JP2008535860A - Abuse-resistant amphetamine prodrug - Google Patents

Abstract

The present invention describes compounds and compositions comprising a chemical moiety covalently linked to amphetamine and methods of using the compounds and compositions. These compounds and compositions are useful for reducing or preventing amphetamine abuse and overdose. These compounds and compositions find certain uses in providing abuse-resistant alternative therapies for certain diseases such as attention deficit hyperactivity disorder (ADHD), ADD, narcolepsy and obesity. The oral bioavailability of amphetamine is maintained at a therapeutically effective dose. Higher doses substantially reduce bioavailability, thus providing a way to reduce the possibility of oral abuse. Furthermore, the compounds and compositions of the present invention reduce the bioavailability of amphetamine by parenteral routes such as intravenous or intranasal administration, further limiting its potential for abuse.
[Selection] Figure 62-B

Description

  The present invention relates to amphetamine compounds and specifically to amphetamine prodrugs comprising amphetamine covalently linked to a chemical moiety. The present invention also relates to pharmaceutical compositions comprising the amphetamine compound and methods for making, delivering and using the amphetamine compound.

Cross-reference of related applications This application is based on the applications of Patent Documents 1 and 2 filed on April 8, 2005, the application of Patent Document 3 filed on May 16, 2005, and the application filed on January 6, 2006. No. 119 of the United States Patent Act, which is based on an application related to US Pat. Claim priority of (e). This application is a continuation-in-part of the application related to Patent Document 7 filed on June 1, 2004, but the application itself related to Patent Document 7 is an application filed on Patent Document 8 filed on February 22, 2002. And a continuation-in-part of the application related to Patent Document 10 filed on Feb. 24, 2003, claiming priority based on the application filed on Mar. 7, 2002 and the application related to Patent Document 9 filed on March 7, 2002. An application relating to Patent Document 7 is also based on the US Patent Law Section 119 based on an application related to Patent Document 11 filed on May 29, 2003 and an application related to Patent Document 12 filed on May 5, 2004. Claim priority of e). The contents of all the above applications are incorporated herein by reference in their entirety.
US Provisional Application No. 60 / 669,385 US Provisional Application No. 60 / 669,386 US Provisional Application No. 60 / 681,170 US Provisional Application No. 60 / 756,548 US Provisional Application No. 60 / 759,958 US patent application Ser. No. 10 / 857,619 US patent application Ser. No. 10 / 858,526 US Provisional Application No. 60 / 358,368 US Provisional Application No. 60 / 362,082 International Application PCT / US03 / 05525 Specification US Provisional Application No. 60 / 473,929 US Provisional Application No. 60 / 567,801

Amphetamines have been used as pharmaceuticals to stimulate the central nervous system (CNS) and treat a variety of diseases including attention deficit hyperactivity disorder (ADHD), obesity and narcolepsy. In ADHD children, powerful CNS stimulants have been used for decades as drug treatments administered alone or as adjuncts to behavioral therapy. Methylphenidate (Ritalin®) was the most frequently prescribed stimulant, but the original prototype of that class, amphetamine (alpha-methylphenethylamine), has been used for some time and is increasingly used in recent years (Non-Patent Document 1).
Bradley C, Bowen M, “Amphetamine (benzedrine) thermal of children's behavioral disorders.” American Journal of Orthochiatry 41: 92-103 (19-103).

  Amphetamines, including amphetamine derivatives and analogs due to their stimulating effects, are prone to abuse. Over time, the user may become dependent on the drugs and their physical and psychological effects, even when these drugs are used for regular therapeutic purposes. Regular amphetamine users who develop drug resistance are particularly prone to accidental addicts because they increase their doses to combat increased resistance to prescribed drugs. In addition, if the individual self-administers the drug inappropriately in excess of the prescribed amount, or changes the product or route of administration (such as inhalation (such as nasal inhalation), injection and smoking) In some cases, this can lead to an immediate release of larger amounts of active agent than prescribed. When ingested in amounts greater than the prescribed dose, amphetamines can temporarily cause a feeling of uplift, a sense of increased energy, and mental arousal.

  Recent new developments in the abuse of prescription drug products increase concerns about the abuse of amphetamine prescribed for ADHD. The National Survey on Drug Use and Health (NSDUH) estimates that in 2003, 1.2 million Americans over 12 years of age abused stimulants such as amphetamine. The high potential for abuse classifies amphetamines into the Schedule II state described in the Regulatory Substances Act (CSA). Schedule II classification is provided for drugs that have an approved medical use but are most likely to be abused.

  Sustained release formulations of amphetamines, such as Adderall XR®, may be abused compared to single dose tablets because each tablet of the formulation contains a high concentration of amphetamine. large. Substance abusers can take high doses of amphetamine that start working quickly by inhaling the powdered crushed tablets from the nose or by dissolving the powder in water and injecting it There are cases. Sustained release formulations may have irregular drug release.

Additional information about amphetamine and abuse of amphetamine may be found in US Pat.
US Patent Application Publication No. 2005/0054561 (US Patent Application No. 10 / 858,526) Specification

  There is a need for additional amphetamine compounds, particularly abuse-resistant amphetamine compounds. There is a further need for amphetamine pharmaceutical compositions that provide sustained release and sustained therapeutic effects.

BRIEF DESCRIPTION OF THE FIGURES FIG. FIG. 5 shows the synthesis of peptide amphetamine conjugate.

  FIG. It is a figure which shows the synthesis | combination of a ricin amphetamine dimesylate.

  FIG. It is a figure which shows the synthesis | combination of a ricin amphetamine hydrochloride.

  FIG. It is a figure which shows the synthesis | combination of a serine amphetamine conjugate.

  FIG. FIG. 2 shows the synthesis of phenylalanine amphetamine conjugate.

  FIG. FIG. 3 shows the synthesis of a triglycine amphetamine conjugate.

  FIG. It is a graph which shows the plasma density | concentration of d-amphetamine from the rat individual | organism | solid which was orally administered d-amphetamine or L-lysine-d-amphetamine hydrochloride.

  The following figures (Figures 8-16) represent the results obtained from studies of oral administration of rats to d-amphetamine sulfate or L-lysine-d-amphetamine dimesylate (ELISA analysis).

  FIG. 2 is a graph showing plasma concentration of d-amphetamine (with a dose of 1.5 mg / kg d-amphetamine base).

  FIG. 2 is a graph showing plasma concentration of d-amphetamine (with a dose of 3 mg / kg d-amphetamine base).

  FIG. 2 is a graph showing plasma concentration of d-amphetamine (with a dose of 6 mg / kg d-amphetamine base).

  FIG. 2 is a graph showing plasma concentration of d-amphetamine (with a dose of 12 mg / kg d-amphetamine base).

  FIG. 2 is a graph showing plasma concentration of d-amphetamine (with a dose of 30 mg / kg d-amphetamine base).

  FIG. 2 is a graph showing plasma concentration of d-amphetamine (with a dose of 60 mg / kg d-amphetamine base).

FIG. Percentage of bioavailability of L-lysine-d-amphetamine dimesylate compared to d-amphetamine sulfate at doses 1.5, 3, 6, 12, 30 and 60 mg / kg d-amphetamine base ( AUC and C _max ).

  FIG. FIG. 3 is a graph showing plasma concentration of d-amphetamine at 30 minutes after administration versus a gradual increase in dose of d-amphetamine base.

  FIG. 2 is a graph showing plasma concentration of d-amphetamine (with a dose of 60 mg / kg d-amphetamine base).

  FIG. Shows plasma concentration of d-amphetamine (ELISA analysis) following intranasal administration of L-lysine-d-amphetamine hydrochloride or d-amphetamine sulfate (with a dose of 3 mg / kg d-amphetamine base) to rats. It is a graph.

  FIG. Plasma concentration of d-amphetamine after intranasal administration of L-lysine-d-amphetamine dimesylate or d-amphetamine sulfate (with a dose of 3 mg / kg d-amphetamine base) to rats (ELISA analysis) It is a graph which shows.

  FIG. Plasma concentration of d-amphetamine after intravenous bolus administration to rats of L-lysine-d-amphetamine dimesylate or d-amphetamine sulfate (with a dose of 1.5 mg / kg d-amphetamine base) It is a graph which shows (ELISA analysis).

  FIG. Dexedrine Spansur® capsules (with a dose of 3 mg / kg d-amphetamine base), ground Dexedrine Spansur® capsules, L-lysine-d-amphetamine FIG. 2 is a graph showing plasma concentration levels (ELISA analysis) of d-amphetamine after oral administration of dimesylate to rats.

  The following figures (Figures 21-30) show the results obtained from studies (LC / MS / MS analysis) of oral administration of d-amphetamine sulfate or L-lysine-d-amphetamine dimesylate to rats. To express.

  21A and 21B. 22 is a graph showing plasma concentrations of d-amphetamine in ng / mL units (FIG. 21A) and nM units (FIG. 21B) (with a dose of 1.5 mg / kg d-amphetamine base).

  22A and 22B. 22 is a graph showing plasma concentrations of d-amphetamine in ng / mL units (FIG. 22A) and nM units (FIG. 22B) (with a dose of 3 mg / kg d-amphetamine base).

  23A and 23B. 24 is a graph showing plasma concentration of d-amphetamine in ng / mL units (FIG. 23A) and nM units (FIG. 23B) (with a dose of 6 mg / kg d-amphetamine base).

  24A and 24B. 24 is a graph showing the plasma concentration of d-amphetamine in ng / mL units (FIG. 24A) and nM units (FIG. 24B) (with a dose of 12 mg / kg d-amphetamine base).

  25A and 25B. FIG. 26 is a graph showing plasma concentration of d-amphetamine in ng / mL units (FIG. 25A) and nM units (FIG. 25B) (with a dose of 60 mg / kg d-amphetamine base).

FIG. 2 is a graph showing the relative bioavailability (C _max ) of L-lysine-d-amphetamine and d-amphetamine proportional to the gradual increase in human equivalent dose.

FIG. FIG. 6 is a graph showing the relative bioavailability (AUC _inf ) of L-lysine-d-amphetamine and d-amphetamine proportional to the gradual increase in dose of d-amphetamine base.

FIG. FIG. 5 is a graph showing the relative bioavailability (AUC _inf ) of L-lysine-d-amphetamine and d-amphetamine proportional to the gradual increase in human equivalent dose.

FIG. FIG. 5 is a graph showing the relative bioavailability (C _max ) of intact L-lysine-d-amphetamine proportional to the gradual increase in human equivalent dose.

FIG. FIG. 5 is a graph showing the relative bioavailability (AUC _inf ) of intact L-lysine-d-amphetamine proportional to the gradual increase in human equivalent dose.

  FIG. Plasma concentration of d-amphetamine (LC / MS) following intranasal administration of L-lysine-d-amphetamine dimesylate or d-amphetamine sulfate (with a dose of 3 mg / kg d-amphetamine base) to rats / MS analysis).

  32A and 32B. Ng / mL units (Figure 32A) and nM units after intranasal administration of L-lysine-d-amphetamine dimesylate or d-amphetamine sulfate (with a dose of 3 mg / kg d-amphetamine base) to rats FIG. 32 is a graph showing plasma concentrations (LC / MS / MS analysis) of d-amphetamine and L-lysine-d-amphetamine in FIG. 32B.

  FIG. Plasma concentration of d-amphetamine after intravenous bolus administration to rats of L-lysine-d-amphetamine dimesylate or d-amphetamine sulfate (with a dose of 1.5 mg / kg d-amphetamine base) It is a graph which shows LC / MS / MS analysis.

  34A and 34B. Ng / mL units (Figure 34A) after intravenous administration of L-lysine-d-amphetamine dimesylate or d-amphetamine sulfate (with a dose of 1.5 mg / kg d-amphetamine base) to rats and FIG. 35 is a graph showing plasma concentration (LC / MS / MS analysis) of d-amphetamine in nM units (FIG. 34B).

  The following figures (FIGS. 35-40) show conscious male beagle dogs with d-amphetamine sulfate (with a dose of 1 mg / kg d-amphetamine base) or L-lysine-d-amphetamine dimesylate. The results obtained from oral and intravenous studies (LC / MS / MS analysis) are represented.

  FIG. It is a graph which shows the time-dependent change of the average plasma concentration of L-lysine-d-amphetamine after intravenous or oral administration (n = 3) of L-lysine-d-amphetamine.

  FIG. It is a graph which shows the time-dependent change of the plasma concentration of d-amphetamine after intravenous or oral administration (n = 3) of L-lysine-d-amphetamine.

  37A and 37B. Mean plasma of L-lysine-d-amphetamine and d-amphetamine in ng / mL units (FIG. 37A) and nM units (FIG. 37B) after intravenous administration of L-lysine-d-amphetamine (n = 3) It is a graph which shows a time-dependent change of a density | concentration level.

  38A and 38B. Mean plasma concentrations of L-lysine-d-amphetamine and d-amphetamine in ng / mL units (FIG. 38A) and nM units (FIG. 38B) after oral administration of L-lysine-d-amphetamine (n = 3). It is a graph which shows a time-dependent change of a level.

  39A and 39B. It is a graph which shows the time-dependent change of the plasma concentration for every individual of L-lysine-d-amphetamine after intravenous administration (FIG. 39A) or oral administration (FIG. 39B) of L-lysine-d-amphetamine.

  40A and 40B. It is a graph which shows the time-dependent change of the plasma density | concentration for every individual | organism | solid of d-amphetamine after intravenous administration (FIG. 40A) or oral administration (FIG. 40B) of L-lysine-d-amphetamine.

  FIG. Shows plasma concentration of d-amphetamine after oral administration to male dogs of L-lysine-d-amphetamine dimesylate or d-amphetamine sulfate (with a dose of 1.8 mg / kg d-amphetamine base). It is a graph.

  FIG. Shows plasma concentration of d-amphetamine following oral administration to female dogs of L-lysine-d-amphetamine dimesylate or d-amphetamine sulfate (with a dose of 1.8 mg / kg d-amphetamine base). It is a graph.

  FIG. It is a graph which shows the average blood pressure after the intravenous injection of L-lysine-d-amphetamine dimesylate or d-amphetamine to male dogs and female dogs.

  FIG. It is a graph which shows the left ventricular blood pressure after the intravenous injection of L-lysine-d-amphetamine dimesylate or d-amphetamine to male dogs and female dogs.

  The following figures (Figures 45-49) show the oral administration of d-amphetamine sulfate or L-lysine-d-amphetamine hydrochloride (with a dose of 6 mg / kg d-amphetamine base) to rats, Figure 3 represents the results obtained from studies of intranasal administration (with kg d-amphetamine base) and intravenous administration (with a dose of 1 mg / kg d-amphetamine base).

  FIG. It is a graph which shows the locomotor activity (time-dependent change of 5 hours) of the rat after oral administration.

  FIG. It is a graph which shows the locomotor activity (time-dependent change of 12 hours) of the rat after oral administration.

  FIG. It is a graph which shows the locomotor activity (1 hour time-dependent change) of the rat after intranasal administration.

  FIG. It is a graph which shows the locomotor activity (time-dependent change of 2 hours) of the rat after intranasal administration (used together with carboxymethylcellulose).

  FIG. It is a graph which shows the locomotor activity (time-dependent change of 3 hours) of the rat after intravenous administration.

  The following figures (Figures 50-58) represent the results obtained from oral, intranasal and intravenous studies (ELISA analysis) of rats with d-amphetamine or amphetamine conjugate hydrochloride.

  FIG. 2 is a graph showing the intranasal bioavailability of abuse-resistant amphetamine amino acids, dipeptides and tripeptide conjugates.

  FIG. 1 is a graph showing the oral bioavailability of abuse-resistant amphetamine amino acids, dipeptides and tripeptide conjugates.

  FIG. It is a graph which shows the intravenous bioavailability of the abuse-resistant amphetamine tripeptide conjugate.

  FIG. It is a graph which shows the intranasal bioavailability of the abuse-resistant amphetamine amino acid conjugate.

  FIG. It is a graph which shows the oral bioavailability of the abuse-resistant amphetamine amino acid conjugate.

  FIG. It is a graph which shows the intravenous bioavailability of the abuse-resistant amphetamine amino acid conjugate.

  FIG. It is a graph which shows the intranasal bioavailability of the abuse-resistant amphetamine tripeptide conjugate.

  FIG. It is a graph which shows the intranasal bioavailability of the abuse-resistant amphetamine amino acid and dipeptide conjugate.

  FIG. 2 is a graph showing intranasal bioavailability of an abuse-resistant amphetamine dipeptide conjugate containing D- and L-amino acid isomers.

  59A and 59B. Serum of d-amphetamine and L-lysine-d-amphetamine after oral administration to rats of L-lysine-d-amphetamine hydrochloride or d-amphetamine sulfate (with a dose of 5 mg / kg d-amphetamine base) FIG. 60 is a graph showing medium concentration (ng / mL unit, FIG. 59A) and brain tissue concentration (ng / g unit, FIG. 59B) (LC / MS / MS analysis).

  FIG. Levels of d-amphetamine and L-lysine-d-amphetamine in steady state plasma obtained from a clinical study of oral administration of 70 mg L-lysine-d-amphetamine dimesylate to humans (LC / MS / MS It is a graph which shows analysis.

  The following figures (FIGS. 61-70) represent the results obtained from a clinical study (LC / MS / MS analysis) of oral administration of L-lysine-d-amphetamine dimesylate to humans.

  61A and 61B. Plasma d-amphetamine and L-lysine for 72 hours after oral administration to humans of L-lysine-d-amphetamine (L-lysine-d-amphetamine dimesylate 25 mg containing 7.37 mg of d-amphetamine base) FIG. 61 is a graph showing the level of d-amphetamine (FIG. 61A is in ng / mL units, and FIG. 61B is in nM units).

  62A and 62B. Plasma d-amphetamine and L-lysine over 72 hours after oral administration to humans of L-lysine-d-amphetamine (75 mg L-lysine-d-amphetamine dimesylate containing 22.1 mg d-amphetamine base) FIG. 62 is a graph showing the level of d-amphetamine (FIG. 62A is in ng / mL units, and FIG. 62B is in nM units).

  63A and 63B. L-lysine-d-amphetamine (75 mg L-lysine-d-amphetamine dimesylate containing 22.1 mg d-amphetamine base) or human of Adelol XR® (35 mg containing 21.9 mg amphetamine base) FIG. 63 is a graph showing the level of d-amphetamine in plasma after oral administration to (FIG. 63A is 0-12 hours, FIG. 63B is 0-72 hours).

  64A and 64B. L-lysine-d-amphetamine (75 mg of L-lysine-d-amphetamine dimesylate containing 22.1 mg of d-amphetamine base) or dexedrine spansul (30 mg containing 22.1 mg of amphetamine base) Is a graph showing the level of d-amphetamine in plasma after oral administration to human (FIG. 64A is 0-12 hours, FIG. 64B is 0-72 hours).

  FIG. 1 is a graph showing the mean plasma concentration of d-amphetamine after oral administration under fasting conditions to pediatric patients with ADHD at a single dose of 30 mg, 50 mg and 70 mg of L-lysine-d-amphetamine dimesylate.

  FIG. Between dose-normalized d-amphetamine AUC and gender after once-daily oral administration of L-lysine-d-amphetamine dimesylate capsules to healthy adult volunteers and ADHD children It is a graph which shows the relationship.

  FIG. Maximum dose-normalized plasma concentration and sex of d-amphetamine after daily oral administration of L-lysine-d-amphetamine dimesylate capsules to healthy adult volunteers and ADHD children It is a graph which shows the relationship between.

  FIG. Maximum dose time normalized d-amphetamine concentration and gender after once-daily oral administration of L-lysine-d-amphetamine dimesylate capsules to healthy adult volunteers and ADHD children It is a graph which shows the relationship between.

  FIG. 2 is a graph showing ADHD-RS at endpoint for pediatric clinical studies.

  FIG. 2 is a graph showing SKAMP score (efficacy) versus time for a pediatric clinical study.

Detailed Description of the Invention The present invention provides amphetamine prodrugs comprising amphetamine covalently linked to a chemical moiety. The amphetamine prodrug may be a conjugate having a covalent bond. The amphetamine prodrugs are conditional bioreversible derivatives (CBDs) in that the amphetamine prodrug is preferably placed in an inactive state until oral administration releases the amphetamine from the chemical moiety. It may be characterized by being.

  In one embodiment, the present invention provides an amphetamine prodrug of Formula I.

  In Formula I, A is amphetamine.

  Each X is an independent chemical moiety.

  Each Z is an independent chemical moiety that acts as an adjuvant and is a chemical moiety that is different from at least one X.

  n is an increment from 1 to 50, preferably from 1 to 10.

  m is an increment from 0 to 50, preferably 0.

  When m is 0, the amphetamine prodrug is a compound of formula (II).

  In the chemical formula (II), each X is an independent chemical moiety.

  Chemical formula (II) may be written as chemical formula (III) to designate a chemical moiety physically bound to the amphetamine.

In chemical formula (III), A is amphetamine. X ₁ is a chemical moiety, preferably a single amino acid. Each X is an independent chemical moiety and is the same or different chemical moiety as X ₁ . n is an increment from 1 to 50.

  A or amphetamine can be either a phenethylamine derivative of a sympathomimetic agent having central nervous system stimulating activity, such as amphetamine, or any derivative, analog or salt thereof. Representative amphetamines include Adelol® amphetamine compounds, amphetamine, methamphetamine, methylphenidate, p-methoxyamphetamine, methylenedioxyamphetamine, 2,5-dimethoxy-4-methylamphetamine, 2,4,4 5-trimethoxyamphetamine and 3,4-methylenedioxymethamphetamine, N-ethylamphetamine, phenethylin, benzphetamine and chlorphentermine, actedron, actemin, adipan, and akedron ), Allodene, alpha-methyl- (±) -benzeneethanamine, alpha-methylbenzeneethanamine, alpha- Tilphenethylamine, amphetamine, amphetamine, anorexine, benzbar, benzedrine, benzylmethyl carbinamine, z, benzolone Aminopropylbenzene, beta-phenylisopropylamine, biphetamine, desoxynophedrine, dietamine, DL-amphetamine, elastonone, fenopromin and fenopromin , Finam and isoami (Isoamyne), isomine, mecodrin, monophos, mydrial, noephedrane, novidrin, obsine, obes obesine), obetolol, octedrine, octedrin, phenamine, phenedrine, alpha-methyl-phenethylamine, percommon, ropromin ), Prophetamine, and propisamine. ne), racephene, raphetamine, liner, sympamin, sympatedrin, sympatina, sympadedrin, sympadedrin ) And the like. Preferred amphetamines include methamphetamine, methylphenidate and amphetamine, with amphetamine being most preferred.

  The amphetamine may have any configuration that includes both dextrorotatory and levorotatory isomers. The dextrorotatory isomer, particularly dextroamphetamine, is preferred.

  The amphetamine is preferably an amphetamine salt. Pharmaceutically acceptable salts such as non-toxic inorganic and organic acid addition salts are known to those skilled in the art. Typical salts are 2-hydroxyethane sulfonate, 2-naphthalene sulfonate, 3-hydroxy-2-naphthoate, 3-phenylpropionate, acetate, adipate, alginate, amsonate Salt (amsonate), aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bicarbonate, bisulfate, bitartrate, borate, butyrate, calcium edetate, camphorate, camphor Sulfate, camsylate, carbonate, citrate, clavularate, cyclopentanepropionate, digluconate, dodecyl sulfate, edetate, edsylate, estolate ( estolate), esylate, ethanesulfonate, final salt (fin) arrate), glucoceptate, glucoheptanoate, gluconate, glutamate, glycerophosphate, glycolyllarsanylate, hemisulphate, heptanoate, hexafluorophosphate Acid salt, hexanoate, hexyl resorcinate, hydrabamine, hydrobromide, hydrochloride, hydroiodide, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate , Laurate, lauryl sulfonate, malate, maleate, mandelate, mesylate, methanesulfonate, methyl bromide, methyl nitrate, methyl sulfate, mucus, naphthylate ( naphthylate), Napsi Acid salt, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, palmitate, pamoate, pantothenate, pectinate, persulfate, phosphoric acid Salt, phosphoric acid diphosphate, picrate, pivalate, polygalacturonate, propionate, p-toluenesulfonate, saccharate, salicylate, stearate, basic acetate Succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, theocric acid, thiocyanate, tosylate, triethiodide, undecanoate and valerate, and these But are not limited to these. (See Berge et al. (1977) “Pharmaceutical Salts”, J Pharm. Sci. 66: 1-19.) Preferred amphetamine salts (such as, for example, L-lysine-d-amphetamine dimesylate). Mesylate.

  Certain salts may be easier to handle because they are less hygroscopic. In preferred embodiments, the amphetamine prodrug is about 0% to about 5%, about 0.1% to about 3%, about 0.25% to about 2%, or increments within that range. Has a water content (by Karl Fischer analysis). When the amphetamine prodrug is formulated in a pharmaceutical composition, the pharmaceutical composition is preferably about 1% to about 10%, about 1% to about 8%, about 2% to about 7%, or the like It has a moisture content that is an incremental number within the range.

  Throughout this application, the term “increment” defines numerical values with various accuracies, for example, to the order of 10, to the order of 1, to the order of 0.1, to the order of 0.01, etc. Used for. The increment number may be rounded to any measurable accuracy. For example, a range of 1 to 100 or an increment number within that range includes ranges such as 20 to 80, 5 to 50, 0.4 to 98, and 0.04 to 98.05.

  The amphetamine binds to one or more chemical moieties designated X and Z. A chemical moiety can be any moiety that decreases the pharmacological activity of amphetamine as compared to unbound (free) amphetamine while attached to the chemical moiety. The chemical moiety attached may be natural or synthetic. Typical chemical moieties include peptides including single amino acids, dipeptides, tripeptides, oligopeptides and polypeptides, glycopeptides, carbohydrates, lipids, nucleosides, nucleic acids, and vitamins. It is not limited. Preferably, the chemical moiety is generally recognized as safe (GRAS).

“Carbohydrate” includes sugars, starches, celluloses, and related compounds, such as (CH ₂ O) _n and C _n (H ₂ O) _n-1 , for example in said (CH ₂ O) _n n is an integer greater than 2, and n is an integer greater than 5 in the C _n (H ₂ O) _n−1 . The carbohydrate may be a monosaccharide, a disaccharide, an oligosaccharide, a polysaccharide, or a derivative thereof (such as a derivative substituted with a sulfo group or a phosphate group). Typical carbohydrates include, but are not limited to, fructose, glucose, lactose, maltose, sucrose, glyceraldehyde, dihydroxyacetone, erythrose, ribose, ribulose, xylulose, galactose, mannose, sedheptulose, neuraminic acid, dextrin and glycogen. Not.

  A “glycopeptide” is a carbohydrate linked to an oligopeptide. Similarly, the chemical moiety may be a glycoprotein, a sugar amino acid or a glycosyl amino acid. A “glycoprotein” is a carbohydrate (eg, a glycan) covalently linked to a protein. A “sugar amino 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 to an amino acid through an (O-, N-, or S-) glycosyl bond.

  “Peptide” includes a single amino acid, dipeptide, tripeptide, oligopeptide, polypeptide or carrier peptide. Oligopeptides contain from 2 to 70 amino acids.

  Preferably the chemical moiety is a peptide, specifically a single amino acid, dipeptide or tripeptide. Preferably, the peptide comprises less than 70 amino acids, less than 50 amino acids, less than 10 amino acids, or less than 4 amino acids. When the chemical moiety is one or more amino acids, the amphetamine is preferably bound to lysine, serine, phenylalanine or glycine. In another embodiment, the amphetamine is preferably bound to lysine, glutamic acid or leucine. In another embodiment, the amphetamine is conjugated to lysine and any additional chemical moiety, such as an additional amino acid. In a preferred embodiment, the amphetamine is linked to a single lysine amino acid.

  In one embodiment, the chemical moiety is 1 to 12 amino acids, preferably 1 to 8 amino acids. In another embodiment, the number of amino acids is 1, 2, 3, 4, 5, 6, or 7. In another embodiment, the molecular weight of the chemical moiety is less than about 2500 kD, more preferably less than about 1,000 kD, and most preferably less than about 500 kD.

  Each amino acid includes alanine (Ala or A), arginine (Arg or R), asparagine (Asn or N), aspartic acid (Asp or D), cysteine (Cys or C), glycine (Gly or G), glutamic acid ( Glu or E), glutamine (Gln or Q), histidine (His or H), isoleucine (Ile or I), leucine (Leu or L), lysine (Lys or K), methionine (Met or M), proline (Pro Or P), natural such as phenylalanine (Phe or F), serine (Ser or S), tryptophan (Trp or W), threonine (Thr or T), tyrosine (Tyr or Y) and valine (Val or V). It may be either the L- or D-enantiomer of an amino acid, preferably the L-enantiomer. In a preferred embodiment, the peptide comprises only naturally occurring amino acids and / or only L-amino acids. Each amino acid is aminohexanoic acid, biphenylalanine, cyclohexylalanine, cyclohexylglycine, diethylglycine, dipropylglycine, 2,3-diaminopropionic acid, homophenylalanine, homoserine, homotyrosine, naphthylalanine, norleucine, ornithine, phenylalanine (4 -Fluoro), phenylalanine (2,3,4,5,6-pentafluoro), phenylalanine (4-nitro), phenylglycine, pipecolic acid, sarcosine, tetrahydroisoquinoline-3-carboxylic acid and tert-leucine It may be a natural, non-standard or synthetic amino acid. Preferably, the synthetic amino acid having an alkyl side chain is selected from an alkyl group having 1 to 17 carbon atoms, preferably an alkyl group having 1 to 6 carbon atoms. In certain embodiments, the peptide 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 peptide is utilized as the underlying short chain amino acid sequence, with additional amino acids added to the terminus or side chain. In another embodiment, the peptide may have one or more amino acid substitutions. The substituted amino acid is preferably similar in 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, and lysine is similar to arginine. Similar, asparagine is similar to glutamine, aspartic acid is similar to glutamic acid, histidine is similar to proline, and glycine is similar to tryptophan.

  The peptide may comprise a homopolymer or heteropolymer of natural or synthetic amino acids. For example, the side chain linkage of amphetamine to the peptide may be a homopolymer or a 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, homopolymers of Glu and Leu, and heterogeneous of (Glu) _n -Leu-Ser. Polymer. In a preferred embodiment, the peptide is Lys, Ser, Phe or Gly-Gly-Gly.

  In one embodiment, the chemical moiety has one or more unbound carboxy and / or amine terminal and / or side chain functional groups in addition to the point of attachment to the amphetamine. The chemical moiety may be in such an unbound state or an ester or salt thereof.

  The chemical moiety may be covalently bonded to the amphetamine directly or indirectly through a linker. The covalent bond may include an ester bond or a carbonate bond. The binding site is typically determined by the functional groups available on the amphetamine. For example, the peptide may bind to amphetamine via the N-terminus, the C-terminus, or the amino acid side chain. For additional methods of combining amphetamine with various representative chemical moieties, each of which is incorporated herein by reference in its entirety, US patent application Ser. No. 10 / 156,527, and PCT / US03 / See 05524 and PCT / US03 / 05525.

  The amphetamine prodrug compounds described above may be synthesized as illustrated in Example 1 and FIG. Preferably further purification and / or crystallization steps are not necessarily required in order to obtain a highly pure product. In one embodiment, the purity of the amphetamine prodrug is at least about 95%, more preferably at least about 96%, 97%, 98%, 98.5%, 99%, 99.5 %, 99.9%, or the number of increments within that range. Known impurities for the synthesis of L-lysine-d-amphetamine are 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 about 2%, less than 1%, less than 0.5%, or less than 0.25%. , Less than 0.15%, less than 0.1%, less than 0.05%, or less than an increment number within that range.

  In one embodiment, the amphetamine prodrug (one of the compounds shown in the above chemical formula) may exhibit one or more of the following advantages over free amphetamine. The amphetamine prodrug may prevent overdosing due to reduced pharmacological activity when a higher dose than the therapeutic dose is administered, eg, greater than the prescribed dose. However, when the amphetamine prodrug is administered at a therapeutic dose, the amphetamine prodrug is similar in pharmacological activity to that obtained by administering unbound amphetamine such as, for example, Adelol XR®. May have. The amphetamine prodrug may also prevent abuse by exhibiting stability under conditions likely to be used by an unauthorized chemist attempting to release the amphetamine. The amphetamine prodrug is biogenic when administered via a parenteral route, such as intravenous (shooting), intranasal (snowing) and / or inhalation (smoking) routes, which are often utilized particularly in abuse. Abuse may be prevented due to reduced availability. Thus, the amphetamine prodrug may also reduce the euphoric effect associated with amphetamine abuse. Thus, the amphetamine prodrug does not follow the manufacturer's instructions such as consuming a higher dose than for the amphetamine prodrug treatment or via a parenteral route of administration. When the amphetamine prodrug is used, it may prevent and / or reduce the possibility of abuse and / or overdose.

  Use of phrases such as “decreased”, “reduced”, “diminished” or “lowered” includes at least a 10% change in pharmacological activity. Larger percentage changes are preferred for reducing the possibility of abuse and overdose. For example, the change is 25%, 35%, 45%, 55%, 65%, 75%, 85%, 95%, 96%, 97%, 98%, 99, % Or other increment numbers greater than 10%.

The use of the phrase “similar pharmacological activity” means that two compounds are substantially the same, preferably within about 30% of each other, more preferably within about 25%, within 20%, or within 10%. Curves with AUC, C _max , T _max , C _min and / or t _1/2 parameters that are within 5%, within 2%, within 1%, or within other increments of less than 30% It means to show.

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

  Preferably, the amphetamine prodrug remains inactive until the orally administered prodrug releases the amphetamine. Although there is no theoretical support, the binding of the chemical moiety can cause binding between the amphetamine and its biological target site (such as the human dopamine (DAT) and norepinephrine (NET) transporter sites). In order to reduce the amphetamine prodrug is believed to be inactive. (Hoebel, B. G., L. Hernandez, et al., “Microdialysis studies of brain 9 ediline citrine, serotonin, and dopamine release incestive behaviour.” See also.) Binding of the chemical moiety reduces the binding between amphetamine and DAT and / or NET, in part because the amphetamine prodrug is unable to cross the blood brain barrier. There is a case. The amphetamine prodrug is activated by oral administration, i.e. the amphetamine is released from the chemical moiety by hydrolysis, such as by enzymes in the stomach, intestine or serum. Since oral administration facilitates activation, activation is reduced when the amphetamine prodrug is administered via a parenteral route that is often utilized by illegal users.

  Furthermore, the amphetamine prodrug is believed to be resistant to abuse and / or overdose due to the natural gating mechanism at the site of hydrolysis, ie the gastrointestinal tract. While this gating mechanism allows the release of therapeutic amounts of amphetamine from the amphetamine prodrug, it is believed to limit the release of larger amounts of amphetamine.

  In another embodiment, the toxicity of the amphetamine prodrug is substantially less than the toxicity of unbound amphetamine. For example, in a preferred embodiment, the acute toxicity is 1 fold, 2 fold, 3 fold, 4 fold, 5 fold, 6 fold, 7 fold, 8 fold or more than oral administration of unbound amphetamine, The fatality is low by 9 times, 10 times, or the number of increments within the range.

Preferably, the amphetamine prodrug provides a serum release curve that does not increase the toxic level of the amphetamine when administered at a higher dose than the therapeutic dose. The amphetamine prodrug may exhibit reduced amphetamine absorption rate and / or increased clearance rate compared to unbound amphetamine. The amphetamine prodrug may exhibit a steady state serum release curve. While the amphetamine prodrug provides bioavailability, it is preferable to prevent either a rapid rise in C _max or an increase in serum concentration. The pharmacokinetic parameters are illustrated in the following examples, particularly the clinical pharmacokinetic examples. In one embodiment, the amphetamine prodrug provides a pharmacological activity similar to that of L-lysine-d-amphetamine dimesylate as measured clinically. For example, the pharmacological parameters (AUC, C _max , T _max , C _min and / or t _1/2 ) are preferably 80% to 125%, 80% to 120% or 85% of a given value. Or 125%, 90% to 110%, or an incremental number within that range. The range may be symmetrical, for example 85% to 105%, but should be considered not essential. For pediatric studies, the pharmacokinetic parameters of d-amphetamine released from L-lysine-d-amphetamine dimesylate are listed in Table 72.

  The amphetamine prodrug may exhibit delayed release properties and / or sustained release properties. Delayed release prevents rapid onset of pharmacological effects, and sustained release is a desirable feature for certain dosage regimes, such as once a day dosage regimes. The amphetamine prodrug may independently acquire the release profile. Alternatively, the amphetamine prodrug may be formulated as a medicament to enhance or achieve such a release profile. For example, it may be desirable to shorten the time to onset of pharmacological effects by prescribing with an immediate product.

  Accordingly, the present invention also provides a method comprising providing, administering, formulating or consuming an amphetamine prodrug. The present invention also provides a pharmaceutical composition comprising an amphetamine prodrug. Such pharmaceutical composition dosage forms may optionally enhance or achieve the desired release profile.

  In one embodiment, the present invention provides a method for treating a patient comprising administering a therapeutically effective amount of amphetamine prodrug, ie, an amount sufficient to prevent, ameliorate and / or eliminate disease symptoms. To do. These methods include, for example, attention deficit disorders and other learning disorders such as ADD and ADHD, obesity, Alzheimer's disease, amnesia and other memory disorders and memory impairments, and fibromuscular Pain, fatigue and chronic fatigue, depression, epilepsy, obsessive-compulsive disorder (OCD), rebellious behavior disorder (ODD), anxiety, resistant depression, and stroke rehabilitation Parkinson's disease, mood disorders, schizophrenia, Huntington's disease, dementia such as AIDS dementia and frontal lobe dementia, movement dysfunction, lethargy, and Pick's disease , Creutzfeldt-Jakob disease and examples Sleep disorders such as narcolepsy, cataplexy, sleep paralysis and sleep-onset hallucinations, brain damage or neurodegenerative disorders such as multiple sclerosis, Tourette syndrome and impotence, and nicotine dependence and withdrawal symptoms It may be used to treat any disease that may benefit from amphetamine-type drugs including but not limited to. Preferred indications include ADD, ADHD, narcolepsy and obesity, with ADHD being most preferred.

  The method of treatment includes combination therapy that further includes administering one or more therapeutic agents in addition to administering the amphetamine prodrug. The active ingredient may be formulated in a single dosage form or may be formulated in multiple dosage forms at once or separately. The active ingredients may be administered simultaneously or sequentially in any order. Exemplary combination therapies include administration of the agents listed in Table 1.

  “Composition” refers broadly to any composition comprising one or more amphetamine prodrugs. The composition may comprise a dry dosage form, an aqueous solution, or a sterile composition. Compositions comprising the compounds described herein may be stored in lyophilized form or may be bound to stabilizers such as carbohydrates. In use, the composition may be placed in an aqueous solution containing a salt such as NaCl, a detergent such as sodium dodecyl sulfate (SDS), and other ingredients.

  In one embodiment, the amphetamine prodrug itself exhibits a sustained release profile. Accordingly, the present invention provides pharmaceutical compositions that exhibit a sustained release profile for amphetamine prodrugs.

  In another embodiment, the sustained release profile is enhanced or achieved by including a hydrophilic polymer in the pharmaceutical composition. Suitable hydrophilic polymers include natural, partially synthetic or fully synthetic hydrophilic gums such as acacia, tragacanth gum, locust bean gum, guar gum and karaya gum, and methylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxypropyl Cellulose derivatives such as ethyl cellulose and carboxymethyl cellulose; proteinaceous substances such as agar, pectin, carrageen and alginate; hydrophilic polymers such as carboxypolymethylene; gelatin; casein; zein; bentonite; Including but not limited to magnesium aluminum silicate, polysaccharides, modified starch derivatives, and other hydrophilic polymers known to those skilled in the art. Since the hydrophilic polymer is a gel and dissolves slowly in an acidic aqueous solution, it preferably forms a gel capable of diffusing amphetamine prodrug from the gel in the stomach. When the gel then reaches a higher pH intestinal fluid, the hydrophilic polymer dissolves to a controlled amount to allow further sustained release. A preferred hydrophilic polymer is hydroxypropyl methylcellulose, such as Methocel ethers such as Methocel E10M (registered trademark, Dow Chemical Company, Midland, Mich.). Those skilled in the art will recognize a variety of structures such as bead structures and coatings useful for obtaining a specific release profile. See U.S. Pat. No. 6,913,768.

  In addition to the amphetamine prodrug, the pharmaceutical composition of the present invention further comprises one or more pharmaceutical additives. Pharmaceutical additives include diluents and bulk materials, binders and adhesives, lubricants, glidants, plasticizers, disintegrants, carrier solvents, buffering agents, colorants, flavors, It includes a wide range of substances including, but not limited to, sweeteners, preservatives, stabilizers, and other pharmaceutical additives known to those skilled in the art. For example, in a preferred embodiment, the pharmaceutical composition comprises magnesium stearate. In another preferred embodiment, the pharmaceutical composition comprises microcrystalline cellulose (such as Avicel® PH-102), croscarmellose sodium and magnesium stearate. See, for example, Table 62.

  Diluents may increase the volume of the dosage form and make it easier to handle. Exemplary diluents include lactose, dextrose, saccharose, cellulose, starch and calcium phosphate for solid dosage forms such as tablets and capsules, olive oil and ethyl oleate for soft capsules, such as suspensions. Including but not limited to water and vegetable oils for liquid dosage forms such as liquids and emulsions. Further suitable diluents include sucrose, dextrates, dextrin, maltodextrin, microcrystalline cellulose (such as Avicel®), microfine cellulose, powdered cellulose, (eg starch Pregelatinized starch (such as 1500 (Star 1500, registered trademark)), calcium phosphate dihydrate, soy polysaccharide (such as Emcosoy (registered trademark)), gelatin, silicon dioxide, calcium sulfate, calcium carbonate, Magnesium carbonate, magnesium oxide, sorbitol, mannitol, kaolin, polymethacrylate (such as Eudragit®), potassium chloride, sodium chloride and Including but not limited to talc. A preferred diluent is microcrystalline cellulose (such as Avicel® PH-102). Preferred ranges for the amount of diluent expressed in weight percentage are about 40% to about 90%, about 50% to about 85%, about 55% to about 80%, about 50% to about 60%, Incremental number within range.

  In embodiments where the pharmaceutical composition is packed into a solid dosage form such as a tablet, a binder may help hold the ingredients together. Binders include sugars such as sucrose, lactose and glucose, corn syrup, soy polysaccharides, gelatin, povidone (such as Kollidon®, Plasdon®), and Pullulan and microcrystalline cellulose, such as hydroxypropylmethylcellulose (such as Methocel®), hydroxypropylcellulose (such as Klucel®), ethylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose And cellulose derivatives such as methylcellulose, acrylic acid and methacrylic acid copolymers, carbomers (such as Carbopol®), polymers, Vinylpolypyrrolidone, polyethylene glycol (Carbowax®), pharmaceutical brighteners, alginates such as alginic acid and sodium alginate, gums such as acacia, guar gum and gum arabic, and tragacanth gum And dextrin and maltodextrin, milk derivatives such as whey, starches such as pregelatinized starch and starch paste, hardened vegetable oils, and magnesium aluminum silicate.

  For tablet dosage forms, the pharmaceutical composition is subjected to pressure from a tablet and a dye. Among other purposes, a lubricant may help prevent the composition from sticking to the surface of the tablet press and dye. Lubricants may be used to coat coating dosage forms. Lubricants are magnesium stearate, calcium stearate, zinc stearate, powdered stearic acid, glyceryl monostearate, glyceryl palmitostearate, glyceryl behenate, silica, magnesium silicate, colloidal silicon dioxide, titanium dioxide , Sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, hydrogenated vegetable oil, talc, polyethylene glycol and mineral oil. A preferred lubricant is magnesium stearate. The amount of lubricant, expressed as a percentage by weight, is preferably less than about 5%, more preferably less than about 4%, less than 3%, less than 2%, less than 1.5%, less than 1%, Less than 5% or less than the number of increments within that range.

  Glidants may improve the fluidity of unpacked solid dosage forms and improve dosing accuracy. Glidants include, but are not limited to, colloidal silicon dioxide, dry silicon dioxide, silica gel, talc, magnesium trisilicate, magnesium stearate or calcium, powdered cellulose, starch and tricalcium phosphate.

  Plasticizers include diethyl phthalate, butyl phthalate, diethyl sebacate, dibutyl sebacate, triethyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, crotic acid, propylene glycol, castor oil, triacetin, polyethylene Includes both hydrophobic and hydrophilic plasticizers such as but not limited to glycol, propylene glycol, glycerin and sorbitol. Plasticizers are particularly useful for pharmaceutical compositions comprising polymers and formulated in soft capsules and film-coated tablets. In one embodiment, the plasticizer facilitates release of the amphetamine prodrug from the dosage form.

  Disintegrants may increase the dissolution rate of the pharmaceutical composition. Disintegrants include alginates such as alginic acid and sodium alginate, carboxymethylcellulose calcium, sodium carboxymethylcellulose (such as, for example, Ac-Di-Sol®, Primerose®), and Colloidal silicon dioxide, croscarmellose sodium, crospovidone (such as Kollidon®, Plasdon®) and polyvinylpolypyrrolidone (Plazone-XL®), , Guar gum, magnesium magnesium silicate, methylcellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, and dent If, pregelatinized starch, (e.g. Explotab (Explotab, registered trademark), gum tragacanth (Primogel, R), such as a) including the sodium starch glycolate is not limited thereto. Preferred disintegrants include croscarmellose sodium and microcrystalline cellulose (such as Avicel® PH-102). Preferred ranges for the amount of disintegrant expressed as a percentage by weight include from about 1% to about 10%, from about 1% to about 5%, from about 2% to about 3%, or an increment number within that range.

  In embodiments where the pharmaceutical composition is formulated as a liquid dosage form, the pharmaceutical composition may contain 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 contain 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 colorant may be used for the purpose of improving the appearance of the pharmaceutical composition or for helping to identify the pharmaceutical composition. See US Federal Regulations, Title 21, Part 74. Typical colorants include Red No. 104 (1), Yellow No. 203, Blue No. 1, Red No. 40, Green No. 3, Yellow No. 5, and edible ink. Preferred colors for gelatin capsules are white, medium orange and light blue.

  The perfume enhances the taste and may be particularly useful for chewable tablets or liquid dosage forms. Perfumes include, but are not limited to, maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol and tartaric acid. Sweeteners include but are not limited to sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol and invert sugar.

  The pharmaceutical composition of the present invention may contain one or more kinds of preservatives and / or stabilizers in order to improve the storage stability. These include, but are not limited to, alcohol, sodium benzoate, butylated hydroxytoluene, butylated hydroxyanisole and ethylenediaminetetraacetic acid.

  Other pharmaceutical additives include gelling agents such as colloidal clays, thickeners such as gum tragacanth and sodium alginate, wetting agents such as lecithin, polysorbate and lauryl sulfate, humectants, vitamin E Antioxidants such as carotene and BHT, adsorbents, foaming agents, emulsifiers, viscosity enhancers, sodium lauryl sulfate, sodium dioctyl sulfosuccinate, triethanolamine, polyoxyethylene sorbitan, poloxalkol and Surfactants such as quaternary ammonium salts and lactose, mannitol, glucose, fructose, xylose, galactose, sucrose, maltose, xylitol, sorbitol and potassium, sodium and magnesium chlorides, sulfates and phosphates And a variety of other excipients such as.

  The pharmaceutical composition may be produced according to any method known to those skilled in the art of pharmaceutical production such as wet granulation, dry granulation, encapsulation, direct compression, slugging and the like. is there. For example, a pharmaceutical composition may be prepared by mixing the amphetamine prodrug with one or more pharmaceutical additives together with an aliquot of liquid, preferably water, to form wet granules. is there. The wet granules may be dried to obtain granules. The resulting granules may be milled, sieved and mixed with various pharmaceutical additives such as water insoluble polymers and additional hydrophilic polymers. In one embodiment, the amphetamine prodrug is mixed with a hydrophilic polymer and an aliquot of water and then dried to obtain granules of the amphetamine prodrug encapsulated by the hydrophilic polymer.

  After granulation, the pharmaceutical composition is preferably encapsulated in, for example, a gelatin capsule. The gelatin capsules may contain, for example, kosher gelatin, titanium dioxide, and optional colorants. Alternatively, the pharmaceutical composition may be shaped as a tablet, eg, compressed and optionally coated with a protective coating that dissolves or disperses in gastric juice.

  The pharmaceutical composition of the present invention may be administered by various dosage forms. Any biologically acceptable dosage form known to those skilled in the art and combinations thereof are contemplated. Examples of preferred dosage forms include, without limitation, tablets including chewable tablets, film-coated tablets, fast dissolving tablets, effervescent tablets, multilayer tablets and bilayer tablets, caplets and powders including reconstitutable powders , Granules, dispersible granules, particles, microparticles, capsules including soft and hard gelatin capsules, troches, chewable troches, capsules and beads An agent, a liquid agent, a solution agent, a suspension agent, an emulsified liquid agent, an elixir agent, and a syrup agent are included.

  The pharmaceutical composition is preferably administered orally. Oral administration allows maximal release of amphetamine, provides sustained release of amphetamine, and maintains abuse resistance. The amphetamine prodrug preferably releases the amphetamine over a longer period of time compared to administration of unbound amphetamine.

  Oral dosage forms may be provided as discrete units such as capsules, caplets or tablets. In a preferred embodiment, the present invention provides a solid oral dosage form comprising an amphetamine prodrug that is smaller in size compared to a solid oral dosage form comprising a therapeutically equivalent amount of unbound amphetamine. In one embodiment, the oral dosage form comprises gelatin capsules of size 2, size 3, or smaller size (eg, size 4). Smaller size amphetamine prodrug dosage forms enhance ease of swallowing.

  Soft gels or soft gelatin capsules may be prepared by dispersing the dosage form in a suitable drug delivery vehicle (eg, vegetable oil) to form a highly viscous mixture, for example. is there. This mixture is then encapsulated with a gelatin film. The industrial units thus formed are then dried to a constant weight.

  Chewable tablets may be prepared by mixing the amphetamine prodrug with an excipient designed to form a tablet dosage form that is relatively soft, flavored and intended to be chewed. is there. Conventional tablet manufacturing machines and methods (such as direct compression, granulation and slugging) may be utilized.

  Film-coated tablets are prepared by coating the tablets using techniques such as rotating pan coating methods and air suspension methods to deposit a film layer in contact on the tablets. There is a case.

  Compressed tablets may be prepared by mixing the amphetamine prodrug with excipients that impart binding properties. The mixture may be compressed directly or may be compressed after granulation.

  Alternatively, the pharmaceutical composition of the present invention may be formulated into 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 oil may be administered by adding a purified and sterilized liquid to the prepared enteral formulation, which is then placed in the patient's supply tube that cannot be swallowed.

  Fine powders or granules containing diluents, dispersants and / or surfactants may be drafts, water or syrups, dried capsules or sachets, non-aqueous which may contain suspensions It may be provided for oral administration in suspension or in suspension in water or syrup. Liquid dispersions for oral administration may be syrups, emulsions or suspensions. The syrup, emulsion or suspension is, for example, natural rubber, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, saccharose, and saccharose used in combination with glycerol, mannitol, sorbitol and polyvinyl alcohol. Such carriers may be included.

  The dosage range of the amphetamine prodrug for humans depends on a number of factors including the age, weight and symptoms of the patient. Tablets and other dosage forms provided in separate units may contain a daily dose of one or more amphetamine prodrugs or an appropriate fraction thereof. The dosage form is one or two doses of about 2.5 mg to about 500 mg, about 10 mg to about 250 mg, about 10 mg to about 100 mg, about 25 mg to about 75 mg, or an incremental number within that range. The above amphetamine prodrug may be included. In a preferred embodiment, the dosage form comprises 30 mg, 50 mg or 70 mg of amphetamine prodrug.

  The dosage forms include immediate release, extended release, pulse release, variable release, controlled release, timed release, sustained release, delayed release, and delayed release, extended release, pulsed release, variable release, controlled release, timed release, sustained release, delayed release and Any known release profile, including but not limited to long-acting forms, or any combination thereof may be utilized.

  The pharmaceutical composition of the present invention may be administered in partial or divided doses once or more than once every 24 hours. Divided doses, 1-fold doses, 2-fold doses, or other multiple doses may be taken at 24 hours, at the same time, or at different times. The doses may be non-uniform doses with respect to each other or with respect to individual components at different administrations. It is preferred that a single dose be administered once a day. The dose may be administered after or before a meal.

  The dosage unit of the pharmaceutical composition may be packaged according to market requirements, for example, as unit doses, rolls, bulk bottles, blister packaging, and the like. For example, the packaging of a pharmaceutical product such as blister packaging may further be the identity of the pharmaceutical composition, a predetermined indication (such as ADHD), and / or the number of times per day, the number of days per week, etc. It may include or be accompanied by an indicia that allows the individual to specify the administration period. The blister package or other pharmaceutical package may contain another pharmaceutical product for combination therapy.

  It will be appreciated that the pharmacological activity of the compositions of the invention may be demonstrated using standard pharmacological models known to those skilled in the art. Furthermore, the compositions of the present invention may be incorporated or encapsulated in a suitable polymer matrix or membrane for site-specific delivery, or have the ability to affect site-specific delivery. It is understood that it can be made to function with a targeted drug. These techniques, as well as other drug delivery techniques, are well known to those skilled in the art.

  Any feature of the above embodiments may be used in combination with any other feature of the above embodiments.

  To assist in a more complete understanding of the present invention, the following examples are provided. However, the scope of the invention is not limited to the specific embodiments disclosed in these examples, which are for illustrative purposes only.

  The following abbreviations are used in the examples and throughout this specification.

  Lys-Amp = L-lysine-d-amphetamine, lysine-amphetamine, K-Amp, K-amphetamine or 2,6-diaminohexanoic acid- (1-methyl-2-phenylethyl) -amide or risdexamphetamine.

  Phe-Amp = phenylalanine-amphetamine, F-Amp 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.

Gly ₃ -Amp = GGG-amphetamine, GGG-Amp or 2-amino-N-({[(1-methyl-2-phenyl-ethylcarbamyl) -methyl] -carbomil} -methyl) -acetamide.

  BOC = t-butyloxycarbonyl.

  CMC = carboxymethylcellulose.

  DIPEA = diisopropylethylamine.

  mp = melting point.

  NMR = nuclear magnetic resonance.

  OSu = hydroxysuccinimide ester.

  Unless otherwise stated throughout the examples, doses are described as the amount of d-amphetamine base. A representative conversion table is provided in Table 2.

General synthesis of peptide amphetamine conjugates Peptide conjugates were synthesized by the general method illustrated in FIG. The iterative approach identifies preferred conjugates by synthesizing and testing single amino acid conjugates and then extending the peptides one amino acid at a time to produce dipeptide and tripeptide conjugates, etc. May be used to A single amino acid prodrug parent candidate may exhibit more or less desirable properties than progeny candidates such as its dipeptides or tripeptides. The iterative approach may quickly suggest whether peptide length affects bioavailability.

General Synthesis of Single Amino Acid Amphetamine Conjugate A solution of protected amino acid succinimidyl ester (2.0 eq) in 1,4-dioxane (30 mL) was added to d-amphetamine sulfate (1.0 eq) and NMM (4.0 equivalents) was added. The resulting mixture was stirred at 20 ° C. for 20 hours. Water (10 mL) was added and the solution was stirred for 10 minutes before removing the solvent under reduced pressure. The crude product was dissolved in EtOAc (100 mL) and washed with 2% AcOH _aq (3 × 100 mL), saturated NaHCO ₃ solution (2 × 50 mL) and brine (1 × 100 mL). The organic extract was dried over MgSO ₄ , filtered and evaporated to dryness to provide a protected amino acid amphetamine conjugate. This intermediate was directly deprotected by adding 4N hydrochloric acid in 1,4-dioxane (20 mL). The solution was stirred at 25 ° C. for 20 hours. To provide the corresponding amino acid amphetamine hydrochloride conjugate, the solvent was evaporated and the product was dried in vacuo. The synthesis of representative single amino acid conjugates is shown in FIGS. 2-6.

General Synthesis of Dipeptide Amphetamine Conjugate A solution of protected dipeptide succinimidyl ester (1.0 eq) in 1,4-dioxane was added to amphetamine sulfate (2.0 eq) and NMM (4.0 eq). Was added. The resulting mixture was stirred at 25 ° C. for 20 hours. The solvent was removed under reduced pressure. Saturated NaHCO ₃ solution (20 mL) was added and the suspension was stirred for 30 minutes. IPAC (100 mL) was added and the organic layer was washed with 2% AcOH _aq (3 × 100 mL) and brine (2 × 100 mL). The organic extract was dried over Na ₂ SO ₄ and the solvent evaporated to dryness to obtain a protected dipeptide amphetamine conjugate. The protected dipeptide conjugate was directly deprotected by adding 4N hydrochloric acid in 1,4-dioxane (20 mL) and the solution was stirred at 25 ° C. for 20 hours. To provide the corresponding dipeptide amphetamine hydrochloride conjugate, the solvent was evaporated and the product was dried in vacuo.

General synthetic amino acid conjugates of tripeptide amphetamine conjugates were synthesized and deprotected according to the general method 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 the protected dipeptide succinate (1.05 eq). The solution was stirred at 25 ° C. for 20 hours. The solvent was removed under reduced pressure. Saturated NaHCO ₃ solution (20 mL) was added and the suspension was stirred for 30 minutes. IPAC (100 mL) was added and the organic layer was washed with 2% AcOH _aq (3 × 100 mL) and brine (2 × 100 mL). To obtain the protected tripeptide amphetamine, the organic extract was dried over Na ₂ SO ₄ and the solvent was evaporated to dryness. Deprotection was performed directly by adding 4N hydrochloric acid in 1,4-dioxane (20 mL). To provide the corresponding tripeptide amphetamine hydrochloride conjugate, the mixture was stirred at 25 ° C. for 20 hours, the solvent was evaporated and the product was dried in vacuo.

  Although the hydrochloride conjugate does not require further purification, many of the deprotected hydrochloride salts are hygroscopic and require special handling between analysis and subsequent in vivo testing.

Synthesis of L-lysine-d-amphetamine L-lysine-d-amphetamine was synthesized by the following method.

a. Preparation of the HCl salt (see FIG. 3)
i. Join

To a solution of Boc-Lys (Boc) -OSu (15.58 g, 35.13 mmol) in dioxane (100 mL) under inert atmosphere, free d-amphetamine base (4.75 g, 35.13 mmol) and DIPEA (0.9 g, 1.22 mL, 7.03 mmol) was added. The resulting mixture was stirred overnight at room temperature. The solvent and excess base were then removed using reduced pressure evaporation. The crude product was dissolved in ethyl acetate and loaded onto a flash column (7 cm wide packed with silica up to 24 cm) and eluted with ethyl acetate. In order to obtain a white solid, the product was isolated, the solvent was removed by rotary evaporation, and the purified protected amide was dried by high vacuum treatment. ¹ H NMR (DMSO-d ₆ ) δ 1.02-1.11 (m, 2H, Lys γ-CH ₂ ), δ 1.04 (d, 3H, Amp α-CH ₃ ), δ 1.22-1.43 (M, 4H, Lys-β and δ-CH ₂ ), δ 1.37 (18H, Boc, 6x CH ₃ ), δ 2.60-2.72 (2H, Amp CH ₂ ), δ 3.75-3.83. (M, 1H, Lys α-H), δ 3.9-4.1 (m, 1H, Amp α-H), δ 6.54-6.61 (d, 1H, amide NH), δ 6.7-6 .77 (m, 1H, amide NH), δ 7.12-7.29 (m, 5H, ArH), δ 7.65-7.71 (m, 1, amide NH); mp = 86-88 ° C.

  ii. Deprotection

The protected amide was dissolved in 50 mL anhydrous dioxane and stirred with the addition of 50 mL (200 mmol) 4M HCl / dioxane and stirred overnight at room temperature. The solvent was then removed by rotary evaporation to provide a viscous oil. Rotary evaporation after the addition of 100 mL of MeOH resulted in a golden solid that was further dried by storage at room temperature under high vacuum. ¹ H NMR (DMSO-d ₆ ) δ 0.86-1.16 (m, 2H, Lys γ-CH ₂ ), δ 1.1 (d, 3H, Amp α-CH ₃ ), δ 1.40-1.56 (M, 4H, Lys-β and δ-CH ₂ ), δ 2.54-2.78 (m, 2H, Amp CH ₂ , 2H, Lys ε-CH ₂ ), 3.63-3.74 (m, 1H, Lys α-H), δ 4.00-4.08 (m, 1H, Amp α-H), 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, amide NH); mp = 120-122 ° C.

b. Preparation of mesylate (see FIG. 2)

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

  i. Join

The 72-L round bottom reactor was equipped with a mechanical stirrer, digital thermocouple, and injection funnel and was purged with nitrogen. The vessel was filled with Boc-Lys (Boc) -OSu (3.8 kg, 8.568 mol, 1.0 equiv) and 1,4-dioxane (20.4 L), and the resulting turbid liquid was 20 Stir at ± 5 ° C for 10 minutes. To the mixture was added N-methylmorpholine (950 g, 9.39 mol, 1.09 equiv) over 1 minute and the mixture was stirred for 10 minutes. Then, while cooling from the outside of the reactor with an ice-water bath, the slightly turbid reaction mixture was added to dextro-amphetamine (1.753 kg, 12.96 mol, 1.51 in 1,4-dioxane (2.9 L). Equivalent) was added over 30 minutes. During the addition operation, the internal temperature was kept below 25 ° C. At the end of the addition, a thick white precipitate appeared. While washing the injection funnel, 1,4-dioxane (2.9 L) was injected into the reaction and the reaction mixture was stirred at 22 ± 3 ° C. Monitoring by the addition was complete 30 minutes after the TLC indicated that the Boc-Lys (Boc) -Osu does not remain, the reaction was quenched with deionized water _{(DI H 2 O, 10L)} . In order to provide a dense white solid, the mixture was stirred at ambient temperature for 1 hour and then concentrated under reduced pressure.

For extraction, an acetic acid / salt solution of NaCl (15 kg) and glacial acetic acid (2 kg) in deionized water (61 L) and a bicarbonate solution of NaHCO ₃ (1.5 kg) in deionized water (30 L). Two types of solutions were prepared.

  The solid was redissolved in IPAC (38 L) and acetic acid / salt solution (39 kg) and transferred into a 150 L reactor. Each layer was mixed for 10 minutes and then separated. The organic layer was drained and washed with another acetic acid / salt solution (39 kg) followed by a bicarbonate solution (31.5 kg). All phase separation occurred within 5 minutes. Silica gel (3.8 kg; silica gel 60) was then added to the organic solution. The resulting slurry was stirred for 45 minutes and then filtered through filter paper. The solid on the filter paper was washed with IPAC (5 × 7.6 L). The filtrate and washings were analyzed by TLC and all were determined to contain product. The filtrate and washings were combined and concentrated under reduced pressure to provide the crude product as a white solid.

  ii. Deprotection

  45-L carboy was added di-Boc-Lys-Amp (3.63 kg, 7.829 mol) and 1,4-dioxane (30.8 L, 8.5 volumes) and the mixture was added under nitrogen. Stirred rapidly for 30 minutes. The resulting solution was filtered and the solid on the filter paper was washed with 1,4-dioxane (2 × 1.8 L).

  The filtrate was then transferred to a 72-L round bottom flask equipped with an automatic stirrer, digital thermocouple, nitrogen inlet and outlet, and a 5 L injection funnel. The temperature of the reaction mixture was adjusted to 21 ± 3 ° C. with a water bath. To the clear, light yellow solution, methanesulfonic acid (3.762 kg, 39.15 mol, 5 eq) was added over 1 hour while maintaining the internal temperature at 21 ± 3 ° C. About 1 hour after the addition was complete, a white precipitate began to appear. After the mixture was stirred at ambient temperature for 20.5 hours, HPLC monitoring showed the disappearance of all starting material. The mixture was filtered through filter paper and the reaction vessel was washed with 1,4-dioxane (3.6 L, 1 volume). The solid on the filter paper was washed with dioxane (3 × 3.6 L) and dried on a rubber dam for 1 hour. The material was then transferred to a drying tray and dried in a vacuum oven at 55 ° C. for ˜90 hours. This procedure provided Lys-Amp dimesylate (3.275 kg, 91.8% yield;> 99% (AUC)) as a white solid.

Synthesis of Ser-Amp Ser-Amp consists of the fact that the amino acid starting material is Boc-Ser (O-tBu) -OSu and that deprotection is performed using a solution of trifluoroacetic acid instead of HCl. Synthesized by a similar method (see FIG. 4) except.

Synthesis of Phe-Amp 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 ＮＭＲ NMR (400 MHZ, DMSO-d ₆ ): δ 8.82 (d, J = 8.0 Hz, 1H), 8.34 (bs, 3H), 7.29-7 .11 (m, 10H), 3.99 (m, 2H), 2.99 (dd, J = 13.6, 6.2 Hz, 1H), 2.88 (dd, J = 13.6, 7. 2 Hz, 1H), 2.64 (dd, J = 13.2, 7.6 Hz, 1H), 2.53 (m, 1H), 1.07 (d, J = 6.4 Hz, 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.

Synthesis Gly ₃ -Amp of Gly ₃ -Amp was synthesized by a similar method except the amino acid starting material is Boc-GGG-OSu (see Figure 6 case.).

Gly ₃ -Amp hydrochloride: mp 212-214 ° C .; ¹ H NMR (400 MHz, DMSO-d ₆ ) 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₎ δ168.91,168.14,166.85,139.45,129.60,128.60,126.48,46.60,42.27,20.30. _{HRMS: (ESI) for C 15} H 22 N 4 O 3 Na (M + Na) +: calcd, 329.1590: found, 329.1590.

Pharmacokinetics of L-lysine-d-amphetamine dihydrochloride compared to d-amphetamine sulfate (ELISA analysis)
Male Sprague-Dawley rats were given water ad libitum, fasted overnight, and gavaged with L-lysine-d-amphetamine dihydrochloride or d-amphetamine sulfate. In all studies, the dose contained an equivalent amount of d-amphetamine base. The plasma concentration of d-amphetamine was measured by ELISA (Amphetamine Ultra, 109319, Neogen, Corporation, Lexington, KY). The assay method is specific for d-amphetamine with minimal (0.6%) reactivity to the major d-amphetamine metabolite (para-hydroxy-d-amphetamine). L-lysine-d-amphetamine dihydrochloride was also determined to be essentially non-reactive (<1%) in the ELISA.

The mean (n = 4) plasma concentration curve of d-amphetamine or L-lysine-d-amphetamine dihydrochloride is shown in FIG. Prolonged release was observed in all four animals dosed with L-lysine-d-amphetamine dihydrochloride, with C _max substantially reduced compared to animals dosed with d-amphetamine sulfate. The plasma concentrations of d-amphetamine in individual animals for d-amphetamine or L-lysine-d-amphetamine dihydrochloride are shown in Table 3. The average plasma concentration of d-amphetamine is shown in Table 4. The peak concentration arrival time for L-lysine-d-amphetamine dihydrochloride was similar to the peak concentration arrival time for d-amphetamine. The pharmacokinetic parameters for oral administration of d-amphetamine or L-lysine-d-amphetamine dihydrochloride are summarized in Table 5.

  This example shows that when the active agents amphetamine and ricin form a conjugate, bioavailability is maintained approximately equal to amphetamine, but the peak level of amphetamine is reduced. The bioavailability of amphetamine released from L-lysine-d-amphetamine is similar to the bioavailability of an equivalent amount of amphetamine sulfate. L-lysine-d-amphetamine therefore maintains its therapeutic value. The incremental release of amphetamine from L-lysine-d-amphetamine and the reduction in peak levels reduce the possibility of overdosing.

Oral bioavailability of L-lysine-d-amphetamine dimesylate at various doses a. Dose approximating human therapeutic dose (1.5, 3 and 6 mg / kg)

  The mean (n = 4) plasma concentration curves of d-amphetamine versus L-lysine-d-amphetamine for rats dosed orally at 1.5, 3 and 6 mg / kg are shown in FIGS. 8, 9 and 10, respectively. Shown in Prolonged release was observed in all three therapeutic doses for animals that received L-lysine-d-amphetamine. The average plasma concentrations for 1.5, 3 and 6 mg / kg are shown in Table 6, Table 7 and Table 8, respectively. The pharmacokinetic parameters for oral administration of d-amphetamine versus L-lysine-d-amphetamine at various doses are summarized in Table 9.

b. Dose increase (12, 30 and 60 mg / kg)
Average (n = 4) plasma concentration curves of d-amphetamine versus L-lysine-d-amphetamine are shown for rats dosed orally at 12, 30, and 60 mg / kg. At these high doses, the bioavailability of L-lysine-d-amphetamine was significantly reduced compared to d-amphetamine.

Oral bioavailable male Sprague of L-lysine-d-amphetamine dimesylate at various doses approximating a range of human therapeutic doses compared to a superpharmacological dose Dory rats are freely fed with water and fasted overnight, L-lysine-d-amphetamine containing 1.5, 3, 6, 12, and 60 mg / kg amphetamine sulfate or equivalent amounts of d-amphetamine. It was administered by gavage. The concentration of d-amphetamine was measured by ELISA.

  When the active agent d-amphetamine and ricin form a conjugate, the level of d-amphetamine 30 minutes after administration has been shown to decrease by about 50% over the dose range of 1.5 to 12 mg / kg. Yes. However, the level of d-amphetamine from L-lysine-d-amphetamine when given a superpharmacological dose (60 mg / kg) is 8% of the level of d-amphetamine observed for d-amphetamine sulfate. (See Table 14, Table 15 and FIG. 15). The substantial reduction in oral bioavailability at high doses significantly reduces the potential for abuse of L-lysine-d-amphetamine.

Reduced oral bioavailability of L-lysine-d-amphetamine dimesylate at high doses An additional oral pharmacokinetic study shown in FIG. 16 shows that 8 levels of blood d-amphetamine levels at 60 mg / kg dose. The change over time is shown. In the case of d-amphetamine, blood levels quickly reached very high levels and 8 out of 12 animals died or were sacrificed due to acute symptoms of toxicity. In contrast, the blood level (Table 16 and Table 17) of the animals administered with L-lysine-d-amphetamine did not reach the peak until 5 hours, and only a small part of the blood levels of the animals administered with amphetamine. Was only reached. (Note: Valid data after 3 hours for d-amphetamine could not be determined due to animal death and sacrifice.)

Oral bioavailable d-amphetamine sulphate long-term release formulation (dextrin) after administration of either (intact or ground) long-release formulation or L-lysine-d-amphetamine dimesylate Cedrin Spansur® capsule (GlaxoSmithKline) is orally administered to rats as either an intact capsule or a crushed capsule, and contains L-lysine-d-amphetamine containing an equivalent amount of d-amphetamine base. Compared to administration (Figure 20). The milled capsules showed 84% and 13% increases in C _max and AUC _inf , respectively, compared to intact capsules (Tables 18 and 19). C _max and AUC _inf of d- amphetamine following administration of contrast L- lysine -d- amphetamine is about the same as C _max and AUC _inf of intact capsules, those long release specific to the compound per se And it cannot be avoided by a simple operation.

  This example illustrates the advantages of the present invention over conventional controlled release formulations of d-amphetamine.

Intranasal bioavailability of L-lysine-d-amphetamine versus amphetamine a. Intranasal (IN) bioavailability of L-lysine-d-amphetamine hydrochloride L-lysine-d-amphetamine in male Sprague-Dawley rats containing 3 mg / kg amphetamine sulfate or equivalent amount of d-amphetamine Hydrochloride was administered by intranasal administration. L-lysine-d-amphetamine released very little d-amphetamine into the blood circulation by IN administration. The mean (n = 4) plasma concentration curve of amphetamine with amphetamine versus L-lysine-d-amphetamine is shown in FIG. The pharmacokinetic parameters for IN administration of L-lysine-d-amphetamine are summarized in Table 20.

b. Intranasal bioavailability of L-lysine-d-amphetamine dimesylate The process of part a was repeated using L-lysine-d-amphetamine mesylate.

  This example shows that when the active agent d-amphetamine and ricin form a conjugate, the bioavailability by the nasal caliber is substantially reduced, thereby reducing the possibility of abuse of the agent by this tract. Is illustrated.

Intravenous bioavailability of amphetamine vs. L-lysine-d-amphetamine dimesylate Male Sprague-Dawley rats receive L-lysine-d- containing 1.5 mg / kg d-amphetamine or an equivalent amount of amphetamine. Amphetamine was administered via tail vein injection. The conjugate did not release significant amounts of d-amphetamine as observed with IN administration. The mean (n = 4) plasma concentration curve with amphetamine versus L-lysine-d-amphetamine is shown in FIG. The pharmacokinetic parameters for IV administration of L-lysine-d-amphetamine are summarized in Table 22.

  This example demonstrates that when the active agent amphetamine and lysine form a conjugate, the bioavailability of amphetamine by the venous caliber is substantially reduced, thereby reducing the likelihood of abuse of the agent by this route. Is illustrated.

Fraction of intact L-lysine-d-amphetamine absorbed after oral administration in oral bioavailable rats of L-lysine-d-amphetamine dimesylate compared to d-amphetamine at escalating doses Minutes increased non-linearly in proportion to escalating doses from 1.5 mg / kg to 12 mg / kg (FIGS. 21-25). The fraction absorbed at the dose of 12 mg / kg increased to 24.6%, while the fraction absorbed at the dose of 1.5 mg / kg was only 2.6%. The fraction absorbed was reduced to 9.3% at the high dose of 60 mg / kg. T _max ranged from 0.25 hours to 3 hours, and peak concentrations were visited earlier for L-lysine-d-amphetamine than for d-amphetamine. L-lysine-d-amphetamine was almost undetectable at the lowest dose by 8 hours and disappeared more rapidly than d-amphetamine.

The bioavailability (AUC) of d-amphetamine from each drug administered was approximately equivalent at the lower dose. The T _max for d-amphetamine derived from L-lysine-d-amphetamine is 0.5 to 1.5 hours after administration, whereas the T _max for d-amphetamine derived from d-amphetamine sulfate is 0.5 to 1.5 hours after administration. And 1.5 hours to 5 hours. The difference in T _max was greater at higher doses. The C _max of d-amphetamine derived from L-lysine-d-amphetamine is d- dose administered at a dose of 1.5 mg / kg to 6 mg / kg, which is a dose approximating therapeutic human equivalent doses (HEDs). Compared with C- _max of d-amphetamine derived from amphetamine sulfate, it decreased to almost half. Thus, at therapeutic doses, the pharmacokinetics of d-amphetamine derived from L-lysine-d-amphetamine was similar to that of sustained release formulations.

  HEDs are defined as equivalent doses for a 60 kg human individual according to the body surface area of the animal model. The adjustment factor for rats is 6.2. The HED for a dose of 1.5 mg / kg d-amphetamine in rats is, for example, equal to 14.52 / 0.7284 = 19.9 mg d-amphetamine sulfate when adjusted for salt content 1.5 / 6.2 × 60 = 14.52 mg d-amphetamine base.

At the superpharmacological dose (12 mg / kg and 60 mg / kg), C _max was reduced by 73% and 84%, respectively, compared to d-amphetamine sulfate. At these high doses, AUCs for d-amphetamine derived from L-lysine-d-amphetamine are substantially reduced compared to AUCs for d-amphetamine derived from d-amphetamine sulfate, with the highest dose (60 mg / Kg), AUC _inf decreased by 76%. At 60 mg / kg, the level of d-amphetamine derived from d-amphetamine sulfate rapidly increased rapidly. Experimental time courses were not completed due to extreme overactivity requiring humane euthanasia.

  In summary, the oral bioavailability of d-amphetamine derived from L-lysine-d-amphetamine was reduced to some extent at high doses. However, for L-lysine-d-amphetamine, the pharmacokinetics with respect to dose is almost linear at doses from 1.5 mg / kg to 60 mg / kg, and the fraction absorbed is (outside the 1.5 mg / kg dose). It was in the range of 52% to 81%. The pharmacokinetics of d-amphetamine sulfate was also approximately linear at lower doses from 1.5 mg / kg to 6 mg / kg, with the fractions absorbed ranging from 62% to 84%. However, in contrast to L-lysine-d-amphetamine, the parameters increased in imbalance at higher doses at the superpharmacological doses of 12 mg / kg and 60 mg / kg for d-amphetamine sulfate and the fraction absorbed Were calculated as 101% and 223%, respectively (extrapolated from the 1.5 mg / kg dose).

The results show that slow hydrolysis of L-lysine-d-amphetamine prevents saturation of d-amphetamine removal capacity at high doses, whereas d-amphetamine does not function when delivered as sulfate. It suggests that the clearance capacity reaches saturation at higher doses. The difference in dose proportionality to bioavailability (C _max and AUC) for d-amphetamine and L-lysine-d-amphetamine is shown in FIGS. 26-28. The pharmacokinetic properties of L-lysine-d-amphetamine compared to d-amphetamine at high doses reduces the ability to increase the dose stepwise. This improves the safety of L-lysine-d-amphetamine as a method of delivering d-amphetamine for the treatment of ADHD or other indications and reduces the potential for abuse.

Intranasal bioavailability of L-lysine-d-amphetamine dimesylate compared to d-amphetamine d-amphetamine after intranasal bolus administration of L-lysine-d-amphetamine as shown in FIG. 31 and FIG. _{Bioavailability} is about 5% of the bioavailability of d-amphetamine after administration of an equivalent amount of d-amphetamine sulfate, and the AUC _inf value is relative to L-lysine-d-amphetamine and d-amphetamine sulfate. Were 56 and 1032 respectively. The C _max of d-amphetamine after administration of L-lysine-d-amphetamine by the nasal tract is also about 5% of the C _max of d-amphetamine after administration of an equivalent amount of d-amphetamine sulfate. -78.6 ng / mL and 1962.9 ng / mL for lysine-d-amphetamine and d-amphetamine sulfate, respectively. The T _max (60 minutes) of d-amphetamine concentration derived from L-lysine-d-amphetamine is substantially delayed compared to the T _max (5 minutes) of d-amphetamine concentration derived from d-amphetamine sulfate, Reflected slow hydrolysis of L-lysine-d-amphetamine. High concentrations of intact L-lysine-d-amphetamine were also detected after intranasal administration. These results suggest that intranasal administration of L-lysine-d-amphetamine provides only minimal release of d-amphetamine because it provides minimal hydrolysis of L-lysine-d-amphetamine. To do.

Intravenous bioavailability of L-lysine-d-amphetamine dimesylate compared to d-amphetamine d-amphetamine after intravenous bolus administration of L-lysine-d-amphetamine as shown in FIG. 33 and FIG. Bioavailability is about one-half that of d-amphetamine bioavailability after administration of an equivalent amount of d-amphetamine sulfate, with AUC _inf values of L-lysine-d-amphetamine and d-amphetamine sulfate. The salt was 237.8 and 420.2, respectively. The C _max of d-amphetamine after administration of L-lysine-d-amphetamine is only about one fourth of C _max after administration of an equivalent amount of d-amphetamine sulfate, and the value is L-lysine-d- 99.5 and 420.2 for amphetamine and d-amphetamine sulfate, respectively. The T _max (30 minutes) of d-amphetamine concentration derived from L-lysine-d-amphetamine is substantially delayed compared to the T _max (5 minutes) of d-amphetamine concentration derived from d-amphetamine sulfate, Reflected slow hydrolysis of L-lysine-d-amphetamine. In conclusion, the bioavailability of d-amphetamine by the intravenous route was substantially reduced and delayed when given as L-lysine-d-amphetamine. Furthermore, bioavailability is less than that obtained by oral administration of an equivalent amount of L-lysine-d-amphetamine.

Summary of LC / MS / MS Bioavailability Data in Rats The following table summarizes the bioavailability data collected in the experiments discussed in Examples 13-15. Tables 24, 25 and 26 summarize the pharmacokinetic parameters of d-amphetamine after oral, nasal and intravenous administration of d-amphetamine or L-lysine-d-amphetamine, respectively.

  Tables 27, 28 and 29 summarize the pharmacokinetic parameters of L-lysine-d-amphetamine after oral, intravenous and intranasal administration of L-lysine-d-amphetamine.

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

  Tables 32-37 summarize the time course of d-amphetamine or L-lysine-d-amphetamine concentrations after oral, nasal and intravenous administration of d-amphetamine or L-lysine-d-amphetamine.

Bioavailability of L-lysine-d-amphetamine dimesylate or d-amphetamine sulfate in dogs (LC / MS / MS analysis)
Example experimental design:
This example is a two treatment level crossover study that is not randomized. All animals were maintained on normal diet and fasted overnight before each dose. The dose of L-lysine-d-amphetamine was set based on the body weight measured in the morning of each administration day. The actual dose delivered was calculated based on the weight of the syringe before and after administration. Blood samples over time were obtained from each animal by direct venipuncture of the jugular vein using vacutainer tubes containing sodium heparin as an anticoagulant. The resulting plasma samples were obtained from Quest Pharmaceutical Services, Inc. It was stored frozen until shipment to (Newwar, DE). The pharmacokinetic analysis of the plasma analysis results was performed by Calvert. Animals were treated as follows.

Test substance administration:
Oral: The test substance was administered by single gavage to each animal. On day 1, the animals received oral gavage using an esophageal tube coupled with a syringe. The dosing tube was washed with about 20 mL of tap water to ensure delivery of the required dosing solution.

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

Sample collection:
Dosage form: After administration, the remaining dosage form was stored and stored frozen.

  Blood: Blood samples over time (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, 12, 24, 48 and 72 hours after oral administration. Blood samples are 0 hours, 0.167 hours, 0.33 hours, 0.49 hours, 0.583 hours, 0.667 hours, 0.75 hours, 1 hour (before stopping infusion) after the start of intravenous infusion. Collected at time points of 2, 3, 4, 8, 12, and 23 hours. The collected blood sample was quickly cooled.

  Plasma: Plasma samples were obtained by centrifugation of blood samples. Two duplicate plasma samples (about 0.2 mL each) were transferred into pre-labeled plastic vials and stored frozen at about -70 ° C.

Sample analysis:
Plasma samples were analyzed for L-lysine-d-amphetamine and d-amphetamine at 1 ng / mL LLOQ for both samples using a validated LC-MS / MS method.

Microsoft Excel (Version 6, Microsoft Corp., Redmond, WA) was used to calculate mean plasma concentrations and to depict the plasma concentration-time data. (Non-compartment) Pharmacokinetic analysis was performed using the WinNonlin® software program (Version 4.1, Pharsight, Inc. Mountain View, CA). The maximum concentration (C _max ) and the time to reach C _max (T _max ) were measured values. The area under the plasma concentration-time curve (AUC) was determined using the linear-logarithmic trapezoidal rule. The apparent terminal rate constant (λz) is determined using linear least squares regression with visual inspection of the data to determine the appropriate number of points (minimum 3 data points) for the calculation of λz. Led. AUC _0-inf was calculated as the sum of AUC _0-t and Cpred / λz, where Cpred was the predicted concentration at the time of the last quantifiable concentration. Plasma clearance (CL / F) was determined as the ratio of dose / AUC _0-inf . Average residence time (MRT) was calculated as the ratio of AUMC _0-inf / AUC _0-inf , where AUMC _0-inf was the area under the first moment curve from time 0 to infinity. . The distribution volume (V _ss ) at steady state was estimated as CL * MRT. The half-life was calculated as ln2 / λz. The oral bioavailability (F) was calculated as the ratio of AUC _0-inf after oral administration to AUC _0-inf after intravenous administration. Descriptive statistics (mean value and standard deviation) of pharmacokinetic parameters were calculated using Microsoft Excel.

  The purpose of this study is to characterize the pharmacokinetics of L-lysine-d-amphetamine and d-amphetamine following administration of L-lysine-d-amphetamine in male beagle dogs. As shown in FIG. 35, in a crossover designed experiment, L-lysine-d-amphetamine was administered orally and intravenously to 3 male beagle dogs. Blood samples were collected up to 24 and 72 hours after intravenous and oral administration, respectively.

  The mean plasma concentration-time profiles of L-lysine-d-amphetamine and d-amphetamine after intravenous or oral administration of L-lysine-d-amphetamine are shown in FIGS. 37 and 38, respectively. Comparative profiles of L-lysine-d-amphetamine versus d-amphetamine after administration by both routes are shown in FIGS. Individual plots are shown in FIGS. 39 and 40. Pharmacokinetic parameters are summarized in Tables 38-46.

After 30 minutes intravenous infusion of L-lysine-d-amphetamine, plasma concentrations reached a peak at the completion of the infusion. The concentration of L-lysine-d-amphetamine after infusion decreases very rapidly in a bicomponent manner, below the limit of quantification (1 ng / mL) by about 8 hours after administration. became. The results of non-compartmental pharmacokinetic analysis show that L-lysine-d-amphetamine is a high clearance compound with a moderate volume of distribution (V _ss ) approximating total body water (0.7 L / kg) Indicates. The average clearance value is 2087 mL / h. kg (34.8 mL / min.kg), which is similar to the hepatic blood flow (40 mL / min.kg) in the dog.

L-lysine-d-amphetamine was rapidly absorbed after oral administration with a T _max of 0.5 hours in all three dogs. The average absolute oral bioavailability was 33%, suggesting that L-lysine-d-amphetamine is very well absorbed in dogs. The apparent terminal half-life was 0.39 hours, indicating rapid removal similar to that observed after intravenous administration.

The plasma concentration-time profile of d-amphetamine after intravenous or oral administration of L-lysine-d-amphetamine was similar. See Table 39. With oral administration of 1 mg / kg L-lysine-d-amphetamine, the mean C _{max of} d-amphetamine was 104.3 ng / mL. The half-life of d-amphetamine was 3.1 to 3.5 hours, much longer compared to L-lysine-d-amphetamine.

  In this study, L-lysine-d-amphetamine was infused over 30 minutes. Due to the rapid clearance of L-lysine-d-amphetamine, the bioavailability of d-amphetamine derived from L-lysine-d-amphetamine is reduced when comparable doses are given by intravenous bolus injection. There is a possibility. Even when given as an infusion, the bioavailability of d-amphetamine derived from L-lysine-d-amphetamine does not exceed the bioavailability when a similar dose is administered orally, and the peak concentration time is substantially Delayed to. This data further supports that L-lysine-d-amphetamine reduces the potential for abuse of d-amphetamine by intravenous injection.

Abbreviations for pharmacokinetic parameters are as follows:
C _max maximum measured plasma concentration T _max Time at which C _max was observed AUC _{0-t Total} area under the plasma concentration versus time curve from 0 to the last data point AUC _{0-inf Total} area under the plasma concentration versus time curve t _{1 / 2} Apparent terminal half-life MRT mean residence time CL / F Oral clearance V _ss Distribution volume in steady state F Bioavailability

Delayed effect systolic and diastolic blood pressure (BP) of L-lysine-d-amphetamine dimesylate compared to d-amphetamine after intravenous infusion is also due to d-amphetamine at therapeutic doses Rose. Since L-lysine-d-amphetamine is expected to release d-amphetamine as a result of systemic metabolism (although slowly), preliminary studies have shown that equimolar doses of d-amphetamine or L- Lysine-d-amphetamine was performed using 4 dogs (2 males and 2 females). The results suggest that the amide prodrug is inactive and that some slow release of d-amphetamine begins 20 minutes after the first dose. However, the effect of L-lysine-d-amphetamine is not strong compared to d-amphetamine. For example, the average blood pressure is illustrated in FIG. Small doses of d-amphetamine have been observed to have a rapid effect on blood pressure, consistent with previously published data (Kohli and Goldberg, 1982). The lowest dose (0.202 mg / kg equimolar with 0.5 mg / kg L-lysine-d-amphetamine) rapidly doubled the mean blood pressure, after which the mean blood pressure slowly recovered over 30 minutes.

  On the other hand, L-lysine-d-amphetamine caused little change in mean blood pressure until about 30 minutes after injection. At that time, blood pressure rose about 20-50%. Perhaps the continuous release of d-amphetamine is responsible for the slow and stable rise in blood pressure over the remainder of the experiment. In subsequent injections, d-amphetamine appears to repeat its effect in a dose-independent manner. That is, a 10-fold increase in dose from the first injection caused an increase to the same maximal blood pressure. This may reflect the state of catecholamine levels at nerve endings with continuous stimulation of bolus injections of d-amphetamine. It should be noted that the increase in mean blood pressure seen after continuous administration of L-lysine-d-amphetamine (FIG. 43) has a more gradual and weaker effect. Similar results were observed for left ventricular pressure (Figure 44). These results further demonstrate a significant reduction in d-amphetamine bioavailability by the intravenous route when given as L-lysine-d-amphetamine. As a result, the rapid onset of the pharmacological effect of the drug occurring in a person injected with d-amphetamine is eliminated.

Pharmacodynamic response to orally administered amphetamine versus L-lysine-d-amphetamine dihydrochloride (spontaneous motor response)
Male Sprague-Dawley rats were supplied with water ad libitum, fasted overnight, and gavaged with either 6 mg / kg amphetamine or L-lysine-d-amphetamine containing an equivalent amount of d-amphetamine. Horizontal locomotor activity (HLA) was recorded during the light period using photocell activity chambers (San Diego Instruments). Total counts were recorded every 12 minutes during the test period. Rats were monitored for 5, 8 and 12 hours, respectively, in three separate experiments. The time versus HLA count numbers for d-amphetamine versus L-lysine-d-amphetamine are shown in FIGS. The time to peak activity was delayed in each experiment, and the pharmacodynamic effect was evidence for prolonged release for L-lysine-d-amphetamine compared to d-amphetamine. The total activity count for HLA in rats administered Lys-Amp was increased (11-41%) compared to the total activity count for HLA induced by d-amphetamine in all three experiments.

Pharmacodynamic response to d-amphetamine versus L-lysine-d-amphetamine dihydrochloride by intranasal administration Male Sprague-Dawley rats receive d-amphetamine or L-lysine-d-amphetamine (1.0 mg / kg) in the nasal cavity It was administered internally. In a second set of similarly administered animals, carboxymethylcellulose (CMC) is about 2 times higher than the concentration of L-lysine-d-amphetamine and about 5 times higher than the content of d-amphetamine. Added to the drug solution at a concentration of 6 mg / mL. The CMC drug mixture was thoroughly suspended before each dose was delivered. Locomotor activity was monitored using the procedure described in Example 18. As shown in FIGS. 47 and 48, activity versus time (1 or 2 hours) is shown for amphetamine / CMC versus L-lysine-d-amphetamine and activity for amphetamine versus L-lysine-d-amphetamine CMC. Compared to time. As seen in FIG. 47, the addition of CMC did not affect the activity due to amphetamine, whereas the addition of CMC to L-lysine-d-amphetamine caused the activity of rats administered IN. The reaction was reduced to a level similar to the water / CMC control. Compared to the activity observed for animals receiving d-amphetamine, the increase in baseline activity of L-lysine-d-amphetamine not combined with CMC was 34% versus CMC. The increase in baseline activity of L-lysine-d-amphetamine was only 9% (Table 51). CMC had no observable effect on d-amphetamine-induced activity induced by IN administration.

Pharmacodynamic response to d-amphetamine versus L-lysine-d-amphetamine dihydrochloride by intravenous administration Male Sprague-Dawley rats received (1.0 mg / kg) d-amphetamine or L-lysine-d-amphetamine. It was administered intravenously. The activity expressed as total activity count over 3 hours is shown in FIG. The activity induced by L-lysine-d-amphetamine was substantially reduced and the peak activity arrival time was delayed. The increase in baseline activity for L-lysine-d-amphetamine was 34% for L-lysine-d-amphetamine compared to the activity observed for animals receiving d-amphetamine (Table 52).

Reduced toxicity of orally administered L-lysine-d-amphetamine dihydrochloride Sprague-Dawley rats with 3 males and 3 females per group were 0.1, 1.0, 10, 60, 100 Alternatively, L-lysine-d-amphetamine was orally administered at a single dose of 1000 mg / kg (Table 53). Each animal was observed for signs of toxicity and death on days 1-7 (starting on day 1 of administration) and 1 rat per group / sex (planned or planned) Necropsyed when he died.

  The key observations in this study include:

  All animals in groups 1-3 showed no observable signs throughout the conduct of this study.

  All animals in groups 4-6 showed an increase in motor activity within 2 hours after administration, which continued until day 2.

  One female rat dosed with 1000 mg / kg was found dead on day 2. Necropsy showed findings of pigment tears, pigmented rhinorrhea, swollen stomach (by gas), enlarged adrenal glands, and swollen intestine with edema.

  A total of 4 rats had skin lesions of different severity on the third day.

  One male rat dosed with 1000 mg / kg was euthanized on day 3 due to an open skin revision of the dorsal neck.

  All remaining animals were normal in appearance from day 4 to day 7.

  The animals were observed for signs of toxicity at 1 hour, 2 hours and 4 hours after dosing, and once daily for 7 days after dosing, and observations beside the cage were recorded. Animals found dead or moribund and sacrificed were necropsied and discarded.

  The observations at the side of the cage and the findings from gross autopsy are summarized as described above. The oral LD50 of d-amphetamine sulfate is 96.8 mg / kg. For L-lysine-d-amphetamine dimesylate, data are not sufficient to determine lethal dose, but since only one death occurred from a group of 6 animals, the study It indicates that the oral lethal dose of ricin-d-amphetamine exceeds 1000 mg / kg. In this dose group, a second animal was euthanized on day 3, which was done for humane reasons and felt that this animal would have recovered completely. The observations suggested drug-induced stress in groups 4-6, characteristic of amphetamine toxicity (NTP, 1990; NISH REGISTRY NUMBER: SI1750000; Goodman et al., 1985). All animals showed no abnormal signs on days 4-7, suggesting complete recovery at each treatment level.

  The lack of data supporting a definitive lethal dose is believed to be due to the presumed protective effect of amphetamine-lysine conjugate formation. Intact L-lysine-d-amphetamine has been shown to be inactive, but becomes active in the unconjugated form (d-amphetamine) by metabolism. Thus, at high doses, saturation of metabolism of L-lysine-d-amphetamine to the unconjugated form may explain the observed lack of toxicity, which is d-amphetamine sulfate (NTP, 1990). Consistent with was expected at doses greater than 100 mg / kg. Both the production rate of d-amphetamine and the amount of amphetamine produced may contribute to the reduction of toxicity. Alternatively, oral absorption of L-lysine-d-amphetamine may saturate at such high concentrations, which may indicate low toxicity due to the limited bioavailability of L-lysine-d-amphetamine. is there.

In vitro evaluation of the pharmacodynamic activity of L-lysine-d-amphetamine dihydrochloride As observed in the amino acid conjugates discussed herein, acylation of amphetamine is a stimulatory activity of the parent drug. Was expected to be significantly reduced. For example, Marvola (1976) showed that N-acetylation of amphetamine completely abolished the effect of increasing locomotor activity in mice. To confirm that the conjugate does not act directly as a stimulant, we used a standard radioligand binding assay and used Lys-Amp (10 ⁻⁹ M to 10 ⁻⁵ M) human recombination. Specific binding to dopamine and norepinephrine transport binding sites was tested (NovaScreen, Hanover, MD). The results (Table 54) show that Lys-Amp did not bind to these sites. In light of these results, the conjugate appears unlikely to retain stimulating activity. (Marvola M. (1976) “Effect of accredited derivatives of some sympathomimetic amines on the acetic acid and locomotor activity and barbits.

In vitro evaluation of the release of amphetamine from L-lysine-d-amphetamine dimesylate “kitchen test” anticipates attempts by unauthorized chemists to release free amphetamine from the amphetamine conjugate. It was implemented. Preferred amphetamine conjugates are resistant to such attempts. An initial kitchen test evaluated the resistance of the amphetamine conjugate to water, acid (vinegar) and base (baking powder and baking soda), and in each case the sample was heated and boiled for 20-60 minutes. . L-lysine-d-amphetamine and GGG-Amp did not release detectable free amphetamine.

The stability of amphetamine conjugates was evaluated under high concentration conditions including hot, concentrated hydrochloric acid and 10N NaOH solutions. A Lys-Amp stock solution was prepared in H ₂ O and diluted 10-fold with concentrated hydrochloric acid to a final concentration of 0.4 mg / mL and a final volume of 1.5 mL. Samples were heated to about 90 ° C. for 1 hour in a water bath, cooled to 20 ° C., neutralized, and analyzed by HPLC for free d-amphetamine. The results suggest that only a minimal amount of d-amphetamine is released under these enrichment conditions.

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

  Only a limited amount of d-amphetamine was released at room temperature. Although only a limited amount of d-amphetamine was released at 90 ° C., the degradation of L-lysine-d-amphetamine was more pronounced. This suggests that the amide bond is stable and that the conjugate normally degrades before a detectable amount is hydrolyzed. At reflux conditions, concentrated hydrochloric acid and 50% sulfuric acid released 85% and 59% of the d-amphetamine content, respectively, but distributed d-amphetamine in the undesired acidic solution. The step of recovering d-amphetamine from the acidic solution further reduces the yield.

  In a similar test, reflux in concentrated hydrochloric acid caused some hydrolysis (28%) after 5 hours and further hydrolysis (76%) after 22 hours. Reflux for 2 hours in concentrated sulfuric acid may have caused complete degradation of Lys-Amp and released d-amphetamine. As mentioned above, recovery of d-amphetamine from the acidic solution further reduces the yield.

  The stability of amphetamine conjugates was also evaluated under basic conditions containing various concentrations of sodium hydroxide, potassium hydroxide, sodium carbonate, ammonium hydroxide, diethylamine and triethylamine. The maximum d-amphetamine release was 25.4% obtained with 3M sodium hydroxide. All other basic conditions resulted in a release of less than 3%.

Stability of L-lysine-d-amphetamine dimesylate salt under treatment with commercial products The stability of L-lysine-d-amphetamine dimesylate salt is confirmed by treatment with commercial acid, base and enzyme mixtures. It was evaluated by. For acid and base (Table 59), 10 mg of Lys-Amp was mixed with 2 mL of each stock solution and the solution was shaken at 20 ° C. For enzyme treatment (Table 60), 10 mg of Lys-Amp was mixed with 5 mL of each enzyme mixture and the solution was shaken at 37 ° C. Aliquots (0, 1 and 24 hours) of the solution were neutralized and filtered before analysis by HPLC, respectively. Many of the commercially available reagents also included various solvents and / or surfactants.

Unless otherwise indicated, the solutions were used directly from the containers and mixed with undiluted Lys-Amp solids. Louis Red Devil® Rye, Enforcer Drain Care® Septical Treatment and Lid-X® Sepp Tick treatment (Rid-X (R) Separation Treatment) was prepared as a saturated aqueous solution. The enzymes used were purchased from Sigma and dissolved directly in water (pepsin 3 mg / mL, pancreatin 10 mg / mL, pronase 3 mg / mL, esterase 3 mg / mL), but Omnigest® ) And vitamin-containing dietary supplements (VitaelZym®) were first crushed or opened (1 tablet or 1 capsule per 5 mL of H ₂ O).

  Commercial acids and bases were ineffective in hydrolyzing Lys-Amp. Only treatment with Miracle-Gro (7% release) and treatment with Olympic deck cleaner (Olympic (R) Deck Cleaner) (4% release) Although release was indicated, the amount of d-amphetamine was negligible even after 24 hours. Of the enzyme products, only a mixture of purified esterase (19% release) or pronase (24% release) succeeded in cleaving lysine (after 24 hours).

Bioavailability oral administration of various peptide amphetamine conjugates (HCl salts) administered by oral route, nasal route and venous route : Male Sprague-Dawley rats are freely fed and fasted overnight. Amphetamine or an amino acid amphetamine conjugate containing an equivalent amount of d-amphetamine was administered by oral gavage.

  Intranasal administration: Male Sprague-Dawley rats were administered amphetamine or lysine-amphetamine (1.8 mg / kg) intranasally.

The relative in vivo performance of various amino acid-amphetamine compounds is shown in FIGS. 50-58 and summarized in Table 61. The intranasal bioavailability of Ser-Amp-derived amphetamine was reduced to some extent compared to free amphetamine. However, this compound was not equivalent to amphetamine when administered by oral route. Phenylalanine was equivalent to amphetamine in vivo when administered by oral route, but little or no decrease in bioavailability was observed when administered by parenteral route. Gly ₃ -Amp had approximately equal (90%) bioavailability according to the oral route and C _max decreased (74%). Furthermore, with Gly ₃ -Amp, bioavailability through the nasal and venous caliber was reduced compared to amphetamine.

  Multiple single amino acid amphetamine conjugates had oral bioavailability comparable to d-amphetamine (80-100%). For example, all of the Lys, Gly and Phe conjugates showed oral bioavailability similar to the parent drug. Dipeptide prodrugs generally showed lower bioavailability than their respective amino acid analogs, and tripeptide compounds showed no discernable tendency. Multiple amino acid amphetamine conjugates have low parenteral bioavailability. Preferred conjugates such as Lys-Amp show both oral bioavailability comparable to d-amphetamine and reduced parenteral bioavailability when compared to d-amphetamine.

Oral administration of d-amphetamine conjugate Reduced C _max Male Sprague-Dawley rats were fed water ad libitum, fasted overnight, and orally administered amphetamine conjugate or d-amphetamine sulfate. All doses contained equivalent amounts of d-amphetamine base. The plasma concentration of d-amphetamine was measured by ELISA (Amphetamine Ultra, 109319, Neogen, Corporation, Lexington, KY). The assay method is specific for d-amphetamine with minimal (0.6%) reactivity to the major d-amphetamine metabolite (para-hydroxy-d-amphetamine). Plasma concentrations of d-amphetamine and L-lysine-d-amphetamine were measured by LC / MS / MS shown in the examples.

Reduction of intranasal bioavailability (AUC and C _max ) of d-amphetamine conjugate Male Sprague-Dawley rats are provided with water ad libitum and the administration contains amphetamine conjugate or d-amphetamine sulfate. 02 mL of water was administered by placing it in the nasal flare. All doses contained equivalent amounts of d-amphetamine base. The plasma concentration of d-amphetamine was measured by ELISA (Amphetamine Ultra, 109319, Neogen, Corporation, Lexington, KY). The assay method is specific for d-amphetamine with minimal (0.6%) reactivity to the major d-amphetamine metabolite (para-hydroxy-d-amphetamine). Plasma concentrations of d-amphetamine and L-lysine-d-amphetamine were measured by LC / MS / MS shown in the examples.

Reduction of intravenous bioavailability (AUC and C _max ) of d-amphetamine conjugate Male Sprague-Dawley rats are provided with water ad libitum and the administration contains amphetamine conjugate or d-amphetamine sulfate. Administered by tail vein injection of 1 mL of water. All doses contained equivalent amounts of d-amphetamine base. The plasma concentration of d-amphetamine was measured by ELISA (Amphetamine Ultra, 109319, Neogen, Corporation, Lexington, KY). The assay method is specific for d-amphetamine with minimal (0.6%) reactivity to the major d-amphetamine metabolite (para-hydroxy-d-amphetamine). Plasma concentrations of d-amphetamine and L-lysine-d-amphetamine were measured by LC / MS / MS shown in the examples.

Conjugation of amphetamine with various chemical moieties The above examples show amphetamines conjugated with chemical moieties such as amino acids that are useful in reducing the potential for overdose while maintaining its therapeutic value. Demonstrate the utility of Although the effectiveness of amphetamine conjugation with a chemical moiety has been demonstrated through conjugation of the amphetamine with lysine (K), the above examples are intended to be exemplary only. As described below, binding of amphetamine to any of various chemical moieties (ie, peptides, glycopeptides, carbohydrates, nucleosides or vitamins) through a similar procedure using the following representative starting materials: Can be implemented.

Example of amphetamine synthesis:
Synthesis Gly ₂ -Amp of Gly ₂ -Amp was synthesized by a similar method except the amino acid starting material is Boc-Gly-Gly-OSu.

Synthesis of Glu ₂ -Phe-Amp Glu2-Phe-Amp is based on the fact that the amino acid starting material is Boc-Glu (OtBu) -Glu (OtBu) -OSu and that the starting drug conjugate is Phe-Amp (Phe-Amp Was synthesized in a similar manner except that

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

Synthesis of Lys-Gly-Amp For Lys-Gly-Amp, the amino acid starting material is Boc-Lys (Boc) -OSu, and the starting drug conjugate is Gly-Amp (see Synthesis of Gly-Amp). Was synthesized by a similar method except that

Synthesis of Lys-Glu-Amp Lys-Glu-Amp is a similar method except that the amino acid starting material is Boc-Lys (Boc) -OSu and the starting drug conjugate is Glu-Amp. Was synthesized.

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

Synthesis of (d) -Lys- (l) -Lys-Amp (d) -Lys- (l) -Lys-Amp is the amino acid starting material Boc- (d) -Lys (Boc)-(l) -Lys It was synthesized by a similar method except that it was (Boc) -OSu.

Synthesis of Gulonic Acid-Amp Gul-Amp was synthesized by a similar method except that the carbohydrate starting material was Guronic Acid-OSu.

No detection of L-lysine-d-amphetamine dihydrochloride in brain tissue after oral administration Male Sprague-Dawley rats were given free access to water and fasted overnight , either L-lysine-d-amphetamine or d- Amphetamine sulfate was administered by oral gavage. All doses contained equivalent amounts of d-amphetamine base. As shown in FIG. 59, similar levels of d-amphetamine were detected in serum and brain tissue after administration of d-amphetamine sulfate or L-lysine-d-amphetamine. L-lysine-d-amphetamine derived d-amphetamine was shown to be persistently present in the brain compared to the level of d-amphetamine derived d-amphetamine sulfate. L-lysine-d-amphetamine conjugate was present in significant amounts in serum but was not detected in brain tissue, indicating that the conjugate does not cross the blood brain barrier due to access to the site of action of the central nervous system It was.

Pharmaceutical composition gelatin capsule dosage forms of L-lysine-d-amphetamine dimesylate were prepared at three dosage strengths. The hard gelatin capsule was printed with NRP104 and the dosage strength. The capsule filling contains white or off-white fine powder of uniform appearance.

  Other diluents, disintegrants, lubricants and colorants may be used. Certain components may also be used to provide functions different from those listed above.

  The pharmaceutical composition was prepared by pulverizing l-lysine-d-amphetamine dimesylate (size 20 mesh) in a lump together with microcrystalline cellulose. The mixture was sieved through a 30 mesh screen and then mixed with croscarmellose sodium. Pre-screened magnesium stearate (size 30 mesh) was added and the composition was mixed until uniform to form a capsule fill.

Clinical pharmacokinetic evaluation and oral bioavailability of 70 mg L-lysine-d-amphetamine dimesylate capsules administered to healthy adults for 7 days under fasting conditions. Healthy adults between the ages of 55 years were administered 70 mg L-lysine-d-amphetamine dimesylate with 8 ounces of water once a day (at 7 am) for 7 consecutive days. It was. Patients fasted at least 10 hours before the last dose and at least 4 hours after the last dose. Venous blood samples (7 mL) were collected at 16 time points (0.5%) before drug administration on day 0, 1, 6, and 7 (in the morning) and after the last dose on day 7. 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 10 hours, 12 hours, 16 hours, 24 hours, 48 hours and 72 hours) Both were collected in EDTA vacutainers. Immediately after sample collection, the vacutainer tube was centrifuged at 3000 rpm, 4 ° C for 10 minutes. Samples were stored at -20 ° C within 1 hour of collection. Plasma samples were analyzed for L-lysine-d-amphetamine and d-amphetamine using a validated LC-MS / MS method.

By the fifth dose, d-amphetamine reached a steady state. After the seventh dose, the average AUC _0-24 was 1113 ng. h / mL, average AUC _0- ∞ is 1453 ng. h / mL, with an average C _max of 90.1 ng. h / mL, with an average T _max of 3.68 hours. See Table 63 and FIG. In comparison, the extended release amphetamine salt has a T _max of 5.8 hours after an overnight fast and 853 ng. h / mL AUC _0- ∞. J. et al. F. Auiler et al. , “Effect of food on early drug exposed from extended-release stimrants: results from the Concert, Ad3XR Food E1 (C3)

Intact L-lysine-d-amphetamine was rapidly converted to d-amphetamine.
After the seventh dose, the average AUC _0-24 was 60.66 ng. h / mL and the average AUC _0- ∞ is 61.06 ng. h / mL. See Table 63 and FIG. In addition, the average C _max for L-lysine-d-amphetamine is 47.9 ng. h / mL, with an average T _max of 1.14 hours. L-lysine-d-amphetamine was completely removed within about 6 hours.

C _max was 12% higher in men after normalization by weight, but there was no gender difference in systemic exposure to d-amphetamine.

  The multiple dose pharmacokinetic profile of d-amphetamine released from the prodrug L-lysine-d-amphetamine is consistent with long-term release characteristics. The adverse events that occurred in this setting are consistent with other stimulants, suggesting that 70 mg of L-lysine-d-amphetamine is well tolerated.

Clinical pharmacokinetic evaluation and oral bioavailability of L-lysine-d-amphetamine dimesylate compared to amphetamine long-term release products Adelol XR® and dexedrine spansur® used in the treatment of ADHD sex

  Clinical evaluation of the pharmacokinetics and oral bioavailability of L-lysine-d-amphetamine in humans was performed. L-lysine-d-amphetamine was orally administered at a dose approximating the lower end (25 mg) and upper end (75 mg) of the therapeutic window based on the d-amphetamine base content in the dosage. In addition, high dose administrations may include Adelol XR® (Shire) or Dexedrine Spansur (R) containing an amount of amphetamine base equivalent to amphetamine base in the high dose of L-lysine-d-amphetamine. Compared to the dose of GlaxoSmithKline). Treatment groups and doses are summarized in Table 64. All levels below the quantifiable limit (blq <0.5 ng / mL) were treated as 0 for pharmacokinetic analysis purposes.

Concentrations of d-amphetamine and intact conjugate of L-lysine-d-amphetamine after administration of L-lysine-d-amphetamine at low and high doses for each individual subject along with pharmacokinetic parameters. 65-70. The d-amphetamine concentration and pharmacokinetic parameters after administration of Adelol XR® or Dexedrine Spansur® for each subject individual are shown in Table 69 and Table 70, respectively. The concentration-time curves showing the intact conjugate of L-lysine-d-amphetamine and d-amphetamine are shown in FIGS. Long-term release of d-amphetamine from L-lysine-d-amphetamine was observed for both doses, and the pharmacokinetic parameters (C _max and AUC) were in dose when the low and high dose results were compared. It was proportional (FIGS. 61 and 62). Significant levels of d-amphetamine were not observed until 1 hour after administration. Intact of L-lysine-d-amphetamine in very small amounts (1.6% and 2.0% of total drug absorption based on AUC _inf calculated as molarity for doses of 25 mg and 75 mg, respectively) Conjugates were detected at a level that reached a peak at about 1 hour (Table 66 and Table 68). The small amount of intact conjugate absorbed was rapidly and completely removed and was not present at detectable concentrations by 5 hours even at the highest dose.

In a crossover design (in which the same subject receives Adelol XR® after a 7 day washout period), the higher dose of L-lysine-d-amphetamine is equivalent to Adelol XR®. ). Adelol XR® is a mixture of d-amphetamine and l-amphetamine salts (equivalent amounts of d-amphetamine sulfate, d- / l-amphetamine sulfate, d-amphetamine saccharate and d- / l-amphetamine). Aspartate) is a once-daily extended-release treatment for ADHD. Equivalent amounts of extended release dexedrine spansul (registered trademark, including extended release formulation of d-amphetamine sulfate) were also included in the study. Oral administration of L-lysine-d-amphetamine as observed in a pharmacokinetic study in rats is similar to the concentration-time curve of Adelol XR® and Dexedrine Spansur®. A concentration-time curve of amphetamine was produced (FIGS. 63 and 64). The bioavailability (AUC _inf ) of d-amphetamine after administration of L-lysine-d-amphetamine was approximately equivalent to both extended release amphetamine products (Table 71). Over the 12 hours typical of the time required for effective once-daily treatment of ADHD, the bioavailability of L-lysine-d-amphetamine is that of Adelol XR® (d-amphetamine and l -Nearly equivalent to bioavailability (at the level of adding amphetamine), more than 20% higher than that of Dexedrine Spansur®. Based on the results of this clinical study, L-lysine-d-amphetamine would be an effective once-daily treatment for ADHD. Furthermore, L-lysine-d-amphetamine provided similar pharmacokinetics in human and animal models, ie delayed release of d-amphetamine resulting in long-term release kinetics. Based on these observations, L-lysine-d-amphetamine should also have abuse resistance properties in humans.

Clinical pharmacokinetic evaluation of L-lysine-d-amphetamine dimesylate and oral bioavailability In children with ADHD (6-12 years old) 30 mg, 50 mg or 70 mg L-lysine-d- The T _max of d-amphetamine after a single oral administration of amphetamine dimesylate was about 3.5 hours. See FIG. The T _max of L-lysine-d-amphetamine dimesylate was about 1 hour. The linear pharmacokinetics of d-amphetamine after a single oral dose of L-lysine-d-amphetamine dimesylate was established over a dose range of 30 mg to 70 mg in children.

  There is no unexpected accumulation of d-amphetamine at steady state in ADHD children and no accumulation of L-lysine-d-amphetamine dimesylate after administration once daily for 7 consecutive days.

Diet does not affect the extent of d-amphetamine absorption after a single oral dose of 70 mg L-lysine-d-amphetamine dimesylate capsules in healthy adults, but T _max (3 Delay about 1 hour (from .78 hours to 4.72 hours after high fat meal). Absorption of d-amphetamine after oral administration of L-lysine-d-amphetamine dimesylate in solution and L-lysine-d-amphetamine dimesylate as an intact capsule after 8 hours of fasting The degree was equivalent.

Although the range of values in children was higher than the range of values in adults, there was no apparent difference between men and women in exposure as measured by dose-normalized C _max and AUC. Since this is the result of a significant correlation between dose-normalized C _max and AUC and body weight, the difference is due to the higher dose in mg / kg administered to children. is there. There was no apparent difference in t _1/2 between male and female subjects, and there was no obvious relationship between t _1/2 and age or weight.

Representative results of clinical pharmacokinetic assessment are shown in FIG. 66 (AUC), FIG. 67 (C _max ) and FIG. 68 (T _max ).

Efficacy of L -lysine-d-amphetamine dimesylate in pediatric clinical trials The effectiveness of L-lysine-d-amphetamine dimesylate is determined by the DSM- Established in a double-blind randomized placebo-controlled parallel group study conducted in 6-12 year old children (N = 290) meeting IV criteria. Patients randomized once a day for 4 weeks in the morning to receive a final dose of 30 mg, 50 mg or 70 mg of L-lysine-d-amphetamine dimesylate or placebo It was done. For patients randomized to 50 mg and 70 mg of L-lysine-d-amphetamine dimesylate, the dose was increased by forced escalation. If the patient received all of the 30 mg / day dose of L-lysine-d-amphetamine dimesylate, the investigator (ADHD Rating Scale (ADHD-RS)) and parent (Conner's Parent Rating Scale (CPRS) )) For all doses of L-lysine-d-amphetamine dimesylate as compared to placebo for a total period of 4 weeks including the first week of treatment and for signs of ADHD and Significant improvement in symptoms has been demonstrated. Additional dose response improvements were demonstrated in the 50 mg and 70 mg groups, respectively. Patients treated with L-lysine-d-amphetamine dimesylate, as measured by CPRS score, compared to placebo-treated patients in the morning (~ 10am), afternoon (~ 2pm) And showed significant improvement in the evening (~ 6 pm), demonstrating efficacy throughout the day. The result of the primary efficacy analysis, ie, the change in the ADHD-RS total score from the baseline to the end point for the ITT population is shown in FIG.

  Efficacy was also measured by SKAMP score. A total of 52 children aged 6-12 years meeting ADHD DSM-IV criteria (combined or hyperactive) participated in a double-blind randomized placebo-controlled crossover study. Patients received fixed and optimal doses of L-lysine-d-amphetamine dimesylate (30 mg, 50 mg, 70 mg), Adelol XR (registered trademark, 10 mg, 20 mg) once a day, once a day for each treatment in the morning. Or 30 mg) or randomized to accept placebo. The primary endpoint in this study is the SKAMP (Swanson, Kotkin, Agler, M. Flynn and Pelham rating scale) -department score. Both L-lysine-d-amphetamine dimesylate and Adelol XR® were highly effective compared to placebo. The striking effect of L-lysine-d-amphetamine occurs within 2 hours after morning administration and continues through 12 hours after morning administration, the last evaluation point, producing a 12-hour duration of action compared to placebo. It was. See FIG.

Potential for abuse of intravenous L-lysine-d-amphetamine To assess the potential for abuse, 50 mg L-lysine-d-amphetamine, 20 mg d-amphetamine, and placebo were double blinded In a crossover design, 9 stimulant abusers were administered intravenously over 48 minutes at 2 minutes. The drug was administered according to the 3x3 balanced Latin square method. On each administration day, the vital signs scale and subjective and behavioral effects are: pre-dose, 0.5 h, 1 h, 1.5 h, 2 h, 3 h, 4 h, 5 h after administration. , 6 hours, 9 hours, 12 hours, 16 hours and 24 hours. Blood samples (5 mL) were taken for evaluation of d-amphetamine levels at these time points and at the 5 minute time point.

  For d-amphetamine, a mean peak plasma level of d-amphetamine of 77.7 ng / mL occurred at the 5 minute time point and then quickly returned to the original level. Administration of d-amphetamine caused the expected d-amphetamine-like effect, resulting in a mean peak response at 15 minutes. The mean maximum response to d-amphetamine at the main variable of the Subjective Preference Visual Analog Scale (Subject VAS) was significantly greater than placebo (p = 0.01).

  For L-lysine-d-amphetamine, a mean peak plasma level of 33.8 ng / mL d-amphetamine occurred at 3 hours and remained at this level throughout the 4 hour observation. L-lysine-d-amphetamine produced d-amphetamine-like subjective, behavioral and vital signs effects, and an average peak response at 1 to 3 hours. For the main variable of the subjective preference visual analog scale, the response was not greater than the placebo (p = 0.29). The change in blood pressure after administration of L-lysine-d-amphetamine was significant.

  At the end of the study, subjects were asked as to which treatment they would like to use again. Six subjects selected 20 mg d-amphetamine, two subjects selected neither of the treatments, and one subject selected 50 mg L-lysine-d-amphetamine. In summary, the rise in blood pressure occurred late, but 50 mg of L-lysine-d-amphetamine did not produce euphoric or amphetamine-like subjective effects. The above 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 is significantly less likely to be abused than immediate release d-amphetamine containing an equivalent amount of d-amphetamine base.

L-Lysine-d-amphetamine versus d-amphetamine in healthy adults with a history of stimulant abuse L- in healthy adults who meet the DSM-IV criteria for presumed stimulant abuse To obtain a preliminary guess of abuse trends for ricin-d-amphetamine (30-150 mg) vs. d-amphetamine sulfate (40 mg) and placebo, this randomized single center dose escalation study used. The subjects were divided into 3 cohorts of 4 patients each. All received a single dose of L-lysine-d-amphetamine with a minimum interval of 48 hours, and the d-amphetamine sulfate (40 mg) and placebo groups were randomly distributed. Cohort 1 was administered L-lysine-d-amphetamine at doses of 30, 50, 70, and 100 mg. Cohort 2 received doses of 50 mg, 70 mg, 100 mg, and 130 mg. Cohort 3 received doses of 70 mg, 100 mg, 130 mg and 150 mg.

The AUC _last of d-amphetamine over the first 4 hours was 100 mg L-lysine-d-amphetamine (165.3-213.com) compared to 40 mg d-amphetamine (245.5-316.8 ng / mL). 1 ng / mL) was substantially low. C _max and AUC _last increased with dose for 30-130 mg L-lysine-d-amphetamine and decreased between doses of 130 mg and 150 mg. T _max was large in the range from 3.78 hours to 4.25 hours for L-lysine-d-amphetamine compared to d-amphetamine sulfate (1.88-2.74 hours). The half-life of L-lysine-d-amphetamine (range: 0.44-0.76 hours) showed rapid clearance. The severity of side effects was mild and there was no significant change in vital signs or ECG parameters. L-lysine-d-amphetamine had a slower release profile of d-amphetamine compared to d-amphetamine sulfate. There appears to be a maximal concentration decrease at the 150 mg high dose, suggesting that higher doses of L-lysine-d-amphetamine do not result in further increases in C _max and AUC _last . These results suggest a drug profile consistent with reduced potential abuse.

  It will be understood that the specific embodiments of the invention shown and described herein are exemplary only. Numerous changes, changes, substitutions and equivalents will occur to those skilled in the art without departing from the spirit and scope of the invention. In particular, terms used in this application should be construed broadly in light of similar terms used in the related applications. Accordingly, all subject matter described in the specification and illustrated in the accompanying drawings is considered to be illustrative only and not restrictive, and the scope of the present invention is defined by the appended claims. It is intended to be determined only by the range.

The figure which shows the synthesis | combination of a peptide amphetamine conjugate. The figure which shows the synthesis | combination of a peptide amphetamine conjugate. The figure which shows the synthesis | combination of a ricin amphetamine dimesylate. The figure which shows the synthesis | combination of a ricin amphetamine hydrochloride. The figure which shows the synthesis | combination of a serine amphetamine conjugate. The figure which shows the synthesis | combination of a phenylalanine amphetamine conjugate. FIG. 3 shows the synthesis of a triglycine amphetamine conjugate. The graph which shows the plasma density | concentration of d-amphetamine from the rat individual | organism | solid which was orally administered d-amphetamine or L-lysine-d-amphetamine hydrochloride. Graph showing plasma concentration of d-amphetamine (with a dose of 1.5 mg / kg d-amphetamine base). Graph showing plasma concentration of d-amphetamine (with a dose of 3 mg / kg d-amphetamine base). Graph showing plasma concentration of d-amphetamine (with a dose of 6 mg / kg d-amphetamine base). Graph showing plasma concentration of d-amphetamine (with a dose of 12 mg / kg d-amphetamine base). Graph showing plasma concentration of d-amphetamine (with a dose of 30 mg / kg d-amphetamine base). Graph showing plasma concentration of d-amphetamine (with a dose of 60 mg / kg d-amphetamine base). Percentage of bioavailability of L-lysine-d-amphetamine dimesylate compared to d-amphetamine sulfate at doses 1.5, 3, 6, 12, 30 and 60 mg / kg d-amphetamine base ( AUC and C _max ). Graph showing the plasma concentration of d-amphetamine 30 minutes after administration versus a gradual increase in the dose of d-amphetamine base. Graph showing plasma concentration of d-amphetamine (with a dose of 60 mg / kg d-amphetamine base). Shows plasma concentration of d-amphetamine (ELISA analysis) following intranasal administration of L-lysine-d-amphetamine hydrochloride or d-amphetamine sulfate (with a dose of 3 mg / kg d-amphetamine base) to rats. Graph. Plasma concentration of d-amphetamine after intranasal administration of L-lysine-d-amphetamine dimesylate or d-amphetamine sulfate (with a dose of 3 mg / kg d-amphetamine base) to rats (ELISA analysis) Graph showing. Plasma concentration of d-amphetamine after intravenous bolus administration to rats of L-lysine-d-amphetamine dimesylate or d-amphetamine sulfate (with a dose of 1.5 mg / kg d-amphetamine base) The graph which shows (ELISA analysis). Dexedrine spansul® capsules (with a dose of 3 mg / kg d-amphetamine base), ground Dexedrine spansul® capsules, or L-lysine-d-amphetamine dimesic acid The graph which shows the plasma concentration level (ELISA analysis) of d-amphetamine after oral administration to the rat of salt. Graph showing plasma concentration of d-amphetamine in ng / mL units (FIG. 21A) and nM units (FIG. 21B) (with a dose of 1.5 mg / kg d-amphetamine base). Graph showing plasma concentration of d-amphetamine in ng / mL units (FIG. 22A) and nM units (FIG. 22B) (with a dose of 3 mg / kg d-amphetamine base). Graph showing plasma concentration of d-amphetamine in ng / mL units (FIG. 23A) and nM units (FIG. 23B) (with a dose of 6 mg / kg d-amphetamine base). Graph showing plasma concentration of d-amphetamine in ng / mL units (FIG. 24A) and nM units (FIG. 24B) (with a dose of 12 mg / kg d-amphetamine base). Graph showing plasma concentration of d-amphetamine in ng / mL units (FIG. 25A) and nM units (FIG. 25B) (with a dose of 60 mg / kg d-amphetamine base). Graph showing the relative bioavailability (C _max ) of L-lysine-d-amphetamine and d-amphetamine proportional to the gradual increase in human equivalent dose. Graph showing the relative bioavailability (AUC _inf ) of L-lysine-d-amphetamine and d-amphetamine proportional to the gradual increase in dose of d-amphetamine base. Graph showing the relative bioavailability (AUC _inf ) of L-lysine-d-amphetamine and d-amphetamine proportional to the gradual increase in human equivalent dose. Graph showing the relative bioavailability (C _max ) of intact L-lysine-d-amphetamine proportional to the gradual increase in human equivalent dose. Graph showing the relative bioavailability (AUC _inf ) of intact L-lysine-d-amphetamine proportional to the gradual increase in human equivalent dose. Plasma concentration of d-amphetamine (LC / MS) following intranasal administration of L-lysine-d-amphetamine dimesylate or d-amphetamine sulfate (with a dose of 3 mg / kg d-amphetamine base) to rats / MS analysis). Ng / mL units (Figure 32A) and nM units after intranasal administration of L-lysine-d-amphetamine dimesylate or d-amphetamine sulfate (with a dose of 3 mg / kg d-amphetamine base) to rats The graph which shows the plasma concentration (LC / MS / MS analysis) of d-amphetamine and L-lysine-d-amphetamine in (FIG. 32B). Plasma concentration of d-amphetamine after intravenous bolus administration to rats of L-lysine-d-amphetamine dimesylate or d-amphetamine sulfate (with a dose of 1.5 mg / kg d-amphetamine base) LC / MS / MS analysis). Ng / mL units (Figure 34A) after intravenous administration of L-lysine-d-amphetamine dimesylate or d-amphetamine sulfate (with a dose of 1.5 mg / kg d-amphetamine base) to rats and FIG. 35 is a graph showing the plasma concentration of d-amphetamine in nM units (FIG. 34B) (LC / MS / MS analysis). The graph which shows the time-dependent change of the average plasma concentration of L-lysine-d-amphetamine after the intravenous or oral administration (n = 3) of L-lysine-d-amphetamine. The graph which shows the time-dependent change of the plasma density | concentration of d-amphetamine after the intravenous or oral administration (n = 3) of L-lysine-d-amphetamine. Mean plasma of L-lysine-d-amphetamine and d-amphetamine in ng / mL units (FIG. 37A) and nM units (FIG. 37B) after intravenous administration of L-lysine-d-amphetamine (n = 3) The graph which shows a time-dependent change of a density | concentration level. Mean plasma concentrations of L-lysine-d-amphetamine and d-amphetamine in ng / mL units (FIG. 38A) and nM units (FIG. 38B) after oral administration of L-lysine-d-amphetamine (n = 3). The graph which shows a time-dependent change of a level. The graph which shows the time-dependent change of the plasma concentration for every individual | organism | solid of L-lysine-d-amphetamine after intravenous administration (FIG. 39A) or oral administration (FIG. 39B) of L-lysine-d-amphetamine. The graph which shows the time-dependent change of the plasma density | concentration for every individual | organism | solid of d-amphetamine after intravenous administration (FIG. 40A) or oral administration (FIG. 40B) of L-lysine-d-amphetamine. Shows plasma concentration of d-amphetamine after oral administration to male dogs of L-lysine-d-amphetamine dimesylate or d-amphetamine sulfate (with a dose of 1.8 mg / kg d-amphetamine base). Graph. Shows plasma concentration of d-amphetamine following oral administration to female dogs of L-lysine-d-amphetamine dimesylate or d-amphetamine sulfate (with a dose of 1.8 mg / kg d-amphetamine base). Graph. The graph which shows the average blood pressure after the intravenous injection of L-lysine-d-amphetamine dimesylate or d-amphetamine to male dogs and female dogs. The graph which shows the left ventricular blood pressure after the intravenous injection of L-lysine-d-amphetamine dimesylate or d-amphetamine to male dogs and female dogs in increased doses. The graph which shows the locomotor activity (time-dependent change of 5 hours) of the rat after oral administration. The graph which shows the locomotor activity (time-dependent change of 12 hours) of the rat after oral administration. The graph which shows the locomotor activity (1 hour time-dependent change) of the rat after intranasal administration. The graph which shows the locomotor activity (time-dependent change of 2 hours) of the rat after intranasal administration (used together with carboxymethylcellulose). The graph which shows the locomotor activity (3 hour time course) of the rat after intravenous administration. Graph showing intranasal bioavailability of abuse-resistant amphetamine amino acids, dipeptides and tripeptide conjugates. Graph showing the oral bioavailability of abuse-resistant amphetamine amino acids, dipeptides and tripeptide conjugates. The graph which shows the intravenous bioavailability of the abuse-resistant amphetamine tripeptide conjugate. The graph which shows the intranasal bioavailability of the abuse-resistant amphetamine amino acid conjugate. The graph which shows the oral bioavailability of the abuse-resistant amphetamine amino acid conjugate. The graph which shows the intravenous bioavailability of the abuse-resistant amphetamine amino acid conjugate. The graph which shows the intranasal bioavailability of the abuse-resistant amphetamine tripeptide conjugate. The graph which shows the intranasal bioavailability of the abuse-resistant amphetamine amino acid and dipeptide conjugate. Graph showing intranasal bioavailability of abuse-resistant amphetamine dipeptide conjugates containing D- and L-amino acid isomers. Serum of d-amphetamine and L-lysine-d-amphetamine after oral administration to rats of L-lysine-d-amphetamine hydrochloride or d-amphetamine sulfate (with a dose of 5 mg / kg d-amphetamine base) 59 is a graph showing medium concentration (ng / mL unit, FIG. 59A) and brain tissue concentration (ng / g unit, FIG. 59B) (LC / MS / MS analysis). Levels of d-amphetamine and L-lysine-d-amphetamine in steady state plasma obtained from a clinical study of oral administration of 70 mg L-lysine-d-amphetamine dimesylate to humans (LC / MS / MS Analysis). Plasma d-amphetamine and L-lysine for 72 hours after oral administration to humans of L-lysine-d-amphetamine (L-lysine-d-amphetamine dimesylate 25 mg containing 7.37 mg of d-amphetamine base) A graph showing the level of d-amphetamine (in ng / mL). Plasma d-amphetamine and L-lysine for 72 hours after oral administration to humans of L-lysine-d-amphetamine (L-lysine-d-amphetamine dimesylate 25 mg containing 7.37 mg of d-amphetamine base) A graph showing the level of d-amphetamine (in nM units). Plasma d-amphetamine and L-lysine over 72 hours after oral administration to humans of L-lysine-d-amphetamine (75 mg L-lysine-d-amphetamine dimesylate containing 22.1 mg d-amphetamine base) A graph showing the level of d-amphetamine (in ng / mL). Plasma d-amphetamine and L-lysine over 72 hours after oral administration to humans of L-lysine-d-amphetamine (75 mg L-lysine-d-amphetamine dimesylate containing 22.1 mg d-amphetamine base) A graph showing the level of d-amphetamine (in nM units). L-lysine-d-amphetamine (75 mg L-lysine-d-amphetamine dimesylate containing 22.1 mg d-amphetamine base) or human of Adelol XR® (35 mg containing 21.9 mg amphetamine base) Shows the level of d-amphetamine (0-12 hours) in plasma after oral administration to s. L-lysine-d-amphetamine (75 mg L-lysine-d-amphetamine dimesylate containing 22.1 mg d-amphetamine base) or human of Adelol XR® (35 mg containing 21.9 mg amphetamine base) Showing the level of d-amphetamine (0-72 hours) in plasma after oral administration to. L-lysine-d-amphetamine (75 mg of L-lysine-d-amphetamine dimesylate containing 22.1 mg of d-amphetamine base) or dexedrine spansul (30 mg containing 22.1 mg of amphetamine base) ) Is a graph showing the level of d-amphetamine (0-12 hours) in plasma after oral administration to humans. L-lysine-d-amphetamine (75 mg of L-lysine-d-amphetamine dimesylate containing 22.1 mg of d-amphetamine base) or dexedrine spansul (30 mg containing 22.1 mg of amphetamine base) ) Is a graph showing the level of d-amphetamine (0-72 hours) in plasma after oral administration to humans. Graph showing the mean plasma concentration of d-amphetamine after oral administration under fasting conditions to pediatric patients with ADHD at 30 mg, 50 mg and 70 mg of L-lysine-d-amphetamine dimesylate. Between dose-normalized d-amphetamine AUC and gender after once-daily oral administration of L-lysine-d-amphetamine dimesylate capsules to healthy adult volunteers and ADHD children The graph which shows the relationship. Maximum dose plasma normalized d-amphetamine plasma concentration and sex after once-daily oral administration of L-lysine-d-amphetamine dimesylate capsules to healthy adult volunteers and ADHD children The graph which shows the relationship between. Maximum dose time normalized d-amphetamine concentration and gender after once-daily oral administration of L-lysine-d-amphetamine dimesylate capsules to healthy adult volunteers and ADHD children The graph which shows the relationship between. Graph showing ADHD-RS at endpoint for pediatric clinical studies. Graph showing SKAMP score (efficacy) versus time for pediatric clinical studies.

Claims (41)

A method of treating narcolepsy comprising administering a compound of formula III or a salt thereof, comprising:

In Formula (III), A is a dextrorotatory isomer of amphetamine, X ₁ is an L-amino acid, X is an independent chemical moiety, and n is an increment from 1 to 50. And how to treat narcolepsy. The method of claim 1, wherein X ₁ is lysine.   The method of claim 1, wherein A is amphetamine, methamphetamine or methylphenidate.   4. The method of claim 3, wherein A is amphetamine.   5. The method of claim 4, wherein the compound is L-lysine-d-amphetamine.   6. The method of claim 5, wherein the compound is L-lysine-d-amphetamine dimesylate.   2. The method of claim 1, wherein the compound is administered once a day. A pharmaceutical composition for oral administration comprising an amphetamine prodrug of formula III or a salt thereof and at least one pharmaceutical additive,

In Formula (III), A is a dextrorotatory isomer of amphetamine, X ₁ is an L-amino acid, X is an independent chemical moiety, n is an increment from 1 to 50, The pharmaceutical composition releases a therapeutically effective amount of amphetamine when the composition is administered orally, wherein the pharmaceutical composition exhibits a reduced rate of amphetamine absorption compared to unbound amphetamine. Composition.   9. The pharmaceutical composition according to claim 8, wherein the amphetamine prodrug is L-lysine-d-amphetamine dimesylate.   10. The pharmaceutical composition of claim 9, comprising about 10 mg to about 250 mg of L-lysine-d-amphetamine dimesylate.   11. The pharmaceutical composition according to claim 10, comprising about 30 mg of L-lysine-d-amphetamine dimesylate.   11. The pharmaceutical composition according to claim 10, comprising about 50 mg L-lysine-d-amphetamine dimesylate.   11. The pharmaceutical composition according to claim 10, comprising about 70 mg of L-lysine-d-amphetamine dimesylate. The _Cmax of released amphetamine is in the range of about 80% to about 120% of the selected value, which is 53.2 ± 9.62 ng / mL, 93.3 ± 18.2 ng / mL. The pharmaceutical composition according to claim 9, which is mL or 134 ± 26.1 ng / mL. The _Tmax of released amphetamine is in the range of about 80% to about 120% of the selected value, which is 3.41 ± 1.09 hours, 3.58 ± 1.18 hours or The pharmaceutical composition according to claim 9, which is 3.46 ± 1.34 hours.   The AUC of released amphetamine is in the range of about 80% to about 120% of the selected value, which is 845 ± 117 ng. h / mL, 1510 ± 242 ng. h / mL or 2157 ± 383 ng. The pharmaceutical composition according to claim 9, which is h / mL.   The pharmaceutical composition of claim 9, wherein the pharmaceutical composition comprises about 40 wt% to about 90 wt% of a diluent.   The pharmaceutical composition of claim 17, wherein the pharmaceutical composition comprises about 55 wt% to about 80 wt% diluent.   The pharmaceutical composition according to claim 18, wherein the diluent is microcrystalline cellulose.   The pharmaceutical composition of claim 9, wherein the pharmaceutical composition comprises about 1 wt% to about 10 wt% disintegrant.   The pharmaceutical composition of claim 20, wherein the pharmaceutical composition comprises about 1 wt% to about 5 wt% disintegrant.   The pharmaceutical composition according to claim 21, wherein the disintegrant is croscarmellose sodium.   The pharmaceutical composition of claim 9, wherein the pharmaceutical composition comprises less than about 5% by weight of a lubricant.   24. The pharmaceutical composition of claim 23, wherein the pharmaceutical composition comprises about 1% to about 1.5% by weight of a lubricant.   25. The pharmaceutical composition according to claim 24, wherein the lubricant is magnesium stearate. The pharmaceutical composition essentially comprises (a) about 10 mg to about 250 mg L-lysine-d-amphetamine dimesylate, and (b) about 40% to about 90% by weight microcrystalline cellulose;
10. The pharmaceutical composition of claim 9, comprising (c) about 1% to about 10% by weight croscarmellose sodium and (d) less than about 5% by weight magnesium stearate.   Essentially (a) about 30 mg L-lysine-d-amphetamine dimesylate, (b) about 151 mg microcrystalline cellulose, (c) about 4.69 mg croscarmellose sodium; 27. The pharmaceutical composition of claim 26, comprising d) about 1.88 mg of magnesium stearate.   Essentially, (a) about 50 mg L-lysine-d-amphetamine dimesylate, (b) about 70 mg microcrystalline cellulose, (c) about 3.12 mg croscarmellose sodium, ( 27. The pharmaceutical composition of claim 26, comprising d) about 1.88 mg of magnesium stearate.   Essentially: (a) about 70 mg L-lysine-d-amphetamine dimesylate; (b) about 98 mg microcrystalline cellulose; (c) about 4.37 mg croscarmellose sodium; 27. The pharmaceutical composition of claim 26, comprising d) about 2.63 mg magnesium stearate.   10. The oral dosage form containing the pharmaceutical composition according to claim 9, wherein the pharmaceutical composition is encapsulated in a size 3 gelatin capsule.   9. The pharmaceutical composition of claim 8, wherein the oral bioavailability of the released amphetamine is at least about 60% AUC.   32. The pharmaceutical composition of claim 31, wherein the oral bioavailability of the released amphetamine is at least about 80% AUC.   34. The pharmaceutical composition of claim 32, wherein the oral bioavailability of the released amphetamine is at least about 90% AUC.   34. The pharmaceutical composition of claim 33, wherein the oral bioavailability of the released amphetamine is at least about 95% AUC.   35. The pharmaceutical composition of claim 34, wherein the oral bioavailability of the released amphetamine is at least about 98% AUC.   9. The pharmaceutical composition of claim 8, wherein the parenteral bioavailability of the released amphetamine is less than about 70% AUC.   37. The pharmaceutical composition of claim 36, wherein the parenteral bioavailability of the released amphetamine is less than about 50% AUC.   38. The pharmaceutical composition of claim 37, wherein the parenteral bioavailability of the released amphetamine is less than about 15% AUC.   39. The pharmaceutical composition of claim 38, wherein the parenteral bioavailability of the released amphetamine is less than about 10% AUC.   40. The pharmaceutical composition of claim 39, wherein the parenteral bioavailability of the released amphetamine is less than about 1% AUC.   9. The oral bioavailability of released amphetamine is at least about 60% AUC and the parenteral bioavailability of released amphetamine is less than about 15% AUC. Pharmaceutical composition.

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