U.S. patent application number 13/029883 was filed with the patent office on 2011-09-01 for polar hydrophilic prodrugs of amphetamine and other stimulants and processes for making and using the same.
Invention is credited to Travis C. Mickle.
Application Number | 20110213034 13/029883 |
Document ID | / |
Family ID | 39591454 |
Filed Date | 2011-09-01 |
United States Patent
Application |
20110213034 |
Kind Code |
A1 |
Mickle; Travis C. |
September 1, 2011 |
Polar Hydrophilic Prodrugs of Amphetamine and Other Stimulants and
Processes for Making and Using the Same
Abstract
Disclosed are amphetamine prodrug compositions comprising at
least one non-standard amino acid conjugate of amphetamine, a salt
thereof, or a combination thereof, and methods of using the
same.
Inventors: |
Mickle; Travis C.;
(Coralville, IA) |
Family ID: |
39591454 |
Appl. No.: |
13/029883 |
Filed: |
February 17, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12477616 |
Jun 3, 2009 |
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13029883 |
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PCT/US08/53363 |
Feb 8, 2008 |
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12477616 |
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60888870 |
Feb 8, 2007 |
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Current U.S.
Class: |
514/565 |
Current CPC
Class: |
A61P 25/20 20180101;
A61P 25/22 20180101; A61K 47/557 20170801; A61K 47/544 20170801;
A61P 25/00 20180101; A61P 25/18 20180101; A61P 25/26 20180101; A61K
47/542 20170801; A61P 25/36 20180101; A61K 47/51 20170801; A61P
3/04 20180101; A61K 47/61 20170801; A61K 47/551 20170801; A61P
25/24 20180101; A61P 25/32 20180101; A61P 43/00 20180101 |
Class at
Publication: |
514/565 |
International
Class: |
A61K 31/198 20060101
A61K031/198; A61P 25/00 20060101 A61P025/00; A61P 3/04 20060101
A61P003/04 |
Claims
1. A method for treating a patient having a disorder or condition
requiring the stimulation of the central nervous system of the
patient, comprising orally administering to the patient a
pharmaceutically effective amount of at least one conjugate, a salt
of the conjugate thereof, or a combination thereof, wherein the
conjugate comprises amphetamine and homoarginine.
2. The method of claim 1, wherein the at least one conjugate is
l-homoarginine-d-amphetamine.
3. The method of claim 1, wherein said step of orally administering
comprises administering a tablet, a capsule, a caplet, a troche, a
lozenge, an oral powder, an oral solution, an oral film, a thin
strip, or an oral suspension.
4. The method of claim 1, wherein the conjugate is administered in
the form of a salt.
5. The method of 4, wherein the salt is a mesylate, a hydrochloride
salt, a sulfate, an oxalate, a triflate, a citrate, a malate, a
tartrate, a phosphate, a nitrate, a benzoate, an acetate, a
carbonate, a hydroxide, a sodium salt, a potassium salt, a
magnesium salt, a calcium salt, a zinc salt, an ammonium salt, or a
mixture thereof.
6. The method of claim 1, comprising administering a dosage form
containing from about 1 mg to about 1000 mg of the conjugate, the
salt thereof, or the combination thereof.
7. The method of claim 1, comprising administering a dosage form
containing from about 5 mg to about 250 mg of the conjugate, the
salt thereof, or the combination thereof.
8. The method of claim 1, comprising administering a dosage form
containing from about 10 mg to about 100 mg of the conjugate, the
salt thereof, or the combination thereof.
9. The method of claim 1, wherein the conjugate, the salt thereof,
or the combination thereof is in an amount sufficient to provide a
therapeutically bioequivalent Area Under the Curve (AUC) when
compared to amphetamine alone, but does not provide a C.sub.max
spike.
10. The method of claim 1, wherein the conjugate, the salt thereof,
or the combination thereof is in an amount sufficient to provide a
therapeutically bio equivalent AUC when compared to amphetamine
alone, but does not provide an equivalent C.sub.max.
11. The method of claim 1, wherein the disorder or condition is
attention deficit hyperactivity disorder, attention deficit
disorder, obesity, narcolepsy, appetite suppression, depression,
anxiety, wakefulness, or a combination thereof.
12. The method of claim 11, wherein the disorder or condition is
obesity.
13. The method of claim 11, wherein the disorder or condition is
appetite suppression.
14. The method of claim 11, wherein the disorder or condition is
depression.
15. The method of claim 11, wherein the disorder or condition is
narcolepsy.
16. The method of claim 11, wherein the disorder or condition is
attention deficit hyperactivity disorder.
17. The method of claim 11, wherein the disorder or condition is
attention deficit disorder.
18. The method of claim 3, wherein the step of orally administering
comprises administering an oral film.
19. The method of claim 3, wherein the step of orally administering
comprises administering a thin strip.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 12/477,616, filed Jun. 2, 2009, which application is a
continuation of PCT/US08/53363, filed Feb. 8, 2008, which claims
priority to and benefit of U.S. provisional patent application No.
60/888,870, filed Feb. 8, 2007.
BACKGROUND OF THE INVENTION
[0002] The present technology describes, in general, novel
prodrugs/compositions of the stimulant amphetamine (i.e.,
1-phenylpropan-2-amine) as well as polar hydrophilic conjugates of
amphetamine, salts thereof, other derivatives thereof, and
combinations thereof. Additionally, the presently described
technology also relates generally to the methods of making and
using these new prodrugs/compositions.
[0003] Stimulants, including amphetamine and its derivatives,
enhance the activity of the sympathetic nervous system and/or
central nervous system (CNS) and are prescribed for the treatment
of a range of conditions and disorders predominantly encompassing,
for example, attention deficit hyperactivity disorder (ADHD),
attention deficit disorder (ADD), obesity, narcolepsy, appetite
suppression, depression, anxiety and wakefulness.
[0004] Attention deficit hyperactivity disorder (ADHD) in children
has been treated with stimulants for many years. However, more
recently, the increase in the number of prescriptions for ADHD
therapy in an adult population has, at times, outperformed the
growth of the pediatric market. Although there are various drugs
currently in use for the treatment of ADHD, such as methylphenidate
(commercially available from, for example, Novartis International
AG (located in Basel, Switzerland) under the trademark
Ritalin.RTM.) and non-stimulant atomoxetine (commercially from Eli
Lilly and Company (located in Indianapolis, Ind.) as
Strattera.RTM.), amphetamine has been the forerunner in ADHD
therapy. Moreover during classroom trials, non-stimulants have been
shown to be less effective in improving behavior and attention of
ADHD afflicted children than amphetamine derivatives.
[0005] Initial drug therapy for ADHD was limited to fast acting
immediate release formulations of stimulants (e.g., Dexedrine.RTM.,
pure dextroamphetamine sulfate, commercially available from Smith
Kline and French located in the United Kingdom) which triggered an
array of potentially undesirable side effects including, for
example, fast wear-off of the therapeutic effect of the stimulant
active ingredient causing rebound symptoms, cardiovascular
stress/disorders (e.g., increased heart rate, hypertension,
cardiomyopathy), other side effects (e.g., insomnia, euphoria,
psychotic episodes), addiction and abuse.
[0006] Behavioral deterioration (rebound/"crashing") is observed in
a significant portion of children with ADHD as the medication wears
off, typically in the afternoon or early evening. Rebound symptoms
include, for example, irritability, crankiness, hyperactivity worse
than in the unmedicated state, sadness, crying and in rare cases
psychotic episodes. The symptoms may subside quickly or last
several hours. Some patients may experience rebound/crashing so
severe that treatment must be discontinued. Rebound/crashing
effects can also give rise to addictive behavior by enticing
patients to administer additional doses of stimulant with the
intent to prevent anticipated rebound/crashing negative outcomes
and side effects.
[0007] Stimulants, such as methylphenidate and amphetamine, have
been shown to exhibit noradrenergic and dopaminergic effects that
can lead to cardiovascular events comprising, for example,
increased heart rate, hypertension, palpitations, tachycardia and
in isolated cases cardiomyopathy, stroke, myocardial infarction and
sudden death. Consequently, currently available stimulants expose
patients with pre-existing structural cardiac abnormalities or
other severe cardiac indications to even greater health risks and
are frequently not used or used with caution in this population. It
is notable, however that the cardiovascular effects of stimulants,
for example on heart rate and blood pressure, is dependent on the
administered dose. As a result, a treatment which maintains the
lowest effective stimulant blood concentrations for a
therapeutically beneficial duration is believed to demonstrate
fewer cardiovascular risks/side effects.
[0008] Amphetamine and many of its derivatives (e.g.,
methamphetamine, 3,4-methylenedioxy-methamphetamine/"Ecstasy") are
widely abused for various purposes such as euphoria, extended
periods of alertness/wakefulness, or rapid weight loss or by actual
ADHD patients who developed excessive self-dosing habits to prevent
rebound symptoms from manifesting, for example, in anxiety or
depression. The effects desired by potential abusers originated
from the stimulation of the central nervous system and prompted a
Schedule II or even Schedule I classification for amphetamine (d-
and l-amphetamine individually and any combination of both are
Schedule II) and certain derivatives thereof after passage of the
Controlled Substance Act (CSA) in 1970. Both classifications are
defined by the high propensity for abuse. Schedule II drugs have an
accepted medical use while Schedule I substances do not pursuant to
the CSA. So far, all amphetamine products, including compositions
with sustained release formulations and prodrugs thereof, are
obligated to include a black box warning on the drug label to
inform patients about the potential for amphetamine abuse and
dependence.
[0009] It has been observed in the conventional art that most side
effects of amphetamines are caused by a large initial spike in
blood concentration of the stimulant which quickly erodes to levels
below therapeutic effectiveness (typically within 4-6 hours). As a
consequence, the high potency of dextroamphetamine (d-amphetamine)
was subsequently modulated by a series of new drugs with
increasingly sustained release profiles achieved by delivering
amphetamine more slowly into the blood stream with the goal to
create safer and less abusable treatment outcomes and regimens. The
methods and technologies for generating smaller spikes in drug
blood concentrations include, for example, use of mixed salts and
isomer compositions (i.e., different salts of d- and less potent
l-amphetamine), extended/controlled/sustained release formulations
(e.g., Adderall X.RTM. commercially available from Shire U.S., Inc.
located in Wayne, Pa.) and, most recently, prodrugs of amphetamine
(Vyvanse.TM. also commercially available from Shire). The ideal
drug treatment option should produce stimulant blood concentrations
within a narrow therapeutic window for an extended time duration
followed by a prolonged fade-out period in order to minimize
cardiovascular stress and behavioral deterioration, and would also
exhibit anti-abuse properties.
[0010] Besides immediate release formulations, newer sustained
release formulations have been developed with the objective to
provide a therapeutic treatment option that offers the convenience
of a single daily dosing regimen versus multiple quotidian
administrations. Such formulations also have the objective of
imparting or rendering a euphoric response. Sustained release
formulations commonly consist of drug particles coated with a
polymer or polymer blend that delays and extends the absorption of
the active drug substance by the gastrointestinal tract for a
relatively defined period of time. Such formulations frequently
embed the therapeutic agent/active ingredient/drug within a
hydrophilic hydrocolloid gelling polymer matrix (e.g.,
hydroxypropyl methylcellulose, hydroxypropyl cellulose or
pullulan). This dosage formulation in turn becomes a gel upon
entering an acidic medium, as found in the stomach of humans and
animals, thereupon slowly effusing the therapeutic agent/active
ingredient/drug. However, the dosage formulation dissolves in an
alkaline medium, as found in the intestines of humans and animals,
concurrently liberating the drug more quickly in an uncontrolled
manner. Some formulations, such as acrylic resins, acrylic latex
dispersions, cellulose acetate phthalate, and hydroxypropyl
methylcellulose phthalate, offer improved sustained release in the
intestines by being resistant to acidic environments and dispensing
the active ingredient only at elevated pH via a diffusion-erosion
mechanism, either by themselves or mixed with hydrophilic
polymers.
[0011] Sustained release formulations have been moderately
effective in providing an improved and extended dosage form over
immediate release tablets. Nonetheless, such formulations are
potentially subject to inconsistent, erratic or premature release
of the therapeutic agent due to failure of the polymer material,
and they also usually allow easy extraction of the active
ingredient utilizing a simple physical procedure. Since single
daily dose formulations contain a greater amount of amphetamine
than immediate release formulations, they are more attractive to
potential abusers, consequently making the extractability of drug
substance an additional undesirable property. It is also, at least
in part, a reason for increased drug diversion, especially evident
by selling or trading of medication by school children who are ADHD
patients and in possession of sustained release amphetamine
capsules. The obtained stimulants are then abused by classmates
without the disorder by either ingesting high doses or snorting the
drug material after crushing it.
[0012] U.S. Pat. No. 7,105,486 (to assignee New River
Pharmaceuticals, hereinafter the "'486 patent") appears to describe
compounds comprising a chemical moiety (namely L-lysine) covalently
attached to amphetamine, compositions thereof, and methods of using
the same. Allegedly, these compounds and their compositions are
useful for reducing or preventing abuse and overdose of
amphetamine. The '486 patent also describes that using any amino
acid other than l-lysine (Table 46) will not give rise to the same
in vivo properties demonstrated by l-lysine-d-amphetamine (Lys-Amp,
Vyvanse.TM.). Additionally, since lysine is a natural and standard
amino acid, the breakdown of the new prodrug occurs faster than
desired to reduce the side effect profile. Thus, quick release of
amphetamine from such standard amino acid conjugate compositions
may cause an increase in blood pressure and heart rate found in
other conventional stimulant treatments. As a result, there still
exists a need within the art for a safer dosage form of
amphetamine, and treatment regimen that is therapeutically
effective and can provide sustained release and sustained
therapeutic effect.
BRIEF SUMMARY OF THE INVENTION
[0013] In general, the presently described technology in at least
one aspect is for example, a slow/sustained controlled release
composition of amphetamine, in prodrug form, that allows
slow/sustained/controlled delivery of the stimulant into the blood
system of a human or animal within a safe therapeutic window upon
oral administration. At least some compositions/formulation of the
current technology can lessen the rebound effect, cardiovascular
stress, addiction/abuse potential and/or other common stimulant
side effects associated with amphetamine and similar compounds.
Such compositions may also increase the duration of therapeutic
efficacy, ease of application, patient compliance and/or any
combination of these characteristics when administered, in
particular, orally.
[0014] Thus, the presently described technology provides
compositions comprising at least one stimulant chemically attached
to a polar hydrophilic ligand, a salt thereof, a derivative
thereof, or a combination thereof, which can diminish or eliminate
pharmacological activity of the stimulant until released in vivo in
a human or an animal. The stimulant chemically attached to
(preferably covalently attached to) the polar hydrophilic ligand of
the present technology is the stimulant in a prodrug form, which
can be referred to as a polar, hydrophilic stimulant prodrug, and
can be converted into its active form in the body by normal
metabolic processes. Although not wanting to be bound by any
particular theory, one or more polar hydrophilic conjugates of the
present technology are believed to be safer than other sustained
release forms of amphetamine by providing controlled blood levels
for a prolonged period of time, thus preventing the rebound effect,
cardiovascular stress and euphoria associated with conventional
stimulant treatment options. One or more polar, hydrophilic
stimulant prodrugs of the present technology are stable in tests
that simulate procedures likely to be used by illicit chemists in
attempts to release the stimulants.
[0015] The presently described technology further provides methods
of controlled therapeutic delivery of amphetamine compositions by
oral administration. Release of amphetamine following oral
administration of the polar hydrophilic conjugates of the present
technology can occur gradually over an extended period of time
thereby eliminating unintended elevations (e.g., blood level
concentration spikes) of drug levels in the bloodstream of a human
or animal patient. Again not wanting to be bound by any particular
theory, it is also believed that such spikes in blood levels can
lead to a euphoric drug "high" and cardiovascular effects like
increased blood pressure and heart rate. Additionally, sustained
blood levels are achieved within an effective therapeutic range for
a longer duration than other conventional therapies, thereby
preventing a rebound effect.
[0016] At least some compositions comprising the stimulant prodrugs
of the present technology are resistant to abuse by parenteral
routes of administration, such as intravenous "shooting,"
intranasal "snorting," or inhalation "smoking," that are often
employed during illicit use. The present technology thus provides a
stimulant based treatment modality and dosage form for certain
disorders requiring the stimulation of the CNS such as ADHD, ADD,
obesity, narcolepsy, appetite suppressant, depression, anxiety,
withdrawals, and wakefulness with reduced or prevented abuse
potential. Although not wanting to be bound by any particular
theory, it is believed that the treatment of such CNS conditions as
noted above with compositions of the present technology results in
substantially decreased abuse liability as compared to existing
stimulant treatment modalities and dosage forms.
[0017] At least some compositions comprising the stimulant prodrugs
of the present technology can also be used for treating stimulant
(cocaine, methamphetamine) abuse and addiction, for improving
battle field alertness, and/or for combating fatigue.
[0018] In a first aspect, the presently described technology
provides a composition for stimulating the central nervous system
of a human or animal, comprising at least one stimulant chemically
attached to a polar hydrophilic ligand, a salt thereof, a
derivative thereof, or a combination thereof.
[0019] Preferably, the polar hydrophilic ligand prior to chemical
attachment to the at least one stimulant comprises one or more
functional groups consisting essentially of hydroxyl, carboxylic
acid, primary amine, secondary amine, ketone, aldehyde, acetyl
halide, phosphate, phosphono, sulfate, sulfonyl, sulfonamide, or
thiol. For example, the polar hydrophilic ligand can be a
non-standard amino acid, a synthetic amino acid, an amino acid
derivative, an amino acid precursor, an amino alcohol, or a mixture
thereof. For another example, the polar hydrophilic ligand can be
from some natural substrates or other hydrophilic groups.
[0020] The compositions of the present technology preferably have
no or a substantially decreased pharmacological activity when
administered through injection or intranasal routes of
administration. However, they remain orally bioavailable. Again,
not wanting to be bound by any particular theory, the
bioavailability can be a result of the hydrolysis of the chemical
linkage (e.g., a covalent linkage) following oral administration.
Hydrolysis of the chemical linkage is time-dependent, thereby
allowing amphetamine or another stimulant to become available in
its active form over an extended period of time. In at least one
embodiment, release of amphetamine or another stimulant is
diminished or eliminated when the composition of the present
technology is delivered by parenteral routes.
[0021] For example, in one embodiment, the composition of the
present technology maintains its effectiveness and abuse resistance
following the crushing of the tablet, capsule or other oral dosage
form. In contrast, conventional extended release formulations used
to control the release of amphetamine, for example, through
incorporation into matrices are subject to release of up to the
entire amphetamine content/dose 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.
[0022] Examples of stimulants that can be chemically attached to
the polar hydrophilic ligands of the present technology include
amphetamine, adrafinil, modafinil, a minorex, benzylpiperazine,
cathinone, chlorphentermine, chlobenzorex, cyclopentamine,
diethylpropion, ephedrine, fenfluramine, 4-methyl-aminorex,
methylone, methylphenidate, pemoline, phentermine, phenylephrine,
propylhexadrine, pseudoephedrine, synephrine, metabolites thereof,
derivatives thereof, and combinations thereof. In some embodiments
of the present technology, the at least one stimulant is
amphetamine, a metabolite thereof, a derivative thereof, or a
mixture thereof. Amphetamine can be in the form of dextro- (d-),
levo- (l-), or racemic. One preferred amphetamine is d-amphetamine,
which preferably is attached to a non-standard amino acid with a
known toxicity profile. In addition, d-amphetamine could be
preferably attached to, for example, l-carnitine, l-lysinol, or
choline.
[0023] In another aspect, the presently described technology
provides a method for treating a human or animal patient with a
disorder or condition requiring the stimulation of the patient's
CNS (Central Nervous System), comprising the step of orally
administering to the patient in need a composition formulated for
oral dosage comprising at least one non-standard amino acid
conjugate of amphetamine of the present technology, wherein the
blood levels of amphetamine in the patient's body are not
unnecessarily elevated (i.e., blood level spikes) thus preventing
additional cardiovascular stress through, for example, increased
blood pressure and/or heart rate.
[0024] In another aspect, the presently described technology
provides a method for treating a human or animal patient with a
disorder or condition requiring the stimulation of the patient's
CNS, comprising orally administering to the patient in need a
composition formulated for oral dosage comprising a
pharmaceutically effective amount of at least one stimulant
chemically attached to a polar hydrophilic ligand, a salt thereof,
a derivative thereof, or a combination thereof. Preferably, after
oral administration in accordance with the present technology, the
blood levels of the stimulant such as amphetamine in the patient's
body can maintain a therapeutically effect level, but do not result
in an euphoric effect (such as that observed with abuse of
amphetamines or other stimulants).
[0025] In at least one embodiment of the present technology, the
chemical attachment (preferably covalent attachment) of the polar
hydrophilic ligand to the stimulant in the composition can
substantially decrease the potential for overdose when the
composition is administered to the patient by decreasing the
toxicity of the stimulant at doses above those considered
therapeutic, while maintaining the active agent/ingredient's
pharmaceutical activity within a normal dose range. Without being
bound by any particular theory, it is believed that the polar
hydrophilic moiety conjugated with amphetamine or another stimulant
may decrease or eliminate the pharmacological activity of the
stimulant. Therefore, restoring activity requires release of the
stimulant from the polar hydrophilic ligand conjugate.
[0026] In a further aspect, the presently described technology
provides a method for delivering amphetamine, comprising providing
a human or animal patient with a therapeutically effective amount
of at least one polar hydrophilic conjugate of amphetamine, which
can provide a therapeutically bioequivalent area under the curve
(AUC) when compared to free amphetamine, but does not provide a
concentration max (C.sub.max) which results in an increased heart
rate, increased blood pressure or drug related euphoria when taken
orally.
[0027] Other objects, advantages and embodiments of the invention
are described below and will be obvious from this description and
practice of the invention.
BRIEF DESCRIPTION OF SEVERAL VIEWS OF THE DRAWINGS
[0028] FIG. 1 compares mean plasma concentrations released from
rats orally administered l-homoarginine-d-amphetamine or
l-lysine-d-amphetamine.
[0029] FIG. 2 compares the relative blood levels of d-amphetamine
released from l-homoarginine-d-amphetamine and
l-lysine-d-amphetamine.
[0030] FIGS. 3 and 4 illustrate the difference in blood levels
obtained from the study results shown in FIG. 2.
[0031] FIG. 5 compares average plasma concentrations from four (4)
oral studies of rats administered l-homoarginine-d-amphetamine or
l-lysine-d-amphetamine.
[0032] FIG. 6 compares mean plasma concentrations released from
rats orally administered l-citrulline-d-amphetamine or
l-lysine-d-amphetamine.
[0033] FIG. 7 compares the mean plasma concentrations of
d-amphetamine released from rats orally administered
l-homocitrulline-d-amphetamine, l-homoarginine
(NO.sub.2)-d-amphetamine or l-lysine-d-amphetamine.
[0034] FIG. 8 compares the mean plasma concentrations of
d-amphetamine released from rats intranasally administered
l-homoarginine-d-amphetamine or l-lysine-d-amphetamine.
[0035] FIG. 9 compares the mean plasma concentrations of
d-amphetamine released from rats intravenously administered
d-amphetamine, l-homoargine-d-amphetamine or
l-lysine-d-amphetamine.
DETAILED DESCRIPTION OF THE INVENTION
[0036] The presently described technology relates to novel
prodrugs/compositions of stimulants, more specifically to
stimulants chemically attached to polar hydrophilic ligands, salts
thereof, derivatives thereof, or combinations thereof. Methods of
making and using the prodrugs/compositions of the present
technology are also disclosed.
[0037] As used herein, a "non-standard" amino acid refers to a
naturally occurring amino acid that is not one of the "standard" 20
amino acids. Non-standard amino acids do not have genetic codon,
nor are they incorporated into proteins of natural origin. One
category of non-standard amino acids are metabolites of other amino
acids.
[0038] As used herein, an "amino acid derivative" is a chemically
modified version of a naturally occurring amino acid (standard or
non-standard). As used herein, an "amino acid precursor" refers to
a molecule that can either chemically or metabolically breakdown
into a naturally occurring amino acid (standard or non-standard).
As used herein, a "synthetic amino acid" is an amino acid that is
not naturally occurring. As used herein, an "amino alcohol" refers
to a derivative of an amino acid (standard or non-standard, natural
or synthetic) wherein the carboxylic acid group has been reduced to
an alcohol.
[0039] As used herein, "amphetamine" shall mean any of the
sympathomimetic phenethylamine derivatives which have central
nervous system stimulant activity, such as but not limited to,
amphetamine (alpha-methyl-phenethylamine), methamphetamine,
p-methoxyamphetamine, methylenedioxyamphetamine,
2,5-dimethoxy-4-methylamphetamine, 2,4,5-trimethoxyamphetamine, and
3,4-methylenedioxy-methamphetamine.
[0040] As used herein, "in a manner inconsistent with the
manufacturer's instructions" or similar expression is meant to
include, but is not limited to, consuming amounts greater than
amounts described on the label or ordered by a licensed physician,
and/or altering by any means (e.g., crushing, breaking, melting,
separating etc.) the dosage formulation such that the composition
maybe injected, inhaled or smoked.
[0041] As used herein, the phrases such as "decreased," "reduced,"
"diminished" or "lowered" is meant to include at least a 10% change
in pharmacological activity with greater percentage changes being
preferred for reduction in abuse potential and overdose potential.
For instance, the change may also be greater than 25%, 35%, 45%,
55%, 65%, 75%, 85%, 95%, 96%, 97%, 98%, 99%, or increments
therein.
[0042] Some abbreviations that may be used in the present
application include: DCC=dicyclohexylcarbodiimide,
NHS=N-hydroxysuccinimide, EtOAc=ethyl acetate, MsOH=methanesulfonic
acid, EDCI=1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide,
PyBrOP=Bromo-tris-pyrrolidino phosphoniumhexafluorophosphate,
NMM=N-methylmorpholine or 4-methylmorpholine, TEA=triethylamine,
CDI=Carbonyl diimidazole, IPAC=isopropyl acetate, DEA=diethylamine,
BOP=(Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium
hexafluorophosphate.
[0043] In accordance with some embodiments, the present technology
provides stimulants such as amphetamine in a prodrug form. More
specifically, the stimulant prodrug comprises at least one
stimulant chemically attached to a polar hydrophilic ligand, a salt
thereof, a derivative thereof, or a combination thereof.
[0044] According to the presently described technology, polar
hydrophilic molecules or ligands can be chemically (preferably
covalently) attached to amphetamine (d-, l-, or racemic form or a
mixture thereof) to produce novel polar, hydrophilic prodrugs of
amphetamine. Other stimulants (including stimulant or
stimulant-like drugs) can also be modified with these ligands. Some
examples of other stimulants include adrafinil, modafinil, a
minorex, benzylpiperazine, cathinone, chlorphentermine,
chlobenzorex, cyclopentamine, diethylpropion, ephedrine,
fenfluramine, 4-methyl-aminorex, methylone, methylphenidate,
pemoline, phentermine, phenylephrine, propylhexadrine,
pseudoephedrine, and Synephrine. Metabolites and derivatives of
these and other stimulants could also be modified with the same
potential benefit. Examples of metabolites of amphetamine include
p-hydroxyamphetamine and p-hydroxyephedrine.
[0045] Please note that although the present technology sometimes
may be described with a reference to amphetamine only, amphetamine
is merely used as an example. It should be understood that any
method or composition of the presently described technology is not
limited to amphetamine.
[0046] In accordance with at least some embodiments, the polar
hydrophilic ligands suitable for the present technology contain at
least one of the following functional groups: hydroxyl, carboxylic
acid, amine (primary or secondary), ketone or aldehyde, acetyl
halide, phosphate, phosphono, sulfate, sulfonyl, sulfonamide, and
thiol. These functional groups can be chemically attached to
amphetamine, for example, through the primary amine of amphetamine
to form the following chemical linkages: carbamate, amide, urea,
phosphonamide, phosphonamide, sulfonamide, or thiourea. The final
prodrug products of the present technology may be in a number of
derivative forms such as salt forms depending on other
functionality of the attached ligands and any deprotection steps
that may or may not be necessary.
[0047] Salts of the stimulant chemically attached to the polar
hydrophilic ligand that can be formed and utilized include, but are
not limited to, mesylate, hydrochloride, sulfate, oxalate,
triflate, citrate, malate, tartrate, phosphate, nitrate, benzoate,
acetate, carbonate, hydroxide, sodium, potassium, magnesium,
calcium, zinc, and ammonium salts. Further, in accordance with some
embodiments, the salts may be required in multiple forms (e.g.,
di-, tri-, or tetra-). Other derivative forms such as free base,
free acid, or neutral forms may also be prepared depending on the
polar hydrophilic ligand used.
[0048] Polar hydrophilic ligands suitable for the presently
described technology can take a number of forms. These forms can be
divided into several categories including non-standard amino acids,
amino acid derivatives, amino acid precursors, amino alcohols,
synthetic amino acid derivatives, natural substrates, and other
hydrophilic groups or ligands. They can be in d-, l- or racemic
form, or a mixture thereof along with a number of other possible
enantiomeric/diastereomeric forms depending on the ligands. For
example, the non-standard amino acid used to produce the stimulant
prodrug of the present technology can be either d- or l-form amino
acid, racemic amino acid, or a mixture thereof.
[0049] Examples of non-standard amino acids suitable for the
presently described technology include homoarginine, citrulline,
homocitrulline, hydroxyproline, 2-hydroxy-4-(methylthio) butanoic
acid (HMB), .gamma.-aminobutyric acid, taurine, glutathione,
statine, homocysteine, selenomethionine, and combinations thereof.
Structures of some non-standard amino acids are shown below.
##STR00001##
Examples of amino acids derivatives or precursors suitable in the
presently described technology include isoserine,
N-.omega.-nitro-arginine, N-.epsilon.,.epsilon.-dimethyl-lysine,
buthionine, cysteic acid, ethionine, (2-amino ethyl) cysteine,
cystathionine, 2-amino-3-ethyoxybutanoic acid, methylserine,
ethoxytheorine, and combinations thereof.
##STR00002##
[0050] Examples of synthetic amino acids suitable for use in the
presently described technology include 2-amino-3-guanidinopropionic
acid, 2-amino-3-ureidopropioninc acid, 4-nitroanthranillic acid,
and combinations thereof. Structures of some synthetic amino acids
for use in the practice of the present technology are provided
below.
##STR00003##
[0051] Examples of amino alcohols suitable for use in the presently
described technology include alaminol, indano, norephedrine,
asparaginol, aspartimol, glutamol, leucinol, methioninol,
phenylalaninol, prolinol, tryptophanol, valinol, isoleucinol,
argininol, serinol, tyrosinol, threoninol, cysteinol, lysinol,
histidinol, and combinations thereof. Structures of some amino
alcohols for use in the practice of the present technology are
provided below.
##STR00004##
[0052] Other polar hydrophilic ligands that can be used to produce
stimulant prodrugs of the present technology include natural
substrates, and other hydrophilic groups.
[0053] As used herein, "natural substrates" refer to polar
molecules that are readily found in humans and can include
essential or non-essential nutrients and biological components.
Other hydrophilic groups or ligands include examples of compounds
that occur in natural or are regarded as non-toxic and could not be
readily classified in the other groupings.
[0054] Examples of some natural substrates suitable for use in the
presently described technology include carnitine, tartaric acid,
biotin, pantothenic acid and salts, choline, cystine dimer, lactic
acid, niacin, riboflavin, and combinations thereof. Structures of
some preferred natural substrates for use in the practice of the
present technology are provided below.
##STR00005##
[0055] Examples of other hydrophilic groups suitable for use in the
presently described technology include t-butylated hydroxyanisole
(BHA), propionic acid, sorbic acid, erythorbic acid, methyl
paraben, propyl gallate, propyl paraben, thiodipropionic acid,
propylene glycol, pyridoxine, adipic acid, malic acid, acetoin,
N-butyric acid, vanillin, geraniol, methyl anthranilate, benzoin,
benzyl alcohol, and combinations thereof. Structures of two
representative hydrophilic groups for use in the practice of the
present technology are provided below.
##STR00006##
[0056] Generally, to produce a stimulant prodrug of the present
technology, a selected polar hydrophilic ligand (e.g., a
commercially available non-standard amino acid or amino acid
derivative) can be added to the stimulant (e.g. amphetamine) in
dextro, levo or racemic forms. Depending on the polar hydrophilic
ligand selected, one or more functional groups on the polar
hydrophilic ligand may or may not need to be protected prior to
coupling the ligand with the stimulant.
[0057] For example, to conjugate an amino acid with amphetamine,
the one or more amino groups are preferably protected before the
amino acid is reacted with amphetamine. Agents and methods for
protecting amino groups in a reactant are known in the art.
Examples of protecting groups that may be used to protect the amino
groups include, but are not limited to, fluorenylmethoxycarbonyl
(Fmoc), t-butylcarbonate (Boc), trifluoroacetate (TFA), acetate
(Ac) and benzyloxycarbonyl (Z). After coupling with any standard
coupling procedure, deprotection can occur with a variety of strong
acids to give the corresponding salt form. Salt forms may also be
switched by first free basing the product and then adding any acid.
Neutral, free base or anionic salts may also be formed. Additional
deprotection may be necessary in the case of some polar hydrophilic
ligands such as homoarginine and any protected urea derivative.
These deprotections usually occur under hydrogenation
conditions.
[0058] For another example, coupling of carnitine (d-, l-, or
racemic) to amphetamine may require protection of the hydroxyl
group prior to coupling. In accordance with some embodiments, use
of a silyl or benzoyl group to protect the hydroxyl group would be
preferred. Deprotection of the silyl can occur in water or slightly
acidic media. On the other hand, deprotection of benzoyl usually
requires strong basic conditions such as in the presence of
NaOMe.
[0059] More specifically, using a non-standard amino acid and
amphetamine as an example, the non-standard amino acid can be
attached to amphetamine to make an amino acid conjugate of
amphetamine or salts thereof in accordance with the presently
described technology. Preferably, the amino acid is covalently
attached to amphetamine through the C-terminus of the amino acid.
The N-terminus or the side chain amino group of the amino acid may
be in a free and unprotected state, or in the form of a salt
thereof. Alternatively, in some embodiments, the amino acid can be
attached to amphetamine through the N-terminus. Examples of salts
of amino acid conjugates of amphetamine that can be formed and
administrated to patients in accordance with the presently
described technology include, but are not limited to, mesylate,
hydrochloride, sulfate, oxalate, triflate, citrate, malate,
tartrate, phosphate, nitrate, and benzoate salts, and mixtures
thereof.
[0060] To conjugate the amino acid with amphetamine, the one or
more amino groups are preferably protected using agents described
above before the amino acid is reacted with amphetamine. The amino
acid whose amino groups are protected can be referred to as an
N-protected amino acid. One can either protect the amino groups in
situ during the production process, or use commercially available
N-protected amino acids directly. Preferably, the carboxylic acid
group in the N-protected amino acid is activated by an acid
activating agent (sometimes also called coupling reagent) to help
the reaction of the N-protected amino acid with amphetamine.
General information about the reaction of amino acids to form
peptide bonds can be found in, for example, G. C. Barett, D. T.
Elmare, Amino Acids and Peptides, page 151-156, Cambridge
University Press, UK (1st edition, 1998); Jones, J., Amino Acid and
Peptide Synthesis, pages 25-41, Oxford University Press, UK (2nd
edition, 2002), which are incorporated herein by reference in their
entirety.
[0061] One category of acid activating agents (coupling reagents)
well known in the art are carbodiimides. Examples of carbodiimide
acid activating agents include, but are not limited to,
dicyclohexylcarbodiimide (DCC),
1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide (EDCI), and
diisopropylcarbodiimide (DIPCDI). Examples of other coupling
reagents that could be used include bromo-tris-pyrrolidino
phosphoniumhexafluorophosphate,
(benzotriazol-1-yloxy)-tris-(dimethylamino)-phosphonium
hexafluorophosphate, PCl.sub.5/PhH, SOCl.sub.2, N.sub.2H.sub.4,
1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, other phosphonium
reagents, and uronium reagents. The use of appropriate acyl halide
or anhydride is also contemplated.
[0062] The N-protected amino acid conjugate of amphetamine
resulting from the reaction of the N-protected amino acid and
amphetamine as described above can then be de- or un-protected with
a strong acid to produce the corresponding final salt form of the
amino acid conjugate of amphetamine.
[0063] Scheme 1 below outlines an exemplary route for the synthesis
of a derivative of amphetamine chemically attached to homoarginine
in accordance with the presently described technology. In this
exemplary reaction scheme, an HCl salt form of
homoarginine-amphetamine is produced. The procedure uses
tert-butyloxycarbonyl (Boc) and nitro protected homoarginine
(Boc-homoarginine(Nitro)) as the starting material. In this
exemplary reaction scheme, coupling agent EDCI is added to
Boc-homoarginine. N-hydroxy succinamide (NHS) is then added to the
reaction mixture in dimethylformamide (DMF). A stable, yet still
activated, succinic ester of Boc-homoarginine(nitro) is formed.
Amphetamine is then added to the resulting succinic ester of
Boc-homoarginine(nitro) to make the corresponding protected
prodrug, Boc-homoarginine(nitro)-Amp. This protected prodrug can be
de- or un-protected using hydrogenation followed by a strong acid
such as methanesulfonic acid (MsOH) or hydrochloric acid to produce
the prodrug of amphetamine, which is a hydrochloride salt of
homoarginine-amphetamine in this exemplary reaction scheme.
##STR00007##
[0064] Examples of other solvents that can be used in the presently
described technology include, but are not limited to, isopropyl
acetate (IPAC), acetone, and dichloromethane (DCM),
dimethylformamide (DMF), ethyl acetate, chloroform, dimethyl
sulfoxide, dioxane, diethyl ether, methyl t-butyl ether, hexanes,
heptane, methanol, ethanol, isopropanol, and butanol. A mixture of
different solvents can also be used. Co-bases such as tertiary
amines may or may not be added in the coupling reaction of the
presently described technology. Examples of suitable co-bases
include, but are not limited to, 1-methylmorpholine (NMM),
4-methylmorpholine, triethylamine (TEA), ammonia or any tertiary
amine base.
[0065] The amphetamine to be chemically attached to polar
hydrophilic ligands of the presently described technology can be in
d-form, l-form, or racemic form, or can be a mixture thereof. In
accordance with some embodiments of the presently described
technology, d-amphetamine (dextroamphetamine) and a non-standard
amino acid with a known toxicity profile are preferably used to
make an amphetamine prodrug. Other preferred polar hydrophilic
ligands to form d-amphetamine prodrugs include, for example,
l-carnitine, l-lysinol, or choline. In accordance with some other
embodiments, the prodrugs of d-amphetamine can be used in
combination with a prodrug of l-amphetamine or l-amphetamine
itself.
[0066] Scheme 2 below outlines an exemplary route for the synthesis
of a derivative of amphetamine chemically attached to
selenomethionine in accordance with the presently described
technology. The amphetamine prodrug produced here is in a sulfate
salt form.
##STR00008##
[0067] Scheme 3 below outlines an exemplary route for the synthesis
of a derivative of amphetamine chemically attached to statine in
accordance with the presently described technology. The amphetamine
prodrug produced here is in an HCl salt form.
##STR00009##
[0068] Scheme 4 below outlines an exemplary route for the synthesis
of a derivative of amphetamine chemically attached to isoserine in
accordance with the presently described technology. The amphetamine
prodrug produced here is in an MsOH salt form.
##STR00010##
[0069] Scheme 5 below outlines an exemplary route for the synthesis
of a derivative of amphetamine chemically attached to cystathionine
in accordance with the presently described technology. The
amphetamine prodrug produced here is in an HCl salt form.
##STR00011##
[0070] Scheme 6 below outlines an exemplary route for the synthesis
of a derivative of amphetamine chemically attached to
ethoxytheorine in accordance with the presently described
technology. The amphetamine prodrug produced here is in an HCl salt
form.
##STR00012##
[0071] Scheme 7 below outlines an exemplary route for the synthesis
of a derivative of amphetamine chemically attached to
2-amino-3-guanidinopropionic acid in accordance with the presently
described technology. The amphetamine prodrug produced here is in
an MsOH salt form.
##STR00013##
[0072] Scheme 8 below outlines an exemplary route for the synthesis
of a derivative of amphetamine chemically attached to
lysinol-carbamate in accordance with the presently described
technology. The amphetamine prodrug produced here is in an HCl salt
form.
##STR00014##
##STR00015##
[0073] Scheme 9 above outlines an exemplary route for the synthesis
of a derivative of amphetamine chemically attached to lysinol-urea
in accordance with the presently described technology.
[0074] Scheme 10 below outlines an exemplary route for the
synthesis of a derivative of amphetamine chemically attached to
carnitine in accordance with the presently described
technology.
##STR00016##
[0075] Scheme 11 below outlines an exemplary route for the
synthesis of a derivative of amphetamine chemically attached to
choline in accordance with the presently described technology.
##STR00017##
[0076] At least some polar, hydrophilic stimulant prodrugs of the
present technology have no or a substantially decreased
pharmacological activity when administered through injection or
intranasal routes of administration. However, they remain orally
bioavailable. The bioavailability can be a result of the hydrolysis
of the covalent linkage following oral administration. Hydrolysis
of a chemical linkage is time-dependent, thereby allowing
amphetamine and other metabolites such as p-hydroxyamphetamine and
p-hydroxyephedrine or another stimulant to become available in its
active form over an extended period of time. Therefore, the prodrug
compounds of the present technology can release amphetamine or
another stimulant over an extended period and provide a
therapeutically area under the curve (AUC) when compared to free
amphetamine or another stimulant, with little or no spike in
concentration max (C.sub.max) or equivalent C.sub.max. Not wanting
to be bound by any particular theory, it is believed that since
non-standard amino acids and the other suitable polar hydrophilic
ligands are used to produce the prodrugs, the in vivo breakdown of
the prodrugs by enzymes would occur at a slower rate than, for
example, when a standard amino acid is used to conjugate the
stimulants. This will allow the prodrugs to release amphetamine or
other stimulants slowly and, preferably, only under in vivo
conditions.
[0077] As a person of ordinary skill in the art will understand,
drug products are considered pharmaceutical equivalents if they
contain the same active ingredient(s), are of the same dosage form,
route of administration and are identical in strength or
concentration. Pharmaceutically equivalent drug products are
formulated to contain the same amount of active ingredient in the
same dosage form and to meet the same or compendial or other
applicable standards (i.e., strength, quality, purity, and
identity), but they may differ in characteristics such as shape,
scoring configuration, release mechanisms, packaging, excipients
(including colors, flavors, preservatives), expiration time, and,
with certain limits, labeling. Drug products are considered to be
therapeutic equivalents only if they are pharmaceutical equivalents
and if they can be expected to have the same clinical effect and
safety profile when administered to patients under the conditions
specified in the labeling. The term "bioequivalent," on the other
hand, describes pharmaceutical equivalent or pharmaceutical
alternative products that display comparable bioavailability when
studied under similar experimental conditions.
[0078] Standard amino acids such as lysine or glutamic acid are not
contemplated for the presently described technology. Because
standard amino acids are essential parts of all dietary
requirements, it would be expected that the prodrug of the present
technology conjugated with a standard amino acid would be released
at a faster rate. By using non-standard amino acids, synthetic
amino acids, amino acid derivatives or precursors, or other polar
hydrophilic ligands of the presently described technology, the
release rate of amphetamine or another stimulant will be reduced
due to the difference in overall digestion rate of the stimulant
prodrug.
[0079] Once produced, the prodrug of amphetamine (or another
stimulant) of the present technology can be administered through
oral routes of delivery and once administered will release the
stimulant under digestive conditions. Due to the hydrophilic and
polar nature of the prodrug and the slow rate of hydrolysis of the
chemical linkage as described above, should high levels of drug be
administered either accidentally or intentionally, the prodrug will
be cleared by metabolic and/or excretory pathways prior to
releasing large amounts of the stimulant. Also, release of
amphetamine (or another stimulant) over an extended period should
alleviate or diminish drug induced side-effects that can limit or
terminate amphetamine therapy. These side effects include increase
in the heart and respiration rates, increased blood pressure,
dilation of the pupils of the eyes, and decreased appetite. Other
side effects include anxiety, blurred vision, sleeplessness, and
dizziness. Also, amphetamines and other stimulants are power
psychostimulants and are prone to substance abuse.
[0080] Substance abuse of stimulants is often characterized by an
escalation of events. First, a substantial "rush" or high may be
obtained from increasing oral dosages. Due to the properties of
these polar, hydrophilic prodrugs, these potential routes for abuse
can be mitigated via the polar nature of the prodrug. That is, once
administered at higher than therapeutic levels, the body will
excrete any remaining prodrug without breakdown into amphetamine.
After oral amounts exceed an attainable amount, other routes can be
explored including smoking, snorting, or injection. In accordance
with the presently described technology, release of amphetamine or
another stimulant would only occur under desired physiological
conditions. Preferably, other routes of administration (e.g.,
intranasal or intravenous) do not break the prodrug down to any
appreciable extent. Also preferably, external means (chemical,
enzymatic or other) will not break the prodrug down to any
appreciable extent either. The breakdown ratio of the prodrug that
can be achieved through external means is preferably less than
about 50%, alternatively less than about 25%, alternatively less
than about 20%, alternatively less than about 10%.
[0081] The presently described technology utilizes covalent
modification of amphetamine by a non-standard amino acid, an amino
acid derivative or any polar hydrophilic group to decrease its
potential for causing behavioral deterioration or the rebound
effect. It is believed that since the amphetamine is covalently
modified to form the polar hydrophilic conjugate of the present
technology and releases slowly over the entire length of the day,
little or no rebound effect can occur due to the slow continuous
release of the active ingredient/drug/therapeutic component.
[0082] Compounds, compositions and methods of the presently
described technology are also believed to provide reduced potential
for rebound, reduced potential for abuse or addiction, and/or
improve amphetamine's stimulant related toxicities. By limiting the
blood level spike, doses are kept at levels required for a
clinically significant effect without the unnecessary levels
administered with other therapies. It is widely held that these
spikes in blood levels can lead to cardiovascular toxicity in the
form of higher blood pressure and rapid heart rate in addition to
the euphoria encountered in drug abuse. Also, with a full day
therapy, the risk of re-dosing is lowered, thus preventing
additional toxicities or drug abuse issues.
[0083] The polar, hydrophilic prodrugs of stimulants of the
presently described technology could be used for any condition
requiring the stimulation of the central nervous system (CNS).
These conditions include, for example, attention deficit
hyperactivity disorder (ADHD), attention deficit disorder (ADD),
obesity, narcolepsy, appetite suppressant, depression, anxiety,
withdrawals (e.g., alcohol withdrawals or drug withdrawals), and
wakefulness. Some stimulants such as amphetamine have also
demonstrated usefulness in treating stimulant (e.g., cocaine,
methamphetamine) abuse and addiction. Amphetamine stimulants have
also been used extensively to improve battle field alertness and to
combat fatigue.
[0084] Therefore, in accordance with some embodiments, the
presently described technology provides stimulant compositions
comprising at least one polar, hydrophilic stimulant prodrug of the
present technology.
[0085] One embodiment is a composition that can prevent behavioral
deterioration of amphetamine dosing comprising at least one polar
hydrophilic conjugate of amphetamine.
[0086] Another embodiment is a composition for safely delivering a
stimulant, comprising a therapeutically effective amount of at
least one polar, hydrophilic prodrug of the stimulant of the
present technology wherein the polar hydrophilic moiety can reduce
the rate of absorption of the stimulant as compared to delivering
the unconjugated stimulant or the stimulant conjugated to a
standard amino acid, for example.
[0087] Another embodiment of the present technology is a
composition that can reduce amphetamine toxicity, comprising at
least one polar hydrophilic prodrug of amphetamine wherein the
non-standard amino acid moiety can release amphetamine over the
entire course of a day providing a limited behavioral deterioration
effect.
[0088] Another embodiment of the present technology is a
composition that can reduce amphetamine toxicity, comprising at
least one polar, hydrophilic prodrug of amphetamine of the present
technology wherein the polar hydrophilic moiety can provide 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.
[0089] Another embodiment of the present technology is a
composition that can reduce bioavailability of amphetamine,
comprising at least one polar, hydrophilic prodrug of amphetamine
of the present technology wherein the amphetamine prodrug can
maintain a steady-state serum release curve which can provide a
therapeutically effective bioavailability but prevent spiking or
increased blood serum concentrations compared to unconjugated
amphetamine or amphetamine conjugated with a standard amino acid
when given at doses exceeding those within the therapeutic range of
amphetamine.
[0090] Another embodiment of the present technology is a
composition comprising at least one polar, hydrophilic prodrug of
amphetamine of the present technology that can prevent a C.sub.max
or equivalent C.sub.max spike for amphetamine when taken by means
other than orally while still providing a therapeutically effective
bioavailability curve if taken orally.
[0091] Another embodiment of the present technology is a
composition that can prevent a toxic release profile in a patient
comprising at least one polar, hydrophilic prodrug of amphetamine
of the present technology wherein the amphetamine prodrug can
maintain a steady-state serum release curve which provides a
therapeutically effective bioavailability but prevents spiking or
increased blood serum concentrations compared to unconjugated
amphetamine or amphetamine conjugated with a naturally occurring
and standard amino acid.
[0092] One or more embodiments of the present technology provide
stimulant such as amphetamine compositions which allow the
stimulant to be therapeutically effective when delivered at the
proper dosage but reduces the rate of absorption or extent of
bioavailability of the stimulant when given at doses exceeding
those within the therapeutic range of the stimulant. One or more
embodiments of the present technology also provide stimulant
compositions wherein the polar hydrophilic moiety increases the
rate of clearance of the stimulant when given at doses exceeding
those within the therapeutic range of the stimulant.
[0093] In one or more embodiments, the stimulant compositions of
the present technology have substantially lower toxicity compared
to unconjugated stimulant or the stimulant conjugated with a
standard amino acid. In one or more embodiments, the stimulant
compositions of the present technology can reduce or eliminate the
possibility of overdose by oral administration. In one or more
embodiments, the stimulant compositions of the present technology
can reduce or eliminate the possibility of overdose by intranasal
administration. In one or more embodiments, the stimulant
compositions of the present technology can reduce or eliminate the
possibility of overdose by injection. In one or more embodiments,
the stimulant compositions of the present technology can reduce or
eliminate the possibility of overdose by inhalation.
[0094] In one or more embodiments, the polar, hydrophilic prodrugs
of stimulants of the present technology 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 stimulant prodrug of the present
technology without reducing the abuse resistance. For instance, a
composition might include: about 70% to about 100% stimulant
prodrug of the present technology 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.
[0095] 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, hydroxymethylcellulose,
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. These hydrophilic polymers gel and would dissolve
slowly in aqueous acidic media thereby allowing the stimulant
prodrug 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 E1OM.
[0096] Other formulations according to one or more embodiments of
the present technology 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. 1 and other various certified color additives
(See 21 CFR, Part 74); binders such as sucrose, lactose, gelatin,
starch paste, acacia, tragacanth, povidone, polyethylene glycol,
Pullulan and corn syrup; glidants such as colloidal silicon dioxide
and talc; surface active agents such as sodium lauryl sulfate,
dioctyl sodium sulfosuccinate, triethanolamine, polyoxyethylene
sorbitan, poloxalkol, and quaternary ammonium salts; preservatives
and stabilizers; excipients such as lactose, mannitol, glucose,
fructose, xylose, galactose, sucrose, maltose, xylitol, sorbitol,
chloride, sulfate and phosphate salts of potassium, sodium, and
magnesium; and/or any other pharmaceutical additives known to those
of skill in the art. In one preferred embodiment, a sustained
release formulation of the present technology further comprises
magnesium stearate and Emerald Green Lake.
[0097] The stimulant compositions of the present technology, which
comprises at least one polar, hydrophilic stimulant prodrug of the
present technology, can be further formulated with excipients, and
may be manufactured according to any appropriate method known to
those of skill in the art of pharmaceutical manufacture. For
instance, the stimulant prodrug 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 the stimulant prodrug. The
resulting granulation may be milled, screened, then blended with
various pharmaceutical additives such as, for example, water
insoluble polymers, and/or additional hydrophilic polymers. The
formulation may then be tableted and may further be film coated
with a protective coating which rapidly dissolves or disperses in
gastric juices.
[0098] It should be noted that the above additives are not required
for the stimulant composition of the present technology to have
sustained release and abuse resistance properties. The stimulant
prodrug of the present technology itself can control the release of
the stimulant 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. In one or more embodiments of the present
technology, 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 stimulant release when taken orally.
[0099] The compounds and compositions of the presently described
technology can be formulated into and administered by a variety of
dosage forms, preferably, through any oral routes of delivery. Once
administered, the prodrugs will release amphetamine or another
stimulant under digestive conditions. Any biologically-acceptable
dosage form known to persons of ordinary skill in the art, now or
in the future, and combinations thereof, are contemplated for use
with the present technology. 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, troches, lozenges, chewable lozenges,
beads, powders, granules, particles, microparticles, dispersible
granules, cachets, thin strips, oral films, transdermal patches,
and combinations thereof. Preferred dosage forms include, but are
not limited to, capsules, thin strips, and solution
formulations.
[0100] Formulations of the present technology 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 can then be placed in
the feeding tube of a patient who is unable to swallow.
[0101] If the capsule form is chosen, for example, excipients used
in the capsule formulation could be broken up into four separate
groups: bulk agent/binder, disintergrant, lubricant and carrier. A
preferred capsule formulation comprises from about 50% to about 90%
by weight of a bulk agent such as various types of microcrystalline
cellulose, from about 1% to about 5% by weight of a disintegrant
such as croscarmellose sodium, from about 0.5% to about 2.5% of a
lubricant such as magnesium stearate or other fatty acid salts. The
carrier can be either hard gelatin capsules, and preferably use the
smaller sized ones such as #3 or #4 hard gelatin capsules.
[0102] Soft gel or soft gelatin capsules may be prepared, for
example, by dispersing the formulation of the present technology in
an appropriate vehicle (vegetable oils are commonly used) to form a
high viscosity mixture. This mixture can then be encapsulated with
a gelatin based film using technology and machinery known to those
in the soft gel industry. The individual units so formed are then
dried to constant weight.
[0103] Chewable tablets, for example, may be prepared by mixing the
formulations of the present technology 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.
[0104] 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.
[0105] Compressed tablets, for example, may be prepared by mixing
the formulation of the present technology with excipients intended
to add binding qualities to disintegration qualities. The mixture
can be 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.
[0106] One preferred formulation of the polar hydrophilic prodrugs
is a fast dissolving oral film or thin strip. Methods and other
ingredients needed to make oral films or thin strips are known in
the art. Potential film forming agents include pullulan,
hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinyl
pyrrolidone, polyvinyl alcohol, sodium alginate, polyethylene
glycol, xanthan gum, tragacanth gum, guar gum, acacia gum, Arabic
gum, polyacrylic acid, amylase, starch, dextrin, pectin, chitin,
chitosin, levan, elsinan, collagen, gelatin, zein, gluten, soy
protein isolate, whey protein isolate, casein, and mixtures
thereof.
[0107] Also, saliva stimulating agents, plasticizing agents,
cooling agents, surfactants, emulsifying agents, thickening agents,
binding agents, sweeteners, flavoring, coloring agents,
preservatives, or taste masking resins may be employed in the oral
films or thin strips. Preferred agents include: pullulan,
triethanol amine stearate, methyl cellulose, starch, triacetin,
polysorbate 80, xanthan gum, maltitol, sorbitol and glycerol.
[0108] The presently described technology also contemplates the use
of biologically-acceptable carriers which may be prepared from a
wide range of materials. Without being limited thereto, such
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.
[0109] 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.
[0110] 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. As
is evident, 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. In contrast, 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.
[0111] It should be understood that in addition to the ingredients
particularly mentioned above, the formulations of the present
technology can include other suitable agents such as flavoring
agents, preservatives and antioxidants. Such antioxidants would be
food acceptable and could include, for example, vitamin E,
carotene, BHT or other antioxidants known to those of skill in the
art.
[0112] Other compounds which may be included 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, 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, polysorbates
or laurylsulphates; and other therapeutically acceptable accessory
ingredients, such as humectants, preservatives, buffers and
antioxidants, which are known additives for such formulations.
[0113] For oral administration, fine powders or granules containing
diluting, dispersing and/or surface-active agents may be presented
in a draught, in water or a syrup, in capsules or sachets in the
dry state, in a non-aqueous suspension wherein suspending agents
may be included, or in a suspension in water or a syrup. Where
desirable or necessary, flavoring, preserving, suspending,
thickening or emulsifying agents can be included.
[0114] Liquid dispersions for oral administration may be syrups,
emulsions or suspensions. The syrups may contain as a 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.
[0115] The dose range for adult or pediatric human beings will
depend on a number of factors including the age, weight and
condition of the patient. Suitable oral dosages of the prodrugs of
one stimulant of the presently described technology can be the
equivalents of those typically found in treatments using that
stimulant. For example, typical dosages for amphetamine salts can
range from about 1 mg to about 100 mg, although higher dosages may
be approved at later dates. Using the molecular weight of the
prodrug of the present technology, the release percentage (%
release) of amphetamine from the prodrug and desired dosage forms
of the required amphetamine, the following equation can be
generated:
grams of a prodrug needed=(dosage/molecular weight of
amphetamine)(% release)(molecular weight of the prodrug)
[0116] Tablets, capsules, and other forms of presentation provided
in discrete units conveniently contain a daily dose, or an
appropriate fraction thereof, of one or more of the prodrug
compounds of the invention. For example, the units may contain from
about 1 mg to about 1000 mg, alternatively from about 5 mg to about
500 mg, alternatively from about 5 mg to about 250 mg,
alternatively from about 10 mg to about 100 mg of one or more of
the prodrug compounds of the presently described technology.
[0117] It is also possible for the dosage form of the present
technology to combine any forms of release known to persons of
ordinary skill in the art. These conventional release forms include
immediate release, extended release, pulse release, variable
release, controlled release, timed release, sustained release,
delayed release, long acting, and combinations thereof. The ability
to obtain immediate release, extended release, pulse release,
variable release, controlled release, timed release, sustained
release, delayed release, long acting characteristics and
combinations thereof is known in the art.
[0118] Compositions of the present technology 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.
[0119] Likewise, the compositions of the present technology may be
provided in a blister pack or other such pharmaceutical package.
Further, the compositions of the present technology 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. For
example, 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.
[0120] It will be appreciated that the pharmacological activity of
the compositions of the present technology can be demonstrated
using standard pharmacological models that are known in the art.
Furthermore, it will be appreciated that the compositions of the
present technology can be incorporated 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.
[0121] In one or more embodiments of the present technology, the
solubility and dissolution rate of the composition can be
substantially changed under different physiological conditions
encountered, for example, in the intestine, at mucosal surfaces, or
in the bloodstream. In one or more embodiments of the present
technology, the solubility and dissolution rate of the composition
can substantially decrease the bioavailability of the amphetamine,
particularly at doses above those intended for therapy. In one
embodiment of the present technology, the decrease in
bioavailability occurs upon intranasal administration. In another
embodiment, the decrease in bioavailability occurs upon intravenous
administration.
[0122] For each of the described embodiments of the present
technology, one or more of the following characteristics can be
realized: The cardiovascular toxicity of the amphetamine prodrug is
substantially lower than that of the unconjugated amphetamine and
amphetamine conjugated with a standard amino acid. The covalently
bound polar hydrophilic moiety reduces or eliminates the
possibility of behavioral deterioration or the rebound effect. The
covalently bound polar hydrophilic moiety reduces or eliminates the
possibility of abuse by intranasal administration. The covalently
bound polar hydrophilic moiety reduces the possibility of abuse by
injection.
[0123] The presently described technology further provides methods
for altering and/or delivering amphetamines and other stimulants in
a manner that can decrease their potential for abuse. Methods of
the present technology provide various ways to regulate
pharmaceutical dosage through conjugating stimulants such as
amphetamine with polar hydrophilic ligands of the present
technology.
[0124] One embodiment provides a method for preventing behavioral
deterioration or the rebound effect by administering to a patient
in need an amphetamine prodrug composition of the present
technology, which comprises at least one polar hydrophilic
conjugate of amphetamine.
[0125] Another embodiment provides a method for safely delivering
amphetamine or another stimulant comprising providing a
therapeutically effective amount of at least one polar, hydrophilic
prodrug of stimulant of the present technology wherein the polar
hydrophilic moiety can reduce the rate of absorption of amphetamine
or another stimulant as compared to delivering the unconjugated
stimulant or the stimulant conjugated with a standard amino acid,
for example.
[0126] Another embodiment provides a method for reducing stimulant
toxicity comprising providing a patient with at least one polar,
hydrophilic prodrug of the stimulant of the present technology,
wherein the polar hydrophilic moiety can increase the rate of
clearance of pharmacologically active stimulant (i.e., released
stimulant such as amphetamine) when given at doses exceeding those
within the therapeutic range of the stimulant.
[0127] Another embodiment provides a method for reducing stimulant
toxicity comprising providing a patient with at least one polar,
hydrophilic stimulant prodrug of the present technology, wherein
the polar hydrophilic moiety can provide a serum release curve
which does not increase above the stimulant's toxicity level when
given at doses exceeding those within the therapeutic range for the
unconjugated stimulant.
[0128] Another embodiment provides a method for reducing
bioavailability of stimulant a comprising providing at least one
polar, hydrophilic stimulant prodrug of the present technology,
wherein the stimulant prodrug can maintain a steady-state serum
release curve which provides a therapeutically effective
bioavailability but prevents spiking or increased blood serum
concentrations compared to unconjugated stimulant when given at
doses exceeding those within the therapeutic range for the
unconjugated stimulant or the stimulant conjugated with a standard
diamino acid, for example.
[0129] Another embodiment provides a method for preventing a
C.sub.max or equivalent C.sub.max spike for amphetamine or another
stimulant while still providing a therapeutically effective
bioavailability curve comprising the step of administering to a
patient at least one polar, hydrophilic prodrug of amphetamine or
another stimulant of the present technology.
[0130] Another embodiment provides a method for preventing a toxic
release profile in a patient comprising administering to a patient
at least one polar, hydrophilic stimulant prodrug of the present
technology, wherein the stimulant prodrug can maintain a
steady-state serum release curve which provides a therapeutically
effective bioavailability but prevents spiking or increased blood
serum concentrations compared to unconjugated stimulant or the
stimulant conjugated to a standard amino acid, particularly when
taken at doses above prescribed amounts.
[0131] Another embodiment of the present technology is a method for
reducing or preventing abuse of a stimulant comprising providing,
administering, or prescribing a composition to a patient in need
thereof, wherein said composition comprises at least one polar,
hydrophilic stimulant prodrug of the present technology such that
the pharmacological activity of the stimulant is decreased when the
composition is used in a manner inconsistent with the
manufacturer's instructions.
[0132] Another embodiment of the present technology is a method for
reducing or preventing abuse of a stimulant such as amphetamine
comprising consuming at least one polar, hydrophilic prodrug of the
stimulant of the present technology, wherein said prodrug comprises
the stimulant covalently attached to a polar hydrophilic ligand
such that the pharmacological activity of the stimulant is
substantially decreased when the composition is used in a manner
inconsistent with the manufacturer's instructions.
[0133] Another embodiment of the present technology is a method of
preventing behavioral deterioration or the rebound effect of
amphetamine or stimulant treatment comprising providing,
administering, or prescribing an amphetamine composition of the
presently described technology to a patient in need thereof,
wherein said composition comprises at least one polar hydrophilic
prodrug of amphetamine that can decrease the potential of
behavioral deterioration or the rebound effect from amphetamine or
stimulant treatment.
[0134] Another embodiment of the present technology is a method for
reducing or preventing the euphoric effect of a stimulant
comprising providing, administering, or prescribing to a human or
animal in need thereof, a composition comprising at least one
polar, hydrophilic stimulant prodrug of the present technology that
can decrease the pharmacological activity of the stimulant when the
composition is used in a manner inconsistent with the
manufacturer's instructions.
[0135] Another embodiment of the present technology is a method for
reducing or preventing the euphoric effect of a stimulant,
comprising consuming a composition comprising at least one polar,
hydrophilic stimulant prodrug of the present technology that can
decrease the pharmacological activity of the stimulant when the
composition is used in a manner inconsistent with the
manufacturer's instructions.
[0136] Another embodiment of the present technology is any of the
preceding methods wherein the stimulant composition used is adapted
for oral administration, and wherein the stimulant prodrug is
resistant to release the stimulant from the polar hydrophilic
moiety when the composition is administered parenterally, such as
intranasally or intravenously. Preferably, the stimulant may be
released from the polar hydrophilic moiety in the presence of acid
and/or enzymes present in the stomach, intestinal tract, or blood
serum. Optionally, the stimulant composition used may be in the
form of a tablet, capsule, oral solution, oral suspension, thin
strip or other oral dosage form discussed herein.
[0137] For one or more of the recited methods, the composition of
the present technology used may yield a therapeutic effect without
substantial euphoria. Preferably, the stimulant composition of the
present technology can provide a therapeutically equivalent AUC
when compared to the stimulant alone but does not provide a
C.sub.max which results in euphoria or an equivalent C.sub.max.
[0138] Another embodiment of the present technology is a method for
reducing or preventing abuse of stimulants such as amphetamine
comprising orally administering a stimulant prodrug composition of
the present technology to a patient, wherein said composition
comprises at least one polar, hydrophilic stimulant prodrug of the
present technology that can decrease the pharmacological activity
of the stimulant when the composition is used in a manner
inconsistent with the manufacturer's instructions.
[0139] Another embodiment is a method for reducing or preventing
the euphoric effect of a stimulant comprising orally administering
a stimulant prodrug composition of the present technology to a
patient in need thereof, wherein said composition comprises at
least one polar, hydrophilic prodrug of the stimulant of the
present technology that can decrease the pharmacological activity
of the stimulant when the composition is used in a manner
inconsistent with the manufacturer's instructions.
[0140] For one or more of the recited methods of the present
technology, the following properties may be achieved through
conjugating amphetamine to a polar hydrophilic group. In one
embodiment, the cardiovascular toxicity or stress of the polar
hydrophilic prodrug of amphetamine of the present technology may be
lower than that of the amphetamine when the amphetamine is
delivered in its unconjugated state, as a compound conjugated to a
standard amino acid, or as a salt thereof. In another embodiment,
the possibility of behavioral deterioration is reduced or
eliminated. In another embodiment, the possibility of abuse by
intranasal administration is reduced or eliminated. In another
embodiment, the possibility of abuse by intravenous administration
is reduced or eliminated.
[0141] Another embodiment of the present technology provides
methods of treating various diseases or conditions requiring the
stimulation of the central nervous system (CNS) comprising
administering compounds or compositions of the present technology
which, optionally, further comprise commonly prescribed active
agents for the respective illness or disease. For instance, one
embodiment of the invention comprises a method of treating
attention deficit hyperactivity disorder (ADHD) comprising
administering to a patient at least one polar, hydrophilic prodrug
of amphetamine of the present technology. Another embodiment
provides a method of treating attention deficit disorder (ADD)
comprising administering to a patient compounds or compositions of
the invention.
[0142] Another embodiment of the invention provides a method of
treating narcolepsy comprising administering to a patient compounds
or compositions of the presently described technology.
[0143] The presently described technology and its advantages will
be better understood by reference to the following examples. These
examples are provided to describe specific embodiments of the
present technology. By providing these specific examples, the
applicants do not limit the scope and spirit of the present
technology. It will be understood by those skilled in the art that
the full scope of the presently described technology encompasses
the subject matter defined by the claims appending this
specification, and any alterations, modifications, or equivalents
of those claims.
Example 1
Comparative Study of Pharmacokinetic Parameters of Released
d-Amphetamine Following Administration of a Polar Hydrophilic
Prodrug of the Non-Standard Amino Acid Type (hArg-Amp) and a
Standard Amino Acid Conjugate (Vyvanse.TM., Lys-Amp)
[0144] The pharmacokinetic parameters of d-amphetamine following
oral administration of a non-standard amino acid conjugate of the
present technology and a standard amino acid conjugate, Vyvanse.TM.
(Lys-Amp), commercially available from Shire, Incorporated of
Wayne, Pa. are studied in this example. The non-standard amino acid
conjugate used in this example is the hydrochloride salt of
hArg-Amp. The results are recorded in the table below:
TABLE-US-00001 TABLE 1 Non-standard amino Acid Parameter %
amp.sup.1 Vyvanse .TM. % total Amp.sup.2 AUC.sub.0-8 h 94% 100%
AUC.sub.0-4 h 77% 100% AUC.sub.inf 95% 100% C.sub.max 76% 100%
T.sub.max 400% 100% .sup.1Percent amphetamine released relative to
Vyvanse .TM. (at an equimolar concentration of amphetamine
contained in the non-standard amino acid prodrug compared to the
total amphetamine contained in Vyvanse .TM.) .sup.2Percent
amphetamine relative to 50 mg Vyvanse .TM. dose
[0145] The study shows that the C.sub.max of a prodrug of the
preset technology is significantly lower than that of Vyvanse.TM.,
a standard amino acid conjugate of d-amphetamine, which can lead to
lower cardiovascular effects (blood pressure, heart rate). Quick
release (higher C.sub.max) of amphetamine has already demonstrated
significant increases in blood pressure and heart rate. In certain
patient populations, these cardiovascular side effects can be dose
limiting or can cause the termination of stimulant therapy.
[0146] The pharmacokinetic parameters of d-amphetamine following
parental administration of hArg-Amp and d-amphetamine are also
studied. The study shows that little release of amphetamine
(<25%) happens when hArg-Amp is taken through parental routes
(intranasal, intravenous) due to differences in enzymes encountered
in the gut versus other routes. When Adderall X.RTM. or other
controlled release formulations of amphetamine are injected or
snorted, the pharmacokinetic parameters of the amphetamine are
significantly altered and an individual can use these changes to
produce euphoria.
Example 2
Preparation of Boc-hArg(NO.sub.2)-Amp
[0147] Boc-hArg(NO.sub.2)--OH (2.667 g, 8 mmol) was dissolved in
DMF (25 ml). EDCI (2.30 g, 12 mmol), NHS (1.012 g, 8.8 mmol),
d-amphetamine (1.269 g, 9.6 mmol) and DIEA (1.138 g, 8.8 mmol) were
then added sequentially. The clear reaction mixture was stirred at
room temperature for 16 hrs. The reaction mixture was quenched with
pH 3 water (150 ml), and the product was extracted with EtOAc
(3.times.50 ml). The combined extracts were washed with pH 3 water
followed by saturated NaCl. The EtOAc layer was dried over
anhydrous MgSO.sub.4. The product was recrystallized from
EtOAc-Hexane two times to give 2.36 g of desired protected
product.
[0148] The product was analyzed using .sup.1H NMR (DMSO-d.sub.6)
.delta.. The result shows 0.9-1.1 (m, 3H, Amp CH.sub.3), 1.1-1.2
(m, 2H, hArg .gamma. CH.sub.2), 1.2-1.5 (m, 13H, Boc CH.sub.3, hArg
.beta.,.delta. CH.sub.2), 2.55-2.75 (m, 2H, Amp .beta. CH.sub.2),
3.1 (m, 2H, hArg .epsilon. CH.sub.2), 3.75 (m, 1H, Amp .alpha. CH),
3.95 (m, 1H, hArg .alpha. CH), 6.65 (t, 1H, hArg guanidino NH),
7.1-7.3 (m, 5H, Amp Ar--H), 7.6-8.2 (br m, 2H, hArg guanidine NH
and amide NH), 8.5 (br s, 1H, hArg NH--NO.sub.2). These results are
consistent with the proposed structure.
Example 3
Preparation of hArg-Amp-2HCl (l-homoarginine-d-amphetamine
dihydrochloride)
[0149] Boc-hArg(NO.sub.2)-Amp (1.5 g) was dissolved in HPLC grade
MeOH (120 ml) and to the clear solution was added the Pd--C
catalyst (10%, Aldrich). A small stir bar was placed in the flask
and the reaction mixture was stirred under a slow stream of
hydrogen overnight after incorporating the 5-6N HCl in 2-propanol
solution (1.5 ml). After the overnight reaction, the solution was
filtered and the solvent evaporated. The white crystalline product
was dried under vacuum to give 1.61 g of the Boc-hArg-Amp
intermediate product.
[0150] The product (1.6 g) was dissolved in 80 ml of HPLC grade
MeOH, and 5-6N HCl in 2-propanol (3.2 mL) was added to the
solution. The reaction mixture was stirred overnight, solvent
removed and re-dissolved in minimum amount of MeOH. The final
product was crashed out with MTBE, and dried under vacuum at
30.degree. C. for about 20 hours to yield 1.12 g of a white
powder.
[0151] The white powder was analyzed using .sup.1H NMR
(DMSO-d.sub.6) .delta.. The result shows 0.9-1.1 (m, 3H, Amp
CH.sub.3), 1.1-1.2 (m, 2H, hArg .gamma. CH.sub.2), 1.35 (m, 2H,
hArg .beta. CH.sub.2), 1.55 (m, 2H, hArg .delta. CH.sub.2), 2.75
(d, 2H, Amp .beta. CH.sub.2), 3.0 (m, 2H, hArg .epsilon. CH.sub.2),
3.75 (m, 1H, Amp .alpha. CH), 4.05 (m, 1H, hArg .alpha. CH),
7.1-7.2 (m, 5H, Amp Ar--H), 7.2-7.8 (br m, 3H, amide NH, HCl), 8.0
(t, 1H, hArg guanidino NH), 8.2 (br s, 2H, amide or guanidino
NH.sub.2), 8.75 (d, 1H, amide NH); .sup.13C NMR (DMSO-d.sub.6)
.delta. 21.08 (Amp CH.sub.3), 21.36 (hArg .gamma.), 28.23 (hArg
.delta.), 32.28 (hArg .beta.), 40.18 (Amp .beta.), 42.19 (hArg
.epsilon.), 46.88 (Amp .alpha.), 52.23 (hArg .alpha.), 126.54
(p-Ar), 128.52 (m-Ar), 129.60 (o-Ar), 139.34 (Ar), 157.61
(C.dbd.O), 167.95 (guanidino C); M+1=306. These results are
consistent with the proposed structure.
Example 4
Preparation of Cit-Amp.HCl (l-citrulline-d-amphetamine
hydrochloride)
[0152] Boc-Cit-OH (0.500 g, 1.82 mmol) was dissolved in anhydrous
THF. To this solution was added NHS (0.209 g, 1.82 mmol) followed
by DCC (0.376 g, 1.82 mmol). Resulting slurry was stirred at
ambient temperature overnight. In a separate flask, d-amphetamine
sulfate (0.306 g, 0.83 mmol) was suspended in THF (10 ml) and NMM
(0.34 ml, 3.64 mmol) was added. The activated ester was filtered
directly into the amphetamine suspension and the resulting
suspension was stirred overnight. The reaction was quenched with 5%
NaHCO.sub.3 and IPAC for 45 min. Organic solvent was then removed.
The aqueous layer was then extracted 3 times with IPAC and the
combined organics were washed with 5% acetic acid, 5% NaHCO.sub.3
and 5% NaCl. The organic layer was then dried over Na.sub.2SO.sub.4
and solvent was removed. Crude product was re-crystallized using
IPAC/heptane to yield 200 mg of a white solid. HPLC: column: YMC
ODS-AQ, 5 .mu.m, 120 .ANG., 4.6.times.250 mm; mobile phase: A=0.1%
TFA/H.sub.2O, B=0.1% TFA/MeCN; method: 0-15 min.:
85/15.fwdarw.60/40, 15-25 min.: 60/40.fwdarw.0/100; flow rate: 1
mL/min.; UV detection: 230 nm; retention time: 8.06 min.
[0153] 10 ml of 4N HCl in dioxane were added to the 200 mg (0.200
g) Boc-Cit-Amp. The mixture was stirred at room temperature for 6
hours and solvent was removed.
Example 5
Preparation of hCit-Amp.HCl (l-homocitrulline-d-amphetamine
hydrochloride)
[0154] Procedure as described for citrulline. However, 1,4-dioxane
was used during amino acid activation and coupling reaction instead
of THF. Crude product was purified via column chromatography
(0-6.5% MeOH/DCM) to give 201 mg (0.49 mmol) of
Boc-l-hCit-d-amphetamine (based on 500 mg of Boc-l-hCit-OH).
[0155] The Boc-protected Boc-l-hCit-d-amphetamine (110 mg, 0.27
mmol) was cooled in an ice-bath and 10 mL of chilled 4 N
HCl/dioxane were added. The mixture was stirred for 4 h and solvent
was evaporated to dryness yielding 92 mg (0.27 mmol) of
l-hCit-d-amphetamine.HCl. HPLC: column: YMC ODS-AQ, 5 .mu.m, 120
.ANG., 4.6.times.250 mm; mobile phase: A=0.1% TFA/H.sub.2O, B=0.1%
TFA/MeCN; method: 0-15 min.: 85/15.fwdarw.60/40, 15-25 min.:
60/40.fwdarw.0/100; flow rate: 1 mL/min.; UV detection: 230 nm;
retention time: 8.92 min.
Example 6
Preparation of hyPro-Amp.HCl (2-hydroxyproline-d-amphetamine
hydrochloride)
[0156] Z-l-hyPro(tBu)-OH (1.000 g, 3.11 mmol) was dissolved in 15
mL of anhydrous THF. NHS (0.358 g, 3.11 mmol) was added and the
solution was stirred for 5 min. DCC (0.642 g, 3.11 mmol) was then
added and the mixture stirred overnight at ambient temperature. In
a separate flask, d-amphetamine sulfate (0.521 g, 1.41 mmol) was
suspended in 15 mL of anhydrous THF and NMM (0.68 mL, 6.22 mmol)
was added. The mixture was stirred for 10 min. Subsequently, the
prior prepared succinimidyl ester was charged to the suspension
through a sintered funnel and the mixture was stirred overnight.
The reaction was quenched with 5% NaHCO.sub.3 solution (75 mL).
IPAC (25 mL) was added and the solution stirred for 45 min. The
mixture was concentrated by evaporating most of the organic
solvents. The aqueous layer was extracted with IPAC (3.times.100
mL). The combined organics were washed with 5% HOAc (1.times.100
mL), 5% NaHCO.sub.3 (1.times.100 mL) and 5% NaCl solution
(2.times.100 mL), dried over Na.sub.2SO.sub.4 and evaporated to
dryness. Crude product was dissolved in 10 mL of Ac.sub.2O at
60.degree. C. and 10 mL water were added while hot. The mixture was
kept overnight at ambient temperature. White crystals formed which
were filtered off, rinsed with water and dried in high vacuum to
yield 877 mg (2.00 mmol) of Z-l-hyPro(tBu)-d-amphetamine.
[0157] Fully protected Z-l-hyPro(tBu)-d-amphetamine (500 mg, 1.14
mmol) was dissolved in 10 mL of MeOH. Pd/C (10 w.t.-% Pd, 250 mg)
was added and the mixture stirred overnight in hydrogen atmosphere
at ambient temperature. The suspension was filtered through
Celite.RTM. and solvent was evaporated to dryness. Crude product
was purified via column chromatography (0-2.5% MeOH/DCM) to give 96
mg (0.32 mmol) of l-hyPro(tBu)-d-amphetamine.
[0158] Hydroxyl-protected l-hyPro(tBu)-d-amphetamine (96 mg, 0.32
mmol) was cooled in an ice-bath and 5 mL of chilled TFA were added.
The ice-bath was removed and the mixture was stirred overnight. The
solvent was evaporated and the remaining residue was dissolved in 4
N HO/dioxane. This process was repeated three times. The product
was dried in high vacuum to yield 90 mg (0.32 mmol) of
l-hyPro-d-amphetamine.HCl. HPLC: column: YMC ODS-AQ, 5 .mu.m, 120
.ANG., 4.6.times.250 mm; mobile phase: A=0.1% TFA/H.sub.2O, B=0.1%
TFA/MeCN; method: 0-15 min.: 85/15.fwdarw.60/40, 15-25 min.:
60/40.fwdarw.0/100; flow rate: 1 mL/min.; UV detection: 230 nm;
retention time: 9.61 min.
Example 7
Preparation of Arg(NO2)-Amp.2HCl (l-arginine(NO2)-d-amphetamine
dihydrochloride)
[0159] Procedure as described for citrulline. Crude product was
purified via column chromatography (0-3.5% MeOH/DCM) to give 471 mg
(1.08 mmol) of Boc-l-Arg(NO.sub.2)-d-amphetamine (based on 1.000 g
of Boc-l-Arg(NO.sub.2)--OH).
[0160] Boc-protected Boc-Arg(NO.sub.2)-d-amphetamine was
deprotected using the procedure described for homocitrulline
yielding 442 mg (1.08 mmol) of l-Arg(NO.sub.2)-d-amphetamine.HCl.
HPLC: column: YMC ODS-AQ, 5 .mu.m, 120 .ANG., 4.6.times.250 mm;
mobile phase: A=0.1% TFA/H.sub.2O, B=0.1% TFA/MeCN; method: 0-15
min.: 85/15.fwdarw.60/40, 15-25 min.: 60/40.fwdarw.0/100; flow
rate: 1 mL/min.; UV detection: 230 nm; retention time: 9.21
min.
Example 8
Preparation of Lysinol-Co-Amp
[0161] Boc-l-Lys(Z)-ol (500 mg, 1.36 mmol) was dissolved in 10 mL
of anhydrous dioxane. CDI was added and the mixture stirred
overnight at ambient temperature. Solvent was evaporated to dryness
and the remaining oily residue was dissolved in 15 mL of anhydrous
THF. Amphetamine sulfate (277 mg, 0.75 mmol) and Et.sub.3N (0.40
mL, 2.86 mmol) were added and the mixture was stirred overnight at
50.degree. C. The reaction was quenched with water and the aqueous
layer extracted with IPAC (3.times.75 mL). The combined organics
were washed with 5% HOAc, sat. NaHCO.sub.3, sat. NaCl and 5% NaCl
solution and dried over Na.sub.2SO.sub.4. Solvents were evaporated
to dryness yielding Boc-l-Lys(Z)-OCONH-d-amphetamine as a white
foam. HPLC: column: YMC ODS-AQ, 5 .mu.m, 120 .ANG., 4.6.times.250
mm; mobile phase: A=0.1% TFA/H.sub.2O, B=0.1% TFA/MeCN; method:
0-15 min.: 85/15.fwdarw.60/40, 15-25 min.: 60/40.fwdarw.0/100; flow
rate: 1 mL/min.; UV detection: 230 nm; retention time: 20.59
min.
Example 9
Preparation of Carn-Amp (O-acetyl-l-carnitine-d-amphetamine
chloride)
[0162] O-Acetyl-l-carnitine.Cl (1.000 g, 4.17 mmol) was dissolved
in 12.5 mL of a mixture of DMF/dioxane/water (2:2:1). NHS (0.528 g,
4.59 mmol) and DCC (0.947 g, 4.59 mmol) were added and the mixture
was stirred overnight at ambient temperature. Solvents were
evaporated and the remaining residue was dried overnight in high
vacuum. The crude succinimidyl ester intermediate was dissolved in
20 mL of anhydrous DMF. Amphetamine sulfate (0.700 g, 1.90 mmol)
and NMM (0.92 mL, 8.34 mmol) were added and the mixture stirred
overnight. Solvent was evaporated to dryness and the remaining
residue was leached with IPA. Solvent was evaporated to yield
Carn-d-amphetamine.
Example 10
Pharmacokinetic Study of hArg-Amp vs. Lys-Amp
[0163] Male Sprague-Dawley rats were fasted overnight and dosed by
oral gavage with either l-homoarginine-d-amphetamine (hArg-Amp) or
l-lysine-d-amphetamine (Vyvanse.TM., Lys-Amp). Water was provided
ad libitum. Doses were calculated at an equivalent 1.5 mg/kg
freebase equivalent of d-amphetamine. Plasma concentrations of
d-amphetamine were measured using ELISA (Neogen Corp. Lexington,
Ky.).
[0164] Mean plasma concentration curves (n=5) of d-amphetamine
released by l-homoarginine-d-amphetamine or l-lysine-d-amphetamine
are shown in FIG. 1. Pharmacokinetic (PK) parameters of this study
are listed in Table 2.
TABLE-US-00002 TABLE 2 Pharmacokinetic Properties of hArg-Amp and
Lys-Amp Vehicle % AUC Tmax Cmax % Tmax % Cmax Lys-Amp 100% 3 h 44
ng/ml 100% 100% hArg-Amp 99% 4 h 44 ng/ml 133% 100%
[0165] This pharmacokinetic (PK) study clearly demonstrates a shift
in the T.sub.max for the polar hydrophilic prodrug of the
non-standard amino acid type (hArg-Amp) compared to the standard
amino acid (Lys-Amp). This shift may be due to a reduction in the
rate of enzymatic hydrolysis of the amide bond of the non-standard
amino acid attached to amphetamine vs. the standard amino acid
attached to amphetamine.
[0166] FIGS. 2-4 represent different ways to view the data
reflected in FIG. 1 and Table 2. As further discussed below, these
figures highlight the differences of hArg-Amp over Lys-Amp during
the first several hours.
[0167] FIG. 2 demonstrates the relative blood levels of
d-amphetamine released from both Lys-Amp and hArg-Amp. The graph
shows that equivalent blood levels do not occur until later time
points and that blood levels do not appear to spike or have a more
significant C.sub.max than Lys-Amp. The amount of d-amphetamine
released from hArg-Amp is gradual and maintains a more steady
concentration over the duration of the study than did Lys-Amp. In
contrast, Lys-Amp blood levels of released d-amphetamine "spiked"
at 3 hours and cleared more quickly than the blood levels obtained
from hArg-Amp.
[0168] FIGS. 3 and 4 show the difference in blood levels obtained
from the study described in FIG. 2. As is shown, the initial blood
levels for both conjugates (Lys-Amp and hArg-Amp) are very
different, with hArg-Amp releasing amphetamine at a more gradual
rate. These differences in blood levels become less during the more
critical duration of action for stimulant treatments and more
importantly, the differences are greater again at later time points
suggesting that hArg-Amp maintains a more consistent dose of
amphetamine when compared to Lys-Amp. The longer duration of
release for hArg-Amp would suggest a much lower opportunity for
behavioral deterioration to occur.
[0169] Other oral studies have been conducted in a similar fashion
and are summarized in Table 3 below. The average PK results for
four (4) oral studies (n=30 per vehicle) are recorded in FIG.
5:
TABLE-US-00003 TABLE 3 Average Results of 6 Oral Studies (n = 30
per compound) Vehicle % AUC Tmax % Tmax % Cmax % AUC 0-4 h Lys-Amp
100% 1 h 100% 100% 100% hArg-Amp 81% 2-4 h 200-400% 69% 67%
Example 11
Comparative Biological Study of Lys-Amp and Cit-Amp
[0170] To compare the amount of release of d-amphetamine among
various polar hydrophilic prodrugs, l-citrulline-d-amphetamine
(Cit-Amp) was dosed with Lys-Amp in another oral pharmacokinetic
study. Mean plasma concentration curves (n=5) of d-amphetamine
released by Cit-Amp and Lys-Amp are shown in FIG. 6.
Pharmacokinetic parameters of this study are listed in Table 4.
[0171] Direct comparison of polar hydrophilic prodrugs especially
non-standard amino acid conjugates of amphetamine (Cit and hArg)
demonstrate the significant ability to shift or change the
pharmacokinetic properties versus the standard amino acids. All
non-standard amino acids studied released amphetamine in an amount
greater than 50%. Homoarginine showed C.sub.max levels far below
that of lysine and homoarginine and citrulline significantly
shifted the T.sub.max compared to Lys-Amp. These changes to the
pharmacokinetic properties of amphetamine when conjugated to
non-standard amino acids represent clinically significant changes
not described or demonstrated by Lys-Amp nor described or
demonstrated by other standard amino acids.
TABLE-US-00004 TABLE 4 Oral Properties of Lys-Amp and Cit-Amp
Vehicle % AUC Tmax Cmax % Tmax % Cmax Lys-Amp 100% 1 h 59 ng/ml
100% 100% Cit-Amp 95% 15 m 129 ng/ml 25% 219%
Example 12
Pharmacokinetic Study of Lys-Amp, hCit-Amp and
hArg(NO.sub.2)-Amp
[0172] To compare the amount of release of d-amphetamine among
various polar hydrophilic prodrugs, l-homocitrulline-d-amphetamine
(hCit-Amp) and l-homoarginine (NO.sub.2)-d-amphetamine
(hArg(NO.sub.2)-Amp) were dosed with Lys-Amp in another oral
pharmacokinetic study. Mean plasma concentration curves (n=5) of
d-amphetamine released by the amphetamine prodrugs are shown in
FIG. 7. Pharmacokinetic parameters of this study are listed in
Table 5.
TABLE-US-00005 TABLE 5 Oral Properties of Lys-Amp, hCit-Amp, and
hArg(NO.sub.2)-Amp Vehicle % AUC Tmax Cmax % Tmax % Cmax Lys-Amp
100% 1 h 54 ng/ml 100% 100% hCit-Amp 78% 1 m 57 ng/ml NA 105%
hArg(NO.sub.2)-Amp 69% 1 h 59 ng/ml NA 109%
Example 13
Intranasal Study of Amp, Lys-Amp and hArg-Amp
[0173] Male Sprague-Dawley rats were fasted overnight and dosed by
intranasal administration with either hArg-Amp, Lys-Amp or
d-amphetamine. Doses were calculated at an equivalent 1.5 mg/kg
freebase equivalent of d-amphetamine. Plasma concentrations of
d-amphetamine were measured using ELISA. Mean plasma concentration
curves (n=5) of d-amphetamine released by hArg-Amp or Lys-Amp are
shown in FIG. 8. Pharmacokinetic parameters of this study are
listed in Table 6. No significant release (<50%) was observed in
either hArg-Amp or Lys-Amp and less release was observed within the
first hour of administration (<25%). Observed levels from
Lys-Amp are significantly higher than previously published
data.
TABLE-US-00006 TABLE 6 Intranasal Properties of d-Amp, hArg-Amp and
Lys-Amp Vehicle % AUC Tmax Cmax % Tmax % Cmax d-amp 100% 5 m 779
ng/ml 100% 100% hArg-Amp 42% 0.5 h 71 ng/ml 600% 9% Lys-Amp 36% 3 h
79 ng/ml 3600% 10%
Example 14
Intravenous Study of d-Amp, hArg-Amp, Lys-Amp
[0174] Male Sprague-Dawley rats were dosed by intravenous
administration through the tail vein with hArg-Amp, Lys-Amp or
d-amphetamine. Doses were calculated at an equivalent 1.5 mg/kg
freebase equivalent of d-amphetamine. Plasma concentrations of
d-amphetamine were measured using ELISA. Mean plasma concentration
curves (n=5) of d-amphetamine released by hArg-Amp or Lys-Amp are
shown in FIG. 9. Pharmacokinetic parameters of this study are
listed in Table 7. No significant release (<15%) was observed in
either hArg-Amp or Lys-Amp though hArg-Amp was significantly less.
Observed levels from Lys-Amp are significantly higher than
previously published data. The initial spike in d-amphetamine
released from hArg-Amp cleared quickly.
TABLE-US-00007 TABLE 7 Intravenous Properties of d-Amp, hArg-Amp
and Lys-Amp Vehicle % AUC Tmax Cmax % Tmax % Cmax d-amp 100% 5 m
554 ng/ml 100% 100% hArg-Amp 8% 5 m 68 ng/ml 100% 12% Lys-Amp 14%
15 m 79 ng/ml 100% 14%
[0175] Results of the studies in above examples clearly show an
unexpected change in the oral pharmacokinetic properties by using
polar hydrophilic prodrugs. By changing the polar hydrophilic group
attached to amphetamine, the conjugates are able to shift T.sub.max
(earlier or later), modify curve shape, lower C.sub.max, and raise
C.sub.max. In addition, the shift in T.sub.max for hArg-Amp may be
clinically significant in that many of the cardiovascular side
effects and toxicity are related to T.sub.max and C.sub.max. The
results demonstrate that by using these polar hydrophilic group, a
shift in the T.sub.max, with a lower C.sub.max occurs without
changing AUC significantly. In addition, the slope of uptake of
hArg-Amp vs. Lys-Amp appears to be more gradual thus leading to a
slower onset which could further alleviate side effects.
[0176] The amphetamine conjugates listed above of the present
technology demonstrates that by using polar hydrophilic prodrugs, a
shift in the T.sub.max occurs while still retaining AUC and
potential clinical effect. By using polar hydrophilic prodrugs, we
are able to demonstrate that hArg-Amp show little release via the
IN (intransal) or IV (intravenous) route yet still maintain a
similar AUC.
[0177] The polar, hydrophilic amphetamine prodrug of the present
technology is chemically stable to in vitro hydrolysis of the amide
linkage to prevent tampering or removing the amphetamine prior to
oral ingestion. Also, the controlled release of amphetamine through
oral administration of the polar, hydrophilic amphetamine prodrug
of the present technology is an inherent property of the molecule,
not related to the formulation. Therefore, the prodrug of the
present technology can be easily formulated to different dosage
forms.
[0178] The invention is now described in such full, clear, concise
and exact terms as to enable any person skilled in the art to which
it pertains, to practice the same. It is to be understood that the
foregoing describes preferred embodiments of the invention and that
modifications may be made therein without departing from the spirit
or scope of the invention as set forth in the appended claims.
* * * * *