BRPI0612440A2 - pharmaceutical composition and use of an amphetamine prodrug - Google Patents

Abstract

PHARMACEUTICAL COMPOSITION AND USE OF A AMPHTAMINE PROPHARMACY The invention describes compounds, compositions, and their methods of use comprising a chemical moiety covalently linked to amphetamine. Such compounds and compositions are useful for reducing or preventing amphetamine abuse and overdose. These compounds and compositions find specific use in providing an abuse-resistant alternative treatment for certain disorders, such as attention-deficit hyperactivity disorder (ADHD). , attention deficit disorder (ADD), narcolepsy and obesity Oral bioavailability of amphetamine is maintained at therapeutically useful doses At higher doses bioavailability is substantially reduced, thus providing a method for reducing the potential for oral abuse. In addition, the compounds and compositions of the invention reduce amphetamine bioavailability through parenteral routes, such as intravenous or intranasal administration, thereby limiting its potential for abuse.

Description

"Pharmaceutical composition and use of an amphetamine drug"

Field of the invention

The invention relates to amphetamine compounds, more particularly to amphetaminic prodrugs comprising amphetamine covalently linked to a chemical moiety. The invention also relates to pharmaceutical compositions comprising the amphetamine compounds and methods for manufacturing, administering and using the amphetamine compounds.

Invention History

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

Due to their stimulating effects, amphetamines, including amphetamine derivatives and analogues, are subject to abuse. A user may, over time, become dependent on these drugs and their physical and psychological effects, even when drugs are used for legitimate therapeutic purposes. Legitimate users of amphetamine who develop drug tolerance are especially likely to become accidental addicts as the dosage is increased to counterbalance their increased tolerance to prescribed drugs. In addition, individuals may inappropriately self-measure with above-prescribed drug amounts or alter the product or route of administration (eg inhalation (aspiration), injection, and fumigation), potentially resulting in immediate release of the active drug in larger quantities. than the prescribed ones. When administered at higher doses than prescribed, amphetamines may cause temporary feelings of euphoria and increased energy and mental alertness.

Recent advances in prescription drug abuse have greatly increased interest in the amphetamine abuse prescribed for ADHD. The National Survey on DRUG Use and Health (NSDUH) estimates that in 2003, 1.2 million Americans 12 years of age and older misused stimulants such as amphetamines. The potential for high abuse includes amphetamines in List II according to the Controlled Substances Act (CSA). Classification in List II is reserved for drugs whose medical status has been accepted but which have the highest potential for abuse.

Slow-release amphetamine formulations, such as Adderall XR®, are more likely to be abused than single-dose tablets, as each slow-release formulation tablet contains a higher concentration of amphetamine. Substance abusers may get a high dose of fast-starting amphetamine by grinding the tablets into powder and aspirating or dissolving the powder in water and then injecting it. Slow deliberation formulations may also provide uneven release.

Additional information on amphetamines and their abuse can be found in US publication No.2005 / 0054561 (USSN 10 / 858.526).

There is a need for additional amphetamine compounds, especially abuse-resistant amphetamine compounds. In addition, there is also a need for pharmaceutical amphetamine compositions that provide slow release and slow therapeutic effect. Brief Description of the Drawings

Figure 1 - Synthesis of amphetaminicospeptide conjugates.

Figure 2 - Synthesis of amphetamine lysine dimesylate.

Figure 3 - HCl synthesis of amphetamine lysine.

Figure 4 - Synthesis of serine amphetamine conjugate.

Figure 5 - Synthesis of phenylalanine amphetamine conjugate.

Figure 6 - Synthesis of amphetamine triglycine conjugate.

Figure 7 - Plasma concentrations of individual d-amphetamine deriving oral d-amphetamine or 1-lysine-d-amphetamine hydrochloride.

The following figures (Fig. 8 - Fig. 16) illustrate results obtained from oral administration studies of d-amphetamine desulfate or 1-lysine-d-amphetamine dimesylate in rats (ELISA analysis):

Figure 8 - Plasma d-amphetamine concentrations (doses of 1.5 mg / kg d-amphetamine base).

Figure 9 - Plasma d-amphetamine concentrations (d-amphetamine base dose 3 mg / kg).

Figure 10 - Plasma d-amphetamine concentrations (dose of 6mg / kg d-amphetamine base).

Figure 11 - Plasma d-amphetamine concentrations (12 mg / kg d-amphetamine base dose).

Figure 12 - Plasma d-amphetamine concentrations (dose of 30 mg / kg d-amphetamine base).

Figure 13 - Plasma d-amphetamine concentrations (at a dose of 60 mg / kg d-amphetamine base).

Figure 14 - Percent bioavailability (AUC and Cmax) of L-lysine-d-amphetamine dedimesilate compared to d-amphetamine sulfate at doses of 1.5, 3, 6, 12, 30 and 60 mg / kg d-amphetamine base.

Figure 15 - Plasma concentrations of d-amphetamine 30minutes post-dose to d-amphetamine base staggered doses.

Figure 16 - Plasma d-amphetamine concentrations (dose of 60 mg / kg d-amphetamine base).

Figure 17 - Plasma d-amphetamine concentrations following intranasal administration of L-lysine-d-amphetamine hydrochloride or d-amphetamine sulfate (at a dose of 3mg / kg d-amphetamine base) in rats (ELISA analysis).

Figure 18 - Plasma d-amphetamine concentrations following intranasal administration of L-lysine-d-amphetamine dimesylate or d-amphetamine sulfate (at a dose of 3mg / kg d-amphetamine base) in rats (ELISA analysis).

Figure 19 - Plasma d-amphetamine concentrations following intravenous bolus administration of L-lysine-d-amphetamine dimesylate or d-amphetamine sulfate (at dose 1.5 mg / kg d-amphetamine base) in rats (ELISA analysis).

Figure 20 0 - Plasma concentrations of d-amphetamine levels after oral administration of Dexedrine Spansule (prolonged release) capsules, Crushed Dexedrine Spansule (prolonged release) capsules, or L-lysine-d-amphetamine dimesylate (at a dose of 3mg / kg d-amphetamine base) in rats (ELISA analysis).

The following figures (Fig. 21 to Fig. 30) illustrate the results obtained from oral administration studies of d-amphetamine desulfate or L-lysine-d-amphetamine dimesylate in rats (LC / MS / MS analysis).

Figure 2IA and Figure 2IB - Plasma d-amphetamine concentrations in ng / ml (Fig. 21A) and nM (Fig. 21B) (at 1.5 mg / kg d-amphetamine base).

Figure 22A and Figure 22B - Plasma d-amphetamine concentrations in ng / ml (Fig. 22A) and nM (Fig. 22B) (at d-amphetamine base dose 3 mg / kg).

Figure 23A and Figure 23B - Plasma d-amphetamine concentrations in ng / ml (Fig. 23A) and nM (Figure 23B) (d-amphetamine base dose of 6 mg / kg).

Figure 24A and Figure 24B - Plasma d-amphetamine concentrations in ng / ml (Fig. 24A) and nM (Fig. 24B) (at 12 mg / kg d-amphetamine base).

Figure 25A and Figure 25B - Plasma d-amphetamine concentrations in ng / ml (Fig. 25A) and nM (Fig. 25B) (at d-amphetamine base dose 60 mg / kg).

Figure 26 6 - Comparative bioavailability (C max) of L-lysine-d-amphetamine and d-amphetamine in proportion to scale equivalent human doses.

Figure 27 - Comparative bioavailability (AUCinf) of L-lysine-d-amphetamine and d-amphetamine in proportion to scale d-amphetamine base doses.

Figure 2 8 - Comparative bioavailability (AUCinf) of L-lysine-d-amphetamine and d-amphetamine in proportion to scale equivalent human doses.

Figure 2 9 - Comparative bioavailability (Cmax) of intact L-lysine-d-amphetamine in proportion to equivalent human escalonardoses.

Figure 30 - Comparative bioavailability (AUCinf) of intact L-lysine-d-amphetamine in proportion to equivalent human scalonardoses.

Figure 31 - Plasma d-amphetamine concentrations following intranasal administration of L-lysine-d-amphetamine dimesylate or d-amphetamine sulphate (at 3 mg / kg d-amphetamine base dose) in rats (LC / MS / MS analysis ).

Figure 32A and Figure 32B - Plasma concentrations of d-amphetamine and L-lysine-d-amphetamine in ng / ml (Figure 32A) and nM (Figure 32B) following intranasal administration of L-lysine-d-amphetamine sulfate or d-amphetamine (at the dose of 3 mg / kg d-amphetamine base) emrates (LC / MS / MS analysis).

Figure 33 - Plasma d-amphetamine concentrations following intravenous bolus administration of L-lysine-d-amphetamine dimesylate or d-amphetamine sulphate (at dose 1.5 mg / kg d-amphetamine base) in rats (LC / MS / MS).

Figure 34A and Figure 34B - Plasma d-amphetamine concentrations in ng / ml (Figure 3 4A) and nM (Figure 3 4B) following intravenous administration of L-lysine-d-amphetamine dimesylate or d-amphetamine sulphate ( dose 1.5 mg / kg d-amphetamine base) in rats (LC / MS / MS analysis).

The following Figures (Fig. 35A - Fig. 40) illustrate the results obtained from intravenous and intravenous administration studies (at the dose of 1 mg / kg d-amphetamine base) d-amphetamine desulfate or L-lysine-d-dimesylate amphetamine to conscious Beagle dogs (LC / MS / MS analysis):

Figure 35 - Time profile of mean plasma concentration of L-lysine-d-amphetamine following intravenous or oral administration of L-lysine-d-amphetamine (n = 3).

Figure 36 - Time profile of plasma amphetamine concentration after intravenous or oral administration of L-lysine-d-amphetamine (n = 3).

Figure 37A and Figure 37B - Mean plasma concentration time profile of L-lysine-d-amphetamine and d-amphetamine levels in ng / ml (Figure 377) and nM (Figure 377) after intravenous administration of L- lysine-d-amphetamine (n = 3).

Figure 388A and Figure 388B - Mean plasma concentration time profile of L-lysine-d-amphetamine and d-amphetamine levels in ng / ml (Fig. 38A) and nM (Fig. 38B) after oral L-administration lysine-d-amphetamine (n = 3).

Figure 39A and Figure 3 9B - Individual plasma concentration time profile of L-lysine-d-amphetamine following intravenous (Fig. 39A) or oral administration (Fig. 39B) of L-lysine-d-amphetamine.

Figure 40A and Figure 40B - Time profile of individual plasma d-amphetamine concentration following intravenous administration (Figure 40A) or oral administration (Figure 40B) of L-lysine-d-amphetamine.

Figure 41 - Plasma d-amphetamine concentrations following oral administration of L-lysine-d-amphetamine dimesylate or d-amphetamine sulfate (at the dose of 1.8 mg / kg d-amphetamine base) to dogs.

Figure 42 - Plasma d-amphetamine concentrations after oral administration of L-lysine-d-amphetamine dimesylto or d-amphetamine sulphate (at the dose of 1.8mg / kg d-amphetamine base) to female dogs.

Figure 43 - Mean arterial pressure after intravenous injection of increasing amounts of L-lysine-d-amphetamine or d-amphetamine dimesylate in dogs and bitches.

Figure 44 - Left ventricular blood pressure after intravenous injection of increasing amounts of L-lysine-d-amphetamine or d-amphetamine in the dogs and bitches.

The following Figures (Fig. 45 - Fig. 49) illustrate the results obtained in oral (at 6 mg / kg d-amphetamine base), intranasal (at 1 mg / kg d-amphetamine base), and intravenous ( at the dose of 1mg / kg d-amphetamine base) d-amphetamine sulfate or L-lysine-d-amphetamine hydrochloride in rats:

Figure 45 - Locomotor activity of rats after oral administration (5 hour time course).

Figure 46 - Locomotor activity of rats after oral administration (12-hour time course).

Figure 47 - Locomotor activity of rats after intranasal administration (1 hour time course).

Figure 48 - Locomotor activity of rats after intranasal administration (with carboxymethylcellulose) (time course 2 hours).

Figure 49 - Locomotor activity of rats after intravenous administration (3 hour time course).

Figure 50 - Intranasal bioavailability of abuse-resistant amphetaminar amino acid tripeptide conjugates.

Figure 51 - Oral bioavailability of amphetamine resistant amino acid dietripeptide conjugates.

Figure 52 - Intravenous bioavailability of an abuse-resistant amphetamine tripeptide conjugate.

Figure 53 - Intranasal bioavailability of an abuse-resistant amphetamine amino acid conjugate. Figure 54 - Oral bioavailability of an abuse-resistant amphetamine amino acid conjugate.

Figure 55 - Intravenous bioavailability of an abuse-resistant amphetamine amino acid conjugate.

Figure 56 - Intranasal bioavailability of an abuse-resistant amphetamine amino acid conjugate tripeptide.

Figure 57 - Intranasal bioavailability of abuse resistant amphetamine amino acid dipeptide conjugates.

Figure 58 - Intranasal bioavailability of an abuse resistant amphetamine dipeptide conjugate containing D and L-amino acid isomers.

Figure 59A and Figure 59B - Plasma concentrations of d-amphetamine and L-lysine-d-amphetamine in ng / ml for serum levels (Figure 59A) and in ng / g for brain tissue (Fig. 59B) after oral administration of L-hydrochloride. lysine-d-amphetamine or d-amphetamine sulfate (5 mg / kg d-amphetamine base dose) in rats (LC / MS / MS analysis).

Figure 60 - Constant-state plasma levels of d-amphetamine and L-lysine-d-amphetamine obtained from clinical studies of oral administration of 70 mg of L-lysine-d-amphetamine dimesylate in humans (LC / MS / MS analysis).

The following Figures (Fig. 61 - Fig. 70) illustrate the results obtained from clinical studies of oral administration of L-lysine-d-amphetamine dimesylate in humans (LC / MS / MS analysis):

Figure 6IA and Figure 61B - Plasma levels of d-amphetamine and L-lysine-d-amphetamine (Fig. 61A, ng / ml; Fig.61B, nM) for a period of 72 hours after oral administration of L-lysine-d- amphetamine (25 mg L-lysine-d-amphetamine dedimesilate containing 7.37 mg d-amphetamine base) in humans.

Figure 62A and Figure 62B - Plasma levels of d-amphetamine and L-lysine-d-amphetamine (Fig. 62A, ng / ml; Fig.62B, nM) for a period of 72 hours after oral administration of L-lysine-d- amphetamine (75 mg L-lysine-d-amphetamine dedimesilate containing 22.1 mg based-amphetamine) in humans.

Figure 63A and Figure 63B - Plasma d-amphetamine levels (Fig. 63A, 0-12 hours; Fig. 63B, 0-72 hours) after oral administration of L-lysine-d-amphetamine (75 mg L-dimesylate lysine-d-amphetamine containing 22.1 mg d-amphetamine base) or Adderall XR® (35 mg containing 21.9 mg amphetamine base) in humans.

Figure 64A and Figure 64B - Plasma d-amphetamine levels (Fig. 64A, 0-12 hours; Fig. 64B, 0-72 hours) after oral administration of L-lysine-d-amphetamine (75 mg L-dimesylate lysine-d-amphetamine containing 22.1 mg d-amphetamine base) or Dexedrine Spansule® (extended release) (30 mg containing 22.1 mg amphetamine base) in humans.

Figure 65 - Mean plasma concentration of d-amphetamine following oral administration of single doses of 30 mg, 50 mg and 70 mg L-lysine-d-amphetamine dimesylate under fasting conditions in pediatric ADHD patients.

Figure 66 - Relationship between dose-normalized d-amphetamine AUC and gender after oral administration of L-lysine-d-amphetamine dimesylate capsules once daily in healthy adult volunteers and children with ADHD.

Figure 67 - Relationship between maximal dose-normalized plasma d-amphetamine concentration and sex after oral administration of L-Iysine-d-amphetamine dimesylate capsules once daily in healthy adult volunteers and children with ADHD.

Figure 68 - Relationship between maximal dose-normalized plasma d-amphetamine time-concentration and sex after oral administration of L-Iysine-d-amphetamine dimesylate capsules once daily in healthy adult volunteers and children with ADHD.

Figure 69 - ADHD-RS (ADHD classification scale) at the final point for a pediatric clinical study.

Figure 70 - SKAMP score (effectiveness) vs. time for pediatric clinical study. Detailed Description of the Invention

The invention provides amphetamine prodrugs comprising amphetamine covalently linked to a chemical moiety. Amphetamine prodrugs may also be characterized as conjugates as they have a covalent bond.

They may also be characterized as conditionally bioreversible derivatives ("CBDs") since the amphetamine drug preferably remains inactive until oral administration releases the amphetamine from the chemical portion.

In one embodiment, the invention provides a prodrug amphetamine of Formula I:

A-Xn-Zm (I) where A is an amphetamine;

each X is independently a chemical moiety;

each Z is independently an adjuvant acting chemical moiety which is different from at least one X; η is an increment from 1 to 50, preferably from 1 to 10; em is an increment from 0 to 50, preferably 0.

When m is 0, the amphetamine prodrug is a compound of Formula (II):

A-Xn (II)

where each X is independently a chemical moiety. Formula (II) may also be written to denote the 25 chemical moiety that is physically bound to amphetamine:

A-Xi- (X) No. 1 (III)

where A is an amphetamine; X 1 is a chemical moiety, preferably a single amino acid; each X is independently a chemical moiety that is equal to or different from Xi; and η is an increment from 1 to 50.

Amphetamine, A, may be any of the sympathomimetic phenethylamine derivatives having central nervous system stimulating activity such as amphetamine, or any similar derivative, analogue or salt. Representative amphetamines include, but are not limited to, amphetamine, methamphetamine, methylphenidate, p-methoxyamphetamine, methylenedioxyamphetamine, 2,5-dimethoxy-4-methylamphetamine, 2,4,5-trimethoxyamphetamine, and 3,4-methylenedioxymethamphetamine, N-phenylethamine benzophetamine, and chlorphenentermine, as well as Adderall® amphetamine compounds; actedron; acetmine; adipan;

acedron; allodene; alpha-methyl- (±) -benzeneethanamine; alpha-methylbenzeneethanamine; alpha-methylphenethylamine;

amphetamine; amphato; anorexin; benzebar; benzedrin, benzyl methyl carbinamine; benzolone; beta-aminopropylbenzene; beta-phenylisopropylamine; bifetamine;

deoxynorephedrine; dietamine; DL-amphetamine; elastonon fenopromin; fine; isoamine; isomine; mechodrine; monophos; midrial; norephedran; novhydrin; obesin; obesin, obetrol; octedrin; octedrin; phenamine; phenedrin, phenethylamine; alpha methyl; percomon; profamine;

propetamine; propisamine; racephen; rafetamine rinalator; sympamine; sympathymine; sympathin;

sympathin and wecamine. Preferred amphetamines include methamphetamine, methylphenidate, and amphetamine with amphetamine being the most preferred.

<formula> formula see original document page 12 </formula>

d-amphetamine (1) Methylphenidate (2)

Amphetamine may have any stereogenic configuration, including both right and right isomers.

Dextroisomer, especially dextroamphetamine, is preferred.

Preferably, amphetamine is an amphetamine salt.

Pharmaceutically acceptable salts, such as non-toxic, inorganic or organic acid addition salts, are known in the art. Representative salts include, but are not limited to, 2-hydroxyethanesulfonate, 2-naphthalenesulfonate, 3-hydroxy-2-naphthoate, 3-phenylpropionate, acetate, adipate, alginate, amsonate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bisulfate, bisulfate, bis borate, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, citrate, clavularate, cyclopentanopropionate, digluconate, dodecylsulfate, edetate, edisylate, estolate, ethanesulfonate, glucarate, glucosulfate, glucosulfonate, glucosulfonate hemisulfate, heptanoate, hexafluorophosphate, hexanoate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroiodide, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, laurylsulfonate, malate, maleate, mandelate, methilate, methylate sulphate naphthylate, napsylate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, palmitate, pamoat pantothenate, pectinate, persulfate, phosphate, phosphatidiphosphate, picrate, pivalate, polygalacturonate, propionate, p-toluenesulfonate, saccharate, salicylate, stearate, subacetate, succinate, sulfate, sulfosaliculate, suramate, tatoate, tateate, tartrate trietiodide, undecanoate, and devalerate salts and the like. (See Berge et al. (1977) "Pharmaceutical Salts", J Pharm. Sci. 66: 1-19). A preferred deanfetamine salt is the mesylate salt (eg, as L-lysine-d-amphetamine emdimesylate).

Specific salts may be less hygroscopic, thus facilitating handling. In a preferred embodiment, the amphetamine prodrug has a water content (Karl Fischer analysis) of from about 0% to about 5%, from about 0.1% to about 3%, from about 0.25% to about 2%. or increments in it. When the prodrug amphetamine is formulated in a pharmaceutical composition, the pharmaceutical composition preferably contains a water content of from about 1% to about 10%, from about 1% to about 8%, from about 2% to about 7%, or increments. same.

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

Amphetamine is bound to one or more chemical moieties, called X and Z. A chemical moiety may be any moiety that reduces the pharmacological activity of amphetamine while bound to the chemical moiety compared to unbound (free) comanfetamine. The bound chemical moiety may be naturally occurring or synthetic. Representative chemical moieties include, but are not restricted to, peptides, including single amino acids, dipeptides, tripeptides, oligopeptides, and polypeptides; carbohydrates; lipids; nucleosides; nucleic acids and vitamins. Preferably, the chemical portion is generally recognized as safe ("GRAS").

"Carbohydrates" include sugars, starches, cellulose and related compounds, such as (CH2O) n where η is an integer greater than 2, and Cn (H2O) nI where η is an integer greater than 5. Carbohydrate may be a monosaccharide, disaccharide, oligosaccharide, polysaccharide, or a derivative thereof (eg, sulfo or phospho-substituted). Representative carbohydrates include, but are not limited to fructose, glucose, lactose, maltose, sucrose, glyceraldehyde, dihydroxyacetone, erythrosis, ribose, ribulose, xylulose, galactose, mannose, sedoheptulose, neuraminic acid and glycogen.

A "glycopeptide" is a carbohydrate bound to an oligopeptide. Similarly, the chemical moiety may also be a glycoprotein, glycol amino acid, or glycosyl amino acid. A "glycoprotein" is a carbohydrate (eg a glycan) covalently linked to a protein. A "glycoamino acid" is a carbohydrate (eg a saccharide) covalently linked to a single amino acid. A "glycosyl amino acid" is a carbohydrate (eg, a saccharide) linked via a glycosyl (O-, N-, or S-) bond to an amino acid.

A "peptide" includes a single amino acid, a dipeptide, a tripeptide, an oligopeptide, a polypeptide or a carrier peptide. An oligopeptide includes from 2 to 70 amino acids.

Preferably, the chemical moiety is a peptide, more particularly a single amino acid, a dipeptide, or a tripeptide. The peptide preferably comprises less than 70 amino acids, less than 50 amino acids, less than 10 amino acids, or less than 4 amino acids. Where the chemical is one or more amino acids, amphetamine is preferably bound to lysine, serine, phenylalanine or glycine. In another embodiment, amphetamine is preferably bound to lysine, glutamic acid, or leucine. In one embodiment, amphetamine is bound to lysine and additional optional chemical moieties, such as additional amino acids. In a preferred embodiment, amphetamine is bound to a single delisin amino acid.

In one embodiment, the chemical moiety is from 1 to 12 amino acids, preferably from 1 to 8 amino acids. In another embodiment, the amino acid number is 1, 2,3, 4, 5, 6, or 7. In another embodiment, the molecular weight of the chemical moiety is less than about 2,500 kD, more preferably less than about 1,000 kD, and most preferably less than about 500 kD. Each amino acid may be any of the naturally occurring L or D-enantiomers, preferably naturally occurring L-enantiomers: alanine (Ala or A), arginine (Arg or R), asparagine (Asn or Ν), aspartic acid (Asp or D), cysteine (Cys or C), glycine (Glyou G), glutamic acid (Glu or Ε), glutamine (Gln or Q), histidine (His or Η), isoleucine (lie or I ), leucine (Leuou L), lysine (Lys or Κ), methionine (Met or Μ), proline (Pro or Ρ), phenylalanine (Phe or F), serine (Ser or S), tryptophan (Trp or W), threonine (Thr or Τ), tyrosine (Tyrou Y), and valine (Val or V). In a preferred embodiment, the peptide comprises only naturally occurring amino acids and / or only L-amino acids. Each amino acid may be an unnatural, non-standard or synthetic amino acid, such as aminohexanoic acid, biphenylalanine, cyclohexylalanine, cyclohexylglycine, diethylglycine, dipropylglycine, 2,3-diaminopropionic acid, homophenylalanine, homothyphinine, homotyrine, phenylalanine (4-fluoro), phenylalanine (2,3,4,5,6-pentafluoro), phenylalanine (4-nitro), phenylglycine, pipecolic acid, sarcosine, tetrahydroisoquinoline-3-carboxylic acid ether-leucine. Preferably synthetic amino acids with side chain chains are selected from C1 -C6 alkyls, preferably C1 -C6 alkyls. In one embodiment, the opeptide comprises one or more amino acid alcohols, such as serine and threonine. In another embodiment, the peptide comprises one or more N-methyl amino acids, such as N-methylaspartic acid.

In one embodiment, the peptides are used as short chain amino acid based sequences and additional amino acids are added to the terminal or side chain. In another embodiment, the peptide may have one or more amino acid substitutions.

Preferably, the substitute amino acid is of similar structure, charge or polarity to the substituted amino acid.

For example, isoleucine is similar to leucine, tyrosine is similar to phenylalanine, serine is similar to threonine, cysteine is similar to methionine, alanine is similar to valine, lysine is similar to arginine, asparagine is similar to glutamine, aspartic acid It is similar to glutamic acid, histidine is similar to proline, and glycine is similar to tryptophan.

The peptide may comprise a naturally occurring or heteropolymer homopolymer or amino acid synthetic. For example, the deanfetamine side chain binding to the peptide may be a homopolymer or heteropolymer containing glutamic acid, aspartic acid, serine, lysine, cysteine, threonine, asparagine, arginine, tyrosine or glutamine.

Representative peptides include Lys, Ser, Phe, Gly-Gly-Gly, Leu-Ser, Leu-Glu, Glu and Leu homopolymers, (Glu) n-Leu-Ser heteropolymers. In a preferred embodiment, the peptide is Lys, Ser, Phe or Gly-Gly-Gly. In one embodiment, the chemical moiety has one or more terminal and / or free carboxy and / or amine side chain group other than the amphetamine binding point. The chemical may be in a free state, or in an ester or salt thereof.

The chemical moiety may be covalently linked to amphetamine either directly or indirectly through a binder. The covalent bond may comprise an ester or carbonate bond. The binding site is typically determined by the functional group (s) available in amphetamine. For example, a peptide may be attached to an amphetamine via the N-terminal, C-terminal or side chain of an amino acid. For additional methods of binding amphetamine to various representative chemical moieties, see U.S. Application Serial No. 10 / 156,527, PCT / US03 / 0552 4, and PCT / US03 / 05525, each of which is incorporated herein by reference in its entirety.

The amphetamine prodrug compounds described above may be synthesized as described in Example 1 and Figure 1. Preferably, additional purification and / or crystallization steps are not required to produce a highly pure product. In one embodiment, the amphetamine prodrug purity is about 95%, more preferably at least 96%, 97%, 98%, 98.5%, 99%, 99.5%, 99.9% or similar increments. . For the synthesis of L-lysine-d-amphetamine, known impurities include Lys-Lys-d-amphetamine, Lys (Lys) -d-amphetamine, d-amphetamine, Lys (Boc) -d-amphetamine, Boc-Lys-d- amphetamine, and Boc-Lys (Boc) -d-amphetamine. In one embodiment, the presence of any single impurity is less than about 3%, more preferably less than 2%, 1%, 0.5%, 0.25%, 0.15%, 0.1%, 0.05%. or increments in it.

In one embodiment, the amphetamine prodrug (a compound of one of the formula described above) may exhibit one or more of the following advantages over free amphetamines. The amphetamine prodrug may prevent overdose by exhibiting reduced pharmacological activity when administered at higher doses than therapeutics, such as higher than the prescribed dose. However, when the amphetamine prodrug is administered at therapeutic doses, the amphetamine prodrug may retain similar pharmacological activity to that obtained by administering unbound amphetamine, such as Adderall XR®. Similarly, amphetamine prodrug can prevent abuse by exhibiting stability under conditions likely to be used by illegal chemists in their attempt to release amphetamine. Amphetamine prodrug can prevent abuse by exhibiting reduced availability when administered via the parental route, especially intravenous ("injection"), intranasal ("aspiration") and / or inhalation ("fumigation") routes that are often employed when used lawfully. Thus, the amphetamine prodrug may reduce the euphoric effect associated with deanfetamine abuse. Thus, the amphetamine prodrug may prevent / or reduce the potential for abuse and / or overdose when it is used in a manner incompatible with the manufacturer's instructions, such as taking the amphetamine prodrug at a dose above therapy or via a non-oral route. administration.

The use of expressions such as "reduced" or "decreased" includes at least a 10% change in pharmacological activity with larger changes in the percentages preferred to reduce abuse potential and overdose potential. For example, the change may also be greater than 25%, 35%, 45%, 55%, 65%, 75%, 85%, 95%, 96%, 97%, 98%, 99%, or other increments greater than 10%. %.

The use of the term "similar pharmacological activity" means that two compounds exhibit curves having substantially the same parameters as AUC, Cmax, Tmax / Cmin, and / or Tij2, preferably in the range of about 30% to each other, more preferably in the range. about 25%, 20%, 10%, 5%, 2%, 1% or other increments of less than 30%.

Preferably, the amphetamine prodrug exhibits an oral unbound amphetamine bioavailability of at least about 60% AUC (area under the curve), more preferably at least about 70%, 80%, 90%, 95%, 96%, 97%. , 98%, 99%, or other increments greater than 60%. Preferably, the amphetamine prodrug exhibits an unbound amphetamine parenteral, such as for example nasal availability less than about 70% of AUC, more preferably less than about 50%, 30%, 20%, 15%, 10%, 5%. , 4%, 3%, 2%, 1% or other increments of less than 70%. For certain treatments, it is desirable that the amphetamine prodrug exhibit both the oral and parenteral bioavailability characteristics described above. See, for example, Table 61.

Preferably, the amphetamine prodrug remains inactive until oral administration releases amphetamine. Without binding to any theory, it is believed that the amphetamine drug is inactive because binding of the chemical portion reduces the binding between amphetamine and its target biological sites (eg, carrier sites). human dedopamine ("DAT") and norepinephrine ("NET"). (VideHoebel, BG, L.Hernandez, et al., "Microdialysis studiesof brain norepinephrine, serotonin, and dopamine released ingestive behavior," Theoretical and Clinical Implications. "Ann NY Acad Sci 575: 171-91 (1989)) Chemical portion alleviation may reduce the binding of amphetamine and DAT and / or NET in part due to the fact that the amphetamine prodrug fails to cross the blood-brain barrier The amphetamine prodrug is activated by oral administration. ie amphetamine is released from the chemical portion through hydrolysis, such as enzymes in the stomach. ago, intestinal tract, or blood serum.

Since oral administration facilitates activation, activation is reduced when prodrug amphetamine is administered via parenteral routes often employed by illegal users.

In addition, the amphetamine prodrug is believed to be resistant to abuse and / or overdose due to a natural gating mechanism at the hydrolysis site, ie the gastrointestinal tract. This transport mechanism allows the release of amphetamine therapeutic amounts from the amphetamine prodrug, but limits the release of larger amounts of amphetamine.

In another embodiment, the toxicity of the prodrug amphetamine is substantially lower than that of unbound amphetaminan. For example, in a preferred embodiment, acute toxicity is 1 time, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, or increments thereof, less lethal than oral administration of unbound amphetamine.

Preferably, the amphetamine prodrug provides a serum release curve that does not increase beyond the level of amphetamine toxicity when administered at doses greater than therapeutic. The amphetamine prodrug may exhibit a reduced rate of amphetamine absorption and / or an increased rate of clearance compared to free amphetamine. The amphetamine prodrug may also display a steady state serum release curve.

Preferably, the amphetamine prodrug provides availability but prevents elevated or increased serum C max concentrations. Pharmacokinetic parameters are described in the Examples below, especially the clinical Pharmacokinetic Examples. In one embodiment, the amphetamine prodrug provides pharmacological activity similar to the medically pharmacokinetic activity of L-lysine-d-amphetamine dimesylate. For example, the pharmacological parameters (AUC, Cmax, Tmax, Cmin / or ti / 2) are preferably in the range of 80%, 125%, 80% to 120%, 85% to 125%, 90% to 110%, or same increments of the given values. It should be recognized that ranges may, but need not be symmetrical, such as 85% to 105%. For a pediatric study, the pharmacokinetic parameters of L-lysine-d-amphetamine-released d-amphetamine released d-amphetamine are listed in Table 72.

The amphetamine prodrug may exhibit delayed and / or slow deliberation characteristics. Delayed release prevents the rapid onset of pharmacological effects and slow release is a desirable feature for specific dosing regimes, such as once daily regimens. The amphetamine prodrug can achieve release profile independently.

Alternatively, the amphetamine prodrug may be pharmaceutically formulated to increase or achieve such release profile. It may be desirable to reduce the amount of time to the onset of the pharmacological effect, for example by formulating with an immediate release product.

Accordingly, the invention also provides methods comprising providing, administering, prescribing, or consuming an amphetamine prodrug. The invention also provides pharmaceutical compositions comprising a prodrug amphetamine. The formulation of such a pharmaceutical composition may optionally increase or achieve the desired deliberation profile.

In one embodiment, the invention provides methods for treating a patient, comprising administering a therapeutically effective amount of an amphetamine prodrug, or an amount sufficient to prevent, ameliorate, or eliminate the symptoms of a disease. These methods can be used to treat any disease that may benefit from amphetamine-type drugs including, but not limited to, attention deficit disorders such as ADHD and ADHD and other learning difficulties; obesity; Alzheimer's disease, amnesia and other disorders and memory impairment; fibromyalgia, fatigue and chronic fatigue; depression; epilepsy; obsessive-compulsive disorder (OCD); challenging position-disordered disorder (ODD); anxiety; resistant depression, stroke rehabilitation; Parkinson's disease; mood disorder; schizophrenia; Huntington's disorder; dementia, such as AIDS-related dementia and frontal lobe dementia; movement dysfunction; apathy; Pick disease; Creutzfeldt-Jakob disease, sleep disorders such as narcolepsy, cataplexy, numb palsy, and hypnagogic hallucinations; conditions related to brain injury or neuronal degeneration, such as multiple sclerosis, Tourette's syndrome, and impotence; and dependence and denicotin withdrawal syndrome. Preferred indications include ADHD, ADHD, narcolepsy, and obesity, with ADHD being the most preferred.

Treatment methods include combination therapies which further comprise administering one or more therapeutic agents in addition to administering an amphetamine prodrug. The active ingredients may be formulated in a single dosage form, or may be formulated together or separately between multiple dosage forms. The active ingredients may be administered simultaneously or sequentially in any order. Representative combination therapies include the administration of drugs listed in Table 1: Table 1 - Representative drug therapies for use in combination with an amphetamine prodrug

<table> table see original document page 23 </column> </row> <table> <table> table see original document page 24 </column> </row> <table> <table> table see original document page 25 < / column> </row> <table>

A "composition" broadly refers to any composition containing one or more amphetaminic prodrugs. The composition may comprise a dry formulation, an aqueous solution, or a sterile composition. Compositions comprising the compounds described herein may be stored in lyophilized form and may be associated with a stabilizing agent such as a carbohydrate. The composition may then be activated in an aqueous solution containing salts such as NaCl, detergents such as sodium dodecyl sulfate (SDS), and other components.

In one embodiment, the amphetamine prodrug itself exhibits a slow release profile. Thus, the invention provides a pharmaceutical composition which exhibits a slow deliberation profile due to the amphetamine prodrug.

In another embodiment, a slow release profile is increased or achieved by including a hydrophilic polymer in the pharmaceutical composition. Suitable hydrophilic polymers include, but are not limited to, natural or partially or wholly synthetic hydrophilic gums such as acacia, tragacanth gum, dealbar gum, and caraia gum; cellulose derivatives such as comethylcellulose, hydroxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, and carboxymethylcellulose; proteinaceous substances such as agar, pectin, carrageenan, ealginates; hydrophilic polymers such as carboxypolymethylene; gelatine; casein; zein; bentonite, magnesium aluminum silicate; polysaccharides; modified starch derivatives; and other hydrophilic polymers known in the art. Preferably, the hydrophilic opolymer forms a gel that dissolves in aqueous acid media allowing the amphetamine drug to disperse from the gel in the stomach.

Then, when the gel reaches the highest pH medium in the intestines, the hydrophilic polymer dissolves in controlled quantities to allow additional slow release. Preferred hydrophilic polymers are ashhydroxypropyl methylcelluloses such as Methocel ethers, such as Methocel E10M® (Dow Chemical Company, Midland, Michigan). One skilled in the art would recognize a variety of structures, such as globule constructions and coatings, useful for achieving specific deliberation profiles. See, for example, US 6,913,768.

In addition to the amphetamine prodrug, the pharmaceutical compositions of the invention further comprise one or more pharmaceutical additives. Pharmaceutical additives include a wide range of materials, including but not limited to diluents and bulk builders, binders and adhesives, lubricants, diluents, plasticizers, disintegrants, carrier solvents, buffers, colorants, flavorings, sweeteners, preservatives and stabilizers, and other pharmaceutical additives. known in the prior art. For example, in a preferred embodiment, the pharmaceutical composition comprises magnesium stearate. In another preferred embodiment, the pharmaceutical composition comprises microcrystalline cellulose (eg Avicel® PH-102), croscarmellose sodium, and magnesium stearate. See, for example, Table 62. Diluents increase the volume of a dosage form and may make it easier to handle. Representative diluents include, but are not limited to lactose, dextrose, sucrose, cellulose, calcium starch phosphate for solid dosage forms, such as tablets and capsules; ethyl olive eoleate for soft capsules; water and vegetable oil for liquid dosage forms such as suspensions and emulsions. Suitable additional diluents include but are not limited to sucrose, dextrates, dextrin, maltodextrin, microcrystalline cellulose (eg Avicel®, microfine cellulose, cellulose powder, pregelatinized starch (eg Starch 1500®), decalcium phosphate dihydrate, polysaccharide (eg Emcosoy®), gelatin, silicon dioxide, calcium sulfate, decalcium carbonate, magnesium carbonate, magnesium oxide, sorbitol, mannitol, kaolin, polymethacrylates (eg Eudragit®), potassium chloride, A preferred diluent is microcrystalline cellulose (eg Avicel® PH-102) Preferred ranges for the weight percent diluent amount include about 40% to about 90%, from about 50% to about 85%. , from about 55% to about 80%, from about 50% to about 60%, and increments therein.

In embodiments where the pharmaceutical composition is compacted into a solid dosage form, such as a tablet, a binder may help the ingredients to aggregate. Binders include, but are not limited to sugars such as sucrose, lactose and glucose; corn syrup; soy polysaccharide, gelatin, povidone (eg Kollidon®, Plasdone®; Pullulan; cellulosal derivatives such as microcrystalline cellulose, hydroxypropyl methylcellulose (eg Methocel®, hydroxypropylcellulose (eg Klucel®, ethyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose sodium; carbamate (eg: Carbopol®); polyvinylpolypyrrolidine; polyethylene glycol (Carbowax®); pharmaceutical finish (gloss); alginates such as alginic acid and sodium alginate; gums such as acacia, guar gum, and gum arabic; tragacanth; dextrinae maltodextrin; milk derivatives such as whey delight; starches such as pregelatinized starch and deamido paste; hydrogenated vegetable oils; and aluminum magnesium silicate.

For tableted dosage forms, the pharmaceutical composition is subjected to the pressure of a matrix slurry. Among other purposes, a lubricant may help prevent the composition from sticking to the surfaces of the pourer and die. A lubricant may also be used in the coating of a coated dosage form.

Lubricants include, but are not limited to, magnesium stearate, calcium stearate, teninc stearate, stearic acid powder, glyceryl monostearate, glyceryl palmitoestearate, glyceryl behenate, silica, magnesium silicate, silicocolloid dioxide, titanium dioxide, benzoate sodium, sodium lauryl sulfate, sodium stearyl fumarate, hydrogenated oleovegetal, talc, polyethylene glycol and oleomineral. A preferred lubricant is magnesium stearate. The amount of lubricant in percent by weight is preferably less than about 5%, more preferably 4%, 3%, 2%, 1.5%, 1% or 0.5% or increments therein.

Diluents can improve the flowability of uncompressed solid finger forms and the accuracy of dosing.

Diluents include, but are not limited to, colloidal silicon dioxide, pyrogenic silicon dioxide, silica gel, talc, magnesium trisilicate, calcium magnesium stearate, cellulose powder, starch and tribasic calcium phosphate.

Plasticizers include both hydrophobic and hydrophilic plasticizers such as, but not limited to, diethyl phthalate, butyl phthalate, diethyl sebacate, dibutyl sebacate, detrietyl citrate, acetyltriethyl citrate, deacetyltributin citrate, propylene glycol troline, polyethylene glycol, propylene glycol, glycerin and sorbitol. Plasticizers are especially useful for pharmaceutical compositions containing a polymer and in film-coated soft capsules and tablets. In one embodiment, the plasticizer facilitates the release of the prodrug amphetamine from the dosage form.

Disintegrants may increase the dissolution rate of a pharmaceutical composition. Disintegrants include, but are not limited to alginates such as alginic acid and sodium alginate, carboxymethylcellulosic calcium, sodium carboxymethylcellulose (eg Ac-Di-Sol®), Primellose®), colloidal silicon dioxide, croscarmelosesodic, crospovidone (eg Kollidon ®, Polyplasdone®, polyvinylpolypyrrolidine (Plasone-XL®), guar gum, aluminum magnesium silicate, methylcellulose, cellulosemicrocrystalline, potassium polacryline, cellulose powder, starch, pregelatinized starch, sodium starch glycolate (eg Explotab®, Primogel Preferred disintegrants include croscarmellose sodium and microcrystalline cellulose (eg Avicel®PH-102) Preferred ranges for the amount of disintegrant by weight include from about 1% to about 10%, from about 1% to about 5%. %, from about 2% to about 3%, and increments in it.

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

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

Any pharmaceutically acceptable dye may be used to improve appearance or to help identify the pharmaceutical composition. See 21 C.F.R., Part 74. Representative dyes include Red D & CNo. 28, D&C Yellow No. 10, FD&C Blue No. 1, FD&C Red No. 40, FD&C Green # 3, FD&C Yellow No. 6 and edible inks. Preferred colors for soft capsules include white, medium orange and light blue.

Flavorings improve palatability and may be especially useful in chewable tablets or liquid dosage forms. Flavorings include, but are not limited to, maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid. Sweeteners include, but are not limited to, asorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar.

The pharmaceutical compositions of the invention may also include one or more preservatives and / or stabilizers to improve storage. They include, but are not limited to, alcohol, sodium benzoate, toluene-butylated hydroxy, butylated hydroxyanisole, and ethylenediaminetetraacetic acid.

Other pharmaceutical additives include freezing agents such as colloidal clays; thickening agents such as gum tragacanth and disodium alginate; wetting agents such as lecithin, polysorbates, and lauryl sulfate; humectants; antioxidants such as vitamin E, caronene and BHT; adsorbents;

effervescent agents; emulsifying agents; viscosity enhancing agents; surfactants such as sodium lauryl sulfate, dioctyl sulfosuccinate sodium, triethanolamine, polyoxyethylene sorbitan,

poloxalcol, and quaternary ammonium salts; and other miscellaneous excipients such as lactose, mannitol, glucose, fructose, xylose, galactose, sucrose, maltose, xylitol, sorbitol, chloride, potassium sulfate and phosphate salts, sodium, and magnesium.

Pharmaceutical compositions may be manufactured according to any method known to those skilled in the art of pharmaceutical manufacture, such as, for example, wet granulation, dry granulation, encapsulation, direct compression, soca, etc. For example, a pharmaceutical composition may be prepared by mixing the amphetamine drug with one or more pharmaceutical additives with an aliquot of liquid, preferably water, to form a wet granulation. Wet granulation can be dried to obtain granules.

The resulting granulation may be milled, filtered and mixed with various pharmaceutical additives such as water insoluble polymers and additional hydrophilic polymers. In one embodiment, an amphetamine prodrug is mixed with a hydrophilic polymer and an aliquot of water and then dried to obtain hydrophilic polymer encapsulated amphetamine prodrug granules.

After granulation, the pharmaceutical composition is preferably encapsulated, as for example in a gelatin capsule. The gelatin capsule may contain, for example, kosher gelatin, titanium dioxide, and optional dyes. Alternatively, the pharmaceutical composition may be compressed into tablets, such as compressed and optionally coated with a protective coating that dissolves or disperses our gastric juices.

The pharmaceutical compositions of the invention may be administered in a variety of fingering forms. Any biologically acceptable dosage form known in the art and its combinations are envisaged. Examples of preferred dosage forms include, without limitation, tablets including chewable tablets, film-coated tablets, rapid dissolving tablets, effervescent tablets, multilayer tablets, bilayer tablets; coated capsules; powders including reconstitutable powders; granules; dispersible granules; particles; microparticles; capsules including soft and hard gelatin capsules; tablets; soft pastilles; discs; blood cells; liquids; solutions, suspensions; emulsions; elixirs and syrups.

The pharmaceutical composition is preferably orally administered. Oral administration allows maximum release of amphetamine, provides slow release of amphetamine, and maintains resistance to abuse.

Preferably, the amphetamine prodrug releases amphetamine over a longer period of time compared to administration of unbound amphetamine.

Oral dosage forms may be presented with discrete units, such as capsules, coated tablets or tablets. In a preferred embodiment, the invention provides a solid oral dosage form comprising an amphetamine prodrug that is larger than a solid oral dosage form containing a therapeutically equivalent amount of unbound amphetamine. In one embodiment, the oral fingering form comprises a gelatin capsule of size 2, 3 or smaller (eg size 4). The smaller size of the amphetamine prodrug dosage forms promotes easier swallowing. Softgel or soft gelatin capsules may be prepared, for example, by dispersing the formulation into an appropriate vehicle (eg vegetable oil) to form a high viscosity mixture. This mixture is then encapsulated with a gelatin based film. The industrial units thus formed are then dried to a constant weight.

Chewable tablets may be prepared by mixing the amphetamine prodrug with excipients designed to form a relatively soft flavored tablet dosage form for chewable purposes. Conventional tableting machinery and procedures (eg, direct compression, granulation and punch) may be used.

Film-coated tablets may be prepared by coating tablets by techniques such as spinner container coating methods and air suspension methods to deposit an adjoining film layer onto a tablet.

Pressed tablets may be prepared by mixing the amphetamine prodrug with excipients which add binding qualities. The mixture may be directly pressed or granulated and then pressed.

The pharmaceutical compositions of the invention may alternatively be formulated in a liquid dosage form, such as a solution or suspension in an aqueous or non-aqueous liquid. The liquid dosage form may be an emulsion, such as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The oils may be administered by adding the purified and sterile liquids to a prepared enteral formula, which is then placed in a patient's feeding tube with difficulty swallowing.

For oral administration, fine powders or granules containing diluent, dispersing, and / or surfactant agents may be presented as an inhalant, in water or in a syrup, in capsules or sachets in a dry state, in a non-aqueous suspension where suspending agents may be included, or in a suspension in water or a syrup. Liquid dispersions for oral administration may be syrups, emulsions or suspensions. Syrups, emulsions or suspensions may contain a carrier, for example, natural umagoma, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, sucrose, saccharides with glycerol, mannitol, sorbitol and polyvinyl alcohol. The dosage range of amphetamine prodrug will depend on of several factors including age, weight and condition of the patient. Tablets and other dosage forms provided in discrete units may contain a daily dose, or an appropriate fraction thereof, of one or more amphetamine prodrugs. The dosage form may contain a dose of from about 2.5 mg to about 500 mg, from about 10 mg to about 250 mg, from about 10 mg to about 100 mg, from about 25 mg to about 75 mg. , or increments therein, of one or more amphetamine prodrugs. In a preferred embodiment, the fingering form contains 30mg, 5 Omg or 70mg of a prodrug-amphetamine.

The dosage form may utilize any or any combination of known release profiles including, but not limited to immediate release, extended release, pulsed release, variable release, controlled release, gradual release, slow release, delayed release, and long-term action.

The pharmaceutical compositions of the invention may be administered in a partial, i.e. dosed, fractionated dose one or more times over a period of 24 hours. Fractional, single, double or other multiple doses may be taken simultaneously or at different times over a period of 24 hours. Doses may be irregular doses to each other or to individual components at different times of administration. Preferably, a single dose is administered once daily. The dose may be administered in the fed or fasted condition.

Dosage units of the pharmaceutical composition may be packaged according to market need, for example in the form of unit doses, cylinders, raspberry bulk, blister packs and so on. Pharmaceutical packaging, such as blister packs, may also include or be accompanied by indications to identify the identity of the pharmaceutical composition, the prescribed indication (eg ADHD) and / or the time periods (eg time of day, day , etc.) for administration. The blister pack or other pharmaceutical pack may also include a second pharmaceutical for combination therapy.

It will be appreciated that the pharmacological activity of the compositions of the invention may be demonstrated using standard pharmacological models which are known in the art. In addition, it will be appreciated that the compositions of the invention may be incorporated into or encapsulated in a suitable polymeric matrix or membrane for site-specific release, or may be functionalized with specific targeting agents capable of site-specific release. These techniques, as well as other drug release techniques are known in the state of the art.

Any feature of the above described embodiments may be used in combination with any other feature of the above described embodiments. To facilitate a more complete understanding of the invention,

Examples are provided below. However, the scope of the invention is not restricted to specific embodiments described in these Examples, which are for illustration purposes only.

EXAMPLES

The following abbreviations are used in the Examples and throughout the patent:

Lys-Amp = L-Lysine-d-Amphetamine, Lysine-Amphetamine, K-Amp, K-Amphetamine or 2,6-diaminohexanoic acid (1-methyl-2-phenylethyl) -amide, or Lys-dexamphetamine.

Phe-Amp = Phenylalanine-Amphetamine, F-Ampi or 2-Amino-3-phenylpropanoic acid- (1-methyl-2-phenylethyl) -amide

Ser-Amp = Serine-Amphetamine, S-Amp or 2-amino-3-hydroxypropanoic acid (1-methyl-2-phenylethyl) -amide,

Gly3-Amp = GGG-Amphetamine, GGG-Amp, or 2-Amino-N - ({[(1-methyl-2-phenyl-ethylcarbomyl) methyl] -carbomyl} -methyl) -acetamide

BOC = t-butyloxycarbonyl

CMC = carboxymethylcellulose

DIPEA = diisopropylethylamine

mp = melting point

NMR = nuclear magnetic resonance

OSu = hydroxysuccinimidate ester

In all Examples, unless otherwise specified, doses are described as the amount of d-amphetamine base. Representative conversions are provided in Table 2.

<table> table see original document page 36 </column> </row> <table>

Example 1 - General Synthesis of Amphetaminicospeptide Conjugates

Peptide conjugates were synthesized by the general method described in Fig. 1. An iterative approach can be used to identify favorable conjugates by synthesizing and testing simplese amino acid conjugates then extending the peptide one amino acid at a time to produce dipeptide and tripeptide conjugates, etc. The original single amino acid prodrug candidate may exhibit more or less desirable characteristics than its descendant di or tripeptide candidates. The iterative approach can quickly suggest whether peptide extension influences bioavailability.

General Synthesis of Simple Amino Acid Amphetamine Conjugates

To a solution of a protected amino acid succinimidyl ester (2.0eq) in 1,4-dioxane (30 ml) was added d-amphetamine desulfate (1.0 eq) and NMM (4.0 eq.). The resulting mixture was allowed to stir for 20h at 20 ° C.

Water (10 ml) was added, and the solution stirred for 10 minutes before removal of solvents under reduced pressure. The crude product was dissolved in EtOAc (100ml) and washed with 2% AcOHaq (3 x 100 ml), saturated NaHCO3 solution (2 x 50 ml) and brine (1 x 100 ml). The organic extract was dried over MgSO4, filtered and evaporated to dryness to give the protected amino acid amphetamine conjugate. This intermediate was directly deprotected by adding 4N HCl in 1,4-dioxane (20 ml). The solution was stirred for 20 to 25 ° C. The solvent was evaporated and the product dried in vacuo to give the corresponding amino acid amphetamine hydrochloride conjugate. The syntheses of representative single amino acid conjugates are shown in Fig. 2 - Fig. 6.

General Overview of Dipeptide Amphetamine Conjugates

To a solution of protected (1.0eq) dipeptide succinimidyl ester in 1,4-dioxane was added deanfetamine sulfate (2.0eq) in NMM (4.0eq). The resulting mixture was stirred for 20 h at 25 ° C. The solvents were removed under reduced pressure. Saturated NaHCO 3 solution (20 mL) was added and the suspension stirred for 30 minutes. IPAC (100 ml) was added, and the organic layer washed with 2% AcOHaq (3 x 100 ml) and brine (2 x 100 ml). The organic extract was dried over Na2SÜ4 and the solvent evaporated to dryness to give protected dipeptide amphetamine conjugate. The protected dipeptide conjugate was directly protected by adding 4N HCl in 1,4-dioxane (20 ml) and the solution stirred for 20 h at 25 ° C. The solvent was evaporated and the product dried in vacuo to give the corresponding dipeptide amphetamine hydrochloride conjugate.

General Synthesis of Tripeptide Amphetamine Conjugates

An amino acid conjugate was synthesized and unprotected according to the general procedure described above. To a solution of the amino acid amphetamine hydrochloride (1.0 eq) in dioxane (20 ml) was added NMM (5.0 eq) and protected dipeptide succinate (1.05 eq.). The solution was stirred for 2 Oh at 25 ° C. The solvent was removed under reduced pressure. Saturated NaHCO 3 solution (20 mL) was added, and the suspension stirred for 30 min.IPAC (100 mL) was added, and the organic layer washed with 2% AcOHaq (3 x 100 mL) and brine (2 χ 100 ml). The organic extract was dried over Na2SÜ4, and the solvent evaporated to dryness to give the protected tripeptide amphetamine. Deprotection was directly performed by adding 4N HCl in 1,4-dioxane (20 ml). The mixture was stirred for 20h at 25 ° C, the solvent evaporated and the product dried in vacuo to give the respective tripeptide amphetamine hydrochloride conjugate.

Hydrochloride conjugates did not need further purification, but many of the unprotected hydrochloride salts were hygroscopic and needed special handling during analysis and later in vivo testing.

Example 2 - Synthesis of L-Lysine-d-Amphetamine

L-lysine-d-amphetamine was synthesized by the following methods.

The. HCl salt preparation (see Fig. 3)

i. Coupling

<table> table see original document page 38 </column> </row> <table> <table> table see original document page 39 </column> </row> <table>

To a solution of Boc-Lys (Boc) -OSu (15.58g, 35.13 mmol) emdioxane (100 ml) under inert atmosphere was added d-amphetamine basel (4.75g, 35.13 mmol) and DIPEA. (0.9g, 1.22ml, 7.03 mmol). The resulting mixture was allowed to stir at room temperature overnight. Excess solvent and base were removed using evaporation under reduced pressure. The crude product was dissolved in ethyl acetate and loaded onto a flash column (7cm wide, filled to 24cm with silica) and eluted with ethyl acetate. The product was isolated, the solvent reduced by rotary evaporation, and the purified protected amide was dried through high vacuum to obtain a white solid. 1H NMR (DMSO-d6) δ 1.02-1.11 (m, 2H, Lys Y-CH2), δ 1.04 (d, 3H, Amp (X-CH3), δ 1.22-1.43 (m, 4H, Lys-β and S-CH2), δ 1.37 (18H, Boc, 6x CH3), δ 2.60-2.72 (2H, Amp CH2), δ 3.75-3.83 (m, 1H, Lys oc-H) δ 3.9-4.1 (m, 1H, Amp α-Η), δ 6.54-6.61 (d, 1H, NH amide), δ 6.7 -6.77 (m, 1H, NH amide), δ 7.12-7.29 (m, 5H, ArH), δ 7.65-7.71 (m, 1, NH amide); 88 ° C.

ii. Unprotection

<table> table see original document page 39 </column> </row> <table>

The protected amide was dissolved in 50 mL of dioxane anhydrous and stirred while 50 mL (200 mmol) of HCl4M / dioxane was added and stirred at room temperature overnight. The solvents were then reduced by rotary evaporation to give a viscous oil. Addition of 100 ml MeOH followed by rotary evaporation resulted in a solid gold-colored material which was purified by storage at room temperature under high vacuum.

1H NMR (DMSO-d6) δ 0.86-1.16 (m, 2H, Lys Y-CH2), δ 1.1 (d, 3H, Amp OC-CH3), δ 1.40-1.56 ( m, 4H, Lys-β and S-CH 2), δ 2.54-2.78 (m, 2H, Amp CH 2, 2H, Lys-E-CH 2), 3.63-3.74 (m, 1H, Lys O-H) δ 4.00-4.08 ((m, 1H, Amp α-Η), δ 7.12-7.31 (m, 5H, Amp ArH), δ 8.13-8.33 ( d, 3H, Lys amine) δ 8.70-8.78 (d, 1H, amine NH); mp = 120-122 ° C.

B. Mesylate Salt Preparation (and see Fig. 2).

Similarly, the peptide conjugate mesylate salt can be prepared using methanesulfonic acid in the deprotection step as described in more detail below.

i. Coupling

A 72L round bottom reactor was equipped with a mechanical imager, digital thermocouple, and nitrogen-purged addition funnel. The vessel was charged with Boc-Lys (Boc) -OSu (3.8kg, 8.568 mol, 1.0eq) and 1,4-dioxane (20.4L) and the resulting cloudy solution was stirred at 20 ± 5 °. During 10 min. To the mixture was added N-methylmorpholine (950g, 9.39mol, 1.09eq) over a period of 1 minute, and the mixture was stirred for 10 min. To the slightly cloudy reaction mixture was then added a solution of dextro-amphetamine (1.753 kg, 12.96 mol, 1.51 eq) in 1,4-dioxane (2.9 L) over a 30 min period while cooling the reactor externally. with a thaw / water bath. The internal temperature was kept below 25 ° C during the addition. At the end of the addition, a thick white precipitate appeared. The addition funnel was rinsed with 1,4-dioxane (2.9 L) in the reactor and the reaction mixture was stirred at 22 ± 3 ° C. TLC monitoring 30 minutes after the addition was complete showed no Boc-Lys (Boc) -Osu remaining, and the reaction was quenched with DI H2O (10 L). The mixture was stirred for 1 hour at room temperature and then concentrated under reduced pressure to give a dense white solid. For extractions, two solutions were prepared: a solution of acetic acid / salt: NaCl (15 kg) and glacial acetic acid (2 kg) in DI H2O (61 L) and a solution of carbonate: NaHCO3 (1.5 kg) in DI H2O (30 L).

The solid was redissolved in IPAC (38 L) and acetic acid / salt solution (39 kg) and transferred to a 150 L reactor. The layers were mixed for 10 minutes and then allowed to separate. The organic layer was drained and washed with another portion (39 kg) of acetic acid / salt solution, followed by washing with debicarbonate solution (31.4 kg). All phase separations occurred within 5 minutes. To the organic solution was then added silica gel (3.8 kg; Silica gel 60). The resulting slurry was stirred for 45 minutes and then filtered on filter paper. The filter cake was washed with IPAC (5 χ 7.6L). The filtrate and washings were analyzed by TLC and it was determined that all contained product. The filtrate and washings were combined and concentrated under reduced pressure to give the product as a white solid.

ii. Unprotection

A 45L container was charged with di-Boc-Lys-Amp (3.63 kg, 7.829 mol) and 1,4-dioxane (30.8 L, 8.5 vol) and the mixture was stirred briefly under nitrogen for 30 minutes. The resulting solution was filtered and the filter cake was washed with 1,4-dioxane (2 x 1.8 L). The filtrates were then transferred to a 72 L round bottom flask, which was equipped with a mechanical stirrer, digital thermocouple, denitrogen inlet and outlet, and 5L addition funnel. The reaction mixture temperature was set at 21 ± 3 ° C with a bath. To the clear and slightly yellow solution was added methanesulfonic acid (3.762 kg, 39.15 mol, 5 eq) over a period of 1 h while maintaining the internal temperature at 21 ± 3 ° C. Approximately 1 hour after complete addition, a white precipitate began to appear. The mixture was stirred at room temperature for 20.5 h, after which HPLC monitoring showed the disappearance of all starting material. The mixture was filtered on filter paper and the flask was washed with 1,4-dioxane (3.6L, 1 vol.). The filter cake was washed with dioxane (3 x 3.6 L) and dried for 1 hour. The material was then transferred to the drying tray and dried in a vacuum oven at 55 ° C for ~ 90 h. This yielded Lys-Amp dimesylate [3.275 kg, 91.8% yield; > 99% (AUC)] as a white solid.

Example 3 - Ser-Amp Synthesis

Ser-Amp was synthesized by a similar method (see Fig. 4) except that the amino acid starting material was Boc-Ser (O-tBu) -OSu and deprotection was performed using a trifluoroacetic acid solution instead of HCl.

Example 4 - Phe-Amp Synthesis

Phe-Amp was synthesized by a similar method (see Fig. 5) except that the amino acid starting material was Boc-Phe-OSu.

Phe-Amp Hydrochloride: Hygroscopic: 1 H NMR (400 MHz, DMSO-d 6): δ 8.82 (d, J = 8.0 Hz, 1H), 8.34 (bs, 3H), 7.29-7 11.11 (m, 10H), 3.99 (m, 2H), 2.99 (dd, J = 13.6, 6.2 Hz, 1H), 2.88 (dd, J = 13.6, 7 2Hz, 1H), 2.64 (dd, J = 13.2, 7.6Hz, 1H), 2.53 (m, 1H), 1.07 (d, J = 6.4Hz, 3H) ; 13 C NMR (100 MHz, DMSO-d 6): δ 167.31, 139.27, 135.49, 130.05,129.66, 128.78, 128.61, 127.40, 126.60, 53.83, 47.04.42.15, 37.27, 20.54; HRMS: (ESI) for C 18 H 23 N 2 O (M + H) +: calcd. 283.1810: found, 283.1806.

Example 5 - Gly3-Amp Synthesis

Gly3-Amp was synthesized by a similar method (see Fig. 6) except that the amino acid starting material was Boc-GGG-OSu.

Gly3-Ampimp Hydrochloride 212-214 ° C; 1H NMR (400 MHz, DMSO-d6) δ 7.28 (m, 5H), 3.96 (m, 1H), 3.86 (m, 2H), 3.66 (m, 4H), 2.76 (m, 1H), 2.75 (m, 1H), 1.02 (d, J = 6.8 Hz, 3H); 13 C NMR (100 MHz, DMSO-d 6) δ 168.91, 168.14, 166.85.139.45, 129.60, 128.60, 126.48, 46.60, 42.27, 20.30.HRMS : (ESI) for C 15 H 22 N 4 O 3 Na (M + Na) +: calcd. 329.1590: Found 329.1590.

Example 6. Pharmacokinetics of L-lysine-d-amphetamine diHCl compared to d-amphetamine sulfate (ELISA analysis)

Sprague-Dawley rats were given free water, fasted overnight, and dosed by oral gavage of L-lysine-d-amphetamine di dHCl or d-amphetamine sulfate. In all studies, the doses contained equivalent amounts of d-amphetamine base. Plasma concentrations of d-amphetamine were measured by ELISA (Amphetamine Ultra, 109319, Neogen, Corporation, Lexington, KY). The assay is specific for d-amphetamine with only minimal reactivity (0.6%) of the main d-amphetamine metabolite (para-hydroxy-d-amphetamine). L-lysine-d-amphetamine diHCl was also determined to be essentially nonreactive in the ELISA (<1%).

The mean plasma concentration (n = 4) curves of d-amphetamine or L-lysine-d-amphetamine diHcl are shown in Fig. 7. Prolonged release was observed in all four animals receiving L-lysine-d-amph diHCl etamine and Cmax were reduced substantially compared to animals receiving d-amphetamine sulfate. The individual animal plasma d-amphetamine concentrations for d-amphetamine or L-lysine-d-amphetamine diHCl are shown in Table 3. The mean plasma concentrations of d-amphetamine are shown in Table 4. The time-peak concentration for L-lysine-d-amphetamine was similar to that of d-amphetamine. Pharmacokinetic parameters for oral administration of d-amphetamine or L-lysine-d-amphetamine diHCl are summarized in Table 5.

Table 3 - Individual deanimal plasma d-amphetamine concentrations given orally d-amphetamine or L-lysine-d-amphetamine diHCl (3 mg / kg d-amphetamine base)

<table> table see original document page 44 </column> </row> <table>

Table 4 - Mean plasma concentrations of d-amphetamine following oral administration of d-amphetamine or L-lysine-d-amphetamine

<table> table see original document page 44 </column> </row> <table>

Table 5 - Pharmacokinetic parameters of d-amphetamine following oral administration of d-amphetamine or L-lysine d-amphetamine

<table> table see original document page 44 </column> </row> <table>

This example illustrates that when lysine is conjugated to the active agent amphetamine, peak amphetamine levels are reduced while bioavailability is approximately equal to amphetamine. Amphetamine bioavailability released from L-lysine-d-amphetamine is similar to amphetamine sulfate at the equivalent dose; thus, L-lysine-d-amphetamine retains its therapeutic value. Gradual release of L-lysine-d-amphetamine amphetamine and reduction in peak levels reduce the possibility of overdose. Example 7. Oral bioavailability of L-lysine-d-amphetamine dimesylate in various doses.

The. Doses approaching therapeutic human doses (1.5, 3 and 6 mg / kg).

Mean plasma concentration curves (n = 4) of d-amphetamine vs. L-lysine-d-amphetamine are shown for orates receiving orally 1.5, 3 and 6 mg / kg in Fig. 8.9 and 10, respectively. Prolonged release was observed in all three therapeutic doses for animals dosed with L-lysine-d-amphetamine. Mean plasma concentrations for 1.5, 3, and 6 mg / kg are shown in Table 6, Table 7, and Table 8, respectively. Pharmacokinetic parameters for oral administration of d-amphetaminavs. L-lysine-d-amphetamine in various doses are summarized in Table 9.

Table 6 - Mean plasma concentrations of d-amphetamine vs. L-lysine-d-amphetamine after oral administration (1.5 mg / kg).

<table> table see original document page 45 </column> </row> <table>

Table 7 - Mean plasma concentrations of d-amphetamine vs. L-lysine-d-amphetamine after oral administration (3 mg / kg)

<table> table see original document page 45 </column> </row> <table> <table> table see original document page 46 </column> </row> <table>

Table 8 - Mean plasma concentrations of d-amphetamine vs. L-lysine-d-amphetamine after oral administration (6 mg / kg)

<table> table see original document page 46 </column> </row> <table>

Table 9 - Pharmacokinetic parameters of d-amphetamine following oral administration of d-amphetamine or L-lysine-d-amphetamine

<table> table see original document page 46 </column> </row> <table>

B. Increased doses (12, 30, and 60 mg / kg)

Mean plasma concentration curves (n = 4) of d-amphetamine vs. L-lysine-d-amphetamine are shown for orates given orally 12, 30 and 60 mg / kg. At these higher doses, the bioavailability of L-lysine-d-amphetamine is markedly reduced compared to d-amphetamine.

Table 10 - Mean plasma concentrations of d-amphetamine vs. L-lysine-d-amphetamine after oral administration (12 mg / kg). <table> table see original document page 47 </column> </row> <table>

Table 11 - Mean plasma concentrations of d-amphetamine vs. L-lysine-d-amphetamine after oral administration (30 mg / kg)

<table> table see original document page 47 </column> </row> <table>

Table 12 - Mean plasma concentrations of d-amphetamine vs. L-lysine-d-amphetamine after oral administration (60 mg / kg)

<table> table see original document page 47 </column> </row> <table>

Table 13 - Pharmacokinetic parameters of d-amphetamine following oral administration of d-amphetamine or L-lysine-d-amphetamine <table> table see original document page 48 </column> </row> <table>

* 0-5h

** 0-1.5h

Example 8 - Oral bioavailability of L-lysine-d-amphetamine dimesylate at various doses close to a human therapeutic dose range compared to a pharmacological dose

Sprague-Dawley rats were given free water, fasted overnight, and dosed by oral gavage with 1.5, 3, 6, 12, and 60 mg / kg of amphetamine sulfate or L-lysine-d-amphetamine containing equivalent amounts of d-amphetamine. The d-amphetamine concentrations were measured by ELISA.

When lysine is conjugated to the reactive agent d-amphetamine, it has been shown that d-amphetamine levels 30 minutes after administration are reduced by approximately 50% over a dosage range of 1.5 to 12 mg / kg. However, when a suprapharmacological dose (60 mg / kg) is given, L-lysine-d-amphetamine d-amphetamine levels only reach 8% of those observed in d-amphetamine sulfate (see Table 14, Table 15 and Figure 15). .

Substantial reduction in oral bioavailability at high levels greatly reduces the potential for abuse of L-lysine-d-amphetamine.

Table 14 - d-Amphetamine Levels vs. dosage 0.5h after dosing with d-amphetamine sulphate

<table> table see original document page 48 </column> </row> <table>

Table 15 - d-Amphetamine Levels vs. dosage 0.5 h after dosing with L-lysine-d-amphetamine <table> table see original document page 49 </column> </row> <table>

Example 9 - Reduced oral bioavailability of high-dose L-lysine-d-amphetamine deimesilate An additional oral PK study illustrated in Figure 16 shows blood levels of d-amphetamine at a dose of 60mg / kg over a time period of 8h. In the case of d-amphetamine, blood levels rapidly reached a very high level, and 8 to 12 animals died or were sacrificed due to acute symptoms of toxicity. Blood levels (Table 16 and Table 17) from animals receiving L-lysine-d-amphetamine, on the other hand, did not peak until 5 hours and only reached a fraction of the levels of animals receiving amphetamine. (Note: Data valid after 3h for d-amphetamine could not be determined due to the death or sacrifice of the animals).

Table 16 - Mean plasma concentrations of d-amphetamine vs. L-lysine-d-amphetamine following high dose oral administration (60 mg / kg)

<table> table see original document page 49 </column> </row> <table>

* n = 2

** n = 1

Table 17 - Pharmacokinetic parameters of d-amphetaminavs. L-lysine-d-amphetamine

<table> table see original document page 49 </column> </row> <table> <table> table see original document page 50 </column> </row> <table>

Example 10 - Oral bioavailability of d-amphetamine following administration of a sustained release formulation (intact or ground) or L-lysine-d-amphetamine dimesylate

Doses of a d-amphetamine desulfate prolonged release formulation (Dexedrine Spansule® Capsules, GlaxoSmithKline) were orally administered to rats as intact capsules or as crushed capsules and compared with a dose of L-lysine-d-amphetamine containing equivalent amount of amphetamine base (Fig. 20). Crushed capsules showed an increase in Cmax and AUCinf of 84 and 13 percent, respectively, compared with intact capsules (Table 18 and Table 19). In contrast, Cmax and AUCinf of d-amphetamine following administration of L-lysine-d-amphetamine were similar to those of the intact capsule illustrating that prolonged release is inherent in the compound itself and cannot be prevented by simple manipulation.

Table 18 - Time course concentrations of d-amphetamine following oral administration of prolonged-release Dexedrine Spansule® capsules, crushed extended-release Dexedrine Spansule® capsules or L-lysine-d-amphetamine (3 mg / kg d-amphetamine base )

<table> table see original document page 50 </column> </row> <table>

Table 19 - Pharmacokinetic parameters of d-amphetamine following oral administration of prolonged-release DexedrineSpansule® capsules, extended-release shredded DexedrineSpansule® capsules or L-Iysine-d-amphetamine base (3 mg / kg d-amphetamine base)

<table> table see original document page 51 </column> </row> <table>

This example illustrates the advantage of the invention over d-amphetamine controlled release formulations.

Example 11 - Reduced intranasal bioavailability of L-lysine-d-amphetamine vs. amphetamine

The. Intranasal (IN) bioavailability of L-lysine-d-amphetamine hydrochloride

Sprague-Dawley rats were dosed by intranasal administration with 3 mg / kg deanfetamine sulfate or L-lysine-d-amphetamin hydrochloride containing equivalent amounts of d-amphetamine. AL-lysine-d-amphetamine did not release any significant amounts of d-amphetamine into the circulation through IN administration. Mean (n = 4) plasma concentration curves of amphetamine vs. L-lysine-d-amphetamine are shown in Fig. 17. The pharmacokinetic parameters for IN administration of L-lysine-d-amphetamine are summarized in Table 20.

Table 20 0 - Pharmacokinetic parameters of d-amphetaminavs. L-lysine-d-amphetamine hydrochloride by IN administration

<table> table see original document page 51 </column> </row> <table>

B. Intranasal bioavailability of L-lysine-d-amphetamine dimesylateThe process of part a. was repeated using the L-lysine-d-amphetamine demesylate salt:

Table 21 - Pharmacokinetic parameters of d-amphetaminavs. L-lysine-d-amphetamine mesylate salt by IN administration.

<table> table see original document page 52 </column> </row> <table>

This example illustrates that when lysine is conjugated to the active agent d-amphetamine, bioavailability via intranasal route is substantially reduced, thereby decreasing the potential for drug abuse via this pathway.

Example 12. Intravenous bioavailability of amphetaminavs. L-lysine-d-amphetamine dimesylate

Sprague-Dawley rats were dosed by intravenous injection into the caudal vein with 1.5 mg / kg d-amphetamine or L-lysine-d-amphetamine containing the equivalent amount of amphetamine. As noted with an IN dosage, the conjugate did not release a significant amount of d-amphetamine. The mean plasma concentration (n = 4) curves of amphetamine vs. L-lysine-d-amphetamine are shown in Fig. 19. The pharmacokinetic parameters for IV administration of L-lysine-d-amphetamine are summarized in Table 22.

Table 22 - Pharmacokinetic parameters of d-amphetaminavs. L-lysine-d-amphetamine by IV administration.

<table> table see original document page 52 </column> </row> <table>

This example illustrates that when lysine is conjugated to the active agent amphetamine, the bioavailability of intravenous amphetamine is substantially reduced, thereby decreasing the potential for drug abuse through that route.

Example 13. Oral bioavailability of L-lysine-d-amphetamine dimesylate compared to d-amphetamine staggered doses

The fraction of intact L-lysine-d-amphetamine absorbed after oral administration in rats increased non-linearly in proportion to staggered doses of 1.5 to 12 mg / kg (Fig. 21 - Fig. 25). The fraction absorbed at a dose of 1.5 mg / kg was only 2.6 percent, while it had increased by 24.6 percent at a dose of 12 mg / kg. The absorbed fraction dropped to 9.3 percent at a high dose of 60mg / kg. Tmax ranged from 0.25 to 3 hours, and peak concentrations occurred earlier for L-lysine-d-amphetamine than for d-amphetamine. L-lysine-d-amphetamine was eliminated faster than d-amphetamine with almost undetectable concentrations at 8 hours at the lowest dose.

The bioavailability (AUC) of d-amphetamine from each drug administered was approximately equivalent at different doses. The T-max for L-lysine-d-amphetamine d-amphetamine ranged from 1.5 to 5 hours compared with 0.5 to 1.5 after d-amphetamine sulfate administration. The difference in Tmax was higher at higher doses. L-lysine-d-amphetamine C-max amphetamine was approximately halved compared with d-amphetamine sulfate administration d-amphetamine Cdtx at doses of 1.5 to 6 mg / kg at doses approximate human equivalent therapeutics (HEDs). Thus, in dosestherapeutics, the pharmacokinetics of L-lysine-d-amphetamine d-amphetamine resembled that of the slow deliberation formulation.

HEDs are defined as the equivalent dose for a 60 kg person according to the body surface area of the animal model. The adjustment factor for rats is 6.2. HED for a rat dose of 1.5 mg / kg d-amphetamine, for example, is equivalent to 1.5 / 6.2 χ 60 = 14.52 d-amphetamine base; which is equivalent to 14.52 / .7284 = 19.9 mg of d-amphetamine sulfate when adjusted for salt content.

Table 23 - D-Amphetamine Sulfate Equivalent Human Doses (HEDs)

<table> table see original document page 54 </column> </row> <table>

At suprapharmacological doses (12 and 60 mg / kg), Cmax was reduced by 73 and 84 percent, respectively, compared with d-amphetamine sulfate. At these high doses, L-lysine-d-amphetamine d-amphetamine AUCs were substantially reduced compared to d-amphetamine sulfate, with AUCinf reduced by 76% at the highest dose (60 mg / kg). At 60 mg / kg, the d-amphetamine sulfate d-amphetamine levels are rapidly increased; The experimental time course cannot be completed due to the extreme hyperactivity necessitating euthanasia.

In summary, the oral bioavailability of d-amphetamine from L-lysine-d-amphetamine decreased to some degree at higher doses. However, the near-linear pharmacokinetics of L-lysine-d-amphetamine at doses of 1.5 to 60 mg / kg with the absorbed fraction ranging from 52 to 81 percent (extrapolated from 1.5 mg / kg dose). The pharmacokinetics of d-amphetamine sulfate were also nearly linear at lower doses of 1.5 to 6 mg / kg with absorbed fraction ranging from 62 to 84 percent. Unlike L-lysine-d-amphetamine, however, the parameters were disproportionately increased at higher doses for d-amphetamine sulfate with the calculated absorbed fraction as 101 and 223 percent (extrapolated from 1.5 mg / kg dose), respectively, for pharmacological doses of 12 and 60 mg / kg.

The results suggest that the ability for d-amphetamine clearance when administered as a sulfat salt becomes saturated at higher doses, whereas gradual L-lysine-d-amphetamine hydrolysis prevents d-amphetamine elimination saturation in higher doses. The difference in dose proportionality for bioavailability (Cmax and AUC) for d-amphetamine and L-lysine-d-amphetamine is illustrated in Fig. 26 - Fig. 28.

The pharmacokinetic properties of L-lysine-d-amphetamine compared to d-amphetamine at higher doses reduces dose escalation capacity. This improves safety and reduces the potential for abuse of L-lysine-d-amphetamine as a method of administering d-amphetamine in the treatment of ADHD or other indicated conditions.

Example 14 - Intranasal bioavailability of L-lysine-d-amphetamine dimesylate compared to d-amphetamine.

As shown in Fig. 31 and Fig. 32, the bioavailability of d-amphetamine following intranasal bolus administration of L-lysine-d-amphetamine was approximately 5 percent over that of d-amphetamine sulphate dose equivalent to AUCinf values. 56 and 1032, respectively. The d-amphetamine C max following intranasal administration of L-lysine-d-amphetamine was also about 5 percent over the equivalent amount of d-amphetamine sulfate at 78.6 ng / ml and 19 62.9 ng / ml. ml, respectively. The concentration concentration of amphetamine was substantially retarded to L-lysine-d-amphetamine (60 minutes) compared to d-amphetamine sulfate (5 minutes), reflecting gradual hydrolysis of L-lysine-d-amphetamine. Similarly, a high concentration of L-lysine-d-amphetaminaintacta was detected after intranasal administration.

These results suggest that intranasal administration of L-lysine-d-amphetamine provides only minimal hydrolysis of L-lysine-d-amphetamine and thus only minimal release of d-amphetamine.

Example 15. Intravenous bioavailability of L-lysine-d-amphetamine dimesylate compared to d-amphetamine

As shown in Fig. 33 and Fig. 34, the availability of d-amphetamine following intravenous bolus administration of L-lysine-d-amphetamine was approximately half that of the equivalent dedamphetamine sulfate dose with AUCinf values of 237.8 and 42. 0.2, respectively. The d-amphetamine cm -1 after administration of L-lysine-d-amphetamine was only about a quarter of the equivalent amount of d-amphetamine with values of 99.5 and 420.2, respectively.

The d-amphetamine concentration max was substantially delayed for L-lysine-d-amphetamine (30 minutes) compared to d-amphetamine sulfate Tmax (5 minutes), reflecting the gradual hydrolysis of L-lysine-d-amphetamine. In conclusion, the bioavailability of intravenous d-amphetamine is substantially reduced and delayed when administered as L-lysine-d-amphetamine. In addition, bioavailability is lower than that obtained by oral administration of the equivalent dose of L-lysine-d-amphetamine.

Data Summary on LC / MS / MS Bioavailability in Mice

The following tables summarize the bioavailability data in the experiments discussed in Examples 13-15. Table 24, Table 25, and Table 2 summarize the pharmacokinetic parameters of d-amphetamine following oral, intranasal and intravenous administration, respectively, of d-amphetamine or L-lysine-d-amphetamine. TABLE 24

<table> table see original document page 57 </column> </row> <table>

TABLE 25

<table> table see original document page 57 </column> </row> <table> TABLE 26

<table> table see original document page 58 </column> </row> <table>

TABLE 27

<table> table see original document page 58 </column> </row> <table> Table 28 - Pharmacokinetic parameters of L-lysine-d-amphetamine following intravenous bolus administration of L-lysine-d-amphetamine

<table> table see original document page 59 </column> </row> <table>

Table 29 - Pharmacokinetic parameters of L-lysine d-amphetamine following intranasal administration of L-lysine d-amphetamine

<table> table see original document page 59 </column> </row> <table>

Tables 30 and 31 summarize the percentage bioavailability of d-amphetamine following oral, intranasal and intravenous administration of L-lysine-d-amphetamine compared to d-amphetamine sulfate.

Table 30 - Percent bioavailability (AUCinf) of d-amphetamine following administration of L-lysine-d-amphetamine via various routes compared to bioavailability after d-amphetamine sulfate administration

<table> table see original document page 59 </column> </row> <table>

Table 31 - Percent bioavailability (Cmax) of d-amphetamine following administration of L-lysine-d-amphetamine via various routes compared to bioavailability after d-amphetamine sulfate administration

<table> table see original document page 59 </column> </row> <table> Tables 32-37 summarize the ongoing concentrations of d-amphetamine and L-lysine-d-amphetamine after oral, intranasal administration. and intravenous d-amphetamine or L-lysine-d-amphetamine

Table 32 - Time course concentrations of d-amphetamine following intravenous bolus administration of L-lysine-d-amphetamine or d-amphetamine sulfate (1.5 mg / kg)

<table> table see original document page 60 </column> </row> <table>

Table 33 - Time course concentrations of L-lysine-d-amphetamine following intravenous bolus administration of L-lysine-d-amphetamine (1.5 mg / kg)

<table> table see original document page 60 </column> </row> <table>

Table 34 - Time course concentrations of d-amphetamine following oral administration of L-lysine-d-amphetamine at various doses.

<table> table see original document page 60 </column> </row> <table> Table 35 - Time course concentrations of d-amphetamine following oral administration of d-amphetamine sulfate in various doses

<table> table see original document page 61 </column> </row> <table>

Table 36 - Time course concentrations of d-amphetamine following intranasal administration of L-lysine-d-amphetamine or d-amphetamine sulfate (3 mg / kg).

<table> table see original document page 61 </column> </row> <table>

Table 37 - Time course concentrations of L-lysine-d-amphetamine following intranasal administration of L-lysine-d-amphetamine (3 mg / kg)

<table> table see original document page 61 </column> </row> <table>

Example 16 - Bioavailability of L-Lysine-d-Amphetamine Dimesylate or D-Amphetamine Sulphate in Dogs (LC / MS / MS Analysis)

Experimental Example Project

It is a crossover, non-randomized double-treatment study. All animals were kept on a normal swab and fasted overnight from each dose administration. The dose of L-lysine-d-amphetamine was based on the body weight measured in the morning of each dosing day. The effective dose administered was based on syringe weight before and after dosing.

Serial blood samples were obtained from each animal through direct jugular vein venipuncture using vacutainer tubes containing sodium heparin as anticoagulant. Plasma samples were stored frozen until shipment to Quest Pharmaceuticals Services, Inc. (Newark, DE). Pharmacokinetic analysis of plasma assay results was conducted by Calvert. The animals were treated as follows:

<table> table see original document page 61 </column> </row> <table>

Test Article Administration

Oral: The test article was administered to each animal through a single oral gavage. On Day 1, the animals received the oral dose by gavage using an esophageal tube attached to a syringe. The dosing tubes were flushed with approximately 10 ml of drinking water to ensure administration of the required dosing solution.

Intravenous: On Day 8, the animals received L-lysine-d-amphetamine as a single 30-minute intravenous infusion into the cephalic vein.

Sample collection:

Dosage Formulations: Post-dosing, the remaining dosing formulation was preserved and stored in the frozen form.

Blood: Serial blood samples (2 ml) were collected using venipuncture tubes containing sodium heparin.

Blood samples were collected at 0, 0.25, 0.5, 1, 2.4, 8, 12, 24, 48, and 72 hours post-oral dosing. Blood samples were collected at 0, 0.167, 0.33, 0.49 (before stopping the infusion), 0.583, 0.667, 0.75, 1.2, 3, 4, 8, 12 and 23 hours from the beginning of the infusion. post intravenous infusion. The blood samples collected were immediately frozen.

Plasma: Plasma samples were obtained by decentrifugation of blood samples. Duplicate blood samples (about 0.2 mL each) were transferred to pre-labeled plastic vials stored frozen at approximately -70 ° C.

Plasma samples were analyzed for L-lysine-d-amphetamine and d-amphetamine using a LC-MS / MS method validated with a 1 ng / ml LLOQ for both analytes.

Microsoft Excel (Version 6, Microsoft Corp., Redmond, WA) was used for calculating mean plasma concentration and for plotting plasma concentration-time data. Pharmacokinetic analysis (non-compartmentalized) was performed using the WinNonlin® software program (Version 4.1, Pharsight, Inc. Mountain View, CA). The maximum concentration (Cmax) and the time for Cmax (Tmax) were observed values. The area under the plasma concentration-time curve (AUC) was determined using the log-trapezoidal linear rule.

The apparent terminal rate constant (λζ) was derived using least squares linear regression with visual data inspection to determine the appropriate number of points (minimum of 3 data points) to calculate λζ. AUCo-inf was calculated as the sum of AUC0-t and Cpred / λζ, where Cpred was the predicted concentration in the last quantifiable concentration. Plasma clearance (CL / F) was determined as Dose / AUCo-inf ratio - Mean residence time (MRT) was calculated as the ratio of AUMC o-inf / AUCo-inf / where AUMC o-inf was the area under the curve of the first moment from time zero to infinity. The constant state distribution volume (Vss) was calculated as CL * MRT. The half-life was calculated as 1η2 / λζ. Oral bioavailability (F) was calculated as the ratio of AUCo-inf after oral dosing of AUCo-inf after intravenous dosing. Descriptive statistics (mean and standard deviation) of pharmacokinetic parameters were calculated using MicrosoftExcel.

The objectives of this study were to characterize the pharmacokinetics of L-lysine-d-amphetamine and d-amphetamine following administration of L-lysine-d-amphetamine in dogbeagle. As shown in Fig. 35, in a crossover design, L-lysine-d-amphetamine was administered to 3 dogs beagleorally or intravenously. Blood samples were collected up to 24 and 72 hours after intravenous and oral doses, respectively.

The mean plasma concentration-time profiles of L-lysine-d-amphetamine and d-amphetamine following an intravenous or oral dose of L-lysine-d-amphetamine are shown in Fig. 37 and Fig. 38, respectively. Comparative profiles of L-lysine-d-amphetamine for d-amphetamine after both lifetimes are shown in Fig. 35 and Fig. 36. Individual graphs are shown in Fig. 39 and Fig. 40. Pharmacokinetic parameters are summarized in Table 38-Table 46.

Following a 30-minute intravenous infusion of L-lysine-d-amphetamine, plasma concentration reached a nofinal infusion peak. The concentration of L-lysine-d-amphetaminate after infusion fell very rapidly exponentially, and fell below the quantifiable limit (1ng / ml) approximately 8 hours post dose. Results from non-compartmentalized pharmacokinetic analysis indicate that L-lysine-d-amphetamine is a high clearance compound with a moderate volume of distribution (Vss) that approximates total body water (0.7 L / kg).

The mean clearance value was 2087 mL / h.kg (34.8mL / min.kg) and similar to the hepatic blood flow in the dog (40 mL / min.kg).

L-lysine-d-amphetamine was rapidly absorbed following oral administration with Tmax at 0.5 hours in the three dogs. The mean absolute oral bioavailability was 33%, which suggests. L-lysine-d-amphetamine is very well absorbed by the dog. Apparent terminal half-life was 0.3 hours, indicating rapid elimination as observed after intravenous administration.

The plasma concentration-time profiles of d-amphetamine following intravenous or oral administration of L-lysine-d-amphetamine were similar. See Table 39. At an oral dose of 1 mg / kg L-lysine-d-amphetamine, the d-amphetamine Cmax was 104.3 ng / ml. The amphetamine half-life was 3.1 to 3.5 hours, much longer compared to L-lysine-d-amphetamine.

In this study, L-lysine-d-amphetamine was injected for a period of 30 minutes. Due to the rapid clearance of L-lysine-d-amphetamine it is likely that the d-amphetamine availability of L-lysine-d-amphetamine would decrease if a similar dose were administered by intravenous bolus injection.

Even when given as an infusion, the d-amphetamine bioavailability of L-lysine-d-amphetamine did not exceed that of a similar dose administered orally and the time-peak concentration was substantially delayed. These data further support that L-lysine-d-amphetamine provides a potential reduction in d-amphetamine abuse through intravenous injection.

Table 38 - Pharmacokinetic parameters of L-lysine-d-amphetamine in beagle dogs following oral or intravenous administration of L-lysine-d-amphetamine (1 mg / kg base of amphetamine).

<table> table see original document page 65 </column> </row> <table>

a: medium (range)

The pharmacokinetic parameter abbreviations are as follows:

Cmax, maximum observed plasma concentration, Tmax, time when Cmax is observed;

AUCo-t / total area under plasma concentration curve versus time from 0 to last data point;

AUCo-inf, total area under plasma concentration versus time curve;

ti / 2, apparent terminal half-life;

MRT, average residence time;

LC / F, oral clearance;

Vss, steady state volume of distribution, F, bioavailability.

Table 3 9 - Pharmacokinetic parameters of d-amphetamine in beagle dogs following oral or intravenous administration of L-lysine-d-amphetamine (1 mg / kg d-amphetamine base)

<table> table see original document page 66 </column> </row> <table>

a: medium (range)

Table 40: Pharmacokinetics of L-lysine-d-amphetamine in Beagle dogs after 30 min intravenous administration of L-lysine-d-amphetamine (1 mg / kg d-amphetamine base)

<table> table see original document page 66 </column> </row> <table>

a: medium (range); b: not determined

CL, clearance after IV administration

Table 41 - Pharmacokinetic parameters of L-lysine-d-amphetamine in Beagle dogs after oral administration of L-lysine-d-amphetamine (1 mg / kg d-amphetamine base)

<table> table see original document page 66 </column> </row> <table> <table> table see original document page 67 </column> </row> <table>

a: medium (range)

Table 42 - Pharmacokinetics of d-amphetamine in Beagle Dogs after 30 minutes of intravenous administration of L-lysine-d-amphetamine (1 mg / kg d-amphetamine base)

<table> table see original document page 67 </column> </row> <table>

a: medium (range)

Table 43 - Pharmacokinetics of d-Amphetamine in Beagle Dogs Following Oral Administration of L-Lysine-d-Amphetamine (1 mg / kg d-Amphetamine Base)

<table> table see original document page 67 </column> </row> <table>

a: medium (range)

Table 44 - Pharmacokinetics of d-amphetamine in Beagle dogs following oral administration of L-lysine-d-amphetamine or d-amphetamine sulfate (1.8 mg / kg d-amphetamine base)

<table> table see original document page 67 </column> </row> <table> Table 45 - Pharmacokinetics of d-amphetamine in Beagle dogs following oral administration of L-lysine-d-amphetamine or d-amphetamine sulfate (1, 8 mg / kg d-amphetamine base)

<table> table see original document page 68 </column> </row> <table>

Table 46 - Pharmacokinetic parameters of d-amphetamine in Beagle dogs and bitches after oral administration of L-lysine-d-amphetamine or d-amphetamine sulfate (1.8 mg / kg d-amphetamine base)

<table> table see original document page 68 </column> </row> <table>

Example 17 - Delayed Cardiovascular Effects of L-Lysine-d-Amphetamine Dedimesylate Compared to d-Amphetamine After Intravenous Infusion

Systolic and diastolic blood pressure increase with ad-amphetamine even at therapeutic doses. Since L-lysine-d-amphetamine is expected to release d-amphetamine (albeit slowly) as a result of systemic metabolism, a preliminary study was performed using equimolar d-amphetamine or L-lysine-d-amphetamine in 4 dogs ( 2 dogs and 2 bitches). Results suggest that the amide prodrug is inactive and that a slow release of some d-amphetamine occurs 20 minutes after the first dose. Regarding d-amphetamine, however, the effects are less pronounced. For example, the mean arterial pressure is graphed in Fig. 43.

Consistent with previously published data (Kohlie Goldberg, 1982), small doses of d-amphetamine have been observed to have rapid effects on blood pressure. The lowest dose (0.2 02 mg / kg, equimolar to 0.5 mg / kg L-lysine-d-amphetamine) produced an acute doubling of mean arterial pressure followed by slow recovery for 30 minutes.

In contrast, L-lysine-d-amphetamine produced very little change in mean arterial pressure until about 30 minutes after injection. At the time, the pressure increased by about 20-50%. Continuous release of d-amphetamine is probably responsible for the steady and increasing blood pressure during the slant of the experiment. Subsequent injections show that d-amphetamine repeats its effects in a non-dose-dependent manner. That is, increasing the dose tenfold from the first injection produced a rise to the same maximum pressure. This may reflect the state of catecholamine levels in the nerve terminals through successive stimulation of d-amphetamine bolus injections. Note that the increase in mean arterial pressure observed after successive doses of L-lysine-d-amphetamine (Fig. 43) produces a more gradual but less intense effect. Similar results were observed in left ventricular pressure (Fig. 44). These results further confirm the significant reduction in the availability of intravenous d-amphetamine when administered as L-lysine-d-amphetamine.

As a result, the rapid onset of the pharmacological effect of d-amphetamine sought by people who inject the drug is eliminated.

Table 47 - Effects of L-lysine-d-amphetamine on cardiovascular parameters in the anesthetized dog (mean values, n = 2).

<table> table see original document page 70 </column> </row> <table>

SAP: systolic blood pressure (mmHg); MAP: mean arterial pressure (mmHg)

PAD: diastolic blood pressure (mmHg); LVP: left ventricular pressure (mmHg)

% change: percentage change of their time 0

Table 48 - Effects of d-amphetamine on cardiovascular parameters in anesthetized dog (mean values, n = 2)

<table> table see original document page 70 </column> </row> <table> <table> table see original document page 71 </column> </row> <table>

Example 18 - Pharmacodynamic (Iocomotor) Response to Amphetamine vs. L-lysine-d-amphetamine diHcl by oral administration

Sprague-Dawley rats were given free water and fasted overnight and dosed by oral gavage with 6 mg / kg of amphetamine or L-lysine-d-amphetamine containing the equivalent amount of d-amphetamine. Horizontal locomotor activity (HLA) was recorded during the light cycle using photocell reactivity cameras (San Diego Instruments). Total scores were recorded every 12 minutes throughout the test. The rats were monitored in three separate experiments for 5, 8 and 12 hours, respectively. The time counts vs. HLA for d-amphetamine vs. L-lysine-d-amphetamine are shown in Figures 45 and 46. In each experiment, the time to peak activity was delayed, and the pharmacodynamic effect was evident over a prolonged time period for L-lysine-d-amphetamine compared with d-amphetamine. Total HLA activity counts of Lys-Amp-dosed rats increased (11-41%) relative to d-amphetamine-induced rats in all three experiments.

Table 49 - Locomotor activity of rats orally administered d-amphetamine vs. L-Lysine-d-Amphetamine (5h)

<table> table see original document page 71 </column> </row> <table> <table> table see original document page 72 </column> </row> <table>

Example 19 - Pharmacodynamic Response to L-Lysine-d-Amphetamine d-Amphetamine vs diHcl by Intranasal Administration

Sprague-Dawley rats were dosed by intranasal administration with d-amphetamine or L-lysine-d-amphetamine (1.0 mg / kg). In a second group of similarly dosed animals, carboxymethyl cellulose (CMC) was added to the drug solutions at a concentration of62.6 mg / ml (approximately 2 times higher than the concentration of L-lysine-d-amphetamine and 5 times higher than d-amphetamine content). ComCMC drug mixtures were totally suspended before each dosis was administered. Locomotor activity was monitored using the procedure described in Example 18. As shown in Fig. 47 and Fig. 48, activity vs.time (1 hour or 2 hours) is shown for amphetamine / CMCvs. L-lysine-d-amphetamine and compared to that of amphetaminavs. L-lysine-d-amphetamine CMC. As noted in Fig. 47, the addition of CMC to L-lysine-d-amphetamine decreases activity response in intranasally dosed (IN) rats at levels similar to water / CMC control, whereas no effect was observed on amphetamine activity by addition of CMC. The increase in activity over the L-lysine-d-amphetamine baseline with CMC was only 9% compared to 34% for L-lysine-d-amphetamine without CMC compared to the activity observed for d-amphetamine dosed animals (Table 51 ). CMC had no observable effect on d-amphetamine activity induced by IN administration.

Table 51 - d-Amphetaminaintranasal Locomotor Activity vs. L-lysine-d-amphetamine with and without CMC

<table> table see original document page 73 </column> </row> <table>

Example 20 - Pharmacodynamic Response to L-Lysine-d-Amphetamine d-Amphetamine vs diHcl by Intravenous Administration

Sprague-Dawley rats were dosed by intravenous administration with d-amphetamine or L-lysine-d-amphetamine (1.0 mg / kg). Activity expressed as total activity counts over a three hour period is shown in Fig. 49. L-lysine-d-amphetamine-induced activity was substantially reduced, and peak-time activity was delayed. The increase in activity over the L-lysine-d-amphetamine baseline was 34% for L-lysine-d-amphetamine when compared to the activity observed for animals dosed with d-amphetamine (Table 52).

Table 52 - Total activity counts after intravenous administration of d-amphetamine vs. L-lysine-d-amphetamine

<table> table see original document page 73 </column> </row> <table> Example 21 - Reduction in toxicity of orally administered L-lysine-d-amphetamine diHcl

Three rats and three Sprague-Dawley rats per group received single oral administration of L-lysine-d-amphetamine at 0.1, 1.0, 10, 60, 100 or 1000 mg / kg (Table53). Each animal was observed for signs of detoxicity and death on Days 1-7 (with Day 1 being the day dose) and one rat / sex / group was necropsied after death (scheduled or unscheduled).

Table 53 - Dosage table for oral administration of L-lysine-d-amphetamine - toxicity test

<table> table see original document page 74 </column> </row> <table>

Key observations from this study include:

All animals in Groups 1-3 showed no observable signs in all study conduct.

All animals in Groups 4-6 exhibited increased motor activity two hours post-dose, which lasted until Day 2.

A rat dosed at 1000 mg / kg was found dead on Day2. Necropsy revealed chromodacryorrhea, chromorinorrhea, distended stomach (gas), enlarged adrenal glands, and distended edematous intestines. A total of 4 rats had varying degrees of cutaneous lesions of severity on Day 3.

A rat dosed at 1000 mg / kg was euthanized on Day 3 due to open skin lesions on the ventral dopulus.

All remaining animals were normal from Day 4 to Day 7.

Animals were observed for signs of toxicity 1, 2 and 4 hours post-dose, and once daily for 7 days after dosing, and observations were recorded in the cage. Animals found dead or sacrificed when dying were necropsied and discarded.

Cage observations and necropsy findings are summarized above. D-Amphetamine Sulphate oral LD50 is 96.8 mg / kg. For L-lysine-d-amphetamine dimesylate, although data are not sufficient to establish a lethal dose, the study indicates that the lethal dose of L-lysine-d-amphetamine is above 1000mg / kg as only one death occurred in a group of six animals. Although, for human reasons, a second animal in this dose group was euthanized on Day 3, it was considered that this animal could have fully recovered. Observations suggested drug-induced stress in Groups 4-6 which is characteristic of amphetamine detoxicity (NTP, 1990; REGISTRONIOSHI: SI1750000; Goodman et.al., 1985). All animals showed abnormal signs on Days 4-7 suggesting complete recovery at each treatment level.

The lack of data to confirm an established dosel is believed to be due to an alleged protective effect of combining amphetamine with lysine. Intact L-lysine-d-amphetamine has been shown to be inactive but to become metabolically unconjugated (d-amphetamine). Thus, at high doses, the dometabolism saturation of L-lysine-d-amphetamine in the non-conjugated form may explain the lack of observed toxicity, which was expected at doses above 100 mg / kg, which is consistent with d-sulfate. amphetamine (NTP, 1990).

The rate of d-amphetamine formation and the extent of amphetamine formation can be attributed to the reduced toxicity. Alternatively, oral absorption of L-lysine-d-amphetamine may also be saturated at such high concentrations, which may suggest low toxicity due to the limited bioavailability of L-lysine-d-amphetamine.

Example 22 - In vivo Evaluation of the Pharmacodynamic Activity of L-Lysine-d-Amphetamine DiHcl It was predicted that amphetamine acylation, as in the amino acid conjugates discussed herein, could significantly reduce the stimulatory activity of the parent drug. For example, Marvola (197 6) showed that amphetamine N-acetylation completely abolished the enhancing effects of locomotor activity in mice. To confirm that the conjugate did not act directly as a stimulant, we tested (NovaScreen, Hanover, MD) specific Lys-Amp binding. (10 '' 9 to 10 -5M) to the enorepinephrine recombinant human dopamine transport deletion sites using standard radioligand binding assays. Results (Table 54) indicate that Lys-Amp did not bind to these sites. It seems unlikely that the conjugate would retain stimulating activity in light of these results. (Marvola M. (197 6) "Effect of acetylated derivatives of some sympathomimetic amines on acutetoxicity, locomotor activity and barbiturate anesthesiatime in mice." Acta Pharmacol Toxicol (Copenh) 38 (5): 474- 89).

Table 54 - Results of radioligand binding experiments using L-lysine-d-amphetamine

<table> table see original document page 76 </column> </row> <table>

* No activity is defined when producing between -20% and 20% radioligand binding inhibition (Novascreen)

Table 55 - Percent inhibition of DAT and NET with L-lysine-d-amphetamine

<table> table see original document page 76 </column> </row> <table>

Example 2 3 - In vitro evaluation for deanfetamine release of L-lysine-d-amphetamine dimesylate "Kitchen tests" were performed in anticipation of illegal chemicals releasing amphetaminal free of amphetamine conjugate. Preferred deanfetamine conjugates are resistant to such attempts.

Initial cooking tests evaluated the deconjugated resistance of amphetamine to water, acid (vinegar) and base (baking powder and sodium bicarbonate) where, in each case, the sample was heated to boiling for 20-60 minutes.

L-lysine-d-amphetamine and GGG-Amp did not release any detectable free amphetamine.

Table 56 - In vitro Evaluation

<table> table see original document page 77 </column> </row> <table>

The stability of the amphetamine conjugate was evaluated under concentrated conditions, including concentrated HCl and ION NaOH solution at elevated temperatures. Concentrated Lys-Amp solutions were prepared in 10-fold H 2 O, diluted with concentrated HCl to a final concentration of 0.4 mg / mL and a final volume of 1.5 mL. The samples were heated in a water bath to about 90 ° C for 1 hour, cooled to 20 ° C, neutralized and analyzed by free d-amphetamine HPLC. The results suggest that only a minimal amount of d-amphetamine is released under these concentrated conditions.

Table 57 - Stability under concentrated conditions

<table> table see original document page 77 </column> </row> <table>

The stability of the amphetamine conjugate was evaluated under acidic conditions.

Table 58 - Acids used for stability study

<table> table see original document page 77 </column> </row> <table> <table> table see original document page 78 </column> </row> <table>

At room temperature, only a limited amount of amphetamine was released. At 90 ° C, only a limited amount of d-amphetamine was released, but the composition of L-lysine-d-amphetamine was more pronounced. This suggests that the amide bond is stable, and that the conjugate generally degrades before an appreciable amount is hydrolyzed. Under reflux conditions, the concentrated hydrochloric acid and 50% sulfuric acid released 85% and 59%, respectively, of the d-amphetamine content, but turned the drug into an undesirable acid solution. The process for recovering d-amphetamine from the acid solution also reduces yield.

In a similar test, reflux in concentrated HCl resulted in some hydrolysis after 5 hours (28%) with additional hydrolysis occurring after 22 hours (76%). Refluxing in concentrated H2 SO4 for 2 hours resulted in complete decomposition of Lys-Amp and potentially released amphetamine. As described above, recovery of amphetamine from the acid solution could further reduce yield.

The stability of amphetamine conjugate was also evaluated under basic conditions, including varying concentrations of sodium hydroxide, potassium hydroxide, sodium carbonate, ammonium hydroxide, diethylamine, ethylethylamine. The maximum release of d-amphetamine was 25.4% obtained through 3M sodium hydroxide; all other basic conditions resulted in less than 3% release.

Example 24 - Stability of L-Lysine-d-Amphetamine Dimesylate Under Treatment with Available Trade Products

The stability of L-lysine-d-amphetamine dimesylate has been evaluated under commercially available acids, bases and enzyme cocktails. For acids and bases (Table 59), 10 mg of Lys-Amp was mixed with 2 ml of each concentrated solution, and the solution was shaken at 20 ° C. For enzymatic treatment (Table 60), 10 mg Lys-Amp was mixed with 5 ml of each enzyme cocktail, and the solution was shaken at 37 ° C. Each aliquot (0.1e 24h) was neutralized and filtered before HPLC analysis. Many of the commercially available reagents contained various solvents and / or surfactants.

Unless otherwise indicated, the solutions were used directly from the container and combined with pure Lys-Amp solid. Lewis Red DevilOLye, Enforcer DrainCare®Septic Treatment (septic treatment) and Rid-X®Septic Treatment (septic treatment) were prepared as saturated solutions in H2O. Enzymes used were purchased from Sigma and directly dissolved in water (3 mg / ml pepsin, 10 mg / ml pancreatin, 3 mg / mlpronase, 3 mg / ml esterase), while enzyme-containing nutraceuticals such as Omnigest® and VitaminMym ® were first either ground or open (1 tablet or capsule per 5 ml H2O).

Commercial acids and bases were ineffective in Lys-Amp hydrolysis. Only treatment with Miracle-Gro® (7% release) and 01ympic®Deck Cleaner (4% release) showed any release, but even after 24 hours, the amount of d-amphetamine was negligible.

Among the enzyme products, only pure deesterase (19% release) or pronase (24% release) mixtures successfully cleaved lysine (after 24 hours).

Table 59 - Stability of L-lysine-d-amphetamine dimesylate under treatment with commercially available acids and bases

<table> table see original document page 79 </column> </row> <table> <table> table see original document page 80 </column> </row> <table>

Table 60 - Stability of L-lysine-d-amphetamine dimesylate under treatment with commercially available enzyme cocktails.

<table> table see original document page 80 </column> </row> <table> Example 25 - Bioavailability of various peptide amphetamine conjugates (HCl salts) administered by oral, intranasal and intravenous routes

Oral administration: Sprague-Dawley rats were given free water and fasted overnight and dosed by oral gavage with amphetamine or amino acid-amphetamine conjugates containing the equivalent amount of amphetamine.

Intranasal administration: Sprague-Dawley rats were dosed by intranasal administration with comanfetamine or lysine-amphetamine (1.8 mg / kg).

The relative in vivo performance of various amine-amphetamine compounds is shown in Fig. 50 - Fig. 58 and summarized in Table 61. The intranasal amphetamine bioavailability of Ser-Amp has been reduced to some degree relative to free amphetamine. However, this compound was not equivalent to amphetamine by oral administration. Phenylalanine was bioequivalent with comanfetamine via the oral route, but there was little or no reduction in availability via parenteral routes of administration. Gly3-Amp had nearly equal oral bioavailability (90%) accompanied by a reduction in Cmax (74%). In addition, Gly3-Amp showed a reduction in the availability of amphetamine via the intranasal and intravenous routes. TABLE 61

<table> table see original document page 82 </column> </row> <table> Several amino acid amphetamine conjugates had comparable oral bioavailability (80-100%) to d-amphetamine. Lys, Gly, and Phe conjugates, for example, demonstrated oral bioavailability similar to that of the original drug. Dipeptide prodrugs generally showed lower bioavailability than their amino acid analogs, and compostostripeptides showed no noticeable trend.

Several amphetamine amino acid conjugates showed reduced parenteral bioavailability.

Preferred conjugates, such as Lys-Amp, exhibit oral as much bioavailability as d-amphetamine with reduced parenteral bioavailability compared to d-amphetamine.

Example 26 - Reduced oral max. Of d-amphetamine conjugates

Sprague-Dawley rats were given free water, fasted overnight, and dosed by oral gavage with amphetamine conjugate or de-amphetamine sulfate. All doses contained equivalent amounts of d-amphetamine base. Plasma d-amphetamine concentrations were measured by ELISA (Amphetamine Ultra, 109319, Neogen, Corporation, Lexington, KY). The assay is specific for d-amphetamine with only minimal reactivity (0.6%) occurring for the main d-amphetamine metabolite (para-hydroxy-d-amphetamine). Plasma d-amphetamine and L-lysine-d-amphetamine concentrations were measured by LC / MS / MS as indicated in the examples.

Example 2 7 - Reduced intranasal bioavailability (AUCe Cmax) of d-amphetamine conjugates

Sprague-Dawley rats were given free water and dosed with 0.2 ml of water containing amphetamine conjugate or d-amphetamine sulfate in the nasal ducts. All doses contained equivalent amounts of d-amphetamine base. Plasma d-amphetamine concentrations were measured by ELISA (Amphetamine Ultra, 109319, Neogen, Corporation, Lexington, KY). The assay is specific for d-amphetamine with only minimal reactivity (0.6%) occurring for the main d-amphetamine metabolite (para-hydroxy-d-amphetamine). Plasma d-amphetamine and L-lysine-d-amphetamine concentrations were measured by LC / MS / MS as indicated in the examples.

Example 2 8 - Reduced intravenous bioavailability (AUCe Cmax) of d-amphetamine conjugates

Sprague-Dawley rats were given free water and doses were administered by intravenous injection and 0.1 ml caudal water containing deanfetamine or d-amphetamine sulfate conjugate. All of these contained equivalent amounts of d-amphetamine base. Plasma concentrations of d-amphetamine were measured by ELISA (Amphetamine Ultra, 109319, Neogen, Corporation, Lexington, KY). The assay is specific for d-amphetamine with only minimal reactivity occurring (0.6%) of the major metabolite of d-amphetamine (parahydroxy-d-amphetamine). At

Plasma concentrations of d-amphetamine and L-lysine-d-amphetamine were measured by LC / MS / MS as indicated in the examples.

Example 2 9 - Binding of Amphetamine to a Variety of Chemical Depositions

The above examples demonstrate the use of a deanfetamine conjugate in a chemical moiety, such as an amino acid, which is useful in reducing the potential for overdose while maintaining its therapeutic value. The effectiveness of amphetamine binding to a chemical moiety has been demonstrated by binding amphetamine to lysine (K), although the above examples are for illustration purposes only. Amphetamine binding is any chemical moiety (i.e. peptides, glycopeptides, carbohydrates, nucleosides, or vitamins) as described below by similar procedures using the following representative materials.

Synthetic Examples of Amphetamine:

Gly2-Amp Synthesis

Gly2-Amp was synthesized by a similar method except that the amino acid starting material was Boc-Gly-Gly-OSu.

Glu2-Phe-Amp Synthesis

Glu2-Phe-Amp was synthesized by a similar method except that the amino acid starting material was Boc-Glu (OtBU) -Glu (OtBu) -OSu and the pharmacological department conjugated was Phe-Amp (see synthesis of Phe-Amp). Amp).

His-Amp synthesis

His-Amp was synthesized by a similar method except that the amino acid starting material was Boc-His (Trt) -OSu.

Lys-Gly-Amp Synthesis

Lys-Gly-Amp was synthesized by a similar method except that the amino acid starting material was Boc-Lys (Boc) -OSu and the starting pharmacological conjugate was Gly-Amp (see Gly-Amp synthesis).

Lys-Glu-Amp Synthesis

Lys-Glu-Amp was synthesized by a similar method except that the amino acid starting material was Boc-Lys (Boc) -OSu and the starting pharmacological conjugate was Glu-Amp.

Glu-Amp Synthesis

Glu-Amp was synthesized by a similar method except that the amino acid starting material was Boc-Glu (OtBU) -OSu.

Synthesis of (d) -Lys- (1) -Lys-Amp

(d) -Lys- (1) -Lys-Amp was synthesized by a similar method except that the amino acid starting material was Boc- (d) -Lys (Boc) - (1) -Lys (Boc) -OSu. .

Gulonic Acid-Amp Synthesis

Gul-Amp was synthesized by a similar method except that the carbohydrate starting material was gulonic acid-Osu.Example 30 - No detection of L-lysine-d-amphetamine diHCl in brain tissue after oral administration

Sprague-Dawley rats were given free water, fasted overnight, and dosed by oral gavage with L-lysine-d-amphetamine or de-amphetamine sulfate. All doses contained equivalent amounts of d-amphetamine base. As shown in Fig. 59, similar levels of d-amphetamine were detected in serum as well as brain tissue following administration of d-amphetamine sulfate or L-lysine-d-amphetamine. L-lysine-d-amphetamine d-amphetamine showed a sustained presence in the brain compared to d-amphetamine sulfate d-amphetamine levels. L-lysine-d-amphetamine conjugate was present in appreciable quantities in serum, but was not detected in brain tissue indicating that the conjugate does not cross the blood-brain barrier to access the central nervous system site of action.

Example 31 - Pharmaceutical Composition of L-Lysine-D-Amphetamine Dimesylate

A gelatin capsule dosage form has been prepared with three dosage strengths. The hard gelatin capsules were imprinted with the inscription NRP104 and the dosage strength. The capsule filler contains a white to off-white, finely divided powder of uniform appearance. TABLE 62 - COMPOSITION OF L-LYSINE-D-AMPHTAMINE DIMESILATE CAPSULES

<table> table see original document page 87 </column> </row> <table> Other thinners, disintegrants, coloring agents, etc. can be used. Similarly, a specific ingredient may be used to fulfill a function other than those listed above.

The pharmaceutical composition was prepared by grinding defragmented L-lysine-d-amphetamine (size 20 mesh) with microcrystalline cellulose. The sieve mixture was passed through 30 mesh and then mixed with croscarmellose sodium. Previously sieved magnesium stearate (30 mesh) was added, and the composition mixed until it became uniform to form a capsule charge.

Example 32 - Clinical pharmacokinetic evaluation and oral bioavailability of L-lysine-d-amphetamine 70-mg capsules in healthy adults under fasting conditions for 7 days.

In this simple open-label study, healthy adults aged 18 to 55 years received 70 mg L-lysine-d-amphetamine dedimesilate with 8 ounces of water once a day (7 am) for 7 consecutive days.

Patients were fasted at least 10 hours before and 4 hours after final dosing. Blood samples (7 ml) were collected in EDTA vacutainers prior to medication dosing on days 0, 1, 6 and 7 (tomorrow) and at 16 time points (hours 0.5, 1, 1.5, 2, 3 , 4, 5, 6, 7, 8, 10, 12, 16, 24, 48 and 72) after final dosing on day 7. Immediately after sample collection, the vacutainer tubes were centrifuged at 3000 rpm at 4 ° C for 10 minutes; within 1 hour of collection they were stored at -20 ° C. Plasma samples were analyzed for L-lysine-d-amphetamine and d-amphetamine using a validated LC / MS / MS method.

At dose 5, d-amphetamine reached constant state.

After dose 7, the average AUC50 was 1113 ng.h / ml, AUCo-00era was 1453 ng.h / ml, average Cmax was 90.1 ng.h / ml, and MeanTime was 3.68 hours. See Table 63 and Fig.60. Comparatively, extended-release amphetamine salts exhibit a Tmax of 5.8 hours and AUCo-o of 853ng.h / ml after an overnight fast. J.F.Auiler etal., "Effect of food on early drug exposure from extended-release stimulants: results from Concerta, Adderall XR Food Evaluation (CAFE) study", Curr Med ResOpin 18: 311-316 at 313 (2002).

The intact L-lysine-d-amphetanine was rapidly converted to d-amphetamine. After dose 7, the mean AUC0-24 was 60.66 ng.h / ml, and the AUC0-24 was 61.0 6 ng.h / ml.

See Table 63 and Fig. 60. In addition, the mean Cmax was 47.9 ng.h / L and the mean Tmax was 1.14 hours for intact L-lysine-d-amphetamine. L-lysine-d-amphetamine was completely eliminated within approximately 6 hours.

There were no gender differences in systemic exposure to d-amphetamine, although Cmax was 12% higher in men after normalization by body weight.

The multidose pharmacokinetic profile of deliberate d-amphetaminal drug prodrug L-lysine-d-amphetamine is compatible with prolonged release properties. Adverse events that occurred in this scenario are consistent with other stimulants and suggest that L-lysine-d-amphetamine70 mg is well tolerated.

Table 63 - Steady-state pharmacokinetic parameters (n = ll)

<table> table see original document page 89 </column> </row> <table> <table> table see original document page 90 </column> </row> <table>

Example 33 - Clinical pharmacokinetic evaluation and oral availability of L-lysine-d-amphetamine dimesylate compared to long-acting amphetamine products Adderall XR® and Dexedrine Spansule® used in the treatment of ADHD.

Table 64 - Treatment and dosage groups for clinical pharmacokinetic evaluation of L-lysine-d-amphetamine compared with Adderall XR®-or Dexedrine Spansule®.

<table> table see original document page 90 </column> </row> <table>

A clinical evaluation of the pharmacokinetics and oral bioavailability of L-lysine-d-amphetamine in humans was performed. L-lysine-d-amphetamine was administered orally at doses approaching the dossor end (25 mg) and the higher dose end (75 mg) of the therapeutic based on the d-amphetamine base content. In addition, the larger dose was compared to doses of Adderall XR® (Shire) or Dexedrine Spansule® (GlaxoSmithKline) containing amphetamine base equivalent to the higher dose of L-lysine-d-amphetamine. Treatment groups and doses are summarized in Table64. All levels below the quantifiable limit (blq <0.5 ng.ml) were treated as zero for pharmacokinetic analysis.

The concentrations of d-amphetamine and intact L-lysine-d-amphetamine conjugate following administration of low and high dose L-lysine-d-amphetamine for each individual subject as well as pharmacokinetic parameters are presented in Table 65-Table 70. Amphetamine concentrations following administration of Adderall XR® or Dexedrine Spansu-le® for each individual subject, as well as pharmacokinetic parameters are presented in Table 69 and Table 70, respectively. Time-concentration curves showing intact conjugate of L-lysine-d-amphetamine and d-amphetamine are shown in FIG. 61 and Fig. 62. Prolonged release of d-amphetamine from L-lysine-d-amphetamine was observed for both doses and pharmacokinetic parameters (Cm ^ and AUC) were dose proportional when lower and higher dose results were compared. (Fig. 61 and Fig.62). Significant levels of d-amphetamine were not observed until half an hour after administration. Only small amounts (1.6 and 2.0 percent total drug absorption, respectively at doses of 25 and 75 mg; AUCinf-molar base) of intact L-lysine-d-amphetamine conjugate were detected with peak levels. about one hour (Table 66 and Table 68). The small amount of absorbed intact conjugate was rapidly and completely eliminated, with no detectable concentrations present within five hours, even at the highest dose.

In a crossover design (identical subjects received doses of Adderall XR® after a 7 day rest period), the higher L-lysine-d-amphetamine dose was compared with an equivalent dose of Adderall XR®. Adderall® is a once daily prolonged-release treatment for ADHD containing a mixture of d-amphetamine and 1-amphetamine salts (equal amounts of d-amphetamine sulfate, d- / 1-amphetamine sulfate, d-amphetamine sulfate). amphetamine and d-1-amphetamine aspartate). One dose of extended-release Dexedrine Spansule® (containing prolonged-release d-amphetamine sulphate formulation) was also included in the study. As observed in pharmacokinetic studies in rats, oral administration of L-lysine-d-amphetamine resulted in d-amphetamine concentration-time curves similar to those for Adderall XR® and

Dexedrine Spansule® (Fig. 63 and Fig. 64). D-amphetamine bioavailability (AUCinf) following administration of L-lysine-d-amphetamine was approximately equivalent to both extended-release amphetamine products (Table 71).

Over the twelve hour period, typically the time required for effective once-daily ADHD treatment, the bioavailability of L-lysine-d-amphetamine was approximately equivalent to that of Adderall XR® (d-amphetamine plus 1-amphetamine levels) and more. than twenty percent larger than that of Dexedrine Spansule®. Based on the results of this clinical study, L-lysine-d-amphetamine could be an effective once-daily treatment for ADHD. In addition, L-lysine-d-amphetamine produced similar pharmacokinetics in humans and animal models, ie delayed release of d-amphetamine resulting in prolonged release kinetics. Based on these observations, L-lysine-d-amphetamine also has abuse-resistant properties in humans. <table> table see original document page 93 </col> </row> <table> <table> table see original document page 94 < / column> </row> <table> TABLE 66

<table> table see original document page 89 </column> </row> <table> TABLE 66 (cont'd)

<table> table see original document page 89 </column> </row> <table> TABLE 67

<table> table see original document page 89 </column> </row> <table> <table> table see original document page 98 </column> </row> <table> <table> table see original document page 99 < / column> </row> <table> TABLE 68 (CONT.)

<table> table see original document page 89 </column> </row> <table> <table> table see original document page 101 </column> </row> <table> <table> table see original document page 102 < / column> </row> <table> <table> table see original document page 103 </column> </row> <table> <table> table see original document page 104 </column> </row> <table> <table> table see original document page 105 </column> </row> <table> Example 34 - Clinical pharmacokinetic evaluation and oral availability of L-lysine-d-amphetamine dimesylate

In pediatric patients (6-12 years) with ADHD, the amphetamine Tmax was approximately 3.5 hours after single dose oral administration of L-lysine-d-amphetamine dimesylate 30 mg, 50 mg or 70 mg after an eight o'clock breakfast overnight. See Fig. 65. The Tmax of L-lysine-d-amphetamine dimesylate was approximately 1 hour. The linear pharmacokinetics of d-amphetamine following single-dose oral administration of L-lysine-d-amphetamine dedimesilate has been established at a dose range of 30 mg to 70 mg in children.

Table 72 - Pharmacokinetic Parameters of L-Lysine-D-Amphetamine d-Amphetamine and D-Amphetamine

<table> table see original document page 106 </column> </row> <table>

There is no expected steady-state accumulation of d-amphetamine in children with ADHD, and no accumulation of L-lysine-d-amphetamine after-dosing once a day for 7 consecutive days.

Food does not affect the degree of absorption of d-amphetamine in healthy adults following single-dose oral administration of 70 mg L-lysine-d-amphetamine dimesylate capsules, but delays Tmax by approximately 1 hour (3.7 hours) fasting at 4.72 hours after high fat meal). After an 8-hour fast, the degree of absorption of d-amphetamine following oral administration of L-lysine-d-amphetamine dimesylate in solution and in the form of intact capsules was equivalent. There were no apparent differences between men and women on exposure as measured by Dose-normalized C max and AUC, although the range was higher in children than in adults. This is a consequence of the significant correlation between dose-normalized Cmax and AUC and body weight and thus the differences are due to the higher mg / kg doses given to children. There were no apparent differences in T1 / 2 between men and women, and no apparent relationship between ti / 2 and age or body weight.

Representative results of clinical pharmacokinetic evaluation are shown in Fig. 66 (AUC), Fig. 67 (Cmax) and Fig. 68 (Tm4x)

Example 35 - Efficacy of L-Lysine-D-Amphetamine Dimesylate in Pediatric Clinical Trials

Efficacy of L-lysine-d-amphetamine dimesylate was established in a randomized, double-blind, placebo-controlled, parallel-group study conducted with 6-12 year-olds (N = 290) who met DSM-IV criteria for ADHD. (of the combined type or the hyperactive-impulsive type). Patients were randomized to fixed-dose treatment groups receiving final doses of 30, 50 or 70 mg L-lysine-d-amphetamine dimesylate or placebo once daily in the morning for four weeks. For patients randomized to 50 and 70 mg L-lysine-d-amphetamine dedimesilate, dosage was increased by forced titration. Significant improvements in ADHD signs and symptoms, as rated by investigators (ADHD Classification Scale; ADHD-RS) and parents (Connorde Parent Rating Scale; CPRS), have been demonstrated for all doses of L-lysine-d-amphetamine dimesylate. compared to placebo, for all four weeks, including the first week of treatment, for all patients treated with L-lysine-d-amphetamine dimethylsilate were receiving a dose of 30 mg / day. Further improvement in dose response was demonstrated in the 50 and 70 mg groups, respectively. Patients treated with L-lysine-d-amphetamine dimesylate showed significant improvements, as measured by CPRS scores, in the morning (-10 morning), after lunch (~ 14h) and in the afternoon (~ 18h) compared with patients treated with CPRS. placebo, demonstrating efficacy throughout the day. The results of the primary efficacy analysis, the change from baseline total score to the end point for the ITT population, are shown in Fig. 69.

Efficacy was also measured by SKAMP score. A total of 52 children aged 6 to 12 years who met the DSM-IV criteria for ADHD (combined or hyperactive-impulsive type) were admitted to a randomized, placebo-controlled, cross-blind study.

Patients were randomized to receive optimal fixase doses of L-lysine-d-amphetamine (30, 50, 70 mg) .Adderall XR® (10, 20, or 30 mg) or placebo once daily in the morning for 1 week to each treatment). The primary efficacy endpoint in this study was the KAMP-behavior score (Swanson, Kotkin, Agler, M.Flynn, and Pelham rating scale). Both L-lysine-d-amphetamine and Adderall XR® were highly effective compared to placebo. The significant effects of L-lysine-d-amphetamine occurred 2 hours after the morning dose and continued throughout the last assessment, 12 hours after the morning dose, compared with placebo, providing a 12 hour duration of donation. See Figure 70.

Example 3 6 - Potential for L-Lysine-d-Amphetaminaintravenous Abuse

L-lysine-d-amphetamine 50 mg, d-amphetamine 20 mg and placebo were administered intravenously for 2 minutes at 48 hour intervals to 9 stimulant abusers in a double-blind crossover design for potential abuse assessment. The drugs were administered according to 3x3 balanced Latin squares. Each dosing day, vital sign measurements, and subjective and behavioral effects were assessed as questionnaires before dosing and at 0.5, 1, 1.5, 2, 3, 4.5, 6, 9, 12, 16, and 24 hours after dosing. . At these hours and at 5 minutes, a blood sample (5 ml) was taken to determine d-amphetamine levels.

For d-amphetamine, the mean plasma peak level of77.7 ng / ml d-amphetamine occurred at 5 minutes and then decreased rapidly. Administration of d-amphetamine produced expected effects similar to d-amphetamine with medium peak responses within 15 minutes. The mean maximum response to d-amphetamine in the primary variable "Subject Liking VAS" was significantly higher than oplacebo (p = 0.01).

For L-lysine-d-amphetamine, the mean peak plasma level of 3 3.8 ng / ml d-amphetamine occurred at 3 hours and remained at this level throughout the 4 hour observation. L-lysine-d-amphetamine produced subjective behavioral effects similar to vital esinal d-amphetamine with mean peak responses at 1 to 3 hours. For the "Subject Liking VAS" primary variable, the response was no greater than placebo (p = 0 , 29). Changes in blood pressure after L-lysine-d-amphetamine were significant.

At the end of the study, subjects were asked which treatment they would undergo again. Six subjects chose d-amphetamine 20 mg, two subjects did not choose any treatment, and one subject chose L-lysine-d-amphetamine 50 mg. In summary, L-lysine-d-amphetamine 50 mg did not cause euphoria or subjective effects similar to amphetamine, although there was a late occurrence of increased blood pressure. Findings suggest that L-lysine-d-amphetamine itself is inactive. After 1 to 2 hours, L-lysine-d-amphetamine is converted to d-amphetamine. When administered intravenously, L-lysine-d-amphetamine had significantly lower potential for abuse than immediate release of d-amphetamine containing an equal amount of d-amphetamine base.

Example 3 7 - Preliminary Evaluations of L-Lysine-d-Amphetamine Reduced Abuse Potential vs. d-amphetamine in healthy adults with a history of stimulant abuse This randomized, single-blind, double-blind, dose-escalating study used pharmacokinetic parameters to obtain preliminary potential abuse assessments for L-lysine-d-amphetamine (30-150 mg) vs. d-amphetamine sulfate (40 mg) and placebo in adult adults who met DSM-IV criteria for stimulant abuse. Subjects were divided into 3 groups of 4 patients each; all received single doses of L-lysine-d-amphetamine at least 48 hours apart, d-amphetamine sulfate (40 mg) and randomly dispersed placebo. Group 1 received doses of L-lysine-d-amphetamine of 30, 50, 70, 100 mg; group 2 received doses of 50, 70, 100, 130 mg; and group 3 received doses of 70,100, 130 and 150 mg.

The d-amphetamine AUCiast during the first 4 hours was substantially lower with 100 mg L-lysine-d-amphetamine (165.3-213.1 ng / ml) vs. 40 mg d-amphetamine245.5-316.8 ng / ml). Cmax and AUCiast increased with the dose to 30-130 mg of L-lysine-d-amphetamine, attenuating between 130 mg and 150 mg. Tmax ranged from 3.78-4.25h with L-lysine-d-amphetamine vs. d-amphetamine sulfate (1.88-2.74). The half-life of L-lysine-d-amphetamine (range, 0.44-0.7 6h) indicated rapid clearance. Adverse reactions were mild in severity, without significant changes in vital signs or ECG parameters. L-lysine-d-amphetamine had a slower release of d-amphetamine compared to d-amphetamine sulfate. At doses as high as 150 mg, there seems to be attenuation of the maximum concentration, suggesting higher L-lysine-d-amphetamine kinase will not lead to further increases in Cmax and AUCiast. These results suggest a consistent drug profile with reduced potential for abuse.

It will be understood that the specific embodiments of the invention shown and described herein are for example purposes only. Various variations, alterations, substitutions and equivalents will occur to those skilled in the art without departing from the spirit and scope of the invention. In particular, the terms used in this application should be read comprehensively in light of similar terms used in related requests. Accordingly, it is intended that all the object described herein and shown in the accompanying drawings be considered as illustrative only, and not restrictive, and that the scope of the invention be solely determined by the appended claims.

Claims (41)

Method for treating narcolepsy, characterized in that it comprises administering a compound or salt thereof of formula III: wherein A is an amphetamine dextroisomer; X1 is an L- amino acid: each X is independently a chemical moiety; eη is an increment from 1 to 50. Method according to claim 1, characterized in that Xi is lysine. Method according to claim 1, characterized in that A is amphetamine, methamphetamine or methylphenidate. Method according to claim 3, characterized in that A is amphetamine. Method according to claim 4, characterized in that the compound is L-lysine-d-amphetamine. Method according to claim 5, characterized in that the compound is L-lysine-d-amphetamine dimesylate. Method according to claim 1, characterized in that the compound is administered once daily. Pharmaceutical composition for oral administration, characterized in that it comprises a prodrug-amphetamine, or a salt thereof, of the formula III: A-X1- (X) nI (III) where A is an amphetamine dextroisomer, Xi is an L-amino acid, each X is independently "a chemical moiety, and η is an increment of 1 to 50; and at least one pharmaceutical additive; wherein the pharmaceutical composition releases a therapeutically effective amount of amphetamine when the pharmaceutical composition is administered orally; The pharmaceutical composition exhibits a reduced rate of amphetamine absorption compared to unbound comanfetamine. Composition according to Claim 8, characterized in that the amphetamine prodrug is L-lysine-d-amphetamine serdimesylate. Composition according to Claim 9, characterized in that it comprises from about 10 mg to about 250 mg of L-lysine-d-amphetamine dimesylate. Composition according to Claim 10, characterized in that it comprises about 30 mg L-lysine-d-amphetamine dedimesilate. Composition according to Claim 10, characterized in that it comprises about 50 mg L-lysine-d-amphetamine dedimesilate. Composition according to Claim 10, characterized in that it comprises 70 mg L-lysine-d-amphetamine dedimesilate. Composition according to Claim 9, characterized in that the released amphetamine C max is in the range of about 80% to about 120% of a selected value, wherein said value is 53.2 ± 9.62 ng / kg. ml, -93.3 ± 18.2 ng / ml or 134 + 26.1 ng / ml. Composition according to Claim 9, characterized in that the released amphetamine T max is in the range of about 80% to about 120% of a selected value, wherein said value is 3.41 ± 1.09 hours, -3.58 ± 1.18 hours, or 3.46 ± 1.34 hours. Composition according to Claim 9, characterized in that the released amphetamine AUC is in the range of about 80% to about 120% of a selected value, wherein said value is 8451117 ng.h / ml, -1510. +242 ng.h / ml, or 21571383 ng.h / ml. Composition according to Claim 9, characterized in that it comprises from about 40% to about 90% by weight of a diluent. Composition according to Claim 17, characterized in that it comprises from about 55% to about 80% by weight of a diluent. Composition according to Claim 18, characterized in that the diluent is cellulosemicrocrystalline. Composition according to Claim 9, characterized in that it comprises from about 1% to about 10% by weight of a disintegrant. Composition according to Claim 20, characterized in that it comprises from about 1% to about 5% by weight of a disintegrant. Composition according to Claim 21, characterized in that the disintegrant seroscarmellose sodium. Composition according to Claim 9, characterized in that it comprises less than about 5% by weight of a lubricant. Composition according to Claim 23, characterized in that it comprises from about 1% to about 1.5% by weight of a lubricant. Composition according to Claim 24, characterized in that the lubricant is magnesium stearate. Composition according to Claim 9, characterized in that it consists essentially of: a. from about 10 mg to about 250 mg L-lysine-d-amphetamine dimesylate, -b. from about 40% to about 90% by weight of cellulosemicrocrystalline c. from about 1% to about 10% by weight of croscarmelosesodium; ed. less than about 5% by weight of magnesium stearate. Composition according to Claim 26, characterized in that it consists essentially of: a. about 30 mg L-lysine-d-amphetamine dimesylate b. about 151 mg microcrystalline cellulose c. about 4.69 mg of croscarmellose sodium d. about 1.88 mg of magnesium stearate. Composition according to Claim 26, characterized in that it consists essentially of: a. about 50 mg of L-lysine-d-amphetamine dimesylate b. about 70 mg microcrystalline cellulose c. about 3.12 mg croscarmellose sodium d. about 1.88 mg of magnesium stearate. Composition according to Claim 26, characterized in that it consists essentially of: a. about 70 mg L-lysine-d-amphetamine dimesylate b. about 98 mg microcrystalline cellulose c. about 4.37 mg of croscarmellose sodium d. about 2.63 mg of magnesium stearate. Oral dosage form, characterized in that it comprises the pharmaceutical composition as defined in claim 9, wherein the pharmaceutical composition is encapsulated in a size 3 gelatin capsule. Composition according to Claim 8, characterized in that the oral bioavailability of released amphetamine is about at least 60% of AUC. Composition according to Claim 31, characterized in that the oral bioavailability of released amphetamine is about at least 80% AUC. Composition according to Claim 32, characterized in that the oral bioavailability of released amphetamine is about at least 90% AUC. Composition according to Claim 33, characterized in that the oral bioavailability of released amphetamine is about at least 95% AUC. Composition according to Claim 34, characterized in that the oral bioavailability of released amphetamine is about at least 98% of AUC. Composition according to Claim 8, characterized in that the parenteral bioavailability of released amphetamine is less than about 70% AUC. Composition according to Claim 36, characterized in that the parenteral bioavailability of released amphetamine is less than about 50% AUC. Composition according to Claim 37, characterized in that the parenteral bioavailability of released amphetamine is less than about 15% AUC. Composition according to Claim 38, characterized in that the parenteral bioavailability of released amphetamine is less than about 10% AUC. Composition according to Claim 39, characterized in that the parenteral bioavailability of released amphetamine is less than about 1% AUC. Composition according to Claim 8, characterized in that the oral bioavailability of released amphetamine is about at least 60% AUC and the parenteral bioavailability of amphetamine released is less than about 15% AUC.