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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 an opioid antagonist and the second compound is a cannabinoid
receptor antagonist. 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 and to antagonize cannabinoid receptor
activity.
Weight Loss Patent Claims
1. A composition for affecting weight loss comprising a first compound
and a second compound, wherein said first compound is an opioid
antagonist and said second compound is a cannabinoid receptor antagonist.
2. The composition of claim 1, wherein the opioid antagonist antagonizes
an opioid receptor in a mammal, said opioid receptor selected from
a .mu.-opioid receptor (MOP-R), a .kappa.-opioid receptor, and a
.delta.-opioid receptor.
3. The composition of claim 1, wherein the opioid antagonist is
selected from the group consisting of alvimopan, norbinaltorphimine,
nalmefene, naloxone, naltrexone, methylnaltrexone, and nalorphine,
and pharmaceutically acceptable salts or prodrugs thereof.
4. The composition of claim 1, wherein the opioid antagonist is
a partial opioid agonist.
5. The composition of claim 4, wherein the partial opioid agonist
is selected from the group consisting of pentacozine, buprenorphine,
nalorphine, propiram, and lofexidine.
6. The composition of claim 1, wherein said second compound is
selected from the group consisting of AM251 [N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-1H-p-
yrazole-3-carboxamide], AM281 [N-(morpholin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-1H-p-
yrazole-3-carboxamide], AM630 (6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxypheny-
l)methanone), LY320135, and SR141716A (rimonabant), and pharmaceutically
acceptable salts or prodrugs thereof.
7. The composition of claim 1, wherein said first compound is naltrexone
and said second compound is AM251 [N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-1H-p-
yrazole-3-carboxamide].
8. The composition of claim 1, wherein said first compound is naloxone
and said second compound is AM251 [N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-
1H-pyrazole-3-carboxamide].
9. The composition of claim 1, wherein said first compound is namafene
and said second compound is AM251 [N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-1H-p-
yrazole-3-carboxamide].
10. A method of affecting weight loss, comprising identifying an
individual in need thereof and treating that individual to antagonize
opioid receptor activity and to antagonize cannabinoid receptor
activity.
11. The method of the claim 10, wherein said individual has a body
mass index greater than 25.
12. The method of the claim 10, wherein opioid receptor activity
is antagonized by administering an opioid receptor antagonist.
13. The method of the claim 12, wherein the opioid receptor antagonist
is a .mu.-opioid receptor (MOP-R) antagonist.
14. The method of the claim 12, wherein the opioid receptor antagonist
is selected from alvimopan, norbinaltorphimine, nalmefene, naloxone,
naltrexone, methylnaltrexone, and nalorphine, and pharmaceutically
acceptable salts or prodrugs thereof.
15. The method of the claim 12, wherein said opioid receptor antagonist
is a partial opioid agonist.
16. The method of the claim 15, wherein said partial opioid agonist
is selected from the group consisting of pentacozine, buprenorphine,
nalorphine, propiram, and lofexidine.
17. The method of the claim 10, wherein cannabinoid receptor activity
is antagonized by administering a compound selected from the group
consisting of AM251 [N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-1H-p-
yrazole-3-carboxamide], AM281 [N-(morpholin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-1H-p-
yrazole-3-carboxamide], AM630 (6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxypheny-
l)methanone), LY320135, and SR141716A (rimonabant), and pharmaceutically
acceptable salts or prodrugs thereof.
18. A method of affecting weight loss in an individual comprising
identifying an individual in need thereof and treating that individual
with a combination of naltrexone and AM251.
19. The method of claim 18, wherein the individual has a BMI greater
than 25.
20. The method of claim 18, wherein the plasma concentration level
of both naltrexone and AM251 follow a similar concentration profile.
Weight Loss Patent Description
RELATED APPLICATIONS
[0001] This application claims priority to U.S. provisional Patent
Application No. 60/564,001, entitled "COMPOSITIONS FOR AFFECTING
WEIGHT LOSS," filed on Apr. 21, 2004, and 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) (World Health Organization.
Physical status: The use and interpretation of anthropometry. Geneva,
Switzerland: World Health Organization 1995. WHO Technical Report
Series), 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.
[0007] Prior to 1994, obesity was generally considered a psychological
problem. The discovery of the adipostatic hormone leptin in 1994
(Zhang et al., "Positional cloning of the mouse obese gene
and its human homologue," Nature 1994; 372:425-432) brought
forth the realization that, in certain cases, obesity may have a
biochemical basis. 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, et 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. Of course, this disorder
is an issue for only a small portion of the population.
[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 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 affect weight loss without having other adverse side effects.
SUMMARY OF THE INVENTION
[0009] Disclosed are compositions for affecting weight loss comprising
a first compound and a second compound, where the first compound
is an opioid antagonist and the second compound is a cannabinoid
receptor antagonist.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0010] In a first aspect, the present invention is directed to
a composition for the treatment of obesity or for affecting weight
loss comprising a first compound and a second compound, where the
first compound is an opioid antagonist and the second compound is
a cannabinoid receptor antagonist.
[0011] In certain embodiments the opioid antagonist antagonizes
a .mu.-opioid receptor (MOP-R) in a mammal. The mammal may 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.
[0012] In some embodiments the opioid antagonist is selected from
the group consisting of alvimopan, norbinaltorphimine, nalmefene,
naloxone, naltrexone, methylnaltrexone, and nalorphine, and pharmaceutically
acceptable salts or prodrugs thereof.
[0013] In other embodiments, the opioid antagonist is a partial
opioid agonist. Compounds of this class have some agonist activity
at opioid receptors. However, because they are weak agonists, they
function as de-facto antagonists. Examples of partial opioid agonists
include pentacozine, buprenorphine, nalorphine, propiram, and lofexidine.
[0014] 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 of the invention with
inorganic 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. Pharmaceutical
salts can also be obtained by reacting a compound of the invention
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 organic bases
such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)
methylamine, and salts thereof with amino acids such as arginine,
lysine, and the like.
[0015] 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 bioavailable by oral administration
whereas the parent is not. 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 would be a compound of the present invention
which is administered as an ester (the "prodrug") to facilitate
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 might be a short peptide
(polyaminoacid) bonded to an acid group where the peptide is metabolized
to provide the active moiety.
[0016] In some embodiments, the second compound is a cannabinoid
receptor antagonist. Examples of this group of compounds include
AM251 [N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-1H-p-
yrazole-3-carboxamide], AM281[N-(morpholin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-
-1H-pyrazole-3-carboxamide], AM630 (6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxypheny-
l)methanone), LY320135, and SR141716A (rimonabant), and pharmaceutically
acceptable salts or prodrugs thereof. LY320135 and SR141716A have
the following structures.
[0017] In another aspect, the present 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 and antagonize cannabanoid receptor activity.
[0018] 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.
[0019] In some embodiments, opioid receptor activity is antagonized
by administering an opioid receptor antagonist. The opioid receptor
antagonist may be a MOP receptor antagonist. In some embodiments,
the opioid receptor antagonist is selected from alvimopan, norbinaltorphimine,
nalmefene, naloxone, naltrexone, methylnaltrexone, and nalorphine,
and pharmaceutically acceptable salts or prodrugs thereof.
[0020] In other embodiments, the cannabinoid receptor activity
is antagonized by administering a cannabinoid receptor antagonist,
as described herein.
[0021] 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 an opioid antagonist
and the second compound is a cannabinoid receptor antagonist.
[0022] In some embodiments the first compound and the second compound
are administered more or less 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.
[0023] 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.
[0024] In another aspect, the present invention relates to a method
of increasing satiety in an individual comprising identifying an
individual in need thereof and treating that individual to antagonize
opioid receptor activity and to antagonize cannabinoid receptor
activity.
[0025] 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 an opioid antagonist
and the second compound is a cannabinoid receptor antagonist.
[0026] In some embodiments the first compound and the second compound
are administered nearly 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.
[0027] In yet another aspect, the present 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 antagonize cannabinoid
receptor activity.
[0028] 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 an opioid antagonist
and the second compound is a cannabinoid receptor antagonist.
[0029] In some embodiments the first compound and the second compound
are administered nearly 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.
[0030] In another aspect, the present 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 antagonize cannabinoid receptor
activity.
[0031] 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 an opioid antagonist
and the second compound is a cannabinoid receptor antagonist.
[0032] In some embodiments the first compound and the second compound
are administered nearly 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.
[0033] 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.
[0034] In another aspect, the invention relates to a pharmaceutical
composition comprising a combination of an opioid antagonist and
a cannabinoid receptor antagonist, as described above, or comprising
a linked molecule, as described herein, and a physiologically acceptable
carrier, diluent, or excipient, or a combination thereof.
[0035] 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 reacting compounds
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.
[0036] The term "carrier" defines 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.
[0037] The term "diluent" defines 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.
[0038] The term "physiologically acceptable" defines
a carrier or diluent that does not abrogate the biological activity
and properties of the compound.
[0039] 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.
[0040] 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.
[0041] 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.
[0042] 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.
[0043] Pharmaceutical compositions for use in accordance with the
present invention thus may be formulated in 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.
[0044] 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.
[0045] 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.
[0046] 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.
[0047] 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.
[0048] For buccal administration, the compositions may take the
form of tablets or lozenges formulated in conventional manner.
[0049] 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.
[0050] The compounds may be formulated for parenteral administration
by injection, e.g., by bolus injection or continuous infusion. Formulations
for injection may 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.
[0051] 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 may contain substances which increase
the viscosity of the suspension, such as sodium carboxymethyl cellulose,
sorbitol, or dextran. Optionally, the suspension may also contain
suitable stabilizers or agents which increase the solubility of
the compounds to allow for the preparation of highly concentrated
solutions.
[0052] Alternatively, the active ingredient may be in powder form
for constitution with a suitable vehicle, e.g., sterile pyrogen-free
water, before use.
[0053] The compounds may 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.
[0054] 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.
[0055] 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.
[0056] 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.
[0057] 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.
[0058] 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 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 a therapeutically effective amount is well within
the capability of those skilled in the art, especially in light
of the detailed disclosure provided herein.
[0059] 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.
[0060] 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. I 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.
[0061] Dosage amount and interval may be adjusted individually
to provide plasma levels of the active moiety which 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.
[0062] Dosage intervals can also be determined using MEC value.
Compositions should be administered using a regimen which maintains
plasma levels above the MEC for 10-90% of the time, preferably between
30-90% and most preferably between 50-90%.
[0063] In cases of local administration or selective uptake, the
effective local concentration of the drug may not be related to
plasma concentration.
[0064] 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.
[0065] 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.
[0066] 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
[0067] Some of the embodiments of the present invention are as
follows:
[0068] 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 an opioid antagonist and
said second compound is a cannabinoid receptor antagonist.
[0069] In the second embodiment, the invention relates to the composition
of the first embodiment, wherein said opioid antagonist antagonizes
an opioid receptor in a mammal.
[0070] 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 K-opioid receptor, and a
.delta.-opioid receptor.
[0071] In the fourth embodiment, the invention relates to the composition
of the second embodiment, wherein said opioid antagonist antagonizes
a .mu.-opioid receptor (MOP-R) in a mammal.
[0072] In the fifth embodiment, the invention relates to the composition
of the first embodiment, wherein said opioid antagonist is selected
from the group consisting of alvimopan, norbinaltorphimine, nalmefene,
naloxone, naltrexone, methylnaltrexone, and nalorphine, and pharmaceutically
acceptable salts or prodrugs thereof.
[0073] In the sixth embodiment, the invention relates to the composition
of the first embodiment, wherein said opioid antagonist is a partial
opioid agonist.
[0074] In the seventh embodiment, the invention relates to the
composition of the sixth embodiment, wherein said partial opioid
agonist is selected from the group consisting of pentacozine, buprenorphine,
nalorphine, propiram, and lofexidine.
[0075] In the eighth embodiment, the invention relates to the composition
of the first embodiment, wherein said second compound is selected
from the group consisting of AM251 [N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-1H-p-
yrazole-3-carboxamide], AM281 [N-(morpholin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-1H-p-
yrazole-3-carboxamide], AM630 (6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxypheny-
l)methanone), LY320135, and SR141716A (rimonabant), and pharmaceutically
acceptable salts or prodrugs thereof.
[0076] In the ninth embodiment, the invention relates to the composition
of the first embodiment, wherein said first compound is naltrexone
and said second compound is AM251.
[0077] In the tenth embodiment, the invention relates to the composition
of the first embodiment, wherein said first compound is naloxone
and said second compound is AM251.
[0078] In the eleventh embodiment, the invention relates to the
composition of the first embodiment, wherein said first compound
is nalmefene and said second compound is AM251.
[0079] In the twelfth embodiment, the invention relates to the
composition of the eleventh embodiment, wherein the naltrexone is
in a time-release formulation.
[0080] In the thirteenth 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 and to antagonize cannabinoid receptor activity.
[0081] In the fourteenth embodiment, the invention relates to the
method of the thirteenth embodiment, wherein said individual has
a body mass index greater than 25.
[0082] In the fifteenth embodiment, the invention relates to the
method of the thirteenth embodiment, wherein opioid receptor activity
is antagonized by administering an opioid receptor antagonist.
[0083] In the sixteenth embodiment, the invention relates to the
method of the fifteenth embodiment, wherein the opioid receptor
antagonist is a MOP receptor antagonist.
[0084] In the seventeenth embodiment, the invention relates to
the method of the thirteenth embodiment, wherein the opioid receptor
antagonist is selected from alvimopan, norbinaltorphimine, nalmefene,
naloxone, naltrexone, methylnaltrexone, and nalorphine, and pharmaceutically
acceptable salts or prodrugs thereof.
[0085] In the eighteenth embodiment, the invention relates to the
method of the fifteenth embodiment, wherein said opioid receptor
antagonist is a partial opioid agonist.
[0086] In the nineteenth embodiment, the invention relates to the
method of the eighteenth embodiment, wherein said partial opioid
agonist is selected from the group consisting of pentacozine, buprenorphine,
nalorphine, propiram, and lofexidine.
[0087] In the twentieth embodiment, the invention relates to the
method of the thirteenth embodiment through the forty fifth embodiment,
wherein cannabinoid receptor activity is antagonized by administering
a compound selected from the group consisting of AM251 [N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-1H-p-
yrazole-3-carboxamide], AM281 [N-(morpholin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-1H-p-
yrazole-3-carboxamide], AM630 (6-iodo-2-methyl- 1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxyphenyl)methanone),
LY320135, and SR141716A (rimonabant), and pharmaceutically acceptable
salts or prodrugs thereof.
[0088] In the twenty first embodiment, the invention relates to
the method of the thirteenth embodiment, wherein said first compound
and said second compound are administered nearly simultaneously.
[0089] In the twenty second embodiment, the invention relates to
the method of the twenty first embodiment, wherein said first compound
is administered prior to said second compound.
[0090] In the twenty third embodiment, the invention relates to
the method of the twenty second embodiment, wherein said first compound
is administered subsequent to said second compound.
[0091] In the twenty fourth embodiment, the invention relates to
a method of increasing satiety in an individual comprising identifying
an individual in need thereof and treating that individual to antagonize
opioid receptor activity and to antagonize cannabinoid receptor
activity.
[0092] In the twenty fifth embodiment, the invention relates to
the method of the twenty fourth 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 is a cannabinoid receptor antagonist.
[0093] In the twenty sixth embodiment, the invention relates to
the method of the twenty fifth embodiment, wherein said first compound
and said second compound are administered nearly simultaneously.
[0094] In the twenty seventh embodiment, the invention relates
to the method of the twenty fifth embodiment, wherein said first
compound is administered prior to said second compound.
[0095] In the twenty eighth embodiment, the invention relates to
the method of the twenty fifth embodiment, wherein said first compound
is administered subsequent to said second compound.
[0096] In the twenty ninth 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 antagonize cannabinoid
receptor activity.
[0097] In the thirtieth embodiment, the invention relates to the
method of the twenty ninth 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 is a cannabinoid receptor antagonist.
[0098] In the thirty first embodiment, the invention relates to
the method of the thirtieth embodiment, wherein said first compound
and said second compound are administered nearly simultaneously.
[0099] In the thirty second embodiment, the invention relates to
the method of the thirtieth embodiment, wherein said first compound
is administered prior to said second compound.
[0100] In the thirty fourth embodiment, the invention relates to
the method of the thirtieth embodiment, wherein said first compound
is administered subsequent to said second compound.
[0101] In the thirty fifth 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 antagonize cannabinoid
receptor activity.
[0102] In the thirty sixth embodiment, the invention relates to
the method of the thirty fifth 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 is a cannabinoid receptor antagonist.
[0103] In the thirty seventh embodiment, the invention relates
to the method of the thirty sixth embodiment, wherein said first
compound and said second compound are administered nearly simultaneously.
[0104] In the thirty eighth embodiment, the invention relates to
the method of the thirty sixth embodiment, wherein said first compound
is administered prior to said second compound.
[0105] In the thirty ninth embodiment, the invention relates to
the method of the thirty sixth embodiment, wherein said first compound
is administered subsequent to said second compound.
[0106] In the fortieth 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 naltrexone and AM251.
[0107] In the forty first embodiment, the invention relates to
the method of the fortieth embodiment, wherein the individual has
a BMI greater than 30.
[0108] In the forty second embodiment, the invention relates to
the method of the fortieth embodiment, wherein the individual has
a BMI greater than 25.
[0109] In the forty third embodiment, the invention relates to
the method of the fortieth embodiment, wherein the naltrexone is
in a time-release formulation.
[0110] In the forty fourth embodiment, the invention relates to
the method of the forty third embodiment, wherein the plasma concentration
level of both naltrexone and AM251 follow a similar concentration
profile.
[0111] In the forty fifth embodiment, the invention relates to
the method of the forty third embodiment, wherein the naltrexone
and the AM251 are administered substantially simultaneously.
[0112] In the forty sixth embodiment, the invention relates to
the method of the forty third embodiment, wherein the naltrexone
is administered prior to the AM251.
[0113] In the forty seventh embodiment, the invention relates to
the method of the forty third embodiment, wherein the naltrexone
is administered subsequent to the AM251.
EXAMPLES
[0114] The examples below are non-limiting and are merely representative
of various aspects of the invention.
Example 1
Combination of AM251 and Naltrexone
[0115] Individuals having a BMI of greater than 25 are identified.
Each individual is instructed to take one 20 mg tablet of AM251
on a daily basis, in addition to one 50 mg tablet of naltrexone
on a daily basis.
[0116] 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.
[0117] If the initial dosage is not effective, then the AM251 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 each of AM251 or naltrexone
can be reduced.
[0118] In some cases, it is beneficial to administer one dose of
AM251 per day in conjunction with two or three or more doses of
naltrexone throughout the day. Naltrexone may also be in a time-release
formulation where the dose is administered once a day, but naltrexone
gradually enters the blood stream throughout the day, or in the
course of a 12 hour period.
Example 2
Combination of AM251 and Nalmefene
[0119] Individuals having a BMI of greater than 25 are identified.
Each individual is instructed to take one 20 mg tablet of AM251
on a daily basis. In addition, each individual is injected with
1 mL of a solution of 100 .mu.g of nalmefene in 1 mL of saline,
intravenously, intramuscularly, or subcutaneously.
[0120] 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.
[0121] If the initial dosage is not effective, then the AM251 dosage
can be increased by 20 mg per day, though never exceeding 80 mg
total per day. In addition, the dosage of nalmefene may be increased
up to 2 mL of a solution of 1 mg of nalmefene in 1 mL of saline.
If the initial dosage results in a more rapid weight loss than the
above rate, the dosage of each of AM251 or nalmefene can be reduced.
Example 3
Combination of AM251 and Naloxone
[0122] Individuals having a BMI of greater than 25 are identified.
Each individual is instructed to take one 20 mg tablet of AM251
on a daily basis. In addition, each individual is injected with
1 mL of a solution of 400 .mu.g of naloxone in 1 mL of saline, intravenously,
intramuscularly, or subcutaneously.
[0123] 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.
[0124] If the initial dosage is not effective, then the AM251 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 each of AM251 or nalmefene
can be reduced.
Example 4
Dose-Response Experiments
[0125] Seventy, four week old, male C57/B16J- mice (Jackson Laboratory),
22-30 g were sham injected daily with 0.1 mL 0.9% saline (pH 7.4)
for 1 week prior to the experiments. Animals were weighed and randomized
to 1 of 7 weight-matched dose groups (0, 1.5, 3, 5.5, 10, 18, and
30 mg/kg; n=10/group for AM251; 0, 1.5, 3, 5.5, 10, 18, and 30 mg/kg;
n=3/group for naltrexone) the day before experiments began. Food
was removed between 4:30-5:30 pm the day before the experiment.
Animals received a 0.3 mL bolus (AM251) or 0.1 mL bolus (naltrexone)
intraperitoneal injection between 9-10:30 am, and food was provided
immediately following injection. 3 animals/group received injections
on each testing day (i.e., 3 runs of 3/group; 1 run of 1/group).
Food was weighed 1, 2, 4, 8, and 24 h post-injection. Cumulative
food intake .+-.SEM was calculated and analyzed using Prizm. The
SEM for these numbers were calculated to be between 0.0062 and 0.11.
Doses were log transformed and fit to a sigmoidal curve, food intake
was expressed as a proportion of the food intake in saline treated
animals. From the curve, the EC.sub.50 at each time point for each
drug was determined.
[0126] The results are set forth in the table below: TABLE-US-00001
Hour 1 Hour 2 Hour 4 Hour 8 Hour 24 MEAN MEAN MEAN MEAN MEAN Saline
1.00 1.00 1.00 1.00 1.00 AM 251 0.97 0.85 0.88 0.90 0.99 Nalmefene
0.0083 0.11 0.57 0.81 0.98 AM 251 + Nalmefene 0.010 0.075 0.30 0.62
0.90 |