Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
  • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/20—Hypnotics; Sedatives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
  • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K4/00—Peptides having up to 20 amino acids in an undefined or only partially defined sequence; Derivatives thereof
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
  • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
  • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
  • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10S436/00—Chemistry: analytical and immunological testing
  • Y10S436/901—Drugs of abuse, e.g. narcotics, amphetamine
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
  • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
  • Y10T436/00—Chemistry: analytical and immunological testing
  • Y10T436/17—Nitrogen containing
  • Y10T436/173845—Amine and quaternary ammonium

Definitions

• the invention relates to amphetamine compounds, compositions and methods of delivery and use comprising amphetamine covalently bound to a chemical moiety.
• the invention relates to compounds comprised of amphetamine covalently bound to a chemical moiety in a manner that diminishes or eliminates pharmacological activity of amphetamine until released.
• the conjugates are stable in tests that simulate procedures likely to be used by illicit chemists in attempts to release amphetamine.
• the invention further provides for methods of therapeutic delivery of amphetamine compositions by oral administration. Additionally, release of amphetamine following oral administration occurs gradually over an extended period of time thereby eliminating spiking of drug levels. When taken at doses above the intended prescription, the bioavailability of amphetamine, including peak levels and total amount of drug absorbed, is substantially decreased.
• compositions are also resistant to abuse by parenteral routes of administration, such as intravenous "shooting", intranasal “snorting”, or inhalation "smoking", that are often employed in illicit use.
• parenteral routes of administration such as intravenous "shooting", intranasal “snorting", or inhalation "smoking", that are often employed in illicit use.
• the invention thus provides a stimulant based treatment for certain disorders, such as attention deficit hyperactivity disorder (ADHD), which is commonly treated with amphetamine.
• ADHD attention deficit hyperactivity disorder
• Treatment of ADHD with compositions of the invention results in substantially decreased abuse liability as compared to existing stimulant treatments.
• the invention is directed to amphetamine conjugate compounds, compositions, and methods of manufacture and use thereof.
• the invention is directed to an anti-abuse/sustained release formulation which maintains its therapeutic effectiveness when administered orally.
• the invention further relates to formulations which diminish or reduce the euphoric effect while maintaining therapeutically effective blood concentrations following oral administration.
• Amphetamine is prescribed for the treatment of various disorders, including attention deficit hyperactivity disorder (ADHD), obesity and narcolepsy.
• ADHD attention deficit hyperactivity disorder
• Amphetamine and methamphetamine stimulate the central nervous system and have been used medicinally to treat ADHD, narcolepsy and obesity.
• amphetamine and its derivatives e.g., amphetamine analogues
• amphetamine and its derivatives e.g., amphetamine analogues
• p-methoxyamphetamine, methylenedioxyamphetamine, 2,5-dimethoxy-4-methylamphetamine, 2,4,5-trimethoxyamphetamine and 3,4- methylenedioxymethamphetamine are also often abused.
• ADHD attention deficit hyperactivity disorder
• potent CNS stimulants have been used for several decades as a drug treatment given either alone or as an adjunct to behavioral therapy. While methylphenidate (Ritalin) has been the most frequently prescribed stimulant, the prototype of the class, amphetamine (alpha-methyl phenethylamine) has been used all along and increasingly so in recent years. (Bradley C, Bowen M, "Amphetamine (Benzedrine) therapy of children's behavior disorders.” American Journal of Orthopsychiatry 11: 92) (1941).
• the potential for abuse of amphetamines is a major drawback to its use.
• the high abuse potential has earned it Schedule II status according to the Controlled Substances Act (CSA).
• Schedule II classification is reserved for those drugs that have accepted medical use but have the highest potential for abuse.
• the abuse potential of amphetamine has been known for many years and the FDA requires the following black box warning in the package inserts of products: AMPHETAMINES HAVE A HIGH POTENTIAL FOR ABUSE.
• ADMINISTRATION OF AMPHETAMINES FOR PROLONGED PERIODS OF TIME MAY LEAD TO DRUG DEPENDENCE AND MUST BE AVOIDED.
• PARTICULAR ATTENTION SHOULD BE PAID TO THE POSSIBILITY OF SUBJECTS OBTAINING AMPHETAMINES FOR NONTHERAPEUTIC USE OR DISTRIBUTION TO OTHERS, AND THE DRUGS SHOULD BE PRESCRIBED OR DISPENSED SPARINGLY.
• Methylphenidate and amphetamine can be abused orally or the tablets can be crushed and snorted or dissolved in water and injected.
• the pattern of abuse is characterized by escalation in dose, frequent episodes of binge use followed by severe depression and an overpowering desire to continue the use of these drugs despite serious adverse medical and social consequences. Rendering this potent stimulant resistant to abuse, particularly by parenteral routes such as snorting or injecting, would provide considerable value to this otherwise effective and beneficial prescription medication.
• sustained release formulations typically contain drug particles mixed with or covered by a polymer material, or blend of materials, which are resistant to degradation or disintegration in the stomach and/or in the intestine for a selected period of time. Release of the drug may occur by leeching, erosion, rupture, diffusion or similar actions depending upon the nature of the polymer material or polymer blend used. Additionally, these formulations are subject to breakdown following relatively simple protocols which allows for abuse of the active ingredient.
• hydrophilic hydrocolloid gelling polymers such as hydroxypropyl methylcellulose, hydroxypropyl cellulose or Pullulan to formulate sustained release tablets or capsules. These polymers first form a gel when exposed to an aqueous environment of low pH thereby slowly diffusing the active medicament which is contained within the polymer matrix. When the gel enters a higher pH environment such as that found in the intestines, however, it dissolves resulting in a less controlled drug release.
• polymers which dissolve only at higher pHs such as acrylic resins, acrylic latex dispersions, cellulose acetate phthalate, and hydroxypropyl methylcellulose phthalate, either alone or in combination with hydrophilic polymers.
• formulations are prepared by combining the medicament with a finely divided powder of the hydrophilic polymer, or the hydrophilic and water-insoluble polymers. These ingredients are mixed and granulated with water or an organic solvent and the granulation is dried. The dry granulation is then usually further blended with various pharmaceutical additives and compressed into tablets. [014] Although these types of formulations have been successfully used to manufacture dosage forms which demonstrate sustained release properties, these formulations are subject to several shortcomings including uneven release and are subject to abuse.
• the invention provides covalent attachment of amphetamine and derivatives or analogs thereof to a variety of chemical moieties.
• the chemical moieties may include any substance which results in a prodrug form, i.e., a molecule which is converted into its active form in the body by normal metabolic processes.
• the chemical moieties may be for instance, amino acids, peptides, glycopeptides, carbohydrates, nucleosides, or vitamins.
• the chemical moiety is covalently attached either directly or indirectly through a linker to the amphetamine.
• the site of attachment is typically determined by the functional group(s) available on the amphetamine.
• the chemical moiety is a carrier peptide as defined herein.
• the carrier peptide may be attached to amphetamine through the carrier's N-terminus, C-terminus or side chain of an amino acid which may be either a single amino acid or part of a longer chain sequence (i.e. a dipeptide, tripeptide, an oligopeptide or a polypeptide).
• the carrier peptide is (i) an amino acid, (ii) a dipeptide, (iii) a tripeptide, (iv) an oligopeptide, or (v) polypeptide.
• the carrier peptide may also be (i) a homopolymer of a naturally occurring amino acid, (ii) a heteropolymer of two or more naturally occurring amino acids, (iii) a homopolymer of a synthetic amino acid, (iv) a heteropolymer of two or more synthetic amino acids, or (v) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
• a further embodiment of the carrier and/or conjugate is that the unattached portion of the carrier/conjugate may be in a free and unprotected state.
• synthetic amino acids with alkyl side chains are selected from alkyls of CpC ⁇ in length and more preferably from C ⁇ -C 6 in length.
• compositions of the invention provide amphetamine covalently attached to a chemical moiety which remains orally bioavailable.
• the bioavailability is a result of the hydrolysis of the covalent linkage following oral administration. Hydrolysis is time-dependent, thereby allowing amphetamine to become available in its active form over an extended period of time.
• the composition provides oral bioavailability which resembles the pharmacokinetics observed for extended release formulations.
• release of amphetamine is diminished or eliminated when delivered by parenteral routes.
• the compositions maintain their effectiveness and abuse resistance following the crushing of the tablet, capsule or other oral dosage form.
• conventional extended release formulations used to control the release of amphetamine through incorporation into matrices are subject to release of up to the entire amphetamine content immediately following crushing. When the content of the crushed tablet is injected or snorted, the large dose of amphetamine produces the "rush" effect sought by addicts.
• the amphetamine is attached to a single amino acid which is either naturally occurring or a synthetic amino acid.
• the amphetamine is attached to a dipeptide or tripeptide, which could be any combination of the naturally occurring amino acids and synthetic amino acids.
• the amino acids are selected from L-amino acids for digestion by proteases.
• the side chain attachment of amphetamine to the polypeptide or amino acid are selected from homopolymers or heteropolymers of glutamic acid, aspartic acid, serine, lysine, cysteine, threonine, asparagine, arginine, tyrosine, and glutamine.
• peptides include, Lys, Ser, Phe, Gly-Gly-Gly, Leu-Ser, Leu-Glu, homopolymers of Glu and Leu, and heteropolymers of (Glu)n- Leu-Ser.
• the composition is selected from Lys-Amp, Ser-Amp, Phe-Amp, and Gly-Gly-Gly-Amp.
• the invention provides a carrier and amphetamine which are bound to each other but otherwise unmodified in structure.
• This embodiment may further be described as the carrier having a free carboxy and/or amine terminal and/or side chain groups other than at the location of attachment for the amphetamine.
• the carrier whether a single amino acid, dipeptide, tripeptide, oligopeptide or polypeptide, comprises only naturally occurring amino acids.
• Another embodiment of the invention provides a method for delivering amphetamine dosage which prevents euphoria, comprising administering to a patient in need a composition formulated for oral dosage comprising amphetamine covalently attached to a chemical moiety wherein said blood levels of amphetamine maintain a therapeutically effect level but do not result in a euphoric effect.
• the covalent attachment of a chemical moiety substantially decreases the potential for overdose by decreasing the toxicity of amphetamine at doses above those considered therapeutic, while maintaining its pharmaceutical activity within a normal dose range.
• Covalent attachment of the chemical moiety may decrease or eliminate the pharmacological activity of amphetamine. Therefore, restoring activity requires release of the amphetamine from the chemical moiety.
• partial or complete saturation of processes responsible for amphetamine release may be reached thus diminishing or eliminating the release of harmful levels of active amphetamine.
• aspects of pharmacological activity, release, saturation are further depicted in figures 1-55.
• the covalent attachment of a chemical moiety substantially decreases the potential for overdose by decreasing the rate or overall amount of absorption of the amphetamine when given at doses above those considered therapeutic.
• the covalent attachment of a chemical moiety substantially decreases the potential for overdose by increasing the rate or overall amount of clearance of amphetamine when given at doses above those considered therapeutic.
• Another embodiment provides a method of treating a patient suffering from attention deficit hyperactivity disorder, narcolepsy or obesity comprising providing, administering, prescribing, etc. compositions of the invention.
• Another embodiment of the invention provides a method for delivering amphetamine, comprising providing a patient with a therapeutically effective amount of amphetamine covalently attached to a chemical moiety which provides a therapeutically bioequivalent AUC when compared to amphetamine alone but does not provide a C max which results in euphoria when taken orally.
• Fig. 6 Plasma concentrations of d-amphetamine from individual animals orally administered d-amphetamine or L-lysine-_Eamphetamine.
• Fig. 7 Plasma concentrations of ⁇ -amphetamine following oral administration of -i-amphetamine sulfate or L-lysine-d-amphetamine (1.5mg/kg d- amphetamine base) to rats (ELISA analysis).
• Fig. 8 Plasma concentrations of -Eamphetamine following oral administration of d-amphetamine sulfate or L-lysine-_Eamphetamine (3 mg/kg d- amphetamine base) to rats (ELISA analysis).
• Fig. 10 Plasma concentrations of J-amphetamine at 30-minutes post-dose for escalating doses of L-lysine- -amphetamine or _i-amphetamine sulfate (ELISA analysis).
• Fig. 11 Plasma concentrations of -amphetamine following oral administration of L-lysine- -amphetamine or J-amphetamine sulfate (60 mg/kg d- amphetamine base) to rats (ELISA analysis).
• Fig. 12 Plasma concentrations of d-amphetamine following intranasal administration of L-lysine- -amphetamine or -Eamphetamine sulfate (3 mg/kg d- amphetamine base) to rats (ELISA analysis).
• Fig. 13 Plasma concentrations of J-amphetamine following bolus intravenous administration of L-lysine- -amphetamine or d-amphetamine sulfate (1.5mg/kg d-amphetamine base) to rats (ELISA analysis).
• Fig. 14 Plasma concentrations of -i-amphetamine levels following oral administration of Dexadrine Spansule capsules, crushed Dexadrine Spansule capsules, or L-lysine-J-amphetamine (3 mg/kg J-amphetamine base) to rats (ELISA analysis).
• Figs. 15A-B Plasma concentrations of -amphetamine in ng/mL (Fig. 15A), and in uM (Fig. 15B), following oral administration of L-lysine- -amphetamine or -Eamphetamine sulfate (1.5mg/kg d- amphetamine base) to rats (LC/MS/MS analysis).
• Figs. 16A-B Plasma concentrations of -i-amphetamine in ng/mL (Fig. 16A), and in uM (Fig. 16B), following oral administration of L-lysine- -amphetamine or -amphetamine sulfate (3 mg/kg d-amphetamine base) to rats (LC/MS/MS analysis).
• Figs. 17A-B Plasma concentrations of -amphetamine in ng/mL (Fig. 17A), and in uM (Fig. 17B), following oral administration of L-lysine-_Eamphetarnine or -amphetamine sulfate (6 mg kg d-amphetamine base) to rats (LC/MS/MS analysis).
• Figs. 18A-B Plasma concentrations of Eamphetamine in ng/mL (Fig. 18A), and in uM (Fig. 18B), following oral administration of L-lysine--Eamphetamine or -i-amphetamine sulfate (12 mg/kg -i-amphetamine base) to rats (LC/MS/MS analysis).
• Figs. 19A-B Plasma concentrations of -i-amphetamine in ng/mL (Fig. 19 A), and in uM (Fig. 19B), following oral administration of or -amphetamine sulfate (60 mg/kg J-amphetamine base) to rats (LC/MS/MS analysis).
• Fig. 20 Comparative bioavailability (C max ) of L-lysine-d-amphetamine and J-amphetamine in proportion to escalating human equivalent doses in rats (mg/kg d- amphetamine base).
• Fig. 21 Comparative bioavailability (AU nf ) of L-lysine--i- amphetamine and -7-amphetamine in proportion to escalating doses in rats (mg/kg -i-amphetamine base).
• Fig. 22 Comparative Bioavailability (AUQnf) of L-lysine-J-amphetamine and -i-amphetamine in proportion to escalating human equivalent doses in rats (mg/kg .i-amphetamine base).
• Fig. 23 Plasma concentrations of -i-amphetamine following intranasal administration of L-lysine-ci-amphetamine or -i-amphetamine sulfate (3 mg/kg d- amphetamine base) to rats (LC/MS/MS analysis).
• Fig. 24 Plasma concentrations of ⁇ -amphetamine and L-lysine-_i- amphetamine in ng/mL (Fig. 24A), and in ⁇ M (Fig. 24B), following intranasal administration of L-lysine-ci-amphetamine or -i-amphetamine sulfate (3 mg/kg _i- amphetamine base) to rats (LC/MS/MS analysis).
• Fig. 25 Plasma concentrations of .i-amphetamine following bolus intravenous administration of L-lysine--i-amphetamine or -i-amphetamine sulfate (1.5 mg/kg -i-amphetamine base) to rats (LC/MS/MS analysis).
• Figs. 26A-B Plasma concentrations of d-amphetamine in ng/mL (Fig. 26A), and in ⁇ M (Fig. 26B), following intranasal administration of L-lysine--i- amphetamine or -i-amphetamine sulfate (3 mg/kg d-amphetamine base) to rats (LC/MS/MS analysis).
• Figs. 31A-B Individual plasma concentration time profile of L-lysine- - amphetamine following intravenous administration (Fig. 31 A) or oral administration (Fig. 3 IB) of L-lysine-_i-amphetamine in conscious male beagle dogs.
• the oral formulation used comprises solution and 0.2 mg/mL in water.
• Figs. 32A-B Individual plasma concentration time profile of -i-amphetamine following intravenous administration (Fig. 32A) or oral administration (Fig. 32B) of L-lysine-_i-amphetamine in conscious male beagle dogs.
• Fig. 33 Plasma concentrations of -i-amphetamine following oral administration of L-lysine-_i-amphetamine or .i-amphetamine sulfate (1.8 mg/kg d- amphetamine base) to male dogs.
• Fig. 34 Plasma concentrations of -i-amphetamine following oral administration of L-lysine-_i-amphetamine or _i-amphetamine sulfate (1.8 mg/kg _i- amphetamine base) to female dogs.
• Fig. 35 Mean blood pressure following intravenous bolus injection of increasing amounts of L-lysine--i-amphetamine or -amphetamine in male and female dogs.
• Fig. 36 Left ventricular blood pressure following intravenous bolus injection of increasing amounts of L-lysine-_i-amphetamine or _i-amphetamine in male and female dogs.
• Fig. 37 Locomotor activity of rats following oral administration of L-lysine- -i-amphetamine or -i-amphetamine (5 hour time-course).
• Fig. 38 Locomotor activity of rats following oral administration of L-lysine- -i-amphetamine or -i-amphetamine (12 hour time-course).
• Fig. 39 Locomotor activity of rats following intranasal administration of L- lysine-d-amphetamine or -i-amphetamine (1 hour time-course).
• Fig. 40 Locomotor activity of rats following intranasal administration (with carboxymethylcellulose) of L-lysine- -amphetamine or .i-amphetamine (2 hour time-course).
• Fig. 41 Locomotor activity of rats following intravenous administration of L-lysine-d-amphetamine or -i-amphetamine (3 hour time-course).
• Fig. 42 Intranasal bioavailability of abuse-resistant amphetamine amino acid-, di-, and tri-peptide conjugates (ELISA analysis).
• Fig. 43 Oral bioavailability of abuse-resistant amphetamine amino acid-, di-, and tri-peptide conjugates (ELISA analysis).
• Fig. 44 Intravenous bioavailability of an abuse-resistant amphetamine tripeptide conjugate (ELISA analysis).
• Fig. 45 Intranasal bioavailability of an abuse-resistant amphetamine amino acid conjugate (ELISA analysis).
• Fig. 46 Oral bioavailability of an abuse-resistant amphetamine amino acid conjugate (ELISA analysis).
• Fig. 47 Intravenous bioavailability of abuse-resistant amphetamine amino acid-, di-, and tri-peptide conjugates (ELISA analysis).
• Fig. 48 Intranasal bioavailability of an abuse-resistant amphetamine amino tri-peptide conjugate (ELISA analysis).
• Fig. 49 Intranasal bioavailability of abuse-resistant amphetamine amino acid-, and di-peptide conjugates (ELISA analysis).
• Fig. 50 Intranasal bioavailability of an abuse-resistant amphetamine dipeptide conjugate containing D- and L- amino acid isomers (ELISA analysis).
• Figs. 51A-B Plasma concentrations of .i-amphetamine and L-lysine-_i- amphetamine in ng/mL for the serum levels (Fig. 51 A), and in ng g for brain tissue (Fig. 5 IB), following oral administration of L-lysine--i-amphetamine or d- amphetamine sulfate (5mg/kg .i-amphetamine base) to rats. Serum and brain tissue J-amphetamine and L-lysine-_i-amphetamine concentrations were measured by LC/MS/MS (compound indicated in parenthesis).
• Figs. 52A-B Plasma J-amphetamine and L-lysine-_i-amphetamine levels (52A, ng/mL; 52B, ⁇ M) over a 72 hour period following oral administration of L- lysine-_i-amphetamine (25 mg L-lysine--i-amphetamine mesylate containing 7.37 mg J-amphetamine base) to humans (LC/MS/MS analysis).
• Figs. 53A-B Plasma J-amphetamine and L-lysine-_i-amphetamine levels (53A, ng/mL; 53B, ⁇ M) over a 72 hour period following oral administration of L- lysine-d-amphetamine (25 mg L-lysine- ⁇ i-amphetamine mesylate containing 22.1 mg d-amphetamine base) to humans (LC/MS/MS analysis).
• Figs. 54A-B Plasma ⁇ .-amphetamine levels (54A, 0-12 hours; 54B, 0-72 hours) following oral administration of L-lysine--i-amphetamine (75 mg L-lysine--i- amphetamine mesylate containing 22.1 mg ⁇ i-amphetamine base) or Adderall XR (35 mg containing 21.9 mg amphetamine base to humans (LC/MS/MS analysis).
• Figs. 55A-B Plasma J-amphetamine levels (55A, 0-12 hours; 55B, 0-72 hours) following oral administration of L-lysine-_i-amphetamine (75 mg L-lysine--i- amphetamine mesylate containing 22.1 mg .i-amphetamine base) or Dexadrine Spansule (30 mg containing 22.1 mg amphetamine base) to humans (LC/MS/MS analysis).
• L-lysine-_i-amphetamine 75 mg L-lysine--i- amphetamine mesylate containing 22.1 mg .i-amphetamine base
• Dexadrine Spansule 30 mg containing 22.1 mg amphetamine base
• the invention utilizes covalent modification of amphetamine to decrease its potential for causing overdose or abuse.
• the amphetamine is covalently modified in a manner that decreases its pharmacological activity, as compared to the unmodified amphetamine, at doses above those considered therapeutic. When given at lower doses, such as those intended for therapy, the covalently modified amphetamine retains pharmacological activity similar to that of the unmodified amphetamine.
• the covalent modification of amphetamine may comprise the attachment of any chemical moiety through conventional chemistry.
• compositions and methods of the invention provide reduced potential for overdose, reduced potential for abuse or addiction, and/or improve amphetamine's characteristics with regard to high toxicities or suboptimal release profiles.
• overdose protection results from a natural gating mechanism at the site of hydrolysis that limits the release of the active amphetamine from the prodrug at greater than therapeutically prescribed amounts. Therefore, abuse resistance is provided by limiting the "rush” or "high” available from the active amphetamine released by the prodrug and limiting the effectiveness of alternative routes of administration. Further, it is believed that the prodrug itself does not cross the blood brain barrier and is thus substantially absent from the central nervous system.
• peptide is meant to include a single amino acid, a dipeptide, a tripeptide, an oligopeptide, a polypeptide, or the carrier peptide. Oligopeptide is meant to include from 2 amino acids to 70 amino acids. Further, at times the invention is described as being an active agent attached to an amino acid, a dipeptide, a tripeptide, an oligopeptide, polypeptide or carrier peptide to illustrate specific embodiments for the active agent conjugate. Preferred lengths of the conjugates and other preferred embodiments are described herein.
• chemical moiety is meant to include at least amino acid(s), peptide(s), glycopeptide(s), carbohydrate(s), lipid(s), nucleoside(s), or vitamin(s).
• Carbohydrates include sugars, starches, cellulose, and related compounds. e.g., (CH 2 O) n , wherein n is an integer larger than 2 or C n (H O) n _ ⁇ , with n larger than 5. More specific examples include, for instance, fructose, glucose, lactose, maltose, sucrose, glyceraldehyde, dihydroxyacetone, erythrose, ribose, ribulose, xylulose, galactose, mannose, sedoheptulose, neuraminic acid, dextrin, and glycogen.
• a glycoprotein is a carbohydrate (or glycan) covalently linked to protein.
• the carbohydrate may be in the form of a monosaccharide, disaccharide(s), oligosaccharide(s), polysaccharide(s), or their derivatives (e.g. sulfo- or phospho- substituted).
• a glycopeptide is a carbohydrate linked to an oligopeptide composed of L- and/or D-amino acids.
• a glyco-amino-acid is a saccharide attached to a single amino acid by any kind of covalent bond.
• a glycosyl-amino- acid is a compound consisting of saccharide linked through a glycosyl linkage (O-, N- or S-) to an amino acid.
• composition refers broadly to any composition containing a described molecule conjugate(s).
• the composition may comprise a dry formulation, an aqueous solution, or a sterile composition.
• Compositions comprising the molecules described herein may be stored in freeze-dried form and may be associated with a stabilizing agent such as a carbohydrate.
• the composition may be deployed in an aqueous solution containing salts, e.g., NaCl, detergents, e.g., sodium dodecyl sulfate (SDS), and other components.
• salts e.g., NaCl
• detergents e.g., sodium dodecyl sulfate (SDS)
• Amphetamine shall mean any of the sympathomimetic phenethylamine derivatives which have central nervous system stimulant activity, such as but not limited to, amphetamine, methamphetamine, p-methoxyamphetamine, methylenedioxyamphetamine, 2,5-dimethoxy-4-methylamphetamine, 2,4,5- trimethoxyamphetamine and 3,4-methylenedioxymethamphetamine.
• Lys- Amp L-lysine--i-amphetamine, Lys-Amph, Lysine- Amphetamine, KAMP, K-amphetamine, or 2,6-diaminohexanoic acid-(l-methyl-2- phenylethyl)-amide
• Phe- Amp Phenylalanine- Amphetamine, FAMP, or 2-amino-3-phenylpropanoic acid-(l-methyl-2-phenylethyl)-amide
• Ser-Amp Serine-Amphetamine, SAMP, or 2-amino-3-hydroxylpropanoic acid-(l-methyl-2-phenylethyl)-amide
• Gly 3 -Amp GGG-Amphetamine, GGGAMP, or 2-Amino-N-( ⁇ [(l-methyl-2-phenyl-ethylcarbomyl)-methyl]-carb
• the amphetamine may be any of the above discussed stimulants.
• the amphetamine is dextroamphetamine or methylphenidate.
• the attached chemical moiety may be any chemical substance that decreases the pharmacological activity until amphetamine is released.
• the chemical moiety is a single amino acid, dipeptide or tripeptide.
• Amphetamine binds to specific sites to produce various effects (Hoebel, et al, 1989).
• the attachment of certain chemical moieties can therefore diminish or prevent binding to these biological target sites.
• the covalent modification may prevent stimulant activity by preventing the drug from crossing the blood-brain barrier.
• abso ⁇ tion of the composition into the brain is prevented or substantially diminished and/or delayed when delivered by routes other than oral administration.
• the attached chemical moiety may further comprise naturally occurring or synthetic substances. This includes, but is not limited to, the attachment of amphetamine to amino acids, peptides, lipids, carbohydrates, glycopeptides, nucleic acids or vitamins. These chemical moieties could be expected to affect delayed release in the gastrointestinal tract and prevent rapid onset of the desired activity, particularly when delivered by parenteral routes. (Hoebel, B. G., L. Hernandez, et al., "Microdialysis studies of brain norepinephrine, serotonin, and dopamine release during ingestive behavior. Theoretical and clinical implications.” Ann N Y Acad Sci 575: 171-91) (1989).
• the amino acid or peptide may comprise of one or more of the naturally occurring (L-) amino acids: alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, proline, phenylalanine, serine, tryptophan, threonine, tyrosine, and valine.
• L- naturally occurring amino acids
• the amino acid or peptide is comprised of one or more of the naturally occurring (D) amino acids: alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, proline, phenylalanine, serine, tryptophan, threonine, tyrosine, and valine.
• D naturally occurring amino acids
• the amino acid or peptide is comprised of one or more unnatural, non-standard or synthetic amino acids such as, aminohexanoic acid, biphenylalanine, cyclohexylalanine, cyclohexylglycine, diethylglycine, dipropylglycine, 2,3- diaminoproprionic acid, homophenylalanine, homoserine, homotyrosine, naphthylalanine, norleucine, ornithine, pheylalanine(4-fluoro), phenylalanine(2,3,4,5,6 pentafluoro), phenylalanine(4-nitro), phenylglycine, pipecolic acid, sarcosine, tetrahydroisoquinoline-3-carboxylic acid, and tert-leucine.
• aminohexanoic acid biphenylalanine, cyclohexylalanine, cyclohexylglycine
• the amino acid or peptide comprises of one or more amino acid alcohols, for example, serine and threonine.
• amino acid or peptide comprises of one or more N-methyl amino acids, for example, N- methyl aspartic acid.
• the specific carriers are utilized as a base short chain amino acid sequence and additional amino acids are added to the terminus or side chain.
• the above amino acid sequence may have one more of the amino acids substituted with one of the 20 naturally occurring amino acids. It is preferred that the substitution be with an amino acid which is similar in structure or charge compared to the amino acid in the sequence.
• isoleucine (IIe)[I] is structurally very similar to leucine (Leu)[L]
• tyrosine (Tyr)[Y] is similar to phenylalanine (Phe)[F]
• serine (Ser)[S] is similar to threonine (Thr)[T]
• cysteine (Cys)[C] is similar to methionine (Met)[M]
• alanine (Ala)[A] is similar to valine (Val)[V]
• lysine (Lys)[K] is similar to arginine (Arg)[R]
• asparagine (Asn)[N] is similar to glutamine (Gln)[Q]
• aspartic acid (Asp)[D] is similar to glutamic acid (Glu)[E]
• histidine (His)[H] is similar to proline (Pro)[P]
• glycine (Gly)[G] is structural
• the preferred amino acid substitutions may be selected according to hydrophilic properties (i.e., polarity) or other common characteristics associated with the 20 essential amino acids. While preferred embodiments utilize the 20 natural amino acids for their GRAS characteristics, it is recognized that minor substitutions along the amino acid chain which do not effect the essential characteristics of the amino acid chain are also contemplated.
• the carrier range is between one to 12 chemical moieties with one to 8 moieties being preferred.
• the number of chemical moieties is selected from 1, 2, 3, 4, 5, 6, or 7.
• the molecular weight of the carrier portion of the conjugate is below about 2,500, more preferably below about 1,000, and most preferably below about 500 kD.
• the chemical moiety is a single lysine. In another embodiment, the chemical moiety is a lysine bound to an additional chemical moiety.
• Another embodiment of the invention is a composition for preventing overdose comprising amphetamine which has been covalently bound to a chemical moiety.
• Another embodiment of the invention is a composition for safely delivering amphetamine comprising a therapeutically effective amount of said amphetamine which has been covalently bound to a chemical moiety wherein said chemical moiety reduces the rate of abso ⁇ tion of the amphetamine as compared to delivering the unbound amphetamine.
• Another embodiment of the invention is a composition for reducing amphetamine toxicity comprising amphetamine which has been covalently bound to a chemical moiety wherein said chemical moiety increases the rate of clearance when given at doses exceeding those within the therapeutic range of said amphetamine.
• Another embodiment of the invention is a composition for reducing amphetamine toxicity comprising amphetamine which has been covalently bound to a chemical moiety wherein said chemical moiety provides a serum release curve which does not increase above amphetamine's toxicity level when given at doses exceeding those within the therapeutic range of amphetamine.
• Another embodiment of the invention is a composition for reducing bioavailability of amphetamine comprising amphetamine covalently bound to a chemical moiety wherein said bound amphetamine maintains a steady-state serum release curve which provides a therapeutically effective bioavailability but prevents spiking or increased blood serum concentrations compared to unbound amphetamine when given at doses exceeding those within the therapeutic range of amphetamine.
• Another embodiment of the invention is a composition for preventing a C max spike for amphetamine when taken by mean other than orally while still providing a therapeutically effective bioavailability curve if taken orally comprising an amphetamine which has been covalently bound to a chemical moiety.
• Another embodiment of the invention is a composition for preventing a toxic release profile in a patient comprising amphetamine covalently bound to a chemical moiety wherein said bound amphetamine maintains a steady-state serum release curve which provides a therapeutically effective bioavailability but prevents spiking or increase blood serum concentrations compared to unbound amphetamine.
• Another embodiment of the invention is a compound of Formula I: A-X n -__- m wherein A is an amphetamine as defined herein; X is a chemical moiety as defined herein and n is between 1 and 50 and increments thereof; and Z is a further chemical moiety different from X which acts as an adjuvant and m is between 1 and 50 and increments thereof.
• n is between 1 and 50, more preferably between 1 and 10, and m is 0.
• Embodiments of the invention provide amphetamine compositions which allow the amphetamine to be therapeutically effective when delivered at the proper dosage but reduces the rate of abso ⁇ tion or extent of bioavailability of the amphetamine when given at doses exceeding those within the therapeutic range of amphetamine.
• Embodiments of the invention also provide amphetamine compositions wherein the covalently bound chemical moiety increases the rate of clearance of amphetamine when given at doses exceeding those within the therapeutic range of the amphetamine.
• the amphetamine compositions have substantially lower toxicity compared to unbound amphetamine.
• the amphetamine compositions reduce or eliminate the possibility of overdose by oral administration.
• the amphetamine compositions reduce or eliminate the possibility of overdose by intranasal administration.
• the amphetamine compositions reduce or eliminate the possibility of overdose by injection.
• the amphetamine compositions reduce or eliminate the possibility of overdose by inhalation.
• the amphetamine conjugates of the invention may further comprise a polymer blend which comprises a hydrophilic polymer and/or a water-insoluble polymer.
• the polymers may be used according to industry standards to further enhance the sustained release/abuse resistant properties of the amphetamine conjugate without reducing the abuse resistance.
• a composition might include: about 70% to about 100% amphetamine conjugate by weight, from about 0.01% to about 10% of a hydrophilic polymer (e.g. hydroxypropyl methylcellulose), from about 0.01% to about 2.5% of a water- insoluble polymer (e.g. acrylic resin), from about 0.01% to about 1.5% of additives (e.g. magnesium stearate), and from about 0.01% to about 1% colorant by weight.
• a hydrophilic polymer e.g. hydroxypropyl methylcellulose
• a water- insoluble polymer e.g. acrylic resin
• additives e.g. magnesium stearate
• Hydrophilic polymers suitable for use in the sustained release formulations include one or more natural or partially or totally synthetic hydrophilic gums such as acacia, gum tragacanth, locust bean gum, guar gum, or karaya gum, modified cellulosic substances such as methylcellulose, hydroxomethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethylcellulose, carboxymethylcellulose; proteinaceous substances such as agar, pectin, carrageen, and alginates; and other hydrophilic polymers such as carboxypolymethylene, gelatin, casein, zein, bentonite, magnesium aluminum silicate, polysaccharides, modified starch derivatives, and other hydrophilic polymers known to those of skill in the art, or a combination of such polymers.
• hydrophilic gums such as acacia, gum tragacanth, locust bean gum, guar gum, or karaya gum
• modified cellulosic substances
• hydrophilic polymers gel and would dissolve slowly in aqueous acidic media thereby allowing the amphetamine conjugate to diffuse from the gel in the stomach. When the gel reaches the intestines it would dissolve in controlled quantities in the higher pH medium to allow further sustained release.
• Preferred hydrophilic polymers are the hydroxypropyl methylcelluloses such as those manufactured by The Dow Chemical Company and known as Methocel ethers, such as Methocel E10M.
• compositions may further comprise pharmaceutical additives including, but not limited to: lubricants such as magnesium stearate, calcium stearate, zinc stearate, powdered stearic acid, hydrogenated vegetable oils, talc, polyethylene glycol, and mineral oil; colorants such as Emerald Green Lake, FD&C Red No. 40, FD&C Yellow No. 6, D&C Yellow No. 10, or FD&C Blue No.
• lubricants such as magnesium stearate, calcium stearate, zinc stearate, powdered stearic acid, hydrogenated vegetable oils, talc, polyethylene glycol, and mineral oil
• colorants such as Emerald Green Lake, FD&C Red No. 40, FD&C Yellow No. 6, D&C Yellow No. 10, or FD&C Blue No.
• a sustained release formulation further comprises magnesium stearate
• An amphetamine conjugate which is further formulated with excipients, may be manufactured according to any appropriate method known to those of skill in the art of pharmaceutical manufacture.
• the amphetamine-conjugate and a hydrophilic polymer may be mixed in a mixer with an aliquot of water to form a wet granulation.
• the granulation may be dried to obtain hydrophilic polymer encapsulated granules of amphetamine-conjugate.
• the resulting granulation may be milled, screened, then blended with various pharmaceutical additives such as, water insoluble polymers, and/or additional hydrophilic polymers.
• the formulation may then tableted and may further be film coated with a protective coating which rapidly dissolves or disperses in gastric juices.
• the amphetamine conjugate controls the release of amphetamine into the digestive tract over an extended period of time resulting in an improved profile when compared to immediate release combinations and prevention of abuse without the addition of the above additives.
• no further sustained release additives are required to achieve a blunted or reduced pharmacokinetic curve (e.g., reduced euphoric effect) while achieving therapeutically effective amounts of amphetamine release when taken orally.
• the compounds of the invention can be administered by a variety of dosage forms. Any biologically-acceptable dosage form known to persons of ordinary skill in the art, and combinations thereof, are contemplated. Examples of preferred dosage forms include, without limitation, chewable tablets, quick dissolve tablets, effervescent tablets, reconstitutable powders, elixirs, liquids, solutions, suspensions, emulsions, tablets, multi-layer tablets, bi-layer tablets, capsules, soft gelatin capsules, hard gelatin capsules, caplets, lozenges, chewable lozenges, beads, powders, granules, particles, microparticles, dispersible granules, cachets and combinations thereof.
• the most effective means for delivering the abuse-resistant compounds of the invention is orally, to permit maximum release of the amphetamine, and provide therapeutic effectiveness and/or sustained release while maintaining abuse resistance.
• the amphetamine is released into circulation, preferably over an extended period of time as compared to amphetamine alone.
• Formulations of the invention suitable for oral administration can be presented as discrete units, such as capsules, caplets or tablets. These oral formulations also can comprise a solution or a suspension in an aqueous liquid or a non-aqueous liquid.
• the formulation can be an emulsion, such as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
• the oils can be administered by adding the purified and sterilized liquids to a prepared enteral formula, which is then placed in the feeding tube of a patient who is unable to swallow.
• Soft gel or soft gelatin capsules may be prepared, for example by dispersing the formulation in an appropriate vehicle (vegetable oils are commonly used) to form a high viscosity mixture. This mixture is then encapsulated with a gelatin based film using technology and machinery known to those in the soft gel industry. The industrial units so formed are then dried to constant weight.
• an appropriate vehicle vegetable oils are commonly used
• Chewable tablets for example may be prepared by mixing the formulations with excipients designed to form a relatively soft, flavored, tablet dosage form that is intended to be chewed rather than swallowed.
• Conventional tablet machinery and procedures that is both direct compression and granulation, i.e., or slugging, before compression, can be utilized.
• Those individuals involved in pharmaceutical solid dosage form production are versed in the processes and the machinery used as the chewable dosage form is a very common dosage form in the pharmaceutical industry.
• Film-coated tablets for example may be prepared by coating tablets using techniques such as rotating pan coating methods or air suspension methods to deposit a contiguous film layer on a tablet.
• Compressed tablets for example may be prepared by mixing the formulation with excipients intended to add binding qualities to disintegration qualities. The mixture is either directly compressed or granulated then compressed using methods and machinery known to those in the industry. The resultant compressed tablet dosage units are then packaged according to market need, i.e., unit dose, rolls, bulk bottles, blister packs, etc.
• the invention also contemplates the use of biologically-acceptable carriers which may be prepared from a wide range of materials.
• materials include diluents, binders and adhesives, lubricants, plasticizers, disintegrants, colorants, bulking substances, flavorings, sweeteners and miscellaneous materials such as buffers and adsorbents in order to prepare a particular medicated composition.
• Binders may be selected from a wide range of materials such as hydroxypropylmethylcellulose, ethylcellulose, or other suitable cellulose derivatives, povidone, acrylic and methacrylic acid co-polymers, pharmaceutical glaze, gums, milk derivatives, such as whey, starches, and derivatives, as well as other conventional binders known to persons skilled in the art.
• Exemplary non-limiting solvents are water, ethanol, isopropyl alcohol, methylene chloride or mixtures and combinations thereof.
• Exemplary non-limiting bulking substances include sugar, lactose, gelatin, starch, and silicon dioxide.
• Preferred plasticizers may be selected from the group consisting of diethyl phthalate, diethyl sebacate, triethyl citrate, cronotic acid, propylene glycol, butyl phthalate, dibutyl sebacate, castor oil and mixtures thereof, without limitation.
• the plasticizers may be hydrophobic as well as hydrophilic in nature.
• Water-insoluble hydrophobic substances such as diethyl phthalate, diethyl sebacate and castor oil are used to delay the release of water-soluble vitamins, such as vitamin B6 and vitamin C.
• hydrophilic plasticizers are used when water- insoluble vitamins are employed which aid in dissolving the encapsulated film, making channels in the surface, which aid in nutritional composition release.
• the formulations of this invention can include other suitable agents such as flavoring agents, preservatives and antioxidants.
• antioxidants would be food acceptable and could include vitamin E, carotene, BHT or other antioxidants known to those of skill in the art.
• Other compounds which may be included by admixture are, for example, medically inert ingredients, e.g., solid and liquid diluent, such as lactose, dextrose, saccharose, cellulose, starch or calcium phosphate for tablets or capsules, olive oil or ethyl oleate for soft capsules and water or vegetable oil for suspensions or emulsions; lubricating agents such as silica, talc, stearic acid, magnesium or calcium stearate and/or polyethylene glycols; gelling agents such as colloidal clays; thickening agents such as gum tragacanth or sodium alginate, binding agents such as starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; disintegrating agents such as starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuff; sweeteners; wetting agents such as lecithin,
• fine powders or granules containing diluting, dispersing and/or surface-active agents may be presented in a draught, in water or a syrup, in capsules or sachets in the dry state, in a non-aqueous suspension wherein suspending agents may be included, or in a suspension in water or a syrup.
• suspending agents may be included, or in a suspension in water or a syrup.
• flavoring, preserving, suspending, thickening or emulsifying agents can be included.
• Liquid dispersions for oral administration may be syrups, emulsions or suspensions.
• the syrups may contain as carrier, for example, saccharose or saccharose with glycerol and/or mannitol and/or sorbitol.
• the suspensions and the emulsions may contain a carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol.
• units may contain from 5 mg to 500 mg, but more usually from 10 mg to 250 mg, of one or more of the compounds of the invention.
• the dosage form may combine any forms of release known to persons of ordinary skill in the art. These include immediate release, extended release, pulse release, variable release, controlled release, timed release, sustained release, delayed release, long acting, and combinations thereof.
• immediate release extended release, pulse release, variable release, controlled release, timed release, sustained release, delayed release, long acting characteristics and combinations thereof.
• compositions of the invention may be administered in a partial, i.e., fractional dose, one or more times during a 24 hour period, a single dose during a 24 hour period of time, a double dose during a 24 hour period of time, or more than a double dose during a 24 hour period of time.
• Fractional, double or other multiple doses may be taken simultaneously or at different times during the 24 hour period.
• the doses may be uneven doses with regard to one another or with regard to the individual components at different administration times.
• compositions of the invention may be provided in a blister pack or other such pharmaceutical package.
• the compositions of the present inventive subject matter may further include or be accompanied by indicia allowing individuals to identify the compositions as products for a prescribed treatment.
• the indicia may additionally include an indication of the above specified time periods for administering the compositions.
• the indicia may be time indicia indicating a specific or general time of day for administration of the composition, or the indicia may be a day indicia indicating a day of the week for administration of the composition.
• the blister pack or other combination package may also include a second pharmaceutical product.
• compositions of the invention can be demonstrated using standard pharmacological models that are known in the art.
• inventive compositions can be inco ⁇ orated or encapsulated in a suitable polymer matrix or membrane for site-specific delivery, or can be functionalized with specific targeting agents capable of effecting site specific delivery. These techniques, as well as other drug delivery techniques, are well known in the art.
• the solubility and dissolution rate of the composition is substantially changed under physiological conditions encountered in the intestine, at mucosal surfaces, or in the bloodstream.
• the solubility and dissolution rate substantially decrease the bioavailability of the amphetamine, particularly at doses above those intended for therapy.
• the decrease in bioavailability occurs upon intranasal administration.
• the decrease in bioavailability occurs upon intravenous administration.
• the toxicity of the amphetamine conjugate is substantially lower than that of the unbound amphetamine.
• the covalently bound chemical moiety reduces or eliminates the possibility of overdose by oral administration.
• the covalently bound chemical moiety reduces or eliminates the possibility of overdose or abuse by intranasal administration.
• the covalently bound chemical moiety reduces or eliminates the possibility of overdose or abuse by injection.
• the invention further provides methods for altering amphetamines in a manner that decreases their potential for abuse.
• Methods of the invention provide various ways to regulate pharmaceutical dosage through covalent attachment of amphetamine to different chemical moieties.
• One embodiment provides a method of preventing overdose comprising administering to an individual amphetamine which has been covalently bound to a chemical moiety.
• Another embodiment provides a method of safely delivering amphetamine comprising providing a therapeutically effective amount of a amphetamine which has been covalently bound to a chemical moiety wherein the chemical moiety reduces the rate of abso ⁇ tion of amphetamine as compared to delivering the unbound amphetamine.
• Another embodiment provides a method of reducing amphetamine toxicity comprising providing a patient with amphetamine which has been covalently bound to a chemical moiety, wherein the chemical moiety increases the rate of clearance of pharmacologically active amphetamine (i.e., released amphetamine) when given at doses exceeding those within the therapeutic range of amphetamine.
• pharmacologically active amphetamine i.e., released amphetamine
• Another embodiment provides a method of reducing amphetamine toxicity comprising providing a patient with amphetamine which has been covalently bound to a chemical moiety, wherein the chemical moiety provides a serum release curve which does not increase above the amphetamine's toxicity level when given at doses exceeding those within the therapeutic range for the unbound amphetamine.
• Another embodiment provides a method of reducing bioavailability of amphetamine comprising providing amphetamine covalently bound to a chemical moiety, wherein the bound amphetamine maintains a steady-state serum release curve which provides a therapeutically effective bioavailability but prevents spiking or increase blood serum concentrations compared to unbound amphetamine when given at doses exceeding those within the therapeutic range for the unbound amphetamine.
• Another embodiment provides a method of preventing a C max spike for amphetamine while still providing a therapeutically effective bioavailability curve comprising providing amphetamine which has been covalently bound to a chemical moiety.
• methods of the invention provide bioavailability curves similar to those of Figures 6-55.
• Another embodiment provides a method for preventing a toxic release profile in a patient comprising administering to a patient amphetamine covalently bound to a chemical moiety, wherein said bound amphetamine maintains a steady-state serum release curve which provides a therapeutically effective bioavailability but prevents spiking or increase blood serum concentrations compared to unbound amphetamine, particularly when taken at doses above prescribed amounts.
• Another embodiment of the invention is a method for reducing or preventing abuse of amphetamine comprising providing, administering, or prescribing said composition to a human in need thereof, wherein said composition comprises a chemical moiety covalently attached to amphetamine such that the pharmacological activity of amphetamine is decreased when the composition is used in a manner inconsistent with the manufacturer's instructions.
• Another embodiment of the invention is a method for reducing or preventing abuse of amphetamine comprising consuming an amphetamine conjugate of the invention, wherein said conjugate comprises a chemical moiety covalently attached to amphetamine such that the pharmacological activity of amphetamine is substantially decreased when the composition is used in a manner inconsistent with the manufacturer's instructions.
• Another embodiment of the invention is a method of preventing overdose of amphetamine comprising providing, administering, or prescribing an amphetamine composition of the invention to a human in need thereof, wherein said composition comprises a chemical moiety covalently attached to amphetamine in a manner that decreases the potential of overdose from amphetamine.
• Another embodiment of the invention is a method of preventing overdose of amphetamine, comprising consuming an amphetamine composition of the invention, wherein said composition comprises a chemical moiety covalently attached to amphetamine in a manner that decreases the potential of overdose from amphetamine.
• Another embodiment of the invention is a method for reducing or preventing the euphoric effect of amphetamine comprising providing, administering, or prescribing said to a human in need thereof, a composition comprising a chemical moiety covalently attached to amphetamine such that the pharmacological activity of amphetamine is decreased when the composition is used in a manner inconsistent with the manufacturer's instructions.
• Another embodiment of the invention is a method for reducing or preventing the euphoric effect of amphetamine, comprising consuming a said composition comprising a chemical moiety covalently attached to amphetamine such that the pharmacological activity of amphetamine is decreased when the composition is used in a manner inconsistent with the manufacturer's instructions.
• Another embodiment of the invention is any of the preceding methods wherein said amphetamine composition is adapted for oral administration, and wherein said amphetamine is resistant to release from said chemical moiety when the composition is administered parenterally, such as intranasally or intravenously.
• said amphetamine may be released from said chemical moiety in the presence of acid and/or enzymes present in the stomach, intestinal tract, or blood serum.
• said composition may be in the form of a tablet, capsule, oral solution, oral suspension, or other oral dosage form discussed herein.
• the chemical moiety may be one or more amino acid(s), oligopeptide(s), polypeptide(s), carbohydrate(s), glycopeptide(s), nucleic acid(s), or vitamin(s).
• said chemical moiety is an amino acid, oligopeptide, or polypeptide or carbohydrate.
• said polypeptide comprises fewer than 70 amino acids, fewer than 50 amino acids, fewer than 10 amino acids, or fewer than 4 amino acids.
• the chemical moiety is an amino acid, preferably said amino acid is lysine, serine, phenylalanine or glycine. Most preferably, said amino acid is lysine.
• covalent attachment may comprise an ester or carbonate bond.
• the composition may yield a therapeutic effect without substantial euphoria.
• said amphetamine composition provides a therapeutically bioequivalent AUC when compared to amphetamine alone but does provide a C max which results in euphoria.
• Another embodiment of the invention is a method for reducing or preventing abuse of amphetamine comprising orally administering an amphetamine composition of the invention to a human in need thereof, wherein said composition comprises an amino acid or peptide (e.g., lysine) covalently attached to amphetamine such that the pharmacological activity of amphetamine is decreased when the composition is used in a manner inconsistent with the manufacturer's instructions.
• an amino acid or peptide e.g., lysine
• Another embodiment is a method of preventing overdose of a amphetamine comprising orally administering an amphetamine composition to a human in need thereof, wherein said composition comprises an amino acid or peptide (e.g., lysine) covalently attached to amphetamine in a manner that decreases the potential of amphetamine to result in overdose.
• an amino acid or peptide e.g., lysine
• Another embodiment is a method for reducing or preventing the euphoric effect of amphetamine comprising orally administering an amphetamine composition to a human in need thereof, wherein said composition comprises an amino acid or peptide (e.g., lysine) covalently attached to amphetamine such that the pharmacological activity of amphetamine is decreased when the composition is used in a manner inconsistent with the manufacturer's instructions.
• an amino acid or peptide e.g., lysine
• the following properties may be achieved through bonding amphetamine to the chemical moiety.
• the toxicity of the compound may be lower than that of the amphetamine when amphetamine is delivered in its unbound state or as a salt thereof.
• the possibility of overdose by oral administration is reduced or eliminated.
• the possibility of overdose by intranasal administration is reduced or eliminated.
• the possibility of overdose by injection administration is reduced or eliminated.
• Another embodiment of the invention provides methods of treating various diseases or conditions comprising administering compounds or compositions of the invention which further comprise commonly prescribed active agents for the respective illness or diseases wherein the amphetamine is covalently attached to a chemical moiety.
• one embodiment of the invention comprises a method of treating attention deficit hyperactivity disorder (ADHD) comprising administering to a patient amphetamine covalently bound to a chemical moiety.
• Another embodiment provides a method of treating attention deficit disorder (ADD) comprising administering to a patient compounds or compositions of the invention, amphetamine covalently bound to a chemical moiety.
• ADHD attention deficit hyperactivity disorder
• ADD attention deficit disorder
• Another embodiment of the invention provides a method of treating narcolepsy comprising administering to a patient compounds or compositions of the invention.
• Ser-Amp was synthesized by a similar method (see Fig. 3) except the amino acid starting material was Boc-Ser(O-tBu)-OSu and the deprotection was done using a solution of trifluoroacetic acid instead of HCl.
• Phe-Amp was synthesized by a similar method (see Fig. 4) except the amino acid starting material was Boc-Phe-OSu.
• Example 6 illustrates that when lysine is conjugated to the active agent amphetamine the peak levels of amphetamine are decreased while bioavailability is maintained approximately equal to amphetamine.
• the bioavailability of amphetamine released from L-lysine-_i-amphetamine is similar to that of amphetamine sulfate at the equivalent dose, thus L-lysine-_i-amphetamine maintains its therapeutic value.
• the gradual release of amphetamine from L-lysine-d- amphetamine and decrease in peak levels reduce the possibility of overdose.
• Example 7 Oral bioavailability of L-lysine-d-amphetamine at various doses approximating a range of therapeutic human doses
• Example 8 Oral bioavailability of L-lysine-d-amphetamine at various doses approximating a range of therapeutic human doses compared to a suprapharmacological dose
• Example 9 Decreased oral bioavailability of L-lysine-d-amphetamine at a high dose
• FIG. 11 An additional oral PK study illustrated in Fig. 11 shows the d-amphetamine blood levels of a 60 mg/kg dose over an 8 h time course.
• d- amphetamine blood levels quickly reached a very high level and 8 of 12 animals either died or were sacrificed due to acute symptoms of toxicity.
• Blood levels (Tables 10-11) of animals administered L-lysine-d-amphetamine did not peak until 5 hours and reached only a fraction of the levels of the animals receiving amphetamine (note: valid data past 3 h for d-amphetamine could not be determined due to death and sacrifice of animals).
• Example 10 Oral Bioavailability of d-amphetamine following administration of an extended release formulation (intact or crushed) or L-lysine-d-amphetamine
• Example 10 illustrates the advantage of the invention over conventional controlled release formulations of d-amphetamine.
• Example 11 Decreased intranasal bioavailability of L-lysine-d-amphetamine vs. amphetamine
• Male Sprague-Dawley rats were dosed by intranasal administration with 3 mg/kg of amphetamine sulfate or L-lysine-d-amphetamine hydrochloride containing the equivalent amounts of d-amphetamine.
• L-lysine-d-amphetamine did not release any significant amount of d-amphetamine into circulation by IN administration.
• Pharmacokinetic parameters for IN administration of L-lysine-d-amphetamine are summarized in Table 14.
• Example 11 illustrates that when lysine is conjugated to the active agent d- amphetamine the bioavailability by the intranasal route is substantially decreased thereby diminishing the ability to abuse the drug by this route.
• Example 12 Intravenous bioavailability of amphetamine vs. L-lysine-d- amphetamine
• Table 15 Pharmacokinetic Parameters of d-amphetamine vs. L-lysine-d- amphetamine by IV Administration.
• Example 12 illustrates that when lysine is conjugated to the active agent amphetamine the bioavailability of amphetamine by the intravenous route is substantially decreased, thereby diminishing the ability to abuse the drug by this route.
• Example 13 Oral Bioavaialability of L-lysine-d-amphetamine compared to d- amphetamine at escalating doses.
• T max ranged from 0.25 to 3 hours and peak concentrations occu ⁇ ed earlier than for d- amphetamine in L-lysine-d-amphetamine dosed rats. L-lysine-d-amphetamine was cleared more rapidly than d-amphetamine with nearly undetectable concentrations by 8 hours at the lowest dose.
• T max for d-amphetamine from L-lysine-d-amphetamine ranged from 1.5 to 5 hours as compared to 0.5 to 1.5 following administration of d-amphetamine sulfate. The difference in time to reach maximum concentration was greater at higher doses.
• C max of d-amphetamine following oral delivery of L-lysine-d-amphetamine was reduced by approximately half as compared to C max following d-amphetamine sulfate administration at doses of 1.5 to 6 mg/kg, approximating human equivalent doses (HEDs) in the therapeutic range (HED d-amphetamine sulfate; 19.9 to 39.9 mg).
• HEDs are defined as the equivalent dose for a 60 kg person in accordance to the body surface area of the animal model.
• the adjustment factor for rats is 6.2.
• C max was reduced by 73 and 84 percent, respectively, as compared to d-amphetamine sulfate.
• AUCs of d- amphetamine following oral administration of L-lysine-d-amphetamine were similar to those of d-amphetamine sulfate at lower doses.
• Example 14 Intranasal Bioavailability of L-lysine-d-amphetamine compared to d- amphetamine.
• T max of d-amphetamine concentration was delayed substantially for L-lysine-d-amphetamine (60 minutes) as compared to T max of d-amphetamine sulfate (5 minutes), again reflecting the gradual hydrolysis of L-lysine-d-amphetamine.
• a high concentration of intact L-lysine-d- amphetamine was detected following intranasal dosing suggesting that the large decrease in bioavailability of d-amphetamine was due to minimal hydrolysis of L- lysine-d-amphetamine when delivered by this route. It appears that only minimal amounts of d-amphetamine can be delivered by intranasal administration of L- lysine-d-amphetamine.
• Example 15 Intravenous Bioavaialability of L-lysine-d-amphetamine compared to d-amphetamine.
• C max of d-amphetamine following L-lysine-d-amphetamine administration was only about one-fourth that of the equivalent amount of d- amphetamine with values of 99.5 and 420.2, respectively.
• T max of d-amphetamine concentration was delayed substantially for L-lysine-d-amphetamine (30 minutes) as compared to T max of d-amphetamine sulfate (5 minutes), reflecting the gradual hydrolysis of L-lysine-d-amphetamine.
• the bioavailability of d- amphetamine by the intravenous route is substantially decreased and delayed when given as L-lysine-d-amphetamine.
• bioavailability is less than that obtained by oral administration of the equivalent dose of L-lysine-d-amphetamine.
• Tables 15-17 summarize the pharmacokinetic parameters of d-amphetamine following oral, intransal, or bolus intravenous administration of d-amphetamine or L-lysine-d-amphetamine.
• Tables 18-20 summarize the pharmacokinetic parameters of L-lysine-d- amphetamine following oral, bolus intravenous, or intransal administration of L- lysine-d-amphetamine.
• Tables 21 and 22 summarize the percent bioavailability of d-amphetamine following oral, intranasal, or intravenous administration of L-lysine-d-amphetamine as compared to d-amphetamine sulfate.
• Tables 23-28 summarize the time-course concentrations of d-amphetamine and L-lysine-d-amphetamine following oral, intranasal or intravenous administration of either d-amphetamine or L-lysine-d-amphetamine.
• Table 23 Time-course Concentrations of d-amphetamine Following Bolus Intravenous Administration of L-lysine-d-amphetamine or d-amphetamine Sulfate at Doses Containing 1.5 mg/kg d-amphetamine Base.
• the mg units in the dose concentration and dose level refer to the free base form of test article.
• Administration of the Test Article [203] Oral: The test article was administered to each animal via a single oral gavage. On Day 1, animals received the oral dose by gavage using an esophageal tube attached to a syringe. Dosing tubes were flushed with approximately 20 mL tap water to ensure the required dosing solution was delivered. [204] Intravenous: On Day 8, animals received L-lysine-d-amphetamine as a single 30-minute intravenous infusion into a cephalic vein. Sample Collection: [205] Dosing Formulations: Post-dosing, remaining dosing formulation was saved and stored frozen.
• Plasma samples were analyzed for L-lysine-d-amphetamine and d- amphetamine using a validated LC-MS/MS method with an LLOQ of 1 ng/mL for both analytes.
• the AUC(O-inf) was calculated as the sum of AUC(O-t) and Cpred/ ⁇ z, where Cpred was the predicted concentration at the time of the last quantifiable concentration.
• the plasma clearance (CL/F) was determined as the ratio of Dose/ AUC (0-inf).
• the mean residence time (MRT) was calculated as the ratio of AUMC(0-inf)/AUC (0- inf), where AUMC(O-inf) was the area under the first moment curve from the time zero to infinity.
• the volume of distribution at steady state (V ss ) was estimated as CL*MRT.
• Half-life was calculated as ln2/ ⁇ z.
• the oral bioavailability (F) was calculated as the ratio of AUC(O-inf) following oral dosing to AUC(O-inf) following intravenous dosing.
• Descriptive statistics (mean and standard deviation) of the pharmacokinetic parameters were calculated using Microsoft Excel.
• the objectives of this study were to characterize the pharmacokinetics of L- lysine-d-amphetamine and d-amphetamine following administration of L-lysine-d- amphetamine in male beagle dogs.
• L- lysine-d-amphetamine was administered to 3 male beagle dogs orally (2 mg/kg) and intravenously (2 mg/kg, 30-minute infusion).
• Blood samples were collected up to 24 and 72 hour after the intravenous and oral does, respectively. Plasma samples were analyzed using a LC-MS/MS assay which provided an LLOQ of 1 ng/mL for both analytes.
• the mean clearance value was 2087 mIJh»kg (34.8 mIJmin»kg) and was similar to the hepatic blood flow in the dog (40 mL/min»kg). Consequently, L-lysine-d-amphetamine is a moderate to high hepatic extraction compound with significant first pass effects (including the conversion to d-amphetamine) following oral administration.
• L-lysine-d-amphetamine was rapidly absorbed after oral administration with T max at 0.5 hours in all three dogs. Mean absolute oral bioavailablity was 33%. Since significant first pass effects are expected for L-lysine-d-amphetamine, a 33% bioavailability suggests that L-lysine-d-amphetamine is very well absorbed in the dog. The apparent terminal half-life was 0.39 hours, indicating rapid elimination, as observed following intravneous administration.
• C max maximum observed plasma concentration
• AUC(O-t) total area under the plasma concentration versus time curve from 0 to the last data point
• AUC(O-inf) total area under the plasma concentration versus time curve
• t ⁇ 2 apparent terminal half-life
• CL clearance following iv administration
• MRT mean residence time
• Vss volume of distribution at steady state.
• C max maximum observed plasma concentration
• T max time when C ma ⁇ observed
• AUC(O-t) total area under the plasma concentration versus time curve from 0 to the last data point
• AUC(O-inf) total area under the plasma concentration versus time curve
• t 1 apparent terminal half-life
• CL/F oral clearance
• MRT mean residence time
• F bioavailability.
• Dose Route Oral Dose : 2 mg/kg of L-lysine-_/-amphetamine (free form)
• C max maximum observed plasma concentration
• T m . x time when C m0 ⁇ observed
• AUC(O-t) total area under the plasma concentration versus time curve from 0 to the last data point
• AUC(O-inf) total area under the plasma concentration versus time curve
• t tn apparent terminal half-life
• CLF oral clearance
• MRT mean residence time
• F bioavailability.
• Table 35 Pharmacokinetics of d-amphetamine in Male Beagle Dogs Following Oral Administration of L-lysine-d-amphetamine or d-amphetamine sulfate (1.8 mg/kg d-amphetamine base).
• Example 20 Delayed Cardiovascular Effects of L-lysine-d-amphetamine as Compared to d-amphetamine Following Intravenous Infusion.
• Systolic and diastolic blood pressure (BP) are increased by d-amphetamine even at therapeutic doses. Since L-lysine-d-amphetamine is expected to release d- amphetamine (albeit slowly) as a result of systemic metabolism, a preliminary study was done using equimolar doses of d-amphetamine or L-lysine-d-amphetamine to 4 dogs (2 male and 2 female).
• the mean blood pressure is graphed in Fig. 35. Consistent with previously published data (Kohli and Goldberg, 1982), small doses of d-amphetamine were observed to have rapid effects on blood pressure. The lowest dose (0.202 mg/kg, equimolar to 0.5 mg/kg of L-lysine-d-amphetamine) produced an acute doubling of the mean BP followed by a slow recovery over 30 minutes.
• L-lysine-d-amphetamine produced very little change in mean BP until approximately 30 minutes after injection. At that time, pressure increased by about 20-50%. Continuous release of d-amphetamine is probably responsible for the slow and steady increase in blood pressure over the remaining course of the experiment.
• d-amphetamine is seen to repeat its effect in a non-dose dependent fashion. That is, increasing dose 10-fold from the first injection produced a rise to the same maximum pressure. This may reflect the state of catecholamine levels in nerve terminals upon successive stimulation of d- amphetamine bolus injections. Note that the rise in mean blood pressure seen after successive doses of L-lysine-d-amphetamine (Fig.
• SAP - systolic arterial pressure (mmHg) MAP - mean arterial pressure (mmHg) DAP - diastolic arterial pressure (mmHg) LVP - left ventricular pressure (mmHg) % Change- percent change from respective Time 0.
• SAP - systolic arterial pressure (mmHg) MAP - mean arterial pressure (mmHg) DAP - diastolic arterial pressure (mmHg) LVP - left ventricular pressure (mmHg) % Change- percent change from respective Time 0.
• Example 21 Pharmacodynamic (Locomotor) Response to Amphetamine vs. L- lysine-d-amphetamine by Oral Administration
• Male Sprague-Dawley rats were provided water ad libitum, fasted overnight and dosed by oral gavage with 6 mg/kg of amphetamine or L-lysine-d-amphetamine containing the equivalent amount of d-amphetamine.
• Horizontal locomotor activity (HLA) was recorded during the light cycle using photocell activity chambers (San Diego Instruments). Total counts were recorded every 12 minutes for the duration of the test. Rats were monitored in three separate experiments for 5, 8, and 12 hours, respectively. Time vs.
• HLA counts for d-amphetamine vs. L-lysine-d- amphetamine is shown in Figs. 37-38. In each experiment the time until peak activity was delayed and the pharmacodynamic effect was evident for an extended period of time for L-lysine-d-amphetamine as compared to d-amphetamine. The total activity counts for HLA of Lys- Amp dosed rats were increased (11-41%) over those induced by d-amphetamine in all three experiments (Tables 40 and 41).
• Example 22 Pharmacodynamic Response to Amphetamine vs. L-lysine-d- amphetamine by Intranasal Administration
• Example 23 Pharmacodynamic Response to Amphetamine vs. L-lysine-d- amphetamine by Intravenous (IV) Administration
• Example 24 Decrease in toxicity of orally administered L-lysine-d-amphetamine [221] Three male and three female Sprague Dawley rats per group were given a single oral administration of L-lysine-d-amphetamine at 0.1, 1.0, 10, 60, 100 or 1000 mg/kg (Table 44). Each animal was observed for signs of toxicity and death on Days 1-7 (with Day 1 being the day of the dose) and one rat/sex/group was necropsied upon death (scheduled or unscheduled). Table 44. Dosing Chart Oral Administration of L-lysine-d-amphetamine Toxicity Testing.
• oral abso ⁇ tion of L-lysine-d-amphetamine may also be saturated at such high concentrations, which may suggest low toxicity due to limited bioavailability of L-lysine-d-amphetamine.
• Example 25 In Vitro Assessment of L-lysine-d-amphetamine Pharmacodynamic Activity. [226] It was anticipated that the acylation of amphetamine, as in the amino acid conjugates discussed here, would significantly reduce the stimulant activity of the parent drug. For example, Marvola (1976) showed that N-acetylation of amphetamine completely abolished the locomotor activity increasing effects in mice.
• Example 27 Bioavailability of Various Amino Acid-Amphetamine Compounds Administered by Oral. Intranasal, and Intravenous Routes.
• Oral Administration Male Sprague-Dawley rats were provided water ad libitum, fasted overnight, and dosed by oral gavage with amphetamine or amino acid-amphetamine conjugates containing the equivalent amount of amphetamine.
• Intranasal Administration Male Sprague-Dawley rats were dosed by intranasal administration with 1.8 mg/kg of amphetamine or lysine-amphetamine containing the equivalent amount of amphetamine.
• Example 28 Decreased Oral Cmax Of d- Amphetamine Conjugates.
• Male Sprague-Dawley rats were provided water ad libitum, fasted overnight and dosed by oral gavage with amphetamine conjugate or d-amphetamine sulfate. All doses contained equivalent amounts of d-amphetamine base.
• Plasma d- amphetamine concentrations were measured by ELISA (Amphetamine Ultra, 109319, Neogen, Corporation, Lexington, KY). The assay is specific for d- amphetamine with only minimal reactivity (0.6%) of the major d-amphetamine metabolite (para-hydroxy-d-amphetamine) occurring.
• Plasma d-amphetamine and L- lysine-d-amphetamine concentrations were measured by LC/MS/MS where indicated in examples.
• Example 29. Decreased Intranasal Bioavailability (AUC and Cm a .) of d- Amphetamine Conjugates.
• Example 30 Decreased Intravenous Bioavailability (AUC and C m ⁇ ) of d- Amphetamine Conjugates.
• the assay is specific for d-amphetamine with only minimal reactivity (0.6%) of the major d-amphetamine metabolite (para-hydroxy-d-amphetamine) occu ⁇ ing.
• Plasma d-amphetamine and L-lysine-d-amphetamine concentrations were measured by LC/MS/MS where indicated in examples.
• Glu 2 -Phe-Amp was synthesized by a similar method except the amino acid starting material was Boc-Glu(OtBu)-Glu(OtBu)-OSu and the starting drug conjugate was Phe-Amp (see Phe-Amp synthesis).
• Lys-Gly-Amp Lys-Gly-Amp was synthesized by a similar method except the amino acid starting material was Boc-Lys(Boc)-OSu and the starting drug conjugate was Gly-Amp (see Gly-Amp synthesis).
• Lys-Glu-Amp Lys-Glu-Amp was synthesized by a similar method except the amino acid starting material was Boc-Lys(Boc)-OSu and the starting drug conjugate was Glu-Amp.
• Glu-Amp was synthesized by a similar method except the amino acid starting material was Boc-Glu(OtBu)-OSu.
• Gulonic acid-Amp was synthesized by a similar method except the carbohydrate starting material was gulonic acid-OSu.
• Example 32 Lack of detection of L-lysine-d-amphetamine in Brain Tissue Following Oral Administration.
• Example 33 Clinical Pharmacokinetic Evaluation and Oral Bioavailability of L- lysine-d-amphetamine Compared to Amphetamine Extended Release Products Adderall XR ® and Dexadrine Spansule ® Used in the Treatment of ADHD
• L-lysine-d-amphetamine was orally administered at doses approximating the lower (25 mg) and higher (75 mg) end of the therapeutic range based on d-amphetamine base content of the doses. Additionally, the higher dose was compared to doses of Adderall XR ® (Shire) or Dexadrine Spansule ® (GlaxoSmithKline) containing equivalent amphetamine base to that of the higher L-lysine-d-amphetamine dose. Treatment groups and doses are summarized in Table 47. All levels below limit quantifiable (blq ⁇ 0.5 ng/mL) were treated as zero for purposes of pharmacokinetic analysis.
• Concentration-time curves showing L-lysine-d-amphetamine intact conjugate and d- amphetamine are presented in Figures 52 and 53.
• Extended release of d-amphetamine from L-lysine- d-amphetamine was observed for both doses and pharmacokinetic parameters (C max and AUC) were proportional to dose when the lower and higher dose results were compared (Table 43, 50 and 54; Figures 52 and 53).
• Significant levels of d- amphetamine were not observed until one-hour post administration.
• Adderall XR ® is a once-daily extended release treatment for ADHD that contains a mixture of d-amphetamine and /-amphetamine salts (equal amounts of d-amphetamine sulfate, d-/Z-amphetamine sulfate, d-amphetamine saccharate, and d-/Z-amphetamine aspartate).
• L-lysine-d-amphetamine Over the course of twelve hours, typically the time needed for effective once- daily treatment of ADHD, the bioavailability for L-lysine-d-amphetamine was approximately equivalent to that of Adderall XR ® (d-amphetamine plus l- amphetamine levels) and over twenty percent higher than that of Dexadrine Spansule ® . Based on the results of this clinical study, L-lysine-d-amphetamine would be an effective once-daily treatment for ADHD. Moreover, L-lysine-d- amphetamine afforded similar pharmacokinetics in humans and animal models, namely, delayed release of d-amphetamine resulting in extended release kinetics. Based on these observations L-lysine-d-amphetamine should also have abuse- resistant properties in humans.

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