

[83] It has been surprisingly found that in some embodiments of the present technology, the prodrugs or conjugates of the present application provide a controlled- release or extended-release profile as compared with unconjugated d-methylphenidate. In some embodiments, the prodrugs or conjugates of the present technology surprisingly provide increased water solubility as compared with unconjugated d-methylphenidate. In some embodiments, the prodrugs or compositions of the present technology have at least about 1 .2 times or at least about 1 .5 times the water solubility of unconjugated d-methylphenidate. In some embodiments, the prodrugs or compositions of the present technology have at least about 1 .7, at least about 2.0, at least about 2.2, at least about 2.5, at least about 3.0, at least about 4.0 or at least about 5 times the water solubility of unconjugated d-methylphenidate, and include any multiples in between or above that have water solubility greater than unconjugated d-methylphenidate. Not to be bound by any particular theory, the increase in water solubility may allow for the conjugate to be formed into certain dosage forms at higher concentrations, dosage strengths or higher dose loading capacities than unconjugated d-methylphenidate. In some embodiments, these dosage forms include, but are not limited to, forms that require water solubility, including, but not limited to, liquids and/or oral thin films or strips.

[84] It is believed that the conjugate is capable of being enzymatically or hydrolytically activated or converted into the active form. Further, the composition or prodrug described herein is believed to release d-methylphenidate, its active metabolites and/or derivatives and their combination, resulting in improved PK profile outcome and/or exposure to d-methylphenidate, its active metabolites and/or derivatives when compared to free or unconjugated d-methylphenidate at equimolar doses.

[85] In a further embodiment, without being bound by any particular theory, it is believed that, in some embodiments, the controlled-release or extended-release PK profile over unconjugated d-methylphenidate, may provide for a better bioavailability of d-methylphenidate referring to certain plasma concentrations over time that result in improved therapeutic onset or duration of action or both.

[86] In one embodiment, the at least one prodrug or conjugate of the present technology would alter the metabolic profile of d-methylphenidate, derivatives thereof or combinations thereof, by, for example, changing the amounts and/or ratio of d-methylphenidate and its metabolites, such as the inactive ritalinic acid within the body. The prodrug or conjugate of the present technology, for example, would decrease the number and/or the amount of metabolites, including active, inactive, toxic or non-toxic metabolites, produced by unconjugated d-methylphenidate. Not wishing to be bound by any particular theory, it is believed that this change in metabolism may potentially alleviate certain side effects of metabolite(s), as well as potentially improve upon the safety profile of d-methylphenidate. In some embodiments, the prodrug or conjugate of the present technology may reduce the overall exposure to ritalinic acid by about 25% up to about 75% as compared to the amount of ritalinic acid produced by an equimolar amount of unconjugated d-methlyphenidate. In some embodiments, the overall exposure to ritalinic acid may be reduced by about 30%, alternatively about 35%, alternatively about 40%, alternatively about 45%, alternatively about 50%, alternatively about 55%, alternatively about 60%, alternatively about 65%, alternatively about 70% as compared to an equimolar amount of unconjugated d-methlyphenidate.

[87] In another embodiment, the prodrugs or conjugates of the present technology would unexpectedly produce reduced interpatient variability of d-methylphenidate plasma concentrations. Not to be bound by any particular theory, it can be assumed that the reduction of interpatient variability of d-methylphenidate plasma concentrations may be due to either increased bioavailability or a modified metabolic pathway or a combination of both. In another embodiment, the prodrug of the present technology would alter the metabolic pathway of the released d-methylphenidate when compared to unconjugated d-methylphenidate. It is believed that in such an embodiment, this metabolism of the prodrug may decrease interpatient variability and/or reduce side effects associated with unconjugated d-methylphenidate or any of its metabolites. Common side effects of methylphenidate are nervousness, agitation, anxiety, and insomnia or drowsiness. Other common side effects are abdominal pain, weight loss, hypersensitivity, nausea, dizziness, palpitation, headache, dyskinesia, blood pressure, pulse changes, tachycardia, angina, and cardiac arrhythmia. [88] In an alternative embodiment, the compositions of the present technology can comprise up to 5% racemic d- and l-methylphenidate which is preferably hydrolyzed to d-methylphenidate in the body and thus delivers more of the therapeutically active d-isomer. Wishing not to be bound by any particular theory, this may reduce potential side effects caused by /-methylphenidate and/or its metabolites.

[89] In another embodiment, the at least one prodrug or conjugate of the present technology is believed to exhibit an improved extended-release PK profile when compared to unconjugated d-methylphenidate when administered orally at equimolar doses.

[90] In another embodiment, the at least one prodrug or conjugate is believed to unexpectedly generate a T_max value of released d-methylphenidate that is longer than the T_max value produced by unconjugated d-methylphenidate when administered orally at equimolar doses.

[91 ] In some embodiments, the AUC is about 50% (or smaller) of the AUC of unconjugated d-methylphenidate, when administered intranasally or intravenously at equimolar doses, for example about 50% to about 0.1 %, alternatively from about 25% to about 0.1 %, alternatively from about 50% to about 1 %, including, but not limited to, about 50%, about 40%, about 30%, about 20%, about 10%, about 1 % or any amounts in between, in increments of about 0.5%, about 1 %, about 2%, about 2.5%, about 5% or about 10%.

[92] D-methylphenidate has rewarding properties and is prone to substance abuse because of its pharmacological similarity to cocaine and amphetamine. Oral abuse has been reported to lead to hallucinations, paranoia, euphoria, and delusional disorder. Oral abuse may subsequently escalate to intravenous and intranasal abuse. Euphoria has been reported after intravenous administration of d-methylphenidate. When administered intranasally the effect is found to be similar to intranasal use of amphetamines.

[93] The compounds, prodrugs, compositions and/or methods of the present technology are believed to provide reduced potential for overdose, reduced potential for abuse and/or improve the characteristics of d-methylphenidate, derivatives thereof or combinations thereof with regard to toxicities or suboptimal release profiles. The prodrugs of the present technology may preferably have no or a substantially decreased pharmacological activity when administered through injection or intranasal routes of administration. However, they remain orally bioavailable. Without wishing to be limited to the below theory, it is believed that overdose protection may occur due to the conjugates being exposed to different enzymes and/or metabolic pathways after oral administration whereby the conjugate of the present technology is exposed to the gut and first-pass metabolism as opposed to exposure to enzymes in the circulation or mucosal membranes in the nose, which limits the ability of the d-methylphenidate, derivatives thereof or combinations thereof, from being released from the conjugate. Therefore, abuse resistance is provided by limiting the effectiveness of alternative routes of administration. Again, not wishing to be bound by any particular theory, the route-specific bioavailability can be a result of differential hydrolysis of the chemical linkage (i.e., a covalent linkage) following oral, intranasal, or intravenous administration. The prodrugs of the present technology are envisioned to not hydrolyze or to hydrolyze at a reduced rate or to a limited extent via non-oral routes. As a result, they are believed to not generate high plasma or blood concentrations of released d-methylphenidate when injected or snorted compared to free d-methylphenidate administered through these routes.

[94] It is contemplated that the prodrugs of the present technology are resistant to abuse by parenteral routes of administration, such as intravenous "shooting," or intranasal "snorting," that are often employed during illicit use. For example, release of d-methylphenidate, derivatives thereof or combinations thereof, is reduced when the composition of the present technology is delivered by parenteral routes. Further, the conjugates of the present technology, since they are believed to include covalently bound d-methylphenidate, derivatives thereof or combinations thereof, are not able to be physically manipulated to release the d-methylphenidate, derivatives thereof or combinations thereof, from the conjugated d-methylphenidate, derivatives thereof or combinations thereof, by methods, for example, of grinding up or crushing of solid forms. The conjugates of the present technology are also contemplated to exhibit resistance to chemical hydrolysis under conditions a potential drug abuser may apply to "extract" the active portion of the molecule, for example, by boiling, or acidic or basic solution treatment of the conjugate. Some compositions containing prodrugs or conjugates of the present technology preferably have no or a substantially decreased pharmacological activity when administered through injection or intranasal routes of administration. However, they remain orally bioavailable.

[95] For example, the prodrug or conjugate of the present technology is contemplated to surprisingly maintain its effectiveness and abuse resistance following the crushing of the tablet, capsule or other oral dosage form utilized to deliver the therapeutic component (i.e., active ingredient/drug) which is believed to be due to the inherent release profile being a property of the composition not formulation. In contrast, conventional extended release formulations used to control the release of d-methylphenidate are subject to release of up to the entire d-methylphenidate content immediately following crushing. When the content of the crushed tablet is injected or snorted, the large dose of d-methylphenidate produces the "rush" effect sought by addicts. In some embodiments, the compositions of the present technology potentially reduce drug liking. Without being bound by theory, since d-methylphenidate is covalently bound in the conjugate, there is a slower of release of d-methylphenidate compared to an equimolar dose of unconjugated d-methylphenidate, which could lead to a reduced drug liking outcome

[96] The present technology provides a stimulant based treatment modality and dosage form for certain disorders requiring the stimulation of the CNS such as, attention-deficit hyperactivity disorder (ADHD), ADD (technically ADHD Predominantly Inattentive Type), autistic spectrum disorder, autism, Asperger's disorder, pervasive developmental disorder, sleep disorder, obesity, depression, bipolar disorder, eating disorder, binge eating disorder, chronic fatigue syndrome, schizophrenia, major depressive disorder narcolepsy, excessive daytime sleepiness (EDS), cocaine dependence, stimulant dependence, or autistic spectrum disorder. In a preferred embodiment, the at least one prodrug or composition of the present technology is used to treat attention-deficit hyperactivity disorder (ADHD).

[97] In some embodiments, the at least one composition or prodrug of the present technology can be used in one or more methods of treating a subject or patient (human or animal, preferably mammal) having at least one disease, disorder or condition requiring stimulation of the central nervous system of one or more subjects, comprising orally administering a pharmaceutically and/or therapeutically effective amount of the at least one composition or prodrug.

[98] In some embodiments, the at least one composition or prodrug of the present technology can be used in one or more methods of treating one or more subjects or patients (human or animal, preferably mammal) having at least one disease, disorder or condition mediated by controlling, preventing, limiting, or inhibiting neurotransmitter uptake/re-uptake or hormone uptake/re-uptake comprising administering to at least one subject a pharmaceutically and/or therapeutically effective amount of the at least one prodrug or composition. In some embodiments, the neurotransmitter is serotonin, dopamine or norepinephrine. In some embodiments, the hormone is catecholamine.

[99] At least some compositions of the present technology comprising the prodrugs of methylphenidate, derivatives thereof or combinations thereof, can also be used for treating stimulant (cocaine, methamphetamine, among others) abuse and addiction, for improving battle field alertness, and/or for combating fatigue.

[100] The prodrug or conjugate of the present technology can be formulated into dosage forms that include but are not limited to sublingual, gummy, chewable tablet, rapidly dissolving tablet, tablet, capsule, caplet, troche, lozenge, powder, suspension, syrup, solution, oral thin film (OTF), oral strip, rectal film, or suppository. In some embodiments, the dosage forms are to be administered orally. Preferred oral administration forms are capsule, tablet, solutions and OTF. Suitable dosing vehicles of the present technology include, but are not limited to, water, phosphate buffered saline (PBS), 10% Tween in water, and 50% PEG-400 in water.

[101 ] Solid dosage forms can optionally include one or more of the following types of excipients: antiadherents, binders, coatings, disintegrants, gel-forming agents, fillers, flavors and colors, glidants, lubricants, preservatives, sorbents and sweeteners.

[102] Oral formulations of the present technology can also be included in a solution, a suspension or a slurry in an aqueous liquid or a non-aqueous liquid. The formulation can be an emulsion, such as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The oils can be administered by adding the purified and sterilized liquids to a prepared enteral formula, which is then placed in the feeding tube of a subject who is unable to swallow.

[103] Soft gel or soft gelatin capsules may be prepared, for example by dispersing the formulation in an appropriate vehicle (vegetable oils are commonly used) to form a high viscosity mixture. This mixture is then encapsulated with a gelatin based film using technology and machinery known to those in the soft gel industry. The individual units so formed are then dried to constant weight.

[104] Chewable tablets, for example, may be prepared by mixing the formulations with excipients designed to form a relatively soft, flavored, tablet dosage form that is intended to be chewed rather than swallowed. Conventional tablet machinery and procedures, for example, direct compression and granulation, i.e., or slugging, before compression, can be utilized. Those individuals involved in pharmaceutical solid dosage form production are versed in the processes and the machinery used, as the chewable dosage form is a very common dosage form in the pharmaceutical industry. [105] Film coated tablets, for example may be prepared by coating tablets using techniques such as rotating pan coating methods or air suspension methods to deposit a contiguous film layer on a tablet.

[106] Compressed tablets, for example may be prepared by mixing the formulation with one or more excipients intended to add binding qualities to disintegration qualities. The mixture is either directly compressed, or granulated and then compressed, using methods and machinery known to those in the industry. The resultant compressed tablet dosage units are then packaged according to market need, for example, in unit dose, rolls, bulk bottles, blister packs, etc.

[107] The present technology contemplates that the conjugates or compositions of the present technology can be formulated into formulations or co-formulations that may further comprise one or more additional components, provided the formulations or co-formulations do not contain any unconjugated d-methylphenidate. For example, such formulations can include biologically-acceptable carriers which may be prepared from a wide range of materials. Without being limited to, such materials include diluents, binders and adhesives, lubricants, gel-forming agents, plasticizers, disintegrants, surfactants, colorants, bulking substances, flavorings, sweeteners and miscellaneous materials such as buffers and adsorbents in order to prepare a particular medicated formulation or co-formulation. In some embodiments, the composition of the present technology comprises from about 5% to about 99% by weight of d- methylphenidate conjugate, or a salt thereof, and one or more additional components to total 100% by weight, based on the total weight of the composition, wherein the composition does not contain unconjugated d-methylphenidate. [108] Binders may be selected from a wide range of materials such as hydroxypropylmethylcellulose, ethylcellulose, or other suitable cellulose derivatives, povidone, acrylic and methacrylic acid co-polymers, pharmaceutical glaze, gums, milk derivatives, such as whey, starches, and derivatives, as well as other conventional binders known to persons working in the art. Exemplary non-limiting solvents are water, ethanol, isopropyl alcohol, methylene chloride or mixtures and combinations thereof. Exemplary non-limiting bulking substances include sugar, lactose, gelatin, starch, and silicon dioxide.

[109] It should be understood that in addition to the ingredients particularly mentioned above, the formulations of the present technology can include other suitable agents, such as flavoring agents, preservatives, and antioxidants, among others. Such antioxidants would be food acceptable and could include, for example, vitamin E, carotene, BHT or other antioxidants. Suitable flavoring agents and preservatives are known to one of skill in the art.

[1 10] Other compounds which may be included by admixture are, for example, medically inert ingredients, e.g., solid and liquid diluents, such as lactose, dextrose, saccharose, cellulose, starch or calcium phosphate for tablets or capsules, olive oil or ethyl oleate for soft capsules and water or vegetable oil for suspensions or emulsions; lubricating agents such as silica, talc, stearic acid, magnesium or calcium stearate, hydrogenated oils, sodium stearyl fumarate, and/or polyethylene glycols; gelling agents such as colloidal clays, polyethylene oxide, hydroxypropylmethyl cellulose, or carbomers; thickening agents such as gum tragacanth or sodium alginate, binding agents such as starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone (povidone); disintegrating agents such as starch, alginic acid, alginates, crospovidone, or sodium starch glycolate; effervescing mixtures; dyestuff; sweeteners; wetting agents such as lecithin, polysorbates, poloxamer, sorbitan monoesters, glyceryl monooleates, or laurylsulfates; and other therapeutically acceptable accessory ingredients, such as humectants, preservatives, buffers and antioxidants, which are known additives for such formulations.

[1 1 1 ] For oral administration, fine powders or granules containing diluting, dispersing and/or surface-active agents may be presented in a draught, in water or a syrup, in capsules or sachets in the dry state, in a non-aqueous suspension wherein suspending agents may be included, or in a suspension in water or a syrup. Where desirable, flavoring, preserving, suspending, thickening or emulsifying agents can be included.

[1 12] Liquid dispersions for oral administration may be syrups, emulsions or suspensions. The syrups may contain as carrier, for example, saccharose or saccharose with glycerol and/or mannitol and/or sorbitol. In particular a syrup for diabetic subjects can contain as carriers only products, for example sorbitol, which do not metabolize to glucose or which metabolize only a very small amount to glucose. The suspensions and the emulsions may contain a carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol.

[1 13] The ingredients mentioned herein are not intended to be exhaustive, and one of skill in the art will be able to formulate suitable compositions using known or to be known ingredients. [1 14] Methylphenidate is being marketed in numerous dosage forms and at various dosage strengths either as a racemic mixture of d- and /-threo-methylphenidate or as a single d-threo-isomer (Table 1 ). Recommended daily doses depend on the dosage form, active ingredient (single isomer or racemic mixture) and individual subject or patient titration.

Table 1 . Examples of marketed methylphenidate dosage forms and dosage strengths.

[1 15] In some embodiments, doses of the prodrug of the present technology can be higher or lower than doses of unconjugated methylphenidate depending on their molecular weight, the respective weight-percentage of methylphenidate as part of the whole conjugate or conjugate salt and their bioavailability (with respect to released methylphenidate). Therefore dosages may be higher or lower than the dosages of free methylphenidate. Dosages can be calculated based on the strengths of dosages of methylphenidate hydrochloride which range between, for example, but not limited to, about 0.5 mg and about 200 mg per dose. Dose conversion from methylphenidate hydrochloride to methylphenidate prodrug can be performed using the following formula:

MW(MPH prodrug) dose(MPH prodrug)= f_BAxdose(MPH hydrochloride) χ

269.77

mol

MPH = methylphenidate MW = molecular weight fsA = correction factor accounting for differences in bioavailability between unmodified methylphenidate and prodrugs of the present technology. This correction factor is specific for each prodrug.

[1 16] In further embodiments, weight amounts or doses of unconjugated or conjugated d-methylphenidate, and any of their salt forms can be expressed as the molar equivalent weight amount or dose of any other compound or a salt thereof. For example, a dose of d-MPH-CO₂CH₂-nicotinoyl-L-Ser chloride can alternatively be expressed as an equimolar dose of d-MPH-CO₂CH₂-nicotinoyl-L-Ser, d- methylphenidate, or d-methylphenidate hydrochloride. Other examples include, but are not limited to, a dose of d-methylphenidate hydrochloride can alternatively be expressed as an equimolar dose of d-methylphenidate, d-MPH-CO₂CH₂-nicotinoyl-L-Ser, or d- MPH-CO₂CH₂-nicotinoyl-L-Ser chloride. The general formula to calculate the molar equivalent dose of Compound 2 from the dose of Compound 1 is as follows: MWiUompound 2)

DoseiCompound 2) = DoseiCompound 1 ) χ ,,,,„. —

' ^{\ /} MW(Compound 1 )

Dose(Compound 1 ) = dose of Compound 1 (in mass units)

MW(Compound 1 ) = molecular weight of Compound 1

MW(Compound 2) = molecular weight of Compound 2

The following table lists the molecular weights of unconjugated d-methylphenidate and a salt form thereof, and an example of a conjugated d-methylphenidate and a salt form thereof.

[1 17] In some embodiments, suitable dosages of the conjugated d- methylphenidate or prodrugs of the present technology include, but are not limited to, formulations including an amount of conjugated d-methylphenidate (and not including unconjugated d-methylphenidate) equimolar to an amount of unconjugated d- methylphenidate from about 0.1 mg or higher, alternatively about 0.5 mg or higher, alternatively from about 1 .0 mg or higher, alternatively from about 2.5 mg or higher, alternatively from about 5.0 mg or higher, alternatively from about 7.5 mg or higher, alternatively from about 10 mg or higher, alternatively from about 20 mg or higher, alternatively from about 30 mg or higher, alternatively from about 40 mg or higher, alternatively from about 50 mg or higher, alternatively from about 60 mg or higher, alternatively from about 70 mg or higher, alternatively from about 80 mg or higher, alternatively from about 90 mg or higher, alternatively from about 1 00 mg or higher, alternatively 1 20 mg or higher, alternatively 200 mg or higher, alternatively 300 mg or higher, alternatively 400 mg or higher, alternatively 500 mg or higher, and include any additional increments thereof, for example, about 0.1 , about 0.2, about 0.25, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.75, about 0.8, about 0.9 or about 1 .0 mg and multiplied factors thereof, (e.g., about χ 1 , about χ2, about χ2.5, about χ5, about x 1 0, about x 1 00, etc.).

[1 1 8] It is contemplated that daily dosing regimens for compositions comprising the conjugated d-methylphenidate of the present technology (and not comprising unconjugated d-methylphenidate) include, but are not limited to, an amount of d- methylphenidate that is molar equivalent to a dose of d-methylphenidate hydrochloride from about 0.1 mg to about 500 mg per day, alternatively about 0.5 mg to about 480 mg per day, alternatively about 0.5 mg to about 450 mg per day, alternatively about 0.5 mg to about 400 mg per day, alternatively about 0.5 mg to about 360 mg per day, alternatively about 0.5 mg to about 350 mg per day, alternatively about 0.5 mg to about 300 mg per day, alternatively about 1 mg to about 250 mg per day, alternatively about 5 mg to about 240 mg per day, alternatively about 1 mg to about 1 00 mg per day, alternatively about 5 mg to about 80 mg per day, alternatively about 1 0 mg to about 40 mg per day, alternatively about 1 0 mg to 200 mg per day, alternatively about 1 0 mg to about 1 80 mg per day, alternatively about 20 mg to about 1 20 mg per day, alternatively about 20 mg to about 1 50 mg per day, alternatively about 30 mg to about 1 00 mg per day, alternatively about 40 mg to about 80 mg per day, alternatively about 50 mg to about 70 mg per day, alternatively about 20 mg to about 40 mg per day, alternatively about 20 mg to about 60 mg per day, a alternatively about 10 mg to about 50 mg per day, alternatively about 20 mg per day, alternatively about 40 mg per day, alternatively about 60 mg per day, alternatively about 80 mg per day, alternatively about 100 mg per day, alternatively about 120 mg per day. It is also contemplated that compositions comprising the conjugated d-MPH of the present technology (and not including unconjugated d-methylphenidate) would have a dosing regimen of one time a day, alternatively two times a day or less, alternatively four times a day or less.

[1 19] It is contemplated that some of the formulations of the present technology would be provided in a unit dose form. "Unit dose form" here means a single entity of a solid therapeutic dosage form (e.g., 1 capsule, 1 tablet) or a single volume dispensed from a non-solid dosage form (e.g., 5 imL of a liquid or syrup). Such a unit dose form can be from about 0.5 mg to about 400 mg per day, alternatively from about 0.1 mg to about 300 mg per day, about 0.5 mg to about 300 mg per day, alternatively about 1 mg to about 250 mg per day, alternatively about 5 mg to about 240 mg per day, alternatively about 1 mg to about 100 mg per day, alternatively about 5 mg to about 80 mg per day, alternatively about 10 mg to about 40 mg per day, alternatively about 10 mg to 200 mg per day, alternatively about 10 mg to about 180 mg per day, alternatively about 20 mg to about 120 mg per day, alternatively about 20 mg to about 150 mg per day, alternatively about 30 mg to about 100 mg per day, alternatively about 40 mg to about 80 mg per day, alternatively about 50 mg to about 70 mg per day, alternatively about 20 mg to about 40 mg per day, alternatively about 20 mg to about 60 mg per day, a alternatively about 10 mg to about 50 mg per day, alternatively about 20 mg per day, alternatively about 40 mg per day, alternatively about 60 mg per day, alternatively about 80 mg per day, alternatively about 100 mg per day, alternatively about 120 mg per day. The present technology also includes dosage formulations including currently approved formulations of d-methylphenidate (See Table 1 ), where the dosage can be calculated using the above-noted formula determined by the amount of d-methylphenidate hydrochloride. The present technology provides for dosage forms formulated as a single therapy or as a combination therapy.

[120] In some embodiments, the compositions of the present technology can further comprise or be combined with one or more active ingredient(s), including but not limited to aripiprazole, atomoxetine, baclofen, clonidine, desipramine, dihydrotetrabenazine, guanfacine, haloperidol, levetiracetam, mecamylamine, etoclopramide, olanzapine, ondansetron, pergolide, pimozide, pramipexole, risperidone, selegiline, sulpiride, tetrabenazine, topiramate, ziprasidone, and ziprasidone.

[121 ] In some embodiments, suitable dosages of the conjugated d-methylphenidate-CO₂CH2-nicotinoyl-L-Ser chloride prodrugs of the present technology include, but are not limited to, formulations including an amount of conjugated d-methylphenidate (and not including unconjugated d-methylphenidate) equimolar to an amount of unconjugated d-methylphenidate from about 0.5 mg or higher, alternatively from about 1 .0 mg or higher, alternatively from about 2.5 mg or higher, alternatively from about 5.0 mg or higher, alternatively from about 7.5 mg or higher, alternatively from about 10 mg or higher, alternatively from about 20 mg or higher, alternatively from about 30 mg or higher, alternatively from about 40 mg or higher, alternatively from about 50 mg or higher, alternatively from about 60 mg or higher, alternatively from about 70 mg or higher, alternatively from about 80 mg or higher, alternatively from about 90 mg or higher, alternatively from about 100 mg or higher, alternatively 120 mg or higher, alternatively 200 mg or higher, alternatively 300 mg or higher, alternatively 400 mg or higher, alternatively 500 mg or higher, and include any additional increments thereof, for example, about 0.1 , about 0.2, about 0.25, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.75, about 0.8, about 0.9 or about 1 .0 mg and multiplied factors thereof, (e.g., about x1 , about χ2, about χ2.5, about χ5, about χ10, about χ100, etc.). It is contemplated that daily dosing regimens for compositions comprising the conjugated d-methylphenidate of the present technology (and not comprising unconjugated d- methylphenidate) include, but are not limited to, an amount of d-methylphenidate that is molar equivalent to a dose of d-methylphenidate hydrochloride from about 0.5 mg to about 500 mg per day, alternatively about 0.5 mg to about 480 mg per day, alternatively about 0.5 mg to about 450 mg per day, alternatively about 0.5 mg to about 400 mg, alternatively about 0.5 mg to about 360 mg per day, alternatively about 0.5 mg to about 350 mg per day, alternatively about 0.5 mg to about 300 mg per day, alternatively about 1 mg to about 250 mg per day, alternatively about 5 mg to about 240 mg per day, alternatively about 1 mg to about 100 mg per day, alternatively about 5 mg to about 80 mg per day, alternatively about 10 mg to about 40 mg per day, alternatively about 10 mg to 200 mg per day, alternatively about 10 mg to about 180 mg per day, alternatively about 20 mg to about 120 mg per day, alternatively about 20 mg to about 150 mg per day, alternatively about 30 mg to about 100 mg per day, alternatively about 40 mg to about 80 mg per day, alternatively about 50 mg to about 70 mg per day, alternatively about 20 mg to about 40 mg per day, alternatively about 20 mg to about 60 mg per day, a alternatively about 10 mg to about 50 mg per day, alternatively about 20 mg per day, alternatively about 40 mg per day, alternatively about 60 mg per day, alternatively about 80 mg per day, alternatively about 100 mg per day, alternatively about 120 mg per day. It is also contemplated that compositions comprising the conjugated d-MPH of the present technology (and not comprising unconjugated d-methylphenidate) would have a dosing regimen of one time a day, alternatively two times a day or less, alternatively four times a day or less. It is contemplated that some of the formulations of the present technology would be provided in a unit dose form. Such a unit dose form can be from about 0.5 mg to about 400 mg per day, alternatively from about 0.1 mg to about 300 mg per day, about 0.5 mg to about 300 mg per day, alternatively about 1 mg to about 250 mg per day, alternatively about 5 mg to about 240 mg per day, alternatively about 1 mg to about 100 mg per day, alternatively about 5 mg to about 80 mg per day, alternatively about 10 mg to about 40 mg per day, alternatively about 10 mg to 200 mg per day, alternatively about 10 mg to about 180 mg per day, alternatively about 20 mg to about 120 mg per day, alternatively about 20 mg to about 150 mg per day, alternatively about 30 mg to about 100 mg per day, alternatively about 40 mg to about 80 mg per day, alternatively about 50 mg to about 70 mg per day, alternatively about 20 mg to about 40 mg per day, alternatively about 20 mg to about 60 mg per day, a alternatively about 10 mg to about 50 mg per day, alternatively about 20 mg per day, alternatively about 40 mg per day, alternatively about 60 mg per day, alternatively about 80 mg per day, alternatively about 100 mg per day, alternatively about 120 mg per day. The present technology also includes dosage formulations including currently approved formulations of d-methylphenidate (See Table 1 ), where the dosage can be calculated using the above-noted formula determined by the amount of d-methylphenidate hydrochloride. The present technology provides for dosage forms formulated as a single therapy or as a combination therapy.

[122] In some embodiments, the conjugates of the present technology have one or more advantages, including, but not limited to, reduced or improved side effect profile, formation of less potentially toxic metabolites, formation of less inactive metabolites, improved water solubility, reduced drug abuse potential and/or reduced interpatient variability in plasma concentrations as compared to unconjugated d-methylphenidate.

Synthetic Schemes

[123] General synthetic schemes for preparing prodrugs of d-methylphenidate are disclosed in U.S. Patent No. 9,079,928, which is herein incorporated by reference. One or more protecting groups may be attached to any additional reactive functional groups that may interfere with the coupling to d-methylphenidate. Any suitable protecting group may be used depending on the type of functional group and reaction conditions. Some protecting group suitable for use in the present technology include, but are not limited to, acetyl (Ac), te/t-butyl (tBu), terf-butyoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), p- methoxybenzylcarbonyl (Moz), 9-fluorenylmethyloxycarbonyl (Fmoc), benzyl (Bn), p- methoxybenzyl (PMB), 3,4 dimethoxybenzyl (DMPM), p-methozyphenyl (PMP), tosyl (Ts), or amides (like acetamides, phthalimides, and the like).

[124] In other embodiments, a base may be required at any step in the synthetic scheme of preparing the prodrug of d-methylphenidate. Suitable bases include, but are not limited to, 4-methylmorpholine (NMM), 4-(dimethylamino)pyridine (DMAP), N,N- diisopropylethylamine (DIPEA), lithium bis(trimethylsilyl)amide, lithium diisopropylamide (LDA), any alkali metal te/t-butoxide (e.g., potassium te/t-butoxide), any alkali metal hydride (e.g., sodium hydride), any alkali metal alkoxide (e.g., sodium methoxide), triethylamine (Et₃N or TEA) or any other tertiary amine.

[125] Suitable solvents that can be used for any reaction at any step in the synthetic scheme of preparing the prodrug of d-methylphenidate include, but are not limited to, acetone, acetonitrile, butanol, chloroform, dichloromethane (DCM), dimethylformamide (DMF), dimethylsulfoxide (DMSO), dioxane, ethanol, ethyl acetate, diethyl ether, heptane, hexane, methanol, methyl te/t-butyl ether (MTBE), isopropanol (IPA), isopropyl acetate (IPAc), diisopropyl ether, tetrahydrofuran, toluene, xylene or water.

[126] In some embodiments, an acid may be used to remove certain protecting groups. Suitable acids include, but are not limited to, hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, acetic acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid and nitric acid. For certain other protecting groups, a catalytic hydrogenation may be used, e.g., palladium on charcoal in the presence of hydrogen gas.

[127] In some embodiments, an anion exchange medium, anion exchange resin, strong or weak anion exchanger including but not limited to Dowex^® 1 x8 chloride (available from Dow Chemical Co, Midland, Michigan) may be used to replace anionic counter ions of the cationic conjugate with a specific new counter anion such as a chloride ion. [128] In some embodiments, the prodrug is hydrophilic and thus more water soluble than the unconjugated d-methylphenidate.

[129] A synthetic scheme for preparing d-MPH-CO₂CH₂-nicotinoyl-L-Ser is as follows:

[130] Scheme 1 : Synthesis of nicotinoyl-Ser(tBu)OtBu 1

Scheme 2: Synthesis of d-f/7reo-MPH-CO₂CH₂-nicotinoyl-L-Ser CH₂CI _{1 Ng|}

A^cet0ne

₄ d-fftreo-MPH-C0₂CH₂-nicotinoyl-L-Ser

[132] 1 ). Nicotinoyl-Ser(tBu)OtBu 1 :

[133] To O-tert-Butyl-L-Serine tert-butyl ester (H-Ser(tBu)OtBu, 5.305 g, 23.17 mmol) in DCM (250 mL) was added Et₃N (5.329 g, 53.29 mmol, 2.3 eq.). The flask was cooled in an ice-water bath (~5 °C). NicotinoyI chloride hydrochloride (4.331 g, 24.33 mmol, 1 .05 eq.) was added in 7 portions over 1 hr. After adding, the water bath was removed and the reaction was stirred for another hour. 60 mL of 5% NH₄CI was added to quench the reaction. The DCM layer was further washed with brine (60 mL) and dried over Na₂SO₄.The product was purified by column (hexanes : ethyl acetate, 1 : 1 .3). 6.977 g of syrup was obtained. The yield was 93.4% and the purity was 98%.

[134] (2ft, 2'ft)-(+)-Methylphenidate hydrochloride 2 {d-threo isomer):

[135] 2 was made by resolution of d-threo-Methylphenidate hydrochloride 2 with O, 0'-dibenzoyl-D-(+)-tartaric acid according to the method developed by Mahavir Prashad { Tetrahedron: Asymmetry 1999, 10, 31 1 1 ). The yield was 40-42%.

[136] (ft)-Chloromethyl 2-((ft)-2-methoxy-2-oxo-1 -phenylethyl)piperidine-1 - carboxylate 3:

[137] d-{+)-threo Methylphenidate hydrochloride (MPH HCI) 2 (8.093 g, 30 mmol) in toluene (150 mL) was added DIPEA (12.4 mL, 75 mmol) under ice-water bath (~5 °C). Then chloromethyl chloroformate (5.029 g, 39 mmol) in toluene (50 mL) was added over 20 min at about 5 °C. After adding, the reaction was stirred at about 5-10 °C for 40 min. 5% NH₄CI (50 mL) was added to quench the reaction. The toluene layer was separated, washed with brine (50 mL) and dried over Na₂SO₄. Solvent was evaporated to give crude 3, which was purified by silica gel chromatography column (hexanes:ethyl acetate, 3:1 ) to give 9.833 gof syrup (solidified when stored in freezer) and the yield was quantitative. [138] 4). 3-((S)-1 -carboxy-2-hydroxyethylcarbamoyl)-1 -(((fl)-2-(2-(fl)-methoxy-2- oxo-1 -phenylethyl)piperidine-1 -carbonyloxy)methyl)pyridium chloride d-threo-MPH- CO₂CH₂-nicotinoyl-L-Ser:

[139] Nicotinoyl-Ser(tBu)OtBu 1 (0.322 g, 1 mmol) and carbamate 3 (0.355 g, 1 .09 mmol, 1 .09 eq.) were dissolved in acetone (10 mL). Then Nal (0.161 g, 1 .08 mmol, 1 .08 eq.) was added. The reaction was refluxed for 1 .5 hr. Upon cooling to room temperature, the reaction mixture was kept at room temperature for 2 hr. The solid (NaCI) was filtered off. The filtrate was concentrated and dried over vacuum for 1 hr to give amorphous solid 0.778 g. The solid in 4 M HCI/dioxane (5 mL) was stirred at room temperature for 2 hr.

[140] Solvent was evaporated and the remaining was coevaporated with DCM (2 times 6 mL), and then dried over vacuum for 1 hr. to give amorphous solid 0.667 g. It was dissolved in 10 mL of ethanol and treated with resin twice (2 times 1 g, Dowex 1 x8, 200-400, CI form, prewashed with water and ethanol, wet). The filtrate after resin treatment was concentrated and dried over vacuum to give amorphous solid 0.617 g. The solid was dissolved in 10 mL of IPA with heating and then 5 mL of IPAc was added. Crystals formed gradually. After 3 hr., solid was collected and washed with IPA/IPAc (2: 1 , 3 times 1 mL), dried over vacuum. 437 mg of white solid (d-MPH-CO₂CH₂- nicotinoyl-L-Ser chloride) was obtained. The yield was 81 .5% and the purity was 97.6%.

[141 ] Preparation of cationic species of d-MPH-CO₂CH₂-nicotinoyl-L-Ser:

[142] The chloride salt of d-MPH-CO₂CH₂-nicotinoyl-L-Ser is dissolved in water. The resulting solution contains free d-MPH-CO₂CH₂-nicotinoyl-L-Ser in cationic form. [143] A synthetic scheme for preparing d-MPH-C0₂CH₂-nicotinoyl-L-Thr is as follows:

[144] Scheme 1 : Synthesis of nicotinoyl-Thr(tBu)OtBu 5

5

[145] Scheme 2: Synthesis of threonine analogue of d-MPH-C0₂CH₂-nicotinoyl-L- Thr.

A^cetone

₆ d-.ftreo-MPH-C0₂CH₂-nicotinoyl-L-Thr [146] Nicotinoyl-Thr(tBu)OtBu 5:

[147] Nicotinoyl-Thr(tBu)OtBu was prepared with the same procedure as nicotinoyl-Ser(tBu)OtBu. The yield was 90.4%.

[148] 3-(((1 S,2R)-1 -carboxy-2-hydroxypropyl)carbamoyl)-1 -(((fl)-2-(2-(fl)- methoxy-2-oxo-1 -phenylethyl)piperidine-1 -carbonyloxy)methyl)pyridium chloride: [149] Nicotinoyl-Thr(tBu)OtBu 5 (0.336 g, 1 mmol) and carbamate 3 (0.355 g, 1 .09 mmol, 1 .09 eq.) were dissolved in acetone (8 mL). Then Nal (0.161 g, 1 .08 mmol, 1 .08 eq.) was added. The reaction was refluxed for 1 .5 hr. Upon cooling to room temperature, the reaction mixture was kept at room temperature for 1 hr. The solid (NaCI) was filtered off. The filtrate was concentrated and dried over vacuum for 1 hr to give amorphous solid 0.796 g. The solid in 4 M HCI/dioxane (5 mL) was stirred at room temperature for 2 hr.

[150] Solvent was evaporated and the remaining was coevaporated with DCM (two times 6 mL), and then dried over vacuum for 1 hr. to give amorphous solid 0.70 g. It was dissolved 10 ml of ethanol and treated with resin twice (two times 1 g, Dowex 1 x8, 200-400, CI form, prewashed with water and ethanol, wet). The filtrate after resin treatment was concentrated and dried over vacuum to give amorphous solid 0.638 g. The solid was dissolved in 4 ml of EtOH and then 6 mL of TBME was added. Crystal formed slowly. After 2 days, solid was collected and washed with EtOH/TBME (1 : 1 , three times 2 mL), dried over vacuum. 390 mg of white solid (d-MPH-CO₂CH₂- nicotinoyl-L-Thr chloride) was obtained. The yield was 70.9% and the purity was 99%.

[151 ] When conjugating d-methylphenidate via carbamate bond to a methylene oxide linker which in turn is connected to the nitrogen of the pyridine ring of a nicotinoyl- amino acid moiety, unexpected differences in solubility and pharmacokinetics were observed between conjugates of racemic threo-methylphenidate (i.e., d and I isomers in a 1 :1 ratio) and conjugates of isomerically pure d-threo-methylphenidate and l-threo- methylphenidate. Moreover, these differences were not limited to varying the chirality of methylphenidate with the same terminal amino acid. Differences were also observed when the conjugate comprised the same form of d-methylphenidate but different amino acids. The conjugates d-MPH-CO₂CH₂-nicotinoyl-L-Ser, l-MPH-CO₂CH₂-nicotinoyl-L- Ser, and d-MPH-CO₂CH₂-nicotinoyl-L-Thr each have three chiral centers.

[152] In one embodiment, the conjugate d/l-MPH-CO₂CH₂-nicotinoyl-L-Ser was recrystallized from a mixture (1 :1 ) of isopropylalcohol (IPA) and isopropylacetate (IPAc) yielding approximately 45.2% of product (purity of about 98% by HPLC). A similar amount of d-MPH-CO₂CH₂-nicotinoyl-L-Ser recrystallized from IPA and IPAc (2:1 ) yielded approximately 81 .5% of product (purity of about 97.6%by HPLC). This result is nonobvious since the yield of the isomerically pure conjugate was significantly higher even though more IPA was used which would be expected to improve the solubility of the conjugate. The results indicated that l-MPH-CO₂CH₂-nicotinoyl-L-Ser has significantly higher solubility in IPA/IPAc when compared to d-MPH-CO₂CH₂- nicotinoyl-L-Ser (Formula I).

[153] In another embodiment, the following compounds were dosed orally in rats at equimolar doses: d-MPH HCI, l-MPH HCI, d-MPH-CO₂CH₂-nicotinoyl-L-Ser, l-MPH- CO₂CH₂-nicotinoyl-L-Ser, d-MPH-CO₂CH₂-nicotinoyl-L-Thr, and l-MPH-CO₂CH₂- nicotinoyl-L-Thr. As shown in Figure 1 and Table 3, when comparing d-MPH HCI and I- MPH HCI, the bioavailability of the d-isomer was significantly higher vs the l-isomer. The d:l-isomer ratios of mean C_max and AUC were about 192% and 124%, respectively, (as shown in Table 3). In addition, the T_max of l-MPH was longer (0.7 hours) compared to d-MPH (0.4 hours)(Table2). [154] Table 2: PK parameters for d-methylphenidate and l-methylphenidate after oral administration of d-MPH HCI and l-MPH HCI in rats.

[155] Table 3: d:l-isomer ratios for unconjugated d-methylphenidate after oral administration in rats.

[156] As shown in Figure 2, relative exposure to d-MPH and l-MPH released from d-MPH-CO₂CH₂-nicotinoyl-L-Thr and l-MPH-CO₂CH₂-nicotinoyl-L-Thr, respectively, were reversed (d:l conjugate ratios of mean C_max and AUC were about 58% and 53%, respectively as shown in Table 4) when compared to unconjugated d-MPH and l-MPH. The relationship between T_max for d-MPH-CO₂CH₂-nicotinoyl-L-Thr and l-MPH-CO₂CH₂- nicotinoyl-L-Thr (0.6 hours vs 1 .1 hours, respectively as shown in Table 4) was similar compared to unconjugated d-MPH and l-MPH.

[157] Table 4: PK parameters for d-methylphenidate and l-methylphenidate after oral administration of d-MPH-CO₂CH₂-nicotinoyl-L-Thr and l-MPH-CO₂CH₂-nicotinoyl-L- Thr in rats. d-MPH-CO₂CH₂- I-MPH-CO2CH2- nicotinoyl-L-Thr nicotinoyl-L-Thr

Analyte d-MPH l-MPH

Cmax (ng/mL) 62.5 107.6

AUC (hours^*ng/ml_) 84.2 160.0

Tmax (hours) 0.6 1 .1

[158] Table 5: d:l-isomer ratios for MPH-CO₂CH2-nicotinoyl-L-Thr after oral administration in rats.

[159] As shown in Figure 3, the conjugates comprising L-serine were again different from the L-threonine conjugates and from unconjugated methylphenidate. While peak exposure (C_max) to d-MPH and l-MPH released from d-MPH-CO₂CH₂- nicotinoyl-L-Ser and l-MPH-CO2CH₂-nicotinoyl-L-Ser, respectively, were similar, overall exposure (AUC) was lower and T_max significantly shorter for I-MPH-CO2CH2- nicotinoyl-L-Ser (d:l conjugate ratios of mean C_max and AUC were about 94% and 73%, respectively as shown Table 7; T_max was 1 .0 and 0.6 hours for d-MPH-CO2CH₂- nicotinoyl-L-Ser and l-MPH-CO2CH₂-nicotinoyl-L-Ser, respectively, as shown in Table 6). [160] Table 6: PK parameters for d-methylphenidate and l-methylphenidate after oral administration of d-MPH-CO₂CH₂-nicotinoyl-L-Ser and l-MPH-CO₂CH₂- nicotinoyl-L-Ser in rats.

[161 ] Table 7: d:l-isomer ratios for MPH-CO₂CH₂-nicotinoyl-L-Ser after oral administration in rats.

[162] In summary, the serine conjugates produced extended release of d-MPH and the threonine conjugates produced a more effective and extended release of I- MPH. Thus, by changing the stereochemistry of methylphenidate, the respective prodrugs exhibited selective absorption and/or clearance of d-MPH vs l-MPH. Results of the human PK study confirmed that at least for d-MPH-CO₂CH₂-nicotinoyl-L-Ser, d-MPH was effectively released in an extended-release fashion and absorbed into the systemic circulation following oral administration. Pharmaceutical Kits

[163] In some embodiments, the present technology provides pharmaceutical kits comprising a prodrug or composition of the present technology that has increased water solubility than compared to the unconjugated d-methylphenidate. In some embodiments, the pharmaceutical kit comprises a specific amount of individual doses in a package, each dose comprising a pharmaceutically and/or therapeutically effective amount of the d-methylphenidate prodrugs or conjugates of the present technology, and not containing unconjugated d-methylphenidate. The pharmaceutical kit may also include instructions for use. In some other embodiments, the kit comprises oral thin films or strips comprising prodrugs or conjugates of the present technology. In some other embodiments, the kit comprises one or more blister packs containing the prodrug or composition of the present technology. It will be appreciated by one skilled in the art that, in some embodiments, the kit may include individual doses that have different dosage amounts.

[164] The present technology provides pharmaceutical kits for the treatment or prevention of any of the indications mentioned above, including ADHD, eating disorder, binge eating disorder, obesity, narcolepsy, chronic fatigue syndrome, EDS, sleep disorder, or drug withdrawal symptoms in a subject. The subject may be a human or animal subject. As used herein the term animal is used in the veterinary sense and does not include humans. Suitable human subjects include neonatal subjects, pediatric subjects, adolescent subjects, adult subjects, geriatric subjects, elderly subjects and normative subjects. The kit comprises a specific amount of the individual doses in a package containing a pharmaceutically and/or therapeutically effective amount of at least one conjugate of d-methylphenidate of the present technology, and not containing unconjugated d-methylphenidate. The kit can further include instructions for use of the kit, wherein the instructions for use of the kit may further comprise methods for treating or preventing any of the indications selected from the group consisting of ADHD, eating disorder, binge eating disorder, obesity, narcolepsy, chronic fatigue, sleep disorder, EDS, cocaine addiction, or drug withdrawal symptoms in a subject. The specified amount of individual doses may be from about 1 to about 1 00 individual dosages, alternatively from about 1 to about 60 individual dosages, alternatively from about 1 0 to about 30 individual dosages, including, about 1 , about 2, about 5, about 1 0, about 1 5, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 70, about 80, about 1 00, and include any additional increments thereof, for example, about 1 , about 2, about 5, about 1 0 and multiplied factors thereof, (e.g., about x 1 , about x2, about χ2.5, about χ5, about χ 1 0, about χ 1 00, etc.). One of skill in the art will appreciate that some embodiments of the kit of the present technology may include graduated individual doses (i.e. dose amounts that increase or decrease over a period of time), and/or a graduated dosing regimen, and instructions for use.

[1 65] In certain embodiments, compositions of the present technology comprising at least one conjugate of d-threo-methylphenidate can be used in neonatal, pediatric, adolescent, adult and/or geriatric subjects with ADHD. For example, in some embodiments, the present compositions can be used for a once-daily dosing with extended release of d-methylphenidate. In an embodiment, the present composition can be used for once daily dosing with longer duration of action attributes that may benefit adult and/or geriatric subjects with ADHD. [166] The presently described technology and its advantages will be better understood by reference to the following examples. These examples are provided to describe specific embodiments of the present technology. By providing these specific examples, it is not intended limit the scope and spirit of the present technology. It will be understood by those skilled in the art that the full scope of the presently described technology encompasses the subject matter defined by the claims appending this specification, and any alterations, modifications, or equivalents of those claims.

EXAMPLES

[167] Example 1 : d-threo-MPH-C0₂CH₂-nicotinoyl-L-Ser and unconjugated d-methylphenidate.

[168] The plasma concentrations of d-methylphenidate were measured by LC- MS/MS over time. The oral plasma concentrations of d-methylphenidate released from d-threo-MPH-CO₂CH2-nicotinoyl-L-Ser were compared with unconjugated d-methylphenidate after oral administration in rats.

[169] Figure 4 demonstrates the PK curve achieved by the d-threo-MPH-CO₂CH₂- nicotinoyl-L-Ser as compared with unconjugated forms and all of the specific pharmacokinetic parameter data is presented in Tables 8 - 9. As shown in Table 8, 4.75 mg of conjugate (d-threo-MPH-CO₂CH₂-nicotinoyl-L-Ser) was used as compared to 2.39 mg unconjugated d-methylphenidate hydrochloride used, however, both had the same amount of the d-MPH (mg/kg), which was 2.06 mg/kg. The human equivalent dose for the conjugate was 0.8 mg/kg as compared to 0.4 mg/kg for unconjugated d-methylphenidate. [170] Table 8. Comparison of prodrugs of d-methylphenidate with unconjugated d-methylphenidate dosed orally in rats.

[171 ] As shown in Table 9, the conjugate of d-threo-MPH-CO₂CH₂- nicotinoyl-L-Ser has a mean AUC₀-₄h of d-methylphenidate of about 86.1 hxng/mL ± 10.0 hxng/mL when administered orally to a rat when compared to unconjugated d-methylphenidate of about 79.5 hxng/mL ± 10.0 hxng/mL. The conjugate has a mean Cmax of d-methylphenidate of about 51 .3 ng/mL ± 10 ng/mL when administered orally to a rat compared to unconjugated d-methylphenidate of about 96.6 ng/mL ± 10 ng/mL. The conjugate has a T_max of d-methylphenidate of about 1 .2 hours ± 10 hours when compared to unconjugated d-methylphenidate of about 0.4 hours ± 10 hours when administered orally to a rat.

[172] Table 9. PK comparison of prodrugs of d-methylphenidate with unconjugated d-methylphenidate dosed orally in rats.

[173] As shown in Figure 4, after 4.75 mg conjugate was fed orally to rats, plasma concentrations of d-methylphenidate released from the conjugate are increased from 0 to about 1 .2 hours following oral administration in a rat when compared to unconjugated d-methylphenidate (2.39 mg) of about 0.4 hour. Plasma concentrations of d-methylphenidate released from the conjugate are slowly increased from about 1 .2 to about 4 hour following oral administration in a rat. Time 0 hours as used herein refers to the time of administration.

[174] As shown in Figure 5 and Table 10, after 4.75 mg conjugate was intranasally administered to rats, plasma concentrations of d-methylphenidate released from the conjugate are substantially flat from about 0 to about 1 hour following intranasal administration in a rat. However, after 2.39 mg unconjugated d-methylphenidate was intranasally administered to rats, plasma concentrations of d-methylphenidate released from the conjugate are dramatically increased from about 0 to about 0.1 hour following intranasal administration in a rat. Conjugated d-methylphenidate was about 6% AUC and 5% C_max of unconjugated d-methylphenidate.

[175] Similar to Figure 5, Figure 6 and Table 10 show that after 4.75 mg conjugate was injected intravenously to rats, plasma concentrations of d-methylphenidate released from the conjugate are substantially flat from about 0 to about 2 hours following intravenous administration in a rat. However, after 2.39 mg unconjugated d-methylphenidate was injected intravenously to rats, plasma concentrations of d-methylphenidate released from the conjugate are dramatically increased from about 0 to about 0.1 hour following intravenous administration in a rat. Conjugated d-methylphenidate was about 17% AUC and 12% C_max of unconjugated d-methylphenidate.

[176] Table 10. PK comparison of prodrugs of d-methylphenidate with unconjugated d-methylphenidate dosed intranasally and intravenously in rats.

[177] Example 2: Human Study of d-threo-MPH-C0₂CH₂-nicotinoyl-L-Ser.

[178] A study was conducted in humans to assess the pharmacokinetics (PK) of 60 mg of d-MPH-CO₂CH2-nicotinoyl-L-Ser (liquid, dissolved in water) using two treatment regimens:

[179] Treatment A: 60 mg d-threo-MPH-CO₂CH₂-nicotinoyl-L-Ser under fasted conditions

[180] Treatment B: 60 mg d-threo-MPH-CO₂CH₂-nicotinoyl-L-Ser 20 minutes after consuming a standard breakfast

[181 ] The Treatment Phase consisted of two treatments, each of which involved a single treatment of one of the Study Treatments separated by a minimum 96-hour washout period. Subjects were crossed over to receive each treatment, as defined by a randomization schedule.

[182] "Fed" state (Treatment B) was assessed following a standard breakfast consumed within 20 minutes prior to dosing. The breakfast consisted of the following items.

a May be partially used with cereal and the rest consumed as drink

[183] As shown in Figure 7, Treatment B provided a higher mean peak plasma concentration (C_max) and higher mean overall systemic exposure (AUC₀-36) of d-methylphenidate released from the conjugate compared to Treatment A. The specific pharmacokinetic data is presented in Table 1 1 .

[184] Table 1 1 . PK parameters of d-methylphenidate following oral administration of 60 mg of d-MPH-CO₂CH₂-nicotinoyl-L-Ser in human subjects in the fasted (Treatment A) and fed (Treatment B) state:

Difference

Parameter³ Treatment A Treatment B Treatment A vs B

AUCiast (hours^*ng/ml_ 120.6 ± 20.2 132.8 ± 33.1 -18.5%

T_max (hours) 8 8

[8 - 36] [4.5 - 24]

T_½ (hours) 25.7 ± 16.9 14.7 ± 4.4

a Arithmetic mean ± standard deviation except T_max for which the median

[Range] is reported.

[185] Figure 8 shows the mean plasma concentration-time profiles for intact dMPH-CO₂CH₂-nicotinoyl-L-Ser in human subjects in the fasted state. Plasma concentrations of the intact prodrug greatly increased from about 0 to about 1 hour following oral administration to subjects in the fasted state. Moreover, plasma concentrations of the intact prodrug remained higher for subjects in the fasted state over a period of 0 to about 24 hours, and gradually decreased over a 24 hour period post administration. The specific pharmacokinetic data is presented in Table 12.

[186] Table 12. PK parameters of intact d-MPH-CO₂CH₂-nicotinoyl-L-Ser following oral administration of 60 mg of d-MPH-CO₂CH₂-nicotinoyl-L-Ser in human subjects in the fasted (Treatment A) state:

a Arithmetic mean ± standard deviation except

T_max for which the median [Range] is reported. [187] Significant concentrations of the intact prodrug conjugate in the fasted state suggest that circulating prodrug levels contribute to the extended release profile by continuously releasing d-MPH over time. The gradual decrease in the plasma concentrations of the intact prodrug further suggests the continuous release of d-MPH over time.

[188] Figure 9 shows the mean molar plasma concentration-time profiles for d-methylphenidate released from d-MPH-CO₂CH₂-nicotinoyl-L-Ser and for intact d-MPH-CO₂CH₂-nicotinoyl-L-Ser following oral administration of 60 mg of d-MPH- CO₂CH₂-nicotinoyl-L-Ser in human subjects in the fasted state. As shown in Figure 9, plasma concentrations of the intact prodrug greatly increased from 0 to about 1 hour following oral administration, and then gradually decreased until about 36 hours after dosing. The plasma concentrations of the released active d-MPH gradually increased from 0 to about 8 hours T_max following oral administration, and remained greater than the plasma concentration of the intact prodrug through 36 hours post-administration. The data shows that d-MPH is gradually released from the prodrug over time, and even at 36 hours post-administration, there is a measurable plasma concentration of d-MPH. The long extended release profile for oral administration of 60 mg of d-MPH-CO₂CH₂- nicotinoyl-L-Ser in human subjects in the fasted state shows that d-MPH exposure can be maintained over at least a 24 hour period, allowing for a desirable single daily dose form of administration.

[189] The mean plasma concentration-time profile for d-MPH released from d- methylphenidate-CO₂CH_2-nicotinoyl-L-Ser after oral administration to humans under fasted conditions was determined and compared to the mean plasma concentration- time profile for 60.4 mg of Concerta following oral administration in humans. The 60.4 mg dose of Concerta^® contains the same amount of d-MPH as 60 mg of d-MPH- CO₂CH₂-nicotinoyl-L-Ser. The data for 60.4 mg of Concerta^® were extrapolated from data collected with commercially available 36 mg Concerta^®, assuming dose proportionality. The results of the comparison are shown in Table 13, and graphically illustrated in Figure 10.

[190] Table 13. Mean plasma concentration-time data for d-methylphenidate released from 60 mg of d-MPH-CO₂CH2-nicotinoyl-L-Ser and 60.4 mg of Concerta^® following oral administration in human subjects.

Time Mean d-methylphenidate Plasma Concentration (ng/mL)

(hours) d-MPH-C0₂CH₂-nicotinoyl-L-Ser Concerta^®

16 3.32 nd

24 2.72 0.98

36 1 .93 nd

nd = no data collected

[191 ] From Figure 10 and Table 13, it can be seen that d-MPH-CO₂CH₂- nicotinoyl-L-Ser provides a more gradual increase in plasma concentrations of d-MPH and a slower and longer extended release profile compared to Concerta^®.

[192] A study was conducted in humans to assess the pharmacokinetics (PK) of 32 mg of d-MPH-CO₂CH₂-nicotinoyl-L-Ser (liquid, dissolved in water) compared with 36 mg of Concerta^® (tablet) after oral administration under fasted conditions (the dose of 32 mg of d-MPH-CO₂CH₂-nicotinoyl-L-Ser contains about 13.9 mg of d- methylphenidate, which was about 10.9% lower compared to the about 15.6 mg of d- methylphenidate in 36 mg of Concerta^®). Twenty-four (24) healthy volunteers were enrolled in this open-label, single-dose, two-treatment, two-period PK trial.

[193] Figure 1 1 shows the mean (N=24) plasma concentration-time profiles of intact d-MPH-CO₂CH₂-nicotinoyl-L-Ser after a single dose of 32 mg was administered as an oral liquid. Plasma concentrations of intact prodrug were increased from about 0 to about 2 hours following oral administration in a human subject and slowly decreased to about 0 at 24 hours postdose.

[194] A proof-of-concept study suggested that one or more compositions of the present technology comprising at least one conjugate of d-threo-methylphenidate may allow for development of a once-daily dosing with a potentially longer duration of action that may benefit adult patients with ADHD.

[195] In the present specification, use of the singular includes the plural except where specifically indicated.

[196] The presently described technology is now described in such full, clear, concise 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 that the foregoing describes preferred embodiments of the technology and that modifications may be made therein without departing from the spirit or scope of the invention as set forth in the appended claims.

Claims

Claims We claim:

1 . A composition comprising a conjugate of d-threo-methylphenidate, or a pharmaceutically acceptable salt thereof, having the following chemical formula:

wherein, the composition does not contain unconjugated d-methylphenidate.

2. The composition of claim 1 , wherein, upon administration to a subject, the composition results in an extended release of d-methylphenidate in the subject compared to the release of d-methylphenidate upon administration of an equivalent molar amount of unconjugated d-methylphenidate.

3. An oral formulation comprising:

a therapeutic dose of d-threo-methylphenidate conjugate, or a pharmaceutically acceptable salt thereof, having the following structure:

wherein, the oral formulation does not contain unconjugated d-methylphenidate.

4 The oral formulation of claim 3, wherein, upon administration to a subject, the oral formulation results in an extended release of d-methylphenidate in the subject compared to the release of d-methylphenidate upon administration of an equivalent molar amount of unconjugated d-methylphenidate.

5. An oral formulation comprising:

a therapeutically effective dose of d-threo-methylphenidate conjugate having the following structure:

wherein, the oral formulation does not contain unconjugated d-methylphenidate.

6. The oral formulation of claim 5, wherein, upon administration to a subject, the oral formulation results in an extended release of d-methylphenidate in the subject compared to the release of d-methylphenidate upon administration of an equivalent molar amount of unconjugated d-methylphenidate.

7. The composition of claim 1 , or the oral formulation of claim 3 or claim 5, wherein the conjugate is a prodrug.

8. The composition of claim 1 or the oral formulation of claim 3, wherein the conjugate is a therapeutically acceptable salt form or salt mixture thereof.

9. The composition or oral formulation of claim 8, wherein the salt form is selected from the group consisting of acetate, l-aspartate, besylate, bicarbonate, carbonate, d-camsylate, l-camsylate, citrate, edisylate, formate, fumarate, gluconate, hydrobromide/bromide, hydrochloride/chloride, d-lactate, l-lactate, d,l-lactate, d,l-malate, l-malate, mesylate, pamoate, phosphate, succinate, sulfate, bisulfate, d-tartrate, martrate, d,l-tartrate, meso-tartrate, benzoate, gluceptate, d-glucuronate, hybenzate, isethionate, malonate, methylsulfate, 2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate, thiocyanate, acefyllinate, aceturate, aminosalicylate, ascorbate, borate, butyrate, camphorate, camphocarbonate, decanoate, hexanoate, cholate, cypionate, dichloroacetate, edentate, ethyl sulfate, furate, fusidate, galactarate, galacturonate, gallate, gentisate, glutamate, glutarate, glycerophosphate, heptanoate, hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate, mandelate, methanesulfonate, myristate, napadisilate, oleate, oxalate, palmitate, picrate, pivalate, propionate, pyrophosphate, salicylate, salicylsulfate, subsalicylate, tannate, terephthalate, thiosalicylate, tribrophenate, valerate, valproate, adipate, 4-acetamidobenzoate, camsylate, octanoate, estolate, esylate, glycolate, thiocyanate, and undecylenate.

10. The composition or oral formulation of claim 8, wherein the salt form is selected from the group consisting of chloride, hydrogen carbonate (bicarbonate), iodide, bromide, citrate, acetate, formate, salicylate, hydrogen sulfate (bisulfate), hydroxide, nitrate, hydrogen sulfite (bisulfite), propionate, benzene sulfonate, hypophosphite, phosphate, bromate, iodate, chlorate, fluoride, nitrite.

1 1 . The composition or oral formulation of claim 8, wherein the salt is a chloride salt.

12. The composition of claim 1 , wherein the composition is in the form comprising a sublingual, gummy, chewable tablet, rapidly dissolving tablet, tablet, a capsule, a caplet, a troche, a lozenge, an oral powder, a solution, a thin strip, an oral thin film (OTF), an oral strip, a rectal film, a syrup, a suspension, or a suppository.

13. The oral formulation of claim 3 or claim 5, wherein the oral formulation is in the form comprising a sublingual, gummy, chewable tablet, rapidly dissolving tablet, tablet, a capsule, a caplet, a troche, a lozenge, an oral powder, a solution, a thin strip, an oral thin film (OTF), an oral strip, a syrup, or a suspension.

14. The composition of claim 1 , or the oral formulation of claim 3 or claim 5, wherein the composition or oral formulation has a dosing regimen that is about two times a day or less.

15. The composition of claim 1 , or the oral formulation of claim 3 or claim 5, wherein the composition or oral formulation has a dosing regimen that is about one time a day.

16. The composition of claim 1 , or the oral formulation of claim 3 or claim 5, wherein the composition or oral formulation has a dosing regimen that is molar equivalent to a dose from about 0.1 mg to about 500 mg d-methylphenidate hydrochloride per day.

17. The composition of claim 1 , or the oral formulation of claim 3 or claim 5, wherein the composition or oral formulation has a dosing regimen that is molar equivalent to a dose from about 0.5 mg to about 300 mg d-methylphenidate hydrochloride per day.

18. The composition of claim 1 , or the oral formulation of claim 3 or claim 5, wherein the composition or oral formulation has a dosing regimen that is molar equivalent to a dose from about 1 mg to about 100 mg d-methylphenidate hydrochloride per day.

19. The composition of claim 1 , or the oral formulation of claim 3 or claim 5, wherein the composition or oral formulation has a dosing regimen that is molar equivalent to a dose from about 5 mg to about 80 mg d-methylphenidate hydrochloride per day.

20. The composition of claim 1 , or the oral formulation of claim 3 or claim 5, wherein the composition or oral formulation has a dosing regimen that is molar equivalent to a dose from about 10 mg to about 40 mg d-methylphenidate hydrochloride per day.

21 . The composition of claim 1 , or the oral formulation of claim 3 or claim 5, wherein the composition or oral formulation has a dosing regimen that is molar equivalent to a dose from about 10 mg to about 200 mg d-methylphenidate hydrochloride per day.

22. The composition of claim 1 , or the oral formulation of claim 3 or claim 5, wherein the composition or oral formulation has a dosing regimen that is molar equivalent to a dose from about 20 mg to about 120 mg d-methylphenidate hydrochloride per day.

23. The composition of claim 1 , or the oral formulation of claim 3 or claim 5, wherein the composition or oral formulation has a dosing regimen that is molar equivalent to a dose from about 30 mg to about 100 mg d-methylphenidate hydrochloride per day.

24. The composition of claim 1 , or the oral formulation of claim 3 or claim 5, wherein the composition or oral formulation has a dosing regimen that is molar equivalent to a dose from about 40 mg to about 80 mg d-methylphenidate hydrochloride per day.

25. The composition of claim 1 , or the oral formulation of claim 3 or claim 5, wherein the composition or oral formulation has a dosing regimen that is molar equivalent to a dose from about 50 mg to about 70 mg d-methylphenidate hydrochloride per day.

26. The composition of claim 1 , or the oral formulation of claim 3 or claim 5, wherein the composition or oral formulation has a dosing regimen that is molar equivalent to a dose about 20 mg, about 40 mg or about 60 mg d-methylphenidate hydrochloride per day.

27. The composition of claim 1 , or the oral formulation of claim 3 or claim 5, wherein the composition or oral formulation has a dosing regimen that is molar equivalent to a dose from about 20 mg to about 40 mg d-methylphenidate hydrochloride per day.

28. The composition of claim 1 , or the oral formulation of claim 3 or claim 5, wherein the composition or oral formulation has a dosing regimen that is molar equivalent to a dose from about 20 mg to about 60 mg d-methylphenidate hydrochloride per day.

29. The composition of claim 1 , or the oral formulation of claim 3 or claim 5, wherein the composition or oral formulation has a dosing regimen that is molar equivalent to a dose from about 10 mg to about 50 mg d-methylphenidate hydrochloride per day.

30. The composition of claim 1 , or the oral formulation of claim 3 or claim 5, wherein the composition or oral formulation is provided in a unit dose form.

31 . The composition or oral formulation of claim 30, wherein the unit dose form is from about 0.5 mg to about 400 mg per day.

32. The composition of claim 1 , or the oral formulation of claim 3 or claim 5, wherein the conjugate is orally administered to a human or an animal subject.

33. The composition of claim 1 , or the oral formulation of claim 3 or claim 5, wherein plasma concentrations of d-methylphenidate released from the conjugate are higher when compared to an equimolar dose of unconjugated d-methylphenidate released from Concerta^® at 24 hours following oral administration in a human subject.

34. The composition of claim 1 , or the oral formulation of claim 3 or claim 5, wherein plasma concentrations of d-methylphenidate released from the conjugate are higher when compared to an equimolar dose of unconjugated d-methylphenidate released from Concerta^® at 36 hours following oral administration in a human subject.

35. A pharmaceutical kit comprising:

a specified amount of individual doses in a package, wherein each dose comprises a pharmaceutically effective amount of a conjugate of d-threo methylphenidate, or a pharmaceutically acceptable salt thereof, wherein the conjugate has the following structure:

and wherein the individual doses do not contain unconjugated d-methylphenidate; the pharmaceutical kit further comprising instructions for use.

36. The pharmaceutical kit of claim 35, wherein the conjugate is a prodrug.

37. The pharmaceutical kit of claim 35, wherein the instructions for use comprise a method of treating or preventing attention deficit hyperactivity disorder symptoms in a human or animal subject.

38. The pharmaceutical kit of claim 35, wherein the instructions for use comprise a method for treating or preventing drug withdrawal symptoms, cocaine dependence, or stimulant dependence in a human or animal subject.

39. The pharmaceutical kit of claim 35, wherein the instructions for use comprise a method for treating or preventing binge eating, eating disorder, or obesity in a human or animal subject.

40. The pharmaceutical kit of claim 35, wherein the instructions for use comprise a method for treating or preventing narcolepsy, excessive daytime sleepiness (EDS), chronic fatigue syndrome, or sleep disorder in a human or animal subject.

41 . The pharmaceutical kit of any one of claims 37-40, wherein the subject is a pediatric subject.

42. The pharmaceutical kit of any one of claims 37-40, wherein the subject is a geriatric subject.

43. The pharmaceutical kit of any one of claims 37-40 wherein the subject is an adult subject.

44. The pharmaceutical kit of any one of claims 37-40, wherein the subject is an adolescent subject.

45. The pharmaceutical kit of claim 38, wherein the patient is a neonatal patient.

46. The pharmaceutical kit of any one of claims 37-40, wherein the individual dose is equimolar to at least about 0.5 mg or higher of d-methylphenidate.

47. The pharmaceutical kit of any one of claims 37-40, wherein the individual dose is equimolar to at least about 2.5 mg or higher of d-methylphenidate.

48. The pharmaceutical kit of any one of claims 37-40, wherein the individual dose is equimolar to at least about 5.0 mg or higher of d-methylphenidate.

49. The pharmaceutical kit of any one of claims 37-40, wherein the individual dose is equimolar to at least about 10 mg or higher of d-methylphenidate.

50. The pharmaceutical kit of any one of claims 37-40, wherein the individual dose is equimolar to at least about 20 mg or higher of d-methylphenidate.

51 . The pharmaceutical kit of any one of claims 37-40, wherein the individual dose is equimolar to at least about 50 mg or higher of d-methylphenidate.

52. The pharmaceutical kit of any one of claims 37-40, wherein the individual dose is equimolar to at least about 200 mg or higher of d-methylphenidate.

53. The pharmaceutical kit of any one of claim 37-40, wherein the individual dose is equimolar to about 20 mg, about 40 mg or about 60 mg of d-methylphenidate.

54. The pharmaceutical kit of any one of claims 37-40, wherein the kit comprises from about 1 to about 60 individual doses.

55. The pharmaceutical kit of any one of claims 37-40, wherein the kit comprises from about 10 to about 30 individual doses.

56. The pharmaceutical kit of any one of claims 37-40 wherein the composition further comprises one or more excipients.

57. The pharmaceutical kit of any one of claims 37-40, wherein the composition further comprises one or more additional pharmaceutically active ingredients.

58. The pharmaceutical kit of any one of claims 37-40, wherein the package is a blister pack.

59. The pharmaceutical kit of any one of claims 37-40, wherein the individual dose results in an extended release of d-methylphenidate compared to an equivalent molar amount of unconjugated d-methylphenidate.

60. A therapeutic kit comprising:

a specified amount of individual doses in a package, wherein each dose comprises a therapeutically effective amount of a conjugate of d-threo methylphenidate, or a therapeutically acceptable salt thereof, wherein the conjugate has the following structure:

61 . A compound having the following chemical formula:

or a pharmaceutically acceptable salt thereof.

62. The compound of claim 61 , wherein the salt is selected from the group consisting of acetate, l-aspartate, besylate, bicarbonate, carbonate, d-camsylate, I- camsylate, citrate, edisylate, formate, fumarate, gluconate, hydrobromide/bromide, hydrochloride/chloride, d-lactate, l-lactate, d,l-lactate, d,l-malate, l-malate, mesylate, pamoate, phosphate, succinate, sulfate, bisulfate, d-tartrate, martrate, d,l-tartrate, meso-tartrate, benzoate, gluceptate, d-glucuronate, hybenzate, isethionate, malonate, methylsulfate, 2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate, thiocyanate, acefyllinate, aceturate, aminosalicylate, ascorbate, borate, butyrate, camphorate, camphocarbonate, decanoate, hexanoate, cholate, cypionate, dichloroacetate, edentate, ethyl sulfate, furate, fusidate, galactarate, galacturonate, gallate, gentisate, glutamate, glutarate, glycerophosphate, heptanoate, hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate, mandelate, methanesulfonate, myristate, napadisilate, oleate, oxalate, palmitate, picrate, pivalate, propionate, pyrophosphate, salicylate, salicylsulfate, subsalicylate, tannate, terephthalate, thiosalicylate, tribrophenate, valerate, valproate, adipate, 4- acetamidobenzoate, camsylate, octanoate, estolate, esylate, glycolate, thiocyanate, and undecylenate.

63. The compound of claim 61 , wherein the salt is selected from the group consisting of chloride, hydrogen carbonate (bicarbonate), iodide, bromide, citrate, acetate, formate, salicylate, hydrogen sulfate (bisulfate), hydroxide, nitrate, hydrogen sulfite (bisulfite), propionate, benzene sulfonate, hypophosphite, phosphate, bromate, iodate, chlorate, fluoride, nitrite.

64. The compound of claim 61 , wherein the salt is a chloride salt.

65 The compound of claim 64, wherein the chloride salt has the following structure:

66. A composition comprising at least one conjugate of d-methylphenidate, and not comprising unconjugated d-methylphenidate, wherein the conjugate has at least two or more chiral centers and the composition is optically active.

67. The composition of claim 66, wherein the conjugate has the following structure:

or a pharmaceutically acceptable salt thereof.

68 The compound of claim 67, wherein the salt is selected from the group consisting of acetate, l-aspartate, besylate, bicarbonate, carbonate, d-camsylate, I- camsylate, citrate, edisylate, formate, fumarate, gluconate, hydrobromide/bromide, hydrochloride/chloride, d-lactate, l-lactate, d,l-lactate, d,l-malate, l-malate, mesylate, pamoate, phosphate, succinate, sulfate, bisulfate, d-tartrate, martrate, d,l-tartrate, meso-tartrate, benzoate, gluceptate, d-glucuronate, hybenzate, isethionate, malonate, methylsulfate, 2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate, thiocyanate, acefyllinate, aceturate, aminosalicylate, ascorbate, borate, butyrate, camphorate, camphocarbonate, decanoate, hexanoate, cholate, cypionate, dichloroacetate, edentate, ethyl sulfate, furate, fusidate, galactarate, galacturonate, gallate, gentisate, glutamate, glutarate, glycerophosphate, heptanoate, hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate, mandelate, methanesulfonate, myristate, napadisilate, oleate, oxalate, palmitate, picrate, pivalate, propionate, pyrophosphate, salicylate, salicylsulfate, subsalicylate, tannate, terephthalate, thiosalicylate, tribrophenate, valerate, valproate, adipate, 4- acetamidobenzoate, camsylate, octanoate, estolate, esylate, glycolate, thiocyanate, and undecylenate.

69. The compound of claim 67 wherein the salt is selected from the group consisting of chloride, hydrogen carbonate (bicarbonate), iodide, bromide, citrate, acetate, formate, salicylate, hydrogen sulfate (bisulfate), hydroxide, nitrate, hydrogen sulfite (bisulfite), propionate, benzene sulfonate, hypophosphite, phosphate, bromate, iodate, chlorate, fluoride, nitrite.

70. The compound of claim 67, wherein the salt is a chloride salt. 71 The compound of claim 70, wherein the chloride salt has the following structure: