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Weight Loss Patent Abstract
Disclosed are compositions for affecting weight loss comprising
a first compound and a second compound, where the first compound
is a metabolite of naltrexone, such as 6-.beta.-naltrexol or a prodrug
of a naltrexone metabolite, and the second compound causes increased
agonism of a melanocortin 3 receptor (MC3-R) and/or a melanocortin
4 receptor (MC4-R), and/or increases the concentration of .alpha.-MSH
in the central nervous system. Also disclosed are methods of affecting
weight loss, increasing energy expenditure, increasing satiety in
an individual, or suppressing the appetite of an individual, comprising
identifying an individual in need thereof and treating that individual
to antagonize opioid receptor activity with a metabolite of naltrexone,
such as 6-.beta.-naltrexol or a prodrug of a naltrexone metabolite,
and treating that individual to enhance .alpha.-MSH activity, e.g.,
by administration of a second compound causes increased agonism
of MC3-R and/or MC4-R, and/or increases the concentration of .alpha.-MSH
in the central nervous system.
Weight Loss Patent Claims
1. A composition for affecting weight loss comprising a first compound
and a second compound; wherein said first compound is a metabolite
of naltrexone; and wherein said second compound increases agonism
of a melanocortin 3 receptor (MC3-R) or melanocortin 4 receptor
(MC4-R), or increases the concentration of .alpha.-MSH in the central
nervous system.
2. The composition of claim 1, wherein said second compound is
bupropion.
3. The composition of claim 1, wherein said first compound is 6-.beta.-naltrexol.
4. The composition of claim 1, wherein said first compound is a
prodrug of the naltrexone metabolite.
5. The composition of claim 4, wherein said first compound is a
compound of the formula (II): wherein at least one of R.sup.1 and
R.sup.2 is a PO.sub.3H group or a salt thereof, or an organic group
containing from 2 to 20 carbons that is selected to form a 3-O-ester
derivative, a 6-O-ester derivative, a 3-O,6-O-diester derivative,
a 3-carbamate derivative, a 6-carbamate derivative, a 3,6-dicarbamate
derivative, a 3-carbonate derivative, a 6-carbonate derivative,
or a 3,6-dicarbonate derivative.
6. The composition of claim 5, wherein one or neither of R.sup.1
and R.sup.2 is H; and wherein at least one of R.sup.1 and R.sup.2
is a group selected from the following:
7. The composition of claim 1, wherein said second compound is
selected from the group consisting of a selective serotonin reuptake
inhibitor (SSRI), a serotonin 2C agonist, a serotonin 1B agonist,
a .gamma.-amino butyric acid (GABA) inhibitor, a GABA receptor antagonist,
a GABA channel antagonist, an anticonvulsant, a dopamine agonist,
a dopamine reuptake inhibitor, a norepinephrine reuptake inhibitor,
a norepinephrine releaser, and a norepinephrine agonist.
8. The composition of claim 7, wherein said second compound is
selected from the group consisting of fluoxetine, fluvoxamine, sertraline,
paroxetine, citalopram, escitalopram, sibutramine, duloxetine, venlafaxine,
sumatriptan, almotriptan, naratriptan, frovatriptan, rizatriptan,
zomitriptan, elitriptan, zonisamide, topiramate, nembutal, lorazepam,
clonazepam, clorazepate, tiagabine, gabapentin, fosphenytoin, phenytoin,
carbamazepine, valproate, felbamate, levetiracetam, oxcarbazepine,
lamotrigine, methsuximide, ethosuxmide, cabergoline, amantadine,
lisuride, pergolide, ropinirole, pramipexole, bromocriptine, phentermine,
bupropion, thionisoxetine, reboxetine, diethylpropion, phendimetrazine,
benzphetamine, and pharmaceutically acceptable salts or prodrugs
thereof.
9. The composition of claim 5, wherein said second compound is
bupropion.
10. A method of affecting weight loss, comprising: identifying
an individual in need thereof; administering an effective amount
of the composition of claim 1.
11. The method of claim 10, wherein the first compound is 6-.beta.-naltrexol
or a prodrug of the naltrexone metabolite.
12. The method of claim 11, wherein the second compound is bupropion.
13. A compound of the formula (II): wherein one or neither of R.sup.1
and R.sup.2 is H; and wherein at least one of R.sup.1 and R.sup.2
is a group selected from the following:
14. A method of affecting weight loss, comprising: identifying
an individual in need thereof; administering an effective amount
of the compound of claim 13.
15. The method of claim 14, further comprising administering an
effective amount of a second compound that increases agonism of
a melanocortin 3 receptor (MC3-R) or melanocortin 4 receptor (MC4-R),
or increases the concentration of .alpha.-MSH in the central nervous
system.
16. The method of claim 15, wherein the second compound is bupropion.
17. A composition for affecting weight loss comprising an effective
amount of a compound of claim 13 and a pharmaceutically acceptable
carrier.
18. The composition of claim 17, further comprising an effective
amount of a second compound that increases agonism of a melanocortin
3 receptor (MC3-R) or melanocortin 4 receptor (MC4-R), or increases
the concentration of .alpha.-MSH in the central nervous system.
19. The composition of claim 18, wherein the second compound is
bupropion.
20. A method of affecting weight loss, comprising: identifying
an individual in need thereof; administering an effective amount
of the composition of claim 18.
21. A method of affecting weight loss, comprising: identifying
an individual in need thereof; and administering an effective amount
of a first compound and a second compound; wherein said first compound
is a metabolite of naltrexone and wherein said second compound increases
agonism of a melanocortin 3 receptor (MC3-R) or melanocortin 4 receptor
(MC4-R), or increases the concentration of .alpha.-MSH in the central
nervous system.
22. The method of claim 21, wherein the first compound and the
second compound are administered substantially simultaneously.
23. The method of claim 21, wherein the first compound is administered
prior to the second compound.
24. The method of claim 21, wherein the first compound is administered
subsequent to the second compound.
25. The method of claim 21, wherein said first compound is 6-.beta.-naltrexol.
26. The method of claim 21, wherein said first compound is a prodrug
of a naltrexone metabolite.
27. The method of claim 26, wherein said first compound is a compound
of the formula (II): wherein at least one of R.sup.1 and R.sup.2
is a PO.sub.3H group or salt thereof, or an organic group containing
from 2 to 20 carbons that is selected to form a 3-O-ester derivative,
a 6-O-ester derivative, a 3-O,6-O-diester derivative, a 3-carbamate
derivative, a 6-carbamate derivative, a 3,6-dicarbamate derivative,
a 3-carbonate derivative, a 6-carbonate derivative, or a 3,6-dicarbonate
derivative.
28. The method of claim 21, wherein said second compound is selected
from the group consisting of a selective serotonin reuptake inhibitor
(SSRI), a serotonin 2C agonist, and a serotonin 1B agonist.
29. The method of claim 28, wherein said second compound is selected
from the group consisting of fluoxetine, fluvoxamine, sertraline,
paroxetine, citalopram, escitalopram, sibutramine, duloxetine, and
venlafaxine, and pharmaceutically acceptable salts or prodrugs thereof.
30. The method of claim 28, wherein said second compound is selected
from the group consisting of sumatriptan, almotriptan, naratriptan,
frovatriptan, rizatriptan, zomitriptan, and elitriptan.
31. The method of claim 21, wherein said second compound is selected
from the group consisting of a .gamma.-amino butyric acid (GABA)
inhibitor, a GABA receptor antagonist, a GABA channel antagonist
and an anticonvulsant.
32. The method of claim 31, wherein said second compound is selected
from the group consisting of zonisamide, topiramate, nembutal, lorazepam,
clonazepam, clorazepate, tiagabine, gabapentin, fosphenytoin, phenytoin,
carbamazepine, valproate, felbamate, levetiracetam, oxcarbazepine,
lamotrigine, methsuximide, and ethosuxmide.
33. The method of claim 21, wherein said second compound is selected
from the group consisting of a dopamine agonist, a dopamine reuptake
inhibitor, a norepinephrine reuptake inhibitor, a norepinephrine
releaser, and a norepinephrine agonist.
34. The method of claim 33, wherein said second compound is selected
from the group consisting of cabergoline, amantadine, lisuride,
pergolide, ropinirole, pramipexole, bromocriptine, phentermine,
bupropion, thionisoxetine, reboxetine, diethylpropion, phendimetrazine
and benzphetamine.
35. The method of claim 34, wherein said second compound is bupropion.
Weight Loss Patent Description
RELATED APPLICATION INFORMATION
[0001] This application claims priority to U.S. Provisional Patent
Application Ser. No. 60/702,877, filed Jul. 27, 2005, which is hereby
incorporated by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention is in the field of pharmaceutical
compositions and methods for the treatment of obesity and for affecting
weight loss in individuals.
[0004] 2. Description of the Related Art
[0005] Obesity is a disorder characterized by the accumulation
of excess fat in the body. Obesity has been recognized as one of
the leading causes of disease and is emerging as a global problem.
Increased instances of complications such as hypertension, non-insulin
dependent diabetes mellitus, arteriosclerosis, dyslipidemia, certain
forms of cancer, sleep apnea, and osteoarthritis have been related
to increased instances of obesity in the general population.
[0006] Obesity has been defined in terms of body mass index (BMI).
BMI is calculated as weight (kg)/[height (m)].sup.2. According to
the guidelines of the U.S. Centers for Disease Control and Prevention
(CDC) and the World Health Organization (WHO), for adults over 20
years old, BMI falls into one of these categories: below 18.5 is
considered underweight, 18.5-24.9 is considered normal, 25.0-29.9
is considered overweight, and 30.0 and above is considered obese
(World Health Organization. Physical status: The use and interpretation
of anthropometry. Geneva, Switzerland: World Health Organization
1995. WHO Technical Report Series).
[0007] Prior to 1994, obesity was generally considered a psychological
problem. The discovery of the adipostatic hormone leptin in 1994
brought forth the realization that, in certain cases, obesity may
have a biochemical basis (Zhang et al., "Positional cloning
of the mouse obese gene and its human homologue," Nature, 372:425-432
(1994)). A corollary to this realization was the idea that the treatment
of obesity may be achieved by chemical approaches. Since then, a
number of such chemical treatments have entered the market. The
most famous of these attempts was the introduction of Fen-Phen,
a combination of fenfluramine and phentermine. Unfortunately, it
was discovered that fenfluramine caused heart-valve complications,
which in some cases resulted in the death of the user. Fenfluramine
has since been withdrawn from the market. There has been some limited
success with other combination therapy approaches, particularly
in the field of psychological eating disorders. One such example
is Devlin, el al., Int. J. Eating Disord. 28:325-332 (2000), in
which a combination of phentermine and fluoxetine showed some efficacy
in the treatment of binge eating disorders.
[0008] In addition to those individuals who satisfy a strict definition
of medical obesity, a significant portion of the adult population
is overweight. These overweight individuals, as well as individuals
at risk for becoming overweight or obese, would also benefit from
the availability of an effective weight-loss composition. Therefore,
there is an unmet need in the art to provide pharmaceutical compositions
that can prevent weight gain and/or affect weight loss without having
significant adverse side effects.
SUMMARY OF THE INVENTION
[0009] An embodiment provides compositions for affecting weight
loss, increasing energy expenditure, increasing satiety in an individual,
and/or suppressing the appetite of an individual, comprising a first
compound and a second compound, where the first compound is a metabolite
of naltrexone and the second compound causes increased agonism of
a melanocortin 3 receptor (MC3-R) and/or a melanocortin 4 receptor
(MC4-R), and/or increases the concentration of .alpha.-MSH in the
central nervous system. The metabolite of naltrexone may be naltrexol
(e.g., 6-.beta.-naltrexol) or a compound of the formula (II):
[0010] wherein at least one of R.sup.1 and R.sup.2 in formula (II)
is a PO.sub.3H group or a salt thereof, or an organic group containing
from 2 to 20 carbons, preferably 3 to 20 carbons, that is selected
to form a 3-O-ester derivative, a 6-O-ester derivative, a 3-O,6-O-diester
derivative, a 3-carbamate derivative, a 6-carbamate derivative,
a 3,6-dicarbamate derivative, a 3-carbonate derivative, a 6-carbonate
derivative, or a 3,6-dicarbonate derivative. Preferably, one or
neither of R.sup.1 and R.sup.2 is H. For example, in an embodiment,
one or neither of R.sup.1 and R2 is H and at least one of R.sup.1
and R.sup.2 is a group selected from the following:
[0011] Another embodiment provides methods of affecting weight
loss, increasing energy expenditure, increasing satiety in an individual,
and/or suppressing the appetite of an individual, comprising identifying
an individual in need thereof, treating that individual to antagonize
opioid receptor activity with a metabolite of naltrexone, and treating
the individual to enhance .alpha.-MSH activity. In an embodiment,
treating the individual comprises administering a first compound
that is a naltrexone metabolite and a second compound that increases
agonism of MC3-R and/or MC4-R, and/or increases the concentration
of .alpha.-MSH in the central nervous system. In some embodiments
the first and second compounds are administered substantially simultaneously,
e.g., by separate substantially simultaneous administration of the
two compounds or by administration of the composition described
above. In other embodiments, the two compounds are administered
sequentially, in either order. The metabolite of naltrexone may
be a naltrexol (e.g., 6-.beta.-naltrexol) or a compound of the formula
(II).
[0012] Another embodiment provides novel compounds of the formula
(II), wherein one or neither of R.sup.1 and R2 is H and wherein
at least one of R.sup.1 and R.sup.2 is a group selected from the
following:
[0013] Another embodiment provides a composition for affecting
weight loss, increasing energy expenditure, increasing satiety in
an individual, and/or suppressing the appetite of an individual,
comprising an effective amount of a compound of formula (II) and
a pharmaceutically acceptable carrier. In preferred embodiments,
the compound of formula (II) is a naltrexone metabolite (e.g., a
prodrug of a naltrexone metabolite). In some embodiments, the compound
of formula (II) is a novel compound as described above. In some
embodiments, the composition further comprises a second compound
that increases agonism of MC3-R and/or MC4-R, and/or increases the
concentration of .alpha.-MSH in the central nervous system.
[0014] Another embodiment provides a method of affecting weight
loss, increasing energy expenditure, increasing satiety in an individual,
and/or suppressing the appetite of an individual, comprising identifying
an individual in need thereof, and administering an effective amount
of a compound of formula II, e.g., by administering a composition
that comprises a compound of formula (II) and a pharmaceutically
acceptable carrier as described above. In preferred embodiments,
the method further comprises administering an effective amount of
a second compound that increases agonism of MC3-R and/or MC4-R,
and/or increases the concentration of .alpha.-MSH in the central
nervous system, e.g., by administering a composition that comprises
the compound of formula (II), the second compound, and the pharmaceutically
acceptable carrier as described above.
[0015] In some embodiments described herein, the first compound
comprises 6-.beta.-naltrexol and/or a prodrug of a naltrexone metabolite
(such as a compound of formula II). In some embodiments disclosed
herein, the first compound can antagonize an opioid receptor in
a mammal, where the opioid receptor is selected from a group consisting
of a .mu.-opioid receptor, a .kappa.-opioid receptor, and a .delta.-opioid
receptor.
[0016] In some of the embodiments described herein, the second
compound is at least one selected from a selective serotonin reuptake
inhibitor (SSRI), a serotonin 2C agonist, and a serotonin 1B agonist.
In some embodiments, the second compound is at least one selected
from fluoxetine, fluvoxamine, sertraline, paroxetine, citalopram,
escitalopram, sibutramine, duloxetine, and venlafaxine, and pharmaceutically
acceptable salts or prodrugs thereof. In other embodiments the second
compound is selected from sumatriptan, almotriptan, naratriptan,
frovatriptan, rizatriptan, zomitriptan, and elitriptan. In some
embodiments, the second compound is selected from a .gamma.-amino
butyric acid (GABA) inhibitor, a GABA receptor antagonist, a GABA
channel antagonist and an anticonvulsant. In some embodiments, the
second compound is selected from zonisamide, topiramate, nembutal,
lorazepam, clonazepam, clorazepate, tiagabine, gabapentin, fosphenytoin,
phenytoin, carbamazepine, valproate, felbamate, levetiracetam, oxcarbazepine,
lamotrigine, methsuximide, and ethosuxmide. In some embodiments,
the second compound is selected from a dopamine agonist, a dopamine
reuptake inhibitor, a norepinephrine reuptake inhibitor, a norepinephrine
releaser, and a norepinephrine agonist. In some embodiments, the
second compound is selected from the group consisting of cabergoline,
amantadine, lisuride, pergolide, ropinirole, pramipexole, bromocriptine,
phentermine, bupropion, thionisoxetine, reboxetine, diethylpropion,
phendimetrazine and benzphetamine. In any of the embodiments described
herein, the second compound can be bupropion.
[0017] These and other embodiments are described in greater detail
below.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0018] Arcuate nucleus neurons are responsive to a wide array of
hormones and nutrients, including leptin, insulin, gonadal steroids,
and glucose. In addition to potential transport mechanisms, peripheral
substances may access these neurons via arcuate cell bodies in and
projections to the median eminence, a region considered to be a
circumventricular organ, which lacks a blood-brain barrier (Cone
et al., "The arcuate nucleus as a conduit for diverse signals
relevant to energy homeostasis," Int'l Journal of Obesity 25,
Suppl 5, S63-S67 (2001)).
[0019] Administration of exogenous leptin activates a number of
different neurons in hypothalamic and brainstem cell groups that
bear leptin receptor. Leptin-responsive neurons in the arcuate nucleus
include both those containing neuropeptide Y (NPY) and agouti-related
peptide (AgRP) in the medial part of the nucleus and those containing
both pro-opiomelanocortin (POMC) and its derivatives, including
.alpha.-melanocyte stimulating hormone (.alpha.-MSH), as well as
cocaine and amphetamine-related transcript (CART) (Saper et al.,
"The need to feed: Homeostatic and hedonic control of eating,"
Neuron, 36:199-211 (2002)).
[0020] The leptin-responsive POMC neurons in the arcuate nucleus
are believed to cause anorexia and weight reduction by the action
of .alpha.-MSH on MC3-R and/or MC4-R. The highest MC3-R expression
level is in the hypothalamus and limbic system, whereas MC4-R mRNA
is expressed in virtually all major brain regions. Some of the metabolic
effects resulting from stimulation of MC4-R are decreased food intake
and an increase in energy expenditure through stimulation of thyrotropin-releasing
hormone and activation of the sympathetic nervous system. Targeted
deletion of the MC4-R gene produces obesity, hyperphagia, hyperinsulinemia,
and reduced energy expenditure. Targeted deletion of MC3-R results
in increased adiposity due to decreased energy expenditure (Korner
et al., "The emerging science of body weight regulation and
its impact on obesity treatment," J. Clin. Invest. 111(5):565-570
(2003)). Thus, it is believed that increased concentrations of .alpha.-MSH
in the central nervous system (CNS) increases its action on MC3-R
and/or MC4-R, resulting in a suppressed appetite.
[0021] POMC neurons also release .beta.-endorphin when they release
.alpha.-MSH. .beta.-endorphin is an endogenous agonist of the .mu.-opioid
receptors (MOP-R), found on the POMC neurons. Stimulation of MOP-R
decreases the release of .alpha.-MSH. This is a biofeedback mechanism
that under normal physiological conditions controls the concentration
of .alpha.-MSH in the CNS. Thus, blocking MOP-R by opioid antagonists
will break the feedback mechanism, which results in continued secretion
of .alpha.-MSH and an increase in its concentration in the CNS.
[0022] A second population of neurons in the arcuate nucleus tonically
inhibits the POMC neurons. These POMC-inhibiting neurons secrete
NPY, the neurotransmitter .gamma.-aminobutyric acid (GABA), and
AgRP. NPY and GABA inhibit POMC neurons, via NPY Y1 receptors and
GABA receptors, respectively. Thus, within the arcuate nucleus NPY
and GABA inhibit the release of .alpha.-MSH, and therefore are stimulators
of feeding. It is known that leptin inhibits the release of GABA
from NPY terminals synapsing onto POMC neurons, whereas ghrelin,
an orexigenic peptide, stimulates the ghrelin receptors on NPY neurons
and increase the secretion of NPY and GABA onto the POMC cells,
which in turn inhibits the release of .alpha.-MSH.
[0023] AgRP stimulates food intake in the rat through antagonism
of the interaction of .alpha.-MSH at MC4-R. Expression of the AgRP
gene is suppressed by leptin.
[0024] Serotonin, also known as 5-hydroxytryptamine or 5-HT, activates
the POMC neurons to secrete .alpha.-MSH. However, serotonin is taken
up and removed from action by specific transporters so that a single
serotonin molecule has short term effects. It is known that selective
serotonin re-uptake inhibitors (SSRIs) prevent the uptake of serotonin
and increase its concentrations in the CNS. Thus, SSRIs also increase
the secretion of .alpha.-MSH and its concentrations in the CNS.
[0025] Dopamine also increases the activity of POMC neurons to
secrete .alpha.-MSH. Like serotonin, dopamine is also taken up and
removed from action so that a single dopamine molecule has short
term effect. Dopamine re-uptake inhibitors, which prevent or reduce
the uptake of dopamine, can also increase the secretion of .alpha.-MSH
and its concentrations in the CNS.
[0026] Therefore, increased secretion of .alpha.-MSH through various
mechanisms, such as serotonin re-uptake inhibition, are among the
strategies that the methods and pharmaceutical compositions of the
present invention can involve to produce a biochemical anorexigenic
effect.
[0027] In some aspects, the present invention provides a multi-faceted
combination therapy approach to the problem of weight loss. It addresses
not just single molecules, messengers, or receptors, but instead
acts on multiple points in the feeding and satiety pathway. Aspects
of the present invention are directed to increasing the concentrations
of .alpha.-MSH in the CNS by stimulating the release of .alpha.-MSH,
suppressing its metabolism, reducing the antagonism of its interaction
at MC3/4-R, and suppressing feedback mechanisms that slow or stop
its release. Aspects of the present invention include pharmaceutical
compositions whose components achieve one or more of these functions.
The present inventors have discovered that a combination of two
or more of the compounds disclosed herein results in a synergistic
effect that affects weight loss more quickly and on a more permanent
basis. Those skilled in the art will appreciate the various discussions
of the mechanisms for appetite suppression and/or weight loss provided
herein, and recognize that those disclosures do not restrict the
scope of the inventions described herein, which are not limited
by theory of operation.
[0028] Various combinations have been disclosed as being useful
for helping in promoting weight loss. For example, a composition
for the treatment of obesity can comprise an opioid antagonist and
a compound that causes increased agonism of MC3-R or MC4-R compared
to normal physiological conditions, see U.S. Patent Publication
No. 2004-0254208, published Dec. 16, 2004, which is hereby incorporated
by reference in its entirety.
[0029] The present inventors have realized that particular opioid
antagonists, such as metabolites of naltrexone, for example, 6-.beta.-naltrexol,
can have especially beneficial properties when used in combination
with an agent that enhances alpha-MSH activity.
[0030] Thus, an embodiment provides a composition for the treatment
of obesity and/or for affecting weight loss, comprising a first
compound and a second compound, where the first compound is a metabolite
of naltrexone, or a pharmaceutically acceptable salt or prodrug
thereof, and the second compound enhances alpha-MSH activity. Similarly,
a method of promoting weight loss using the metabolite of naltrexone
is also contemplated. In some embodiments, the metabolite of naltrexone
is administered alone or without other weight loss promoting compounds
in order to promote weight loss. In other embodiments, the metabolite
of naltrexone is administered with an anticonvulsant, such as zonisamide
or topiramate.
[0031] In certain embodiments, the metabolite of naltrexone is
6-.beta.-naltrexol. The chemical structure of 6-.beta.-naltrexol
is shown below in Formula (I).
[0032] In certain embodiments, the second compound causes increased
activity of the POMC neurons, leading to greater agonism at MC3-R
and/or MC4-R.
[0033] In certain embodiments, the metabolite of naltrexone antagonizes
a .mu.-opioid receptor (MOP-R) in a mammal. The mammal can be selected
from the group consisting of mice, rats, rabbits, guinea pigs, dogs,
cats, sheep, goats, cows, primates, such as monkeys, chimpanzees,
and apes, and humans.
[0034] A method for synthesizing 6-.beta.-naltrexol is described
in U.S. Pat. No. 4,089,855. Additionally, a discussion of the use
of 6-.beta.-naltrexol in the treatment of drug dependency can be
found in U.S. Pat. No. 6,713,488. Both U.S. Pat. Nos. 4,089,855
and 6,713,488 are hereby incorporated by reference herein in their
entireties, including any drawings.
[0035] The term "pharmaceutically acceptable salt" refers
to a formulation of a compound that does not cause significant irritation
to an organism to which it is administered and does not abrogate
the biological activity and properties of the compound. Pharmaceutical
salts can be obtained by reacting a compound with an acid such as
hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic
acid, salicylic acid and the like. Pharmaceutical salts can also
be obtained by reacting a compound with a base to form a salt such
as an ammonium salt, an alkali metal salt (such as a sodium or a
potassium salt), an alkaline earth metal salt (such as a calcium
or a magnesium salt), a salt of an organic base (such as dicyclohexylamine,
N-methyl-D-glucamine, and/or tris(hydroxymethyl) methylamine salt),
or a salt of an amino acid (such as an arginine or lysine salt).
[0036] A "prodrug" refers to an agent that is converted
into the parent drug in vivo. Prodrugs are often useful because,
in some situations, they may be easier to administer than the parent
drug. They may, for instance, be more bioavailable by oral administration
than the parent. The prodrug may also have improved solubility in
pharmaceutical compositions over the parent drug, or may demonstrate
increased palatability or be easier to formulate. An example, without
limitation, of a prodrug is an ester of a naltrexone metabolite
that facilitates transmittal across a cell membrane where water
solubility is detrimental to mobility but which then is metabolically
hydrolyzed to the carboxylic acid, the active entity, once inside
the cell where water-solubility is beneficial. A further example
of a prodrug is a naltrexone metabolite containing a short peptide
(polyaminoacid) bonded to an acid group where the peptide is metabolized
to provide the active moiety.
[0037] References herein to compositions containing metabolites
of naltrexone or methods of using such naltrexone metabolites will
be understood by those skilled in the art to include prodrugs of
those metabolites unless the context clearly dictates otherwise.
For example, in an embodiment, a naltrexone metabolite useful in
the methods and/or compositions described herein is a naltrexol
prodrug of the general formula (II):
[0038] In formula (II), at least one of R.sup.1 and R.sup.2 is
a PO.sub.3H group or salt thereof, or an organic group containing
from 2 to 20 carbons, preferably 3 to 20 carbons, that is selected
to form a 3-O-ester derivative; a 6-O-ester derivative; a 3-O,6-O-diester
derivative; a 3-carbamate derivative; a 6-carbamate derivative;
a 3,6-dicarbamate derivative; 3-carbonate derivative; a 6-carbamate
derivative; or a 3,6-dicarbonate derivative. For example, in an
embodiment, least one of R.sup.1 and R.sup.2 in formula (II) is
selected from [0039] PO.sub.3H group or salt thereof; [0040] n organic
group containing from 2 to 20 carbons, preferably 3 to 20 carbons,
that is selected to form a 3-O-ester derivative, a 6-O-ester derivative,
or a 3-O,6-O-diester derivative; and [0041] an organic group containing
from 2 to 20 carbons that is selected to form a 3-carbomate derivative,
a 6-carbamate derivative, a 3,6-dicarbamate derivative, a 3-carbonate
derivative, a 6-carbonate derivative, or a 3,6-dicarbonate derivative.
[0042] Reference herein to compositions or methods that contain
or utilize metalbolites of naltrexone will be understood to include
such naltrexol prodrugs of the general formula (II).
[0043] Examples of 3-O-ester derivatives, 6-O-ester derivatives
and 3-O, 6-O-diester derivatives of the formula (II) include mono-
and di-methyl esters, mono- and di-ethyl esters, mono- and di-propyl
esters, mono- and di-isopropyl esters, mono- and di-dimethylaminoethyl
esters, mono- and di-tert-butyl esters, mono- and di-isobutyl esters,
optionally arly-substituted mono- and di-phenyl esters, and mono-
and di-succinyl esters. The phenyl esters may be optionally substituted
on the aryl ring(s) with one or more substituents such as halo,
C.sub.1-6 alkoxy and C.sub.1-6 alkyl. The esters may be mixed esters,
e.g., 3-O-methyl, 6-O-ethyl ester of 6-.beta.-naltrexol. In an embodiment,
Formula (II) represents an ester or diester prodrug of a naltrexol
(such as 6-.beta.-naltrexol) in which one or neither of R.sup.1
and R.sup.2 is H and in which at least one of R.sup.1 and R.sup.2
is a group selected from the following:
[0044] Examples of 3-carbamate derivatives, 6-carbamate derivatives
and 3,6-dicarbamate derivatives of the formula (II) include mono-
and di-methyl carbamates, mono- and di-ethyl carbamates, mono- and
di-propyl carbamates, mono- and di-isopropyl carbamates, mono- and
di-(dimethylamino)ethyl carbamates, mono- and di-tert-butyl carbamates,
mono- and di-isobutyl carbamates, and optionally aryl-substituted
mono- and di-phenyl carbamates. The phenyl carbamates may be optionally
substituted on the aryl ring(s) with one or more substituents such
as halo, C.sub.1-6 alkoxy and C.sub.1-6 alkyl. The carbamates may
be mixed carbamates, e.g., 3-methyl, 6-ethyl carbamate of 6-.beta.-naltrexol.
In an embodiment, Formula (II) represents a carbamate or dicarbamate
prodrug of naltrexol in which one or neither of R.sup.1 and R.sup.2
is H and in which at least one of R.sup.1 and R.sup.2 is a group
selected from the following:
[0045] Examples of 3-carbonate derivatives, 6-carbonate derivatives
and 3,6-dicarbonate derivatives of the formula (II) include mono-
and di-methyl carbonates, mono- and di-ethyl carbonates, mono- and
di-propyl carbonates, mono- and di-isopropyl carbonates, mono- and
di-(dimethylamino)ethyl carbonates, mono- and di-tert-butyl carbonates,
mono- and di-isobutyl carbonates, mono- and di-benzyl carbonates,
and mono- and di-phenyl carbonates. The benzyl and phenyl carbonates
may be optionally substituted on the aryl ring(s) with one or more
substituents such as halo, C.sub.1-6 alkoxy and C.sub.1-6 alkyl.
The carbonates may be mixed carbonates, e.g., 3-methyl, 6-ethyl
carbonate of 6-.beta.-naltrexol. In an embodiment, Formula (II)
represents a carbonate or dicarbonate prodrug of naltrexol in which
one or neither of R.sup.1 and R.sup.2 is H and in which at least
one of R.sup.1 and R.sup.2 is a group selected from the following:
[0046] Prodrugs of the formula (II) can be made by reacting naltrexol
with the appropriate derivatizing agent. Those skilled in the art,
guided by the descriptions provided herein, will be able to make
such prodrugs using routine experimentation. For example, 3-O-ester
derivatives, 6-O-ester derivatives and 3-O, 6-O-diester derivatives
of the formula (II) can be made in various ways. In an embodiment,
the 3-O-ester derivatives can be prepared by dissolving 6-.beta.-naltrexol
in a suitable solvent (such as tetrahydrofuran (THF) or DMF), deprotonating
by reacting with an equivalent of a base (e.g., solidum methoxide
or lithium di-isopropyl amine) and reacting with an equivalent of
the appropriate acylating agent, such as 2-dimethylaminoacetyl chloride
or the appropriate acid anhydride (e.g., acetic, propionic, butyric,
isobutyric, succinic, or benzoic anhydride) with stirring at room
temperature or with gentle heating. Work up can be accomplished
by partitioning between methylene chloride and aqueous sodium bicarbonate,
following by drying over sodium sulfate and concentrating to yield
the desired 3-O ester. The 6-O-ester derivatives can be prepared
in a similar fashion. In an embodiment, the 3-O, 6-O-diester derivatives
can be prepared by dissolving 6-.beta.-naltrexol in a suitable solvent
(such as methylene chloride or dimethylformamide (DMF)) and reacting
it with an appropriate excess of 2-dimethylaminoacetyl chloride
or the appropriate acid anhydride (e.g., 4 equivalents of acetic,
propionic, butyric, isobutyric, succinic, or benzoic anhydride)
with stirring at room temperature or with gentle heating in the
presence of excess base (e.g., 4.5 equivalents of triethylamine).
Work up can be accomplished by sodium bicarbonate extraction, following
by drying over sodium sulfate and concentrating to yield the desired
ester.
[0047] Dicarbamate prodrugs of the formula (II) can also be made
in various ways. In an embodiment, the 3-carbamate derivatives can
be prepared by dissolving 6-.beta.-naltrexol in a suitable solvent
(such as THF or DMF), deprotonating by reacting with a slight excess
(e.g., 1.1 equivalent) of a base (e.g., lithium di-isopropyl amine)
at 0.degree. C., and reacting with a slight excess (e.g., 1.1 equivalent)
of an appropriate isocyanate (e.g., methyl, ethyl, propyl, butyl
or phenyl isocyanate) with stirring. Work up can be accomplished
by partitioning between methylene chloride and aqueous sodium bicarbonate,
following by drying over sodium sulfate and concentrating to yield
the desired 3-carbamate. The corresponding 6-carbamate derivatives
can be prepared in a similar fashion. In an embodiment, the 3-(dimethylamino)ethyl
carbamates can be prepared by dissolving 6-.beta.-naltrexol in a
suitable solvent (such as THF or DMF), deprotonating by reacting
with an equivalent of a base (e.g., lithium di-isopropyl amine)
at 0.degree. C., and reacting with a slight excess (e.g., 1.1 equivalent)
of dimethylcarbamoyl chloride with stirring. Work up can be accomplished
by partitioning between methylene chloride and aqueous sodium bicarbonate,
following by drying over sodium sulfate and concentrating to yield
the desired 3-(dimethylamino)ethyl carbamate. The corresponding
6-(dimethylamino)ethyl carbamate derivatives can be prepared in
a similar fashion. In an embodiment, the 3, 6-dicarbamate derivatives
can be prepared by dissolving 6-.beta.-naltrexol in a suitable solvent
(such as THF or DMF) and reacting with an excess of an appropriate
isocyanate (e.g., 2.5 equivalents of methyl, ethyl, propyl, butyl
or phenyl isocyanate) with stirring at room temperature or with
gentle heating. Work up can be accomplished by partitioning between
methylene chloride and aqueous sodium bicarbonate, following by
drying the methylene chloride layer over sodium sulfate and concentrating
to yield the desired 3, 6-dicarbamate. In an embodiment, the 3,
6-di-(dimethylamino)ethyl carbamates can be prepared by dissolving
6-.beta.-naltrexol in a suitable solvent (such as THF or DMF) and
reacting with an excess (e.g., 2.5 equivalents) of dimethylcarbamoyl
chloride in the presence of excess base (e.g., 3 equivalents triethylamine)
with stirring at 0.degree. C. Work up can be accomplished by partitioning
between methylene chloride and aqueous sodium bicarbonate, following
by drying the methylene chloride layer over sodium sulfate and concentrating
to yield the desired 3, 6-di-(dimethylamino)ethyl carbamate.
[0048] Dicarbonate prodrugs of the formula (II) can also be made
in various ways. In an embodiment, the 3-carbonate derivatives can
be prepared by dissolving 6-.beta.-naltrexol in a suitable solvent
(such as THF or DMF), deprotonating by treatment with a slight excess
of a base (e.g., 1.2 equivalents of lithium di-isopropyl amine at
0.degree. C.),then reacting with a slight excess of an appropriate
chloroformate (e.g., 1.1 equivalents of methyl, ethyl, propyl, butyl
or phenyl chloroformate). Work up can be accomplished by partitioning
between methylene chloride and aqueous sodium bicarbonate, following
by drying the methylene chloride layer over sodium sulfate and concentrating
to yield the desired 3-carbonate. The corresponding 6-carbonate
can be prepared in a similar fashion. In an embodiment, the 3, 6-dicarbonate
derivatives can be prepared by dissolving 6-.beta.-naltrexol in
a suitable solvent (such as THF or DMF) and reacting with an excess
of an appropriate chloroformate (e.g., 3 equivalents of methyl,
ethyl, propyl, butyl or phenyl chloroformate) in the presence of
excess base (e.g., 4 equivalents triethylamine) with stirring at
0.degree. C. Work up can be accomplished by partitioning between
methylene chloride and aqueous sodium bicarbonate, following by
drying the methylene chloride layer over sodium sulfate and concentrating
to yield the desired 3, 6-dicarbonate.
[0049] In some embodiments, the second compound in the pharmaceutical
compositions described herein triggers the release of .alpha.-MSH.
The second compound may increase the extracellular serotonin concentrations
in the hypothalamus. In some embodiments, the second compound is
selected from the group consisting of a selective serotonin reuptake
inhibitor (SSRI), a serotonin 2C agonist, and a serotonin 1B agonist.
In further embodiments, the second compound is selected, e.g., from
the group consisting of fluoxetine, fluvoxamine, sertraline, paroxetine,
citalopram, escitalopram, sibutramine, duloxetine, and venlafaxine,
and pharmaceutically acceptable salts or prodrugs thereof.
[0050] The terms "serotonin 1B receptor," "serotonin
2C receptor," "5-HT1b receptor," and "5-HT2c
receptor" refer to receptors found more commonly in rodents.
It is understood by those of skill in the art that other mammals
have serotonin receptors on various neurons that are analogous in
function and form to these receptors. Agonists or antagonists at
these non-rodent, preferably human, serotonin receptors are within
the scope of the present invention.
[0051] In certain embodiments, the second compound suppresses the
expression of the AgRP gene or the production or release of agouti-related
protein (AgRP). In some of these embodiments, the second compound
suppresses the activity of neurons that express AgRP.
[0052] In other embodiments, the second compound suppresses the
expression of the NPY gene or the production or release of neuropeptide
Y (NPY). In some of these embodiments, the second compound suppresses
the activity of neurons that express NPY. In further embodiments,
the second compound is selected from the group consisting of NPY
antagonists, ghrelin antagonists, and leptin. In certain other embodiments,
the second compound agonizes the NPY Y2 receptor.
[0053] Other embodiments of the present invention include those
in which the second compound is selected from the group consisting
of a .gamma.-amino butyric acid (GABA) inhibitor, a GABA receptor
antagonist, and a GABA channel antagonist. By "GABA inhibitor"
it is meant a compound that reduces the production of GABA in the
cells, reduces the release of GABA from the cells, or reduces the
activity of GABA on its receptors, either by preventing the binding
of GABA to GABA receptors or by minimizing the effect of such binding.
The GABA inhibitor may be a 5-HT1b agonist or another agent that
inhibits the activity of NPY/AgRP/GABA neurons. In addition, the
GABA inhibitor may suppress the expression of the AgRP gene, or
the GABA inhibitor may suppress the production or release of AgRP.
It is, however, understood that a 5-HT1b agonist may inhibit the
NPY/AgRP/GABA neuron (and therefore activate POMC neurons) without
acting as an inhibitor of the GABA pathway.
[0054] In certain other embodiments the GABA inhibitor increases
the expression of the POMC gene. In some of these embodiments, the
GABA inhibitor increases the production or release of pro-opiomelanocortin
(POMC) protein. In certain other of these embodiments, the GABA
inhibitor increases the activity on POMC expressing neurons. In
some embodiments, the GABA inhibitor is topiramate.
[0055] In other embodiments the second compound is a dopamine reuptake
inhibitor. Phretermine is an example of a dopamine reuptake inhibitor.
In certain other embodiments, the second compound is a norepinephrine
reuptake inhibitor. Examples of norepinephrine reuptake inhibitors
include thionisoxetine and reboxetine. Other embodiments include
those in which the second compound is a dopamine agonist. Some dopamine
agonists that are commercially available include cabergoline, amantadine,
lisuride, peroglide, ropinirole, pramipexole, and bromocriptine.
In further embodiments, the second compound is a norepinephrine
releaser, for example diethylpropion, or a mixed dopamine/norepinephrine
reuptake inhibitor, for example, bupropion, and atomoxatine.
[0056] In certain other embodiments, the second compound is a 5-HT1b
agonist, such as sumpatriptan, almotriptan, naratriptan, frovatriptan,
rizatriptan, zomitriptan, and elitriptan.
[0057] In further embodiments, the second compound is an anticonvulsant.
The anticonvulsant may be selected from the group consisting of
zonisamide, topiramate, nembutal, lorazepam, clonazepam, clorazepate,
tiagabine, gabapentin, fosphenytoin, phenytoin, carbamazepine, valproate,
felbamate, levetiracetam, oxcarbazepine, lamotrigine, methsuximide,
and ethosuxmide.
[0058] In certain embodiments, the second compound itself can be
a combination of two or more compounds, or the second compound can
be a single compound having two or more functions. For example,
the second compound may be a combination of a dopamine reuptake
inhibitor and a norepinephrine reuptake inhibitor, e.g. bupropion
and mazindol. Alternatively, the second compound may be a combination
of a SSRI and a norepinephrine reuptake inhibitor, such as sibutramine,
venlafaxine, and duloxetine.
[0059] In certain embodiments, the second compound is an activator
of the POMC neurons. Examples of POMC activators include Ptx1 and
interleukin 1beta, (IL-1.beta.).
[0060] In some embodiments, the first compound is 6-.beta.-naltrexol
or a prodrug of the formula (II) and the second compound is bupropion.
[0061] In another aspect, the present invention provides a method
of affecting weight loss, comprising identifying an individual in
need thereof and treating that individual to antagonize opioid receptor
activity and to enhance .alpha.-MSH activity. In some embodiments,
opioid receptor activity is antagonized by administering a metabolite
of naltrexone or a pharmaceutically acceptable salt or prodrug thereof.
In some embodiments, other metabolites of an opioid antagonist are
used.
[0062] In some embodiments, the metabolite of naltrexone is 6-.beta.-naltrexol.
[0063] In certain embodiments, the individual has a body mass index
(BMI) greater than 25. In other embodiments, the individual has
a BMI greater than 30. In still other embodiments, the individual
has a BMI greater than 40. However, in some embodiments, the individual
may have a BMI less than 25. In these embodiments, it may be beneficial
for health or cosmetic purposes to affect weight loss, thereby reducing
the BMI even further.
[0064] In some of the embodiments set forth above, .alpha.-MSH
activity is enhanced by administering a second compound, where the
compound triggers release of .alpha.-MSH or increases the activity
of neurons that express .alpha.-MSH. The first compound is 6-.beta.-naltrexol
or a prodrug of the formula (II). In some embodiments, the second
compound is a dopamine or norepinephrine reuptake inhibitor, which
preferably is selected from group consisting of bupropion, thionisoxetine,
atomoxetine, and reboxetine. In certain embodiments, the second
compound is bupropion.
[0065] Individuals suffering from depression may gain weight as
a result of their depression. In addition, certain depressed individuals
gain weight as a side effect of the depression therapy. In certain
embodiments, the method of invention set forth above is practiced
with the proviso that the individual is not suffering from depression.
In some embodiments, the individual's overweight state was not caused
by treatment for depression.
[0066] Certain antidepressant drugs cause weight gain in individuals
who take them. In some embodiments, the methods of the invention
are directed to prevent weight gain associated with the administration
of antidepressants. In other embodiments, the methods of the invention
are directed to cause weight loss in individuals who have gained
weight as the result of antidepressant therapy.
[0067] In some embodiments, the treating step of the above method
comprises administering to the individual a first compound and a
second compound, where the first compound is a metabolite of naltrexone,
such as 6-.beta.-naltrexol or a prodrug of the formula (II), and
the second compound enhances .alpha.-MSH activity.
[0068] In some embodiments the first compound and the second compound
are administered substantially simultaneously. In other embodiments
the first compound is administered prior to the second compound.
In yet other embodiments, the first compound is administered subsequent
to the second compound. In other embodiments, one of the compounds
is administered while the other compound is being administered.
[0069] In certain embodiments, the first compound and the second
compound are administered individually. In other embodiments, the
first compound and the second compound are covalently linked to
each other such that they form a single chemical entity. The single
chemical entity is then digested and is metabolized into two separate
physiologically active chemical entities, one of which is the first
compound and the other one is the second compound.
[0070] In some embodiments, the compositions of the present invention
are selected from the following combinations of compounds: [0071]
a SSRI in combination with 6-.beta.-naltrexol; [0072] serotonin
in combination with 6-.beta.-naltrexol; [0073] a dopamine reuptake
inhibitor in combination with 6-.beta.-naltrexol; [0074] a dopamine/norepinephrine
reuptake inhibitor in combination with 6-.beta.-naltrexol; [0075]
a dopamine agonist in combination with 6-.beta.-naltrexol; [0076]
a compound of the formula (II) in combination with bupropion.
[0077] Examples of norepinephrine agonists include phendimetrazine
and benzphetamine. Examples of adenosine compounds include all xanthine
derivatives, such as adenosine, theophylline, theobromine, and aminophylline.
An example of a cholinergic receptor antagonist is nicotine.
[0078] In another aspect, the present invention provides a method
of increasing satiety in an individual comprising identifying an
individual in need thereof and treating that individual to antagonize
opioid receptor activity with a metabolite of naltrexone and to
ehance .alpha.-MSH activity.
[0079] In some embodiments, treating the individual comprises administering
to the individual a first compound and a second compound, where
the first compound is a metabolite of naltrexone and the second
compound enhances .alpha.-MSH activity.
[0080] In some embodiments the first compound and the second compound
are administered substantially simultaneously. In other embodiments
the first compound is administered prior to the second compound.
In yet other embodiments, the first compound is administered subsequent
to the second compound.
[0081] In yet another aspect, the present invention provides a
method of suppressing the appetite of an individual comprising identifying
an individual in need thereof and treating that individual to antagonize
opioid receptor activity and to enhance .alpha.-MSH activity. In
some embodiments, treating the individual comprises administering
to the individual a first compound and a second compound, where
the first compound is a metabolite of naltrexone and the second
compound enhances .alpha.-MSH activity.
[0082] In some embodiments, the metabolite of naltrexone is 6-.beta.-naltrexol.
[0083] In another aspect, the present invention provides a method
of increasing energy expenditure in an individual comprising identifying
an individual in need thereof and treating that individual to antagonize
opioid receptor activity and to enhance .alpha.-MSH activity. In
some embodiments, treating the individual comprises administering
to the individual a first compound and a second compound, where
the first compound is a metabolite of naltrexone and the second
compound enhances .alpha.-MSH activity.
[0084] In certain embodiments disclosed herein, an individual is
given a pharmaceutical composition comprising a combination of two
or more compounds to affect weight loss. In some of these embodiments,
each compound is a separate chemical entity. However, in other embodiments,
the two compounds are joined together by a chemical linkage, such
as a covalent bond, so that the two different compounds form separate
parts of the same molecule. The chemical linkage is selected such
that after entry into the body, the linkage is broken, such as by
enzymatic action, acid hydrolysis, base hydrolysis, or the like,
and the two separate compounds are then formed.
[0085] Thus, in another aspect, the present invention provides
synthetic routes to novel molecules in which 6-.beta.-naltrexol
is linked by a flexible linker to a selective serotonin reuptake
inhibitor (SSRI).
[0086] In another aspect, the invention relates to a pharmaceutical
composition comprising a combination of a metabolite of naltrexone
and a compound that causes increased agonism of MC3-R and/or MC4-R
compared to normal physiological conditions, as described above,
or comprising a linked molecule, as described herein, and a physiologically
acceptable carrier, diluent, or excipient, or a combination thereof.
[0087] The term "pharmaceutical composition" refers to
a mixture of a compound of the invention with other chemical components,
such as diluents or carriers. The pharmaceutical composition facilitates
administration of the compound to an organism. Multiple techniques
of administering a compound exist in the art including, but not
limited to, oral, injection, aerosol, parenteral, and topical administration.
Pharmaceutical compositions can also be obtained by forming derivatives
of the compounds described herein, e.g., by reacting with inorganic
or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric
acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic
acid, p-toluenesulfonic acid, salicylic acid and the like.
[0088] The term "carrier" refers to a chemical compound
that facilitates the incorporation of a compound into cells or tissues.
For example dimethyl sulfoxide (DMSO) is a commonly utilized carrier
as it facilitates the uptake of many organic compounds into the
cells or tissues of an organism.
[0089] The term "diluent" refers to chemical compounds
diluted in water that will dissolve the compound of interest as
well as stabilize the biologically active form of the compound.
Salts dissolved in buffered solutions are utilized as diluents in
the art. One commonly used buffered solution is phosphate buffered
saline because it mimics the salt conditions of human blood. Since
buffer salts can control the pH of a solution at low concentrations,
a buffered diluent rarely modifies the biological activity of a
compound.
[0090] The term "physiologically acceptable" defines
a carrier or diluent that does not abrogate the biological activity
and properties of the compound.
[0091] The pharmaceutical compositions described herein can be
administered to a human patient per se, or in pharmaceutical compositions
where they are mixed with other active ingredients, as in combination
therapy, or suitable carriers or excipient(s). Techniques for formulation
and administration of the compounds of the instant application may
be found in "Remington's Pharmaceutical Sciences," Mack
Publishing Co., Easton, Pa, 18th edition, 1990.
[0092] Suitable routes of administration may, for example, include
oral, rectal, transmucosal, or intestinal administration; parenteral
delivery, including intramuscular, subcutaneous, intravenous, intramedullary
injections, as well as intrathecal, direct intraventricular, intraperitoneal,
intranasal, or intraocular injections.
[0093] Alternately, one may administer the compound in a local
rather than systemic manner, for example, via injection of the compound
directly in the renal or cardiac area, often in a depot or sustained
release formulation. Furthermore, one may administer the drug in
a targeted drug delivery system, for example, in a liposome coated
with a tissue-specific antibody. The liposomes will be targeted
to and taken up selectively by the organ.
[0094] The pharmaceutical compositions of the present invention
may be manufactured in a manner that is itself known, e.g., by means
of conventional mixing, dissolving, granulating, dragee-making,
levigating, emulsifying, encapsulating, entrapping or tabletting
processes.
[0095] Pharmaceutical compositions as described herein may be formulated
in a conventional manner using one or more physiologically acceptable
carriers comprising excipients and auxiliaries which facilitate
processing of the active compounds into preparations which can be
used pharmaceutically. Proper formulation is dependent upon the
route of administration chosen. Any of the well-known techniques,
carriers, and excipients may be used as suitable and as understood
in the art; e.g., in Remington's Pharmaceutical Sciences, above.
[0096] For injection, the agents of the invention may be formulated
in aqueous solutions, preferably in physiologically compatible buffers
such as Hanks's solution, Ringer's solution, or physiological saline
buffer. For transmucosal administration, penetrants appropriate
to the barrier to be permeated are used in the formulation. Such
penetrants are generally known in the art.
[0097] For oral administration, the compounds can be formulated
readily by combining the active compounds with pharmaceutically
acceptable carriers well known in the art. Such carriers enable
the compounds of the invention to be formulated as tablets, pills,
dragees, capsules, liquids, gels, syrups, slurries, suspensions
and the like, for oral ingestion by a patient to be treated. Pharmaceutical
preparations for oral use can be obtained by mixing one or more
solid excipient with pharmaceutical combination of the invention,
optionally grinding the resulting mixture, and processing the mixture
of granules, after adding suitable auxiliaries, if desired, to obtain
tablets or dragee cores. Suitable excipients are, in particular,
fillers such as sugars, including lactose, sucrose, mannitol, or
sorbitol; cellulose preparations such as, for example, maize starch,
wheat starch, rice starch, potato starch, gelatin, gum tragacanth,
methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose,
and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents
may be added, such as the cross-linked polyvinyl pyrrolidone, agar,
or alginic acid or a salt thereof such as sodium alginate.
[0098] Dragee cores are provided with suitable coatings. For this
purpose, concentrated sugar solutions may be used, which may optionally
contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene
glycol, and/or titanium dioxide, lacquer solutions, and suitable
organic solvents or solvent mixtures. Dyestuffs or pigments may
be added to the tablets or dragee coatings for identification or
to characterize different combinations of active compound doses.
[0099] Pharmaceutical preparations which can be used orally include
push-fit capsules made of gelatin, as well as soft, sealed capsules
made of gelatin and a plasticizer, such as glycerol or sorbitol.
The push-fit capsules can contain the active ingredients in admixture
with filler such as lactose, binders such as starches, and/or lubricants
such as talc or magnesium stearate and, optionally, stabilizers.
In soft capsules, the active compounds may be dissolved or suspended
in suitable liquids, such as fatty oils, liquid paraffin, or liquid
polyethylene glycols. In addition, stabilizers may be added. All
formulations for oral administration should be in dosages suitable
for such administration.
[0100] For buccal administration, the compositions can take the
form of tablets or lozenges formulated in conventional manner.
[0101] For administration by inhalation, the compounds for use
according to the present invention are conveniently delivered in
the form of an aerosol spray presentation from pressurized packs
or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane,
trichlorofluoromethane, dichlorotetrafluoroethane; carbon dioxide
or other suitable gas. In the case of a pressurized aerosol the
dosage unit may be determined by providing a valve to deliver a
metered amount. Capsules and cartridges of, e.g., gelatin for use
in an inhaler or insufflator may be formulated containing a powder
mix of the compound and a suitable powder base such as lactose or
starch.
[0102] The compounds can be formulated for parenteral administration
by injection, e.g., by bolus injection or continuous infusion. Formulations
for injection can be presented in unit dosage form, e.g., in ampoules
or in multi-dose containers, with an added preservative. The compositions
may take such forms as suspensions, solutions or emulsions in oily
or aqueous vehicles, and may contain formulatory agents such as
suspending, stabilizing and/or dispersing agents.
[0103] Pharmaceutical formulations for parenteral administration
include aqueous solutions of the active compounds in water-soluble
form. Additionally, suspensions of the active compounds may be prepared
as appropriate oily injection suspensions. Suitable lipophilic solvents
or vehicles include fatty oils such as sesame oil, or synthetic
fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
Aqueous injection suspensions can contain substances that increase
the viscosity of the suspension, such as sodium carboxymethyl cellulose,
sorbitol, or dextran. Optionally, the suspension can also contain
suitable stabilizers or agents that increase the solubility of the
compounds to allow for the preparation of highly concentrated solutions.
[0104] Alternatively, the active ingredient may be in powder form
for constitution with a suitable vehicle, e.g., sterile pyrogen-free
water, before use.
[0105] The compounds can also be formulated in rectal compositions
such as suppositories or retention enemas, e.g., containing conventional
suppository bases such as cocoa butter or other glycerides.
[0106] In addition to the formulations described previously, the
compounds may also be formulated as a depot preparation. Such long
acting formulations may be administered by implantation (for example
subcutaneously or intramuscularly) or by intramuscular injection.
Thus, for example, the compounds may be formulated with suitable
polymeric or hydrophobic materials (for example as an emulsion in
an acceptable oil) or ion exchange resins, or as sparingly soluble
derivatives, for example, as a sparingly soluble salt.
[0107] A pharmaceutical carrier for the hydrophobic compounds of
the invention is a cosolvent system comprising benzyl alcohol, a
nonpolar surfactant, a water-miscible organic polymer, and an aqueous
phase. A common cosolvent system used is the VPD co-solvent system,
which is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar
surfactant Polysorbate 80.TM., and 65% w/v polyethylene glycol 300,
made up to volume in absolute ethanol. Naturally, the proportions
of a co-solvent system may be varied considerably without destroying
its solubility and toxicity characteristics. Furthermore, the identity
of the co-solvent components may be varied: for example, other low-toxicity
nonpolar surfactants may be used instead of POLYSORBATE 80.TM.;
the fraction size of polyethylene glycol may be varied; other biocompatible
polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone;
and other sugars or polysaccharides may substitute for dextrose.
[0108] Alternatively, other delivery systems for hydrophobic pharmaceutical
compounds may be employed. Liposomes and emulsions are well known
examples of delivery vehicles or carriers for hydrophobic drugs.
Certain organic solvents such as dimethylsulfoxide also may be employed,
although usually at the cost of greater toxicity. Additionally,
the compounds may be delivered using a sustained-release system,
such as semipermeable matrices of solid hydrophobic polymers containing
the therapeutic agent. Various sustained-release materials have
been established and are well known by those skilled in the art.
Sustained-release capsules may, depending on their chemical nature,
release the compounds for a few weeks up to over 100 days. Depending
on the chemical nature and the biological stability of the therapeutic
reagent, additional strategies for protein stabilization may be
employed.
[0109] Many of the compounds used in the pharmaceutical combinations
of the invention may be provided as salts with pharmaceutically
compatible counterions. Pharmaceutically compatible salts may be
formed with many acids, including but not limited to hydrochloric,
sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts
tend to be more soluble in aqueous or other protonic solvents than
are the corresponding free acid or base forms.
[0110] Pharmaceutical compositions suitable for use in the present
invention include compositions where the active ingredients are
contained in an amount effective to achieve its intended purpose.
More specifically, a an effective or therapeutically effective amount
means an amount of compound effective to prevent, alleviate or ameliorate
symptoms of disease or prolong the survival of the subject being
treated. Determination of an effective amount is well within the
capability of those skilled in the art, especially in light of the
detailed disclosure provided herein.
[0111] The exact formulation, route of administration and dosage
for the pharmaceutical compositions of the present invention can
be chosen by the individual physician in view of the patient's condition.
See e.g., Fingl et al. 1975, in "The Pharmacological Basis
of Therapeutics", Ch. 1 p. 1. Typically, the dose range of
the composition administered to the patient can be from about 0.5
to 1000 mg/kg of the patient's body weight. The dosage may be a
single one or a series of two or more given in the course of one
or more days, as is needed by the patient. Note that for almost
all of the specific compounds mentioned in the present disclosure,
human dosages for treatment of at least some condition have been
established. Thus, in most instances, the present invention will
use those same dosages, or dosages that are between about 0.1% and
500%, more preferably between about 25% and 250% of the established
human dosage. Where no human dosage is established, as will be the
case for newly-discovered pharmaceutical compounds, a suitable human
dosage can be inferred from ED.sub.50 or ID.sub.50 values, or other
appropriate values derived from in vitro or in vivo studies, as
qualified by toxicity studies and efficacy studies in animals.
[0112] Although the exact dosage will be determined on a drug-by-drug
basis, in most cases, some generalizations regarding the dosage
can be made. The daily dosage regimen for an adult human patient
may be, for example, an oral dose of between 0.1 mg and 500 mg of
each ingredient, preferably between 1 mg and 250 mg, e.g. 5 to 200
mg or an intravenous, subcutaneous, or intramuscular dose of each
ingredient between 0.01 mg and 100 mg, preferably between 0.1 mg
and 60 mg, e.g. 1 to 40 mg of each ingredient of the pharmaceutical
compositions of the present invention or a pharmaceutically acceptable
salt thereof calculated as the free base, the composition being
administered 1 to 4 times per day. Alternatively the compositions
of the invention may be administered by continuous intravenous infusion,
preferably at a dose of each ingredient up to 400 mg per day. Thus,
the total daily dosage by oral administration of each ingredient
will typically be in the range 1 to 2000 mg and the total daily
dosage by parenteral administration will typically be in the range
0.1 to 400 mg. Suitably the compounds will be administered for a
period of continuous therapy, for example for a week or more, or
for months or years.
[0113] In some embodiments, the amount of the naltrexone metabolite
(e.g., a natrexol such as 6-.beta.-naltrexol, 2-hydroxy-3-methoxy-6-b-naltrexol,
or 2-hydroxy-3-methyl-naltrexone, or a naltrexol prodrug) is minimized,
but is present in an amount sufficient to allow for a beneficial
effect on weight or on the appetite of the subject. In some embodiments,
the amount of the naltrexone metabolite is an amount effective to
reduce weight, and that amount is less than the amount of naltrexone
or other non-6-.beta.-naltrexol opioid antagonist that might otherwise
be used. In some embodiments, the amount of the naltrexone metabolite
used is an amount no more than the amount that induces unwanted
side effects. In some embodiments, the naltrexone metabolite is
administered in an amount that does not induce side-effects associated
with naltrexone, for example, side effects that occur at doses of
50-100 mg of naltrexone. In some embodiments, the side-effects include
nausea, headache, dizziness, fatigue, insomnia, anxiety, and sleepiness.
[0114] In some embodiments, the amount of naltrexone metabolite
administered or in the composition is between 800 and 50 mg. In
other embodiments, the amount of naltrexone metabolite is between
1 and 50 mg, for example 1-5, 5-10, 10-15, 15-20, 20-25, 25-30,
30-35, 35-40, 40-45, and 45-50 mg. In some embodiments, the amount
of naltrexone metabolite used is more than an amount of naltrexone
that can be used without detrimental side-effects, for example,
more than 50 mg of 6-.beta.-naltrexol can be used. For example,
in some embodiments, the amount of naltrexone metabolite used is
50 mg, 50-100 , 100-150, 150-200, 200-250, 250-300, 300-350, 350-400,
or more milligrams of 6-.beta.-naltrexol. In some embodiments, the
fact that a naltrexone metabolite (instead of naltrexone) is utilized
is advantageous in the sense that the method or means of administration
of the first compound to the patient may be adjusted. For example,
a method that might normally take longer for the compound to be
effective, e.g., patch delivery (e.g., compared to I.V.) can be
used to administer the naltrexone metabolite in a situation where
a faster method might be required using naltrexone itself.
[0115] Dosage amount and interval may be adjusted individually
to provide plasma levels of the active moiety that are sufficient
to maintain the modulating effects, or minimal effective concentration
(MEC). The MEC will vary for each compound but can be estimated
from in vitro data. Dosages necessary to achieve the MEC will depend
on individual characteristics and route of administration. However,
HPLC assays or bioassays can be used to determine plasma concentrations.
[0116] Dosage intervals can also be determined using MEC value.
Compositions should be administered using a regimen that maintains
plasma levels above the MEC for 10-90% of the time, preferably between
30-90% and most preferably between 50-90%.
[0117] In cases of local administration or selective uptake, the
effective local concentration of the drug may not be related to
plasma concentration.
[0118] The amount of composition administered will, of course,
be dependent on the subject being treated, on the subject's weight,
the severity of the affliction, the manner of administration and
the judgment of the prescribing physician.
[0119] The compositions may, if desired, be presented in a pack
or dispenser device which may contain one or more unit dosage forms
containing the active ingredient. The pack may for example comprise
metal or plastic foil, such as a blister pack. The pack or dispenser
device may be accompanied by instructions for administration. The
pack or dispenser may also be accompanied with a notice associated
with the container in form prescribed by a governmental agency regulating
the manufacture, use, or sale of pharmaceuticals, which notice is
reflective of approval by the agency of the form of the drug for
human or veterinary administration. Such notice, for example, may
be the labeling approved by the U.S. Food and Drug Administration
for prescription drugs, or the approved product insert. Compositions
comprising a compound of the invention formulated in a compatible
pharmaceutical carrier may also be prepared, placed in an appropriate
container, and labeled for treatment of an indicated condition.
[0120] It will be understood by those of skill in the art that
numerous and various modifications can be made without departing
from the spirit of the present invention. Therefore, it should be
clearly understood that the forms of the present invention are illustrative
only and are not intended to limit the scope of the present invention.
SOME EMBODIMENTS OF THE INVENTION
[0121] Some of the embodiments of the present invention are as
follows:
[0122] In the first embodiment, the invention relates to a composition
for affecting weight loss comprising a first compound and a second
compound, wherein said first compound is a naltrexone metabolite
and said second compound causes 1) increased agonism of MC3-R and/or
MC4-R compared to normal physiological conditions, and/or 2) enhances
alpha-MSH activity. In a preferred embodiment of the first embodiment,
the first compound is 6-.beta.-naltrexol.
[0123] In the second embodiment, the invention relates to the composition
of the first embodiment, wherein the first compound antagonizes
an opioid receptor in a mammal.
[0124] In the third embodiment, the invention relates to the composition
of the second embodiment, wherein said opioid receptor is selected
from a .mu.-opioid receptor (MOP-R), a .kappa.-opioid receptor,
and a .delta.-opioid receptor.
[0125] In the fourth embodiment, the invention relates to the composition
of the second embodiment, wherein said first compound antagonizes
a .mu.-opioid receptor (MOP-R) in a mammal.
[0126] In the fifth embodiment, the invention relates to the composition
of the first embodiment, wherein said second compound triggers the
release of .alpha.-melanocyte stimulating hormone (.alpha.-MSH).
[0127] In the sixth embodiment, the invention relates to the composition
of the fifth embodiment, wherein said second compound increases
the extracellular serotonin concentrations in the hypothalamus.
[0128] In the seventh embodiment, the invention relates to the
composition of the sixth embodiment, wherein said second compound
is selected from the group consisting of a selective serotonin reuptake
inhibitor (SSRI), a serotonin 2C agonist, and a serotonin 1B agonist.
[0129] In the eighth embodiment, the invention relates to the composition
of the seventh embodiment, wherein said second compound is selected
from the group consisting of fluoxetine, fluvoxamine, sertraline,
paroxetine, citalopram, escitalopram, sibutramine, duloxetine, and
venlafaxine, and pharmaceutically acceptable salts or prodrugs thereof.
[0130] In the ninth embodiment, the invention relates to the composition
of the first embodiment, wherein said second compound suppresses
the expression of the AgRP gene or the production or release of
agouti-related protein (AgRP).
[0131] In the tenth embodiment, the invention relates to the composition
of the first embodiment, wherein said second compound suppresses
the activity of neurons that express AgRP.
[0132] In the eleventh embodiment, the invention relates to the
composition of the first embodiment, wherein said second compound
suppresses the expression of the NPY gene or the production or release
of neuropeptide Y (NPY).
[0133] In the twelfth embodiment, the invention relates to the
composition of the first embodiment, wherein said second compound
suppresses the activity of neurons that express NPY.
[0134] In the thirteenth embodiment, the invention relates to the
composition of the first embodiment, wherein said second compound
is selected from the group consisting of NPY Y1 receptor antagonists,
ghrelin antagonists, and leptin.
[0135] In the fourteenth embodiment, the invention relates to the
composition of the first embodiment, wherein said second compound
agonizes NPY Y2 receptor.
[0136] In the fifteenth embodiment, the invention relates to the
composition of the first embodiment, wherein said second compound
is selected from the group consisting of a .gamma.-amino butyric
acid (GABA) inhibitor, a GABA receptor antagonist, and a GABA channel
antagonist.
[0137] In the sixteenth embodiment, the invention relates to the
composition of the fifteenth embodiment, wherein said GABA inhibitor
is a 5-HT1b agonist, which may be selection from sumatriptan, almotriptan,
naratriptan, frovatriptan, rizatriptan, zomitriptan, and elitriptan.
[0138] In the seventeenth embodiment, the invention relates to
the composition of the fifteenth embodiment, wherein said GABA inhibitor
suppresses the expression of the AgRP gene.
[0139] In the eighteenth embodiment, the invention relates to the
composition of the fifteenth embodiment, wherein said GABA inhibitor
suppresses the production or release AgRP gene.
[0140] In the nineteenth embodiment, the invention relates to the
composition of the fifteenth embodiment, wherein said GABA inhibitor
increases the expression of the POMC gene.
[0141] In the twentieth embodiment, the invention relates to the
composition of the fifteenth embodiment, wherein said GABA inhibitor
increases the production or release of .alpha.-MSH from pro-opiomelanocortin
(POMC) neurons.
[0142] In the twenty first embodiment, the invention relates to
the composition of the fifteenth embodiment, wherein said GABA inhibitor
increases the activity of POMC expressing neurons. In a preferred
embodiment of the twenty-first embodiment, the GABA inhibitor is
topiramate.
[0143] In the twenty second embodiment, the invention relates to
the composition of the first embodiment, wherein said second compound
is a dopamine reuptake inhibitor.
[0144] In the twenty third embodiment, the invention relates to
the composition of the twenty second embodiment, wherein said dopamine
reuptake inhibitor is phentermine.
[0145] In the twenty fourth embodiment, the invention relates to
the composition of the first embodiment, wherein said second compound
is a norepinephrine reuptake inhibitor.
[0146] In the twenty fifth embodiment, the invention relates to
the composition of the twenty fourth embodiment, wherein said norepinephrine
reuptake inhibitor is selected from bupropion, thionisoxetine, and
reboxetine.
[0147] In the twenty sixth embodiment, the invention relates to
the composition of the first embodiment, wherein said second compound
is a dopamine agonist.
[0148] In the twenty seventh embodiment, the invention relates
to the composition of the twenty sixth embodiment, wherein said
dopamine agonist is selected from the group consisting of cabergoline,
amantadine, lisuride, pergolide, ropinirole, pramipexole, and bromocriptine.
[0149] In the twenty eighth embodiment, the invention relates to
the composition of the first embodiment, wherein said second compound
is a norepinephrine releaser.
[0150] In the twenty ninth embodiment, the invention relates to
the composition of the twenty eighth embodiment, wherein said norepinephrine
releaser is diethylpropion.
[0151] In the thirtieth embodiment, the invention relates to the
composition of the first embodiment, wherein said second compound
is a combination of a dopamine reuptake inhibitor and a norepinephrine
reuptake inhibitor.
[0152] In the thirty first embodiment, the invention relates to
the composition of the thirtieth embodiment, wherein said second
compound is selected from bupropion and mazindol.
[0153] In the thirty second embodiment, the invention relates to
the composition of the first embodiment, wherein said second compound
is a combination of a SSRI and a norepinephrine reuptake inhibitor.
[0154] In the thirty third embodiment, the invention relates to
the composition of the thirty second embodiment, wherein said second
compound is selected from sibutramine, venlafaxine, and duloxetine.
[0155] In the thirty fourth embodiment, the invention relates to
the composition of the first embodiment, wherein said second compound
is fluoxetine.
[0156] In the thirty fifth embodiment, the invention relates to
the composition of the thirty fourth embodiment, wherein the naltrexone
metabolite (e.g., 6-.beta.-naltrexol or a compound of the formula
(II)) is in a time-release formulation whereas the fluoxetine is
in an immediate release formulation.
[0157] In the thirty sixth embodiment, the invention relates to
a method of affecting weight loss, comprising identifying an individual
in need thereof and treating that individual to antagonize opioid
receptor activity through the administration of a naltrexone metabolite
and the enhancement of .alpha.-MSH activity. In a preferred embodiment
of the thirty sixth embodiment, the naltrexone metabolite is 6-.beta.-naltrexol
or a compound of the formula (II).
[0158] In the thirty seventh embodiment, the invention relates
to the method of the thirty sixth embodiment, wherein said individual
has a body mass index greater than 25.
[0159] In the thirty eighth embodiment, the invention relates to
the method of the thirty sixth embodiment, further comprising administering
a partial opioid agonist selected from the group consisting of pentacozine,
buprenorphine, nalorphine, propiram, and lofexidine.
[0160] In the thirty ninth embodiment, the invention relates to
the method of the thirty sixth embodiment through the thirty eighth
embodiment, wherein .alpha.-MSH activity is enhanced by administering
a compound, wherein said compound triggers release of .alpha.-MSH
or increase the activity of neurons that express .alpha.-MSH.
[0161] In the fortieth embodiment, the invention relates to the
method of the thirty ninth embodiment, wherein said compound is
a selective serotonin reuptake inhibitor (SSRI) or a specific 5-HT
receptor agonist.
[0162] In the forty first embodiment, the invention relates to
the method of the fortieth embodiment, wherein said 5-HT receptor
is selected from 5-HT1b receptor and 5-HT2c receptor.
[0163] In the forty second embodiment, the invention relates to
the method of the fortieth embodiment, wherein said SSRI is selected
from fluoxetine, fluvoxamine, sertraline, paroxetine, citalopram,
escitalopram, sibutramine, duloxetine, and venlafaxine, and pharmaceutically
acceptable salts or prodrugs thereof.
[0164] In the forty third embodiment, the invention relates to
the method of the thirty nine embodiment, wherein said second compound
is a y-amino butyric acid (GABA) inhibitor.
[0165] In the forty fourth second embodiment, the invention relates
to the method of the forty third embodiment, wherein said GABA inhibitor
is a 5-HT1b receptor agonist.
[0166] In the forty fifth embodiment, the invention relates to
the method of the forty third embodiment, wherein said GABA inhibitor
suppresses the expression of the AgRP gene.
[0167] In the forty sixth embodiment, the invention relates to
the method of the forty third embodiment, wherein said GABA inhibitor
suppresses the production or release of AgRP.
[0168] In the forty seventh embodiment, the invention relates to
the method of the forty third embodiment, wherein said 5-HT agonists
inhibits the NPY/AgRP/GABA neurons.
[0169] In the forty eighth embodiment, the invention relates to
the method of the forty third embodiment, wherein said GABA inhibitor
suppresses the activity of neurons that express AgRP.
[0170] In the forty ninth embodiment, the invention relates to
the method of the forty third embodiment, wherein said GABA inhibitor
is topiramate.
[0171] In the fiftieth embodiment, the invention relates to the
method of the thirty ninth embodiment, wherein said compound is
selected from the group consisting of a dopamine reuptake inhibitor,
a norepinephrine reuptake inhibitor, a dopamine agonist, a norepinephrine
releaser, a combination of a dopamine reuptake inhibitor and a norepinephrine
reuptake inhibitor, and a combination of a SSRI and a norepinephrine
reuptake inhibitor.
[0172] In the fifty first embodiment, the invention relates to
the method of the fiftieth embodiment, wherein said compound is
not phentermine.
[0173] In the fifty second embodiment, the invention relates to
the method of the thirty sixth embodiment, with the proviso that
the individual is not suffering from Prader-Willi syndrome.
[0174] In the fifty third embodiment, the invention relates to
the method of the thirty sixth embodiment, with the proviso that
.alpha.-MSH is not stimulated with fluoxetine.
[0175] In the fifty fourth embodiment, the invention relates to
the method of the thirty sixth embodiment, wherein said treating
step comprises administering to said individual a first compound
and a second compound, wherein said first compound is an opioid
antagonist and said second compound enhances .alpha.-MSH activity.
[0176] In the fifty fifth embodiment, the invention relates to
the method of the fifty fourth embodiment, wherein said first compound
and said second compound are administered nearly simultaneously.
[0177] In the fifty sixth embodiment, the invention relates to
the method of the fifty fifth embodiment, wherein said first compound
is administered prior to said second compound.
[0178] In the fifty seventh embodiment, the invention relates to
the method of the fifty fifth embodiment, wherein said first compound
is administered subsequent to said second compound.
[0179] In the fifty eighth embodiment, the invention relates to
a method of increasing satiety in an individual comprising identifying
an individual in need thereof and treating that individual with
a first compound, said first compound comprising a naltrexone metabolite
to antagonize opioid receptor activity and a second compound to
enhance .alpha.-MSH activity. In a preferred embodiment of the fifty
eighth embodiment, said naltrexone metabolite is 6-.beta.-naltrexol.
In another preferred embodiment of the fifty eighth embodiment,
said naltrexone metabolite is a compound of the formula (II).
[0180] In the fifty ninth embodiment, the invention relates to
the method of the fifty eighth embodiment, wherein said first compound
and said second compound are administered substantially simultaneously.
[0181] In the sixtieth embodiment, the invention relates to the
method of the fifty eighth embodiment, wherein said first compound
is administered prior to said second compound.
[0182] In the sixty first embodiment, the invention relates to
the method of the fifty eighth embodiment, wherein said first compound
is administered subsequent to said second compound.
[0183] In the sixty second embodiment, the invention relates to
a method of increasing energy expenditure in an individual comprising
identifying an individual in need thereof and treating that individual
to antagonize opioid receptor activity and to enhance .alpha.-MSH
activity, wherein treating the individual comprises administering
to said individual a first compound and a second compound, wherein
said first compound is a naltrexone metabolite and said second compound
enhances .alpha.-MSH activity. In a preferred embodiment of the
sixty second embodiment, the naltrexone metabolite is 6-.beta.-naltrexol.
In another preferred embodiment of the sixty second embodiment,
the naltrexone metabolite is a compound of the formula (II).
[0184] In the sixty third embodiment, the invention relates to
the method of the sixty second embodiment, wherein said first compound
and said second compound are administered nearly simultaneously.
[0185] In the sixty fourth embodiment, the invention relates to
the method of the sixty second embodiment, wherein said first compound
is administered prior to said second compound.
[0186] In the sixty fifth embodiment, the invention relates to
the method of the sixty second embodiment, wherein said first compound
is administered subsequent to said second compound.
[0187] In the sixty sixth embodiment, the invention relates to
a method of suppressing the appetite of an individual comprising
identifying an individual in need thereof and treating that individual
to antagonize opioid receptor activity and to enhance .alpha.-MSH
activity, wherein treating the individual comprises administering
to said individual a first compound and a second compound, wherein
said first compound is a naltrexone metabolite and said second compound
enhances .alpha.-MSH activity. In a preferred embodiment of the
sixty sixth embodiment, the naltrexone metabolite is 6-.beta.-naltrexol.
In another preferred embodiment of the sixty sixth embodiment, the
naltrexone metabolite is a compound of the formula (II).
[0188] In the sixty seventh embodiment, the invention relates to
the method of the sixty sixth embodiment, wherein said first compound
and said second compound are administered nearly simultaneously.
[0189] In the sixty eighth embodiment, the invention relates to
the method of the sixty sixth embodiment, wherein said first compound
is administered prior to said second compound.
[0190] In the sixty ninth embodiment, the invention relates to
the method of the sixty sixth embodiment, wherein said first compound
is administered subsequent to said second compound.
[0191] In the seventieth embodiment, the invention relates to a
method of affecting weight loss in an individual comprising identifying
an individual in need thereof and treating that individual with
a combination of a naltrexone metabolite and an SSRI, provided that
the individual does not suffer from Prader-Willi syndrome or binge
eating disorder. In a preferred embodiment of the seventieth embodiment,
the naltrexone metabolite is 6-.beta.-naltrexol or a compound of
the formula (II) and the SSRI is fluoxetine.
[0192] In the seventy first embodiment, the invention relates to
the method of the seventieth embodiment, wherein the individual
has a BMI greater than 30.
[0193] In the seventy second embodiment, the invention relates
to the method of the seventieth embodiment, wherein the individual
has a BMI greater than 25.
[0194] In the seventy third embodiment, the invention relates to
the method of the seventieth embodiment, wherein the naltrexone
metabolite (e.g., 6-.beta.-naltrexol or a compound of the formula
(II)) is in a time-release formulation whereas the SSRI (e.g., fluoxetine)
is in an immediate release formulation.
[0195] In the seventy fourth embodiment, the invention relates
to the method of the seventy third embodiment, wherein the plasma
concentration level of both the naltrexone metabolite and SSRI follow
a similar concentration profile.
[0196] In the seventy fifth embodiment, the invention relates to
the method of the seventy third embodiment, wherein the naltrexone
metabolite and the SSRI are administered substantially simultaneously.
[0197] In the seventy sixth embodiment, the invention relates to
the method of the seventy third embodiment, wherein the naltrexone
metabolite is administered prior to the SSRI.
[0198] In the seventy seventh embodiment, the invention relates
to the method of the seventy third embodiment, wherein the naltrexone
metabolite is administered subsequent to the SSRI.
[0199] In the seventy eighth embodiment, the invention relates
to any of the above methods, wherein the amount of naltrexone metabolite
administered is less than an amount of naltrexone that would have
to be administered to achieve substantially the same amount of weight
loss.
[0200] In the seventy ninth embodiment, the invention relates to
any of the above methods, wherein the amount of naltrexone metabolite
(e.g., 6-.beta.-naltrexol or compound of the formula (II)) administered
is selected from the group consisting of 50, 45, 40, 35, 30, 25,
20, 15, 10, 5, and 1 mg.
[0201] In the eightieth embodiment, the invention relates to any
of the above compositions, wherein the amount of naltrexone metabolite
(e.g., 6-.beta.-naltrexol or compound of the formula (II)) in the
composition is less than an amount of naltrexone that would have
to be administered to achieve substantially the same amount of weight
loss with the particular composition.
[0202] In the eighty first embodiment, the invention relates to
any of the above compositions, wherein the amount of naltrexone
metabolite (e.g., 6-.beta.-naltrexol or compound of the formula
(II)) in the composition is selected from the group consisting of
50, 45, 40, 35, 30, 25, 20, 15, 10, 5, and 1 mg.
[0203] In the eighty second embodiment, the invention relates to
a method of affecting weight loss comprising administering to the
patient or subject in need of treatment an effective amount of a
metabolite of naltrexone. In a preferred embodiment, the naltrexone
metabolite is 6-.beta.-naltrexol.
[0204] In the eighty third embodiment, the invention relates to
a method or composition of any one of the first through eighty second
embodiments in which the naltrexone metabolite is a prodrug, e.g.,
a compound of the formula (II).
[0205] In the eighty fourth embodiment, the invention relates to
a method or composition of any one of the first through eighty third
embodiments in which the 6-.beta.-naltrexol is a prodrug.
[0206] In the eighty fifth embodiment, the invention relates to
a compound of the formula (II) in which at least one of R.sup.1
and R.sup.2 is selected from a PO.sub.3H group or slat thereof;
an organic group containing from 2 to 20 carbons, preferably 3 to
20 carbons, that is selected to form a 3-O-ester derivative, a 6-O-ester
derivative, or a 3-O,6-O-diester derivative; and an organic group
containing from 2 to 20 carbons, preferably 3 to 20 carbons, that
is selected to form a 3- carbamate derivative, a 6- carbamate derivative,
a 3,6-dicarbamate derivative, 3-carbonate derivative, a 6-carbonate
derivative or a 3,6-dicarbonate derivative.
[0207] In the eighty sixth embodiment, the invention relates to
a compound of the eighty fifth embodiment in which one or neither
of R.sup.1 and R.sup.2 is H and in which at least one of R.sup.1
and R.sup.2 is a group selected from the following:
[0208] In the eighty seventh embodiment, the invention relates
to a method or composition of any one of the above embodiments,
wherein said naltrexone metabolite is the compound of the eighty
fifth or eighty sixth embodiment.
[0209] In an eighty eighth embodiment, the invention relates to
a method of manufacturing a medicament using any of the compounds
or compositions disclosed herein for the treatment of a disease,
condition, or for affecting a beneficial outcome where the disease,
condition of beneficial outcome includes: obesity, affecting weight
loss, increasing energy expenditure, increasing satiety in an individual,
or suppressing the appetite of an individual.
EXAMPLES
[0210] The examples below are non-limiting and are merely representative
of various aspects of the invention.
Example 1
Combination of 6-.beta.-naltrexol and Bupropion:
[0211] Individuals having a BMI of greater than 25 are identified.
Each individual is instructed to take 20 to 50 mg of 6-.beta.-naltrexol
on a daily basis. In addition, each individual is instructed to
take bupropion. The usual adult dose is 300 mg per day, given three
times daily. Dosing should begin at 200 mg per day, given as 100
mg twice daily. Based on clinical response, this dose may be increased
to 300 mg per day, given as 100 mg three times daily. No single
dose is to exceed 150 mg.
[0212] The individuals are monitored for a period of months. It
is recommended that the dosage be adjusted so that each individual
loses weight at a rate of 10% of initial weight every 6 months.
However, the rate of weigh loss for each individual may be adjusted
by the treating physician based on the individual's particular needs.
Example 2
Combinations with 6-.beta.-naltrexol:
[0213] In a multicenter, randomized, blinded, placebo-controlled
clinical trial with 6 groups, the following drug combinations are
tested: [0214] Group 1: Fluoxetine 60 mg po QD plus 6-.beta.-naltrexol
50 mg po QD [0215] Group 2: Fluoxetine 60 mg po QD plus N-placebo
po QD [0216] Group 3: Bupropion-SR 150 mg po BID plus 6-.beta.-naltrexol
50 mg po QD [0217] Group 4: Bupropion-SR 150 mg po BID plus N-placebo
po QD [0218] Group 5: P-placebo po BID plus 6-.beta.-naltrexol 50
mg po QD [0219] Group 6: P-placebo po BID plus N-placebo po QD
[0220] In any of the above groups, the dosage of fluoxetine may
be in the range between 6 mg and 60 mg, for example, 6 mg, 10 mg,
12 mg, 18 mg, 20 mg, 24 mg, 30 mg, 36 mg, 40 mg, 42 mg, 45 mg, 48
mg, 54 mg, and 60 mg. Bupropion may be administered in doses in
the range between 30 mg and 300 mg, for example, 30 mg, 40 mg, 50
mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg,
140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg,
220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg,
300 mg. 6-.beta.-naltrexol may be administered in doses in the range
between 5 mg and 50 mg, for example, 5 mg, 10 mg, 15 mg, 20 mg,
25 mg, 30 mg, 35 mg, 40 mg, 45 mg, and 50 mg.
[0221] Subjects are evaluated as out-patients during this study.
All subjects in this trial receive diet instruction, behavior modification
advice and instruction to increase their activity, a regimen shown
to give weight loss. Subjects are randomized to receive study drugs
in various combinations.
[0222] Subjects in groups 5 and 6 cross-over to treatment with
fluoxetine plus 6-.beta.-naltrexol or bupropion SR plus 6-.beta.-naltrexol
after week 16 for the extension treatment period which provide additional
data on safety of the combination therapies.
[0223] The primary endpoint is percent and absolute change from
baseline in body weight at 16 weeks. Secondary endpoints include
weight loss at 24, 36, and 48 weeks, number and proportion of subjects
who achieve at least a 5% weight loss and a 10% weight loss (responder
analysis), changes in obesity-associated cardiovascular risk factors
(total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides,
glucose and insulin) and waist circumference, and safety and tolerability.
Adverse events, laboratory parameters, vital signs, and the Hospital
Anxiety and Depression (HAD) Scale are used to monitor safety and
tolerability.
Example 3
6-.beta.-naltrexol vs. Naltrexone in Weight Loss:
[0224] Individuals having a BMI of greater than 25 are identified.
The individuals are divided into two groups. The first group is
instructed to take one 50 mg tablet of 6-.beta.-naltrexol on a daily
basis. The second group is instructed to take one 50 mg tablet of
naltrexone on a daily basis.
[0225] The individuals are monitored for a period of months. It
is recommended that the dosage be adjusted so that each individual
loses weight at a rate of 10% of initial weight every 6 months.
However, the rate of weight loss for each individual may be adjusted
by the treating physician based on the individual's particular needs.
[0226] If the initial dosage is not effective, then either dosage
can be increased by 20 mg per day, though never exceeding 80 mg
total per day. If the initial dosage results in a more rapid weight
loss than the above rate, the dosage of either can be reduced.
[0227] This can demonstrate that 6-.beta.-naltrexol can be more
effective in promoting weight loss than naltrexone.
Example 4
Dose of Allowable 6-.beta.-naltrexol:
[0228] This example will allow one to determine the range of safe
levels of 6-.beta.-naltrexol to administer to a patient. A patient
is first administered 40 mg of naltrexol and then examined over
a period of time to determine if there are any unwanted side-effects.
Following this time period, if there are no unwanted side effects,
the dosage is increased to 50, 60, 70 mg, etc. to determine the
amount of 6-.beta.-naltrexol that a patient can receive. In addition
to the examination for unwanted side effects (e.g., those displayed
from high doses of naltrexone) the patient's weight can also be
examined. In particular, any decrease in weight of the patient can
be monitored as well as any decrease in patient appetite. This can
further allow for the effectiveness of 6-.beta.-naltrexol to be
examined in the patient.
[0229] Following these initial rounds, a second compound, e.g.,
one that enhances alpha-MSH activity, can be added and similarly
titrated, with any unwanted side effects and loss in weight or appetite
of the subject being examined.
[0230] In the alternative, instead of raising the level of 6-.beta.-naltrexol,
one can titrate the amount downward and thereby obtain a minimal
amount of 6-.beta.-naltrexol required to obtain the favorable results.
[0231] It will be appreciated by those skilled in the art that
various modifications and changes can be made without departing
from the scope of the embodiments disclosed herein. Such modifications
and changes are intended to fall within the scope of the embodiments
disclosed herein, as defined by the appended claims.
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