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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 antidiabetic and the second compound is a anticonvulsant.
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 with an antidiabetic
and an anticonvulsant.
Weight Loss Patent Claims
What is claimed is:
1. A composition for affecting weight loss comprising a first compound
and a second compound, wherein said first compound is an antidiabetic
and said second compound is an anticonvulsant.
2. The composition of claim 1, wherein said antidiabetic is selected
from the group consisting of biguanides, glucosidase inhbitors,
insulins, meglitinides, sulfonylureas, thiazolidinediones, and pharmaceutically
acceptable salts or prodrugs thereof.
3. The composition of claim 2, wherein the biguanide is metformin
or metformin hydrochloride.
4. The composition of claim 2, wherein the glucosidase inhibitor
is selected from the group consisting of acarbose, miglitol, and
combinations thereof.
5. The composition of claim 2, wherein the meglitinide is selected
from the group consisting of nateglinide, repaglinide, and combinations
thereof.
6. The composition of claim 2, wherein the sulfonylurea is selected
from the group consisting of glimepiride, glyburide, glibenclamide,
gliquidone, gliclazide, chlorpropamide, tolbutamide, tolazamide
and glipizide, and combinations thereof.
7. The composition of claim 2, wherein the thiazolidinedione is
selected from a group consisting of rosiglitazone and pioglitazone.
8. The composition of claim 1, wherein said second compound is
selected from the group consisting of a barbiturate, a benzodiazepine,
GABA analogue, hydantoins, miscellaneous anticonvulsant, phenyltriazine,
a succinimide, pharmaceutically acceptable salts or prodrugs thereof,
and combinations thereof.
9. The composition of claim 8, wherein said barbiturate is pentobarbital.
10. The composition of claim 8, wherein said benzodiazepine is
selected from the group consisting of clonazepam, clorazepate, diazepam,
and combinations thereof.
11. The composition of claim 8, wherein said GABA analogue is selected
from the group consisting of tiagabine, pregabalin, gabapentin,
and combinations thereof.
12. The composition of claim 8, wherein said hydantoin is selected
from the group consisting of fosphenytoin, phenytoin, 5,5-Diphenylhydantoin,
and combinations thereof.
13. The composition of claim 8, wherein said miscellaneous anticonvulsant
is selected from the group consisting of carbamazepine, oxcarbazepine,
valproate, valproic acid, divalproex, valrocemide, felbamate, lacosamide,
talampanel, retigabine, levetiracetam, topiramate, zonisamide, and
combinations thereof.
14. The composition of claim 8, wherein said phenyltriazine is
lamotrigine.
15. The composition of claim 8, wherein said succinimide is selected
from the group consisting of methsuximide, ethosuximide, and combinations
thereof.
16. The composition of claim 1, wherein said first compound is
an antihyperglycemic and said second compound is a zonisamide.
17. The composition of claim 1, wherein said first compound is
metformin hydrochloride and said second compound is zonisamide.
18. The composition of claim 1, wherein said first compound is
topiramate and said second compound is zonisamide.
19. A method of affecting weight loss, comprising identifying an
individual in need thereof and treating that individual with an
antidiabetic and an anticonvulsant.
20. The composition of claim 19, wherein the antidiabetic is selected
from the group consisting of metformin hydrochloride, acarbose,
miglitol, human insulin, pork insulin, beef insulin, beef-pork insulin,
insulin glargine, insulin lispro, insulin aspart, nateglinide, repaglinide,
glimepiride, glyburide, chlorpropamide, tolazamide, glibenclamide,
gliclazide, gliquidone, tolbutamide, glibenclamide, glipizide, extended
release formulations of the above drugs, and combinations of the
above drugs.
21. The composition of claim 19, wherein the anticonvulsant is
selected from the group consisting of pentobarbital, clonazepam,
clorazepate, diazepam, tiagabine, gabapentin, pregabalin, fosphenytoin,
phenytoin, phenytoin, 5,5-Diphenylhydantoin, carbamazepine, oxcarbazepine,
valproate, valproic acid, divalproex, valrocemide, felbamate, levetiracetam,
topiramate, zonisamide, lamotrigine, methsuximide, ethosuximide,
retigabine, lacosamide, talampanel, extended release formulation
of the above drugs, and combinations of the above drugs.
22. A method of affecting weight loss in an individual comprising
identifying an individual in need thereof and treating that individual
with a combination of metformin hydrochloride and zonisamide.
Weight Loss Patent Description
RELATED APPLICATIONS
[0001] This application claims priority to the U.S. Provisional
Patent Application Ser. No. 60/567,922, entitled "COMPOSITIONS
FOR AFFECTING WEIGHT LOSS," and filed on May 3, 2004, by Ranga
Krishnan, which is hereby incorporated by reference herein 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 antidiabetic and the second compound is an anticonvulsant.
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 antidiabetic and the second compound is an
anticonvulsant.
[0011] In certain embodiments the antidiabetic is effective in
reducing the level of glucose in the blood of a mammal. In certain
embodiments, the anticonvulsant is effective in reducing convulsions
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 antidiabetic is one of the following:
a biguanide, glucosidase inhibitor, insulin, meglitinide, sulfonylurea,
or a thiazolidinedione. An example of a biguanide is metformin hydrochloride.
Examples of glucosidase inhibitors include acarbose and miglitol.
Examples of insulin include human insulin, pork insulin, beef insulin,
beef-pork insulin, insulin from different sources such as recombinant
DNA and animal sources, as well as regular, NPH, and LENTE.RTM.
types of insulin. Other examples of insulin include mixtures of
the various forms of insulin (e.g. NPH and regular human and pork
insulin). Other examples of insulin include mixtures of Insulin
Lispro Protamine and Insulin Injection (rDNA origin), a 50/50 (or
a 70/30) mixture of Human Insulin Isophane Suspension and Human
Insulin Injection, a 70/30 mixture of NPH Human Insulin Isophane
Suspension and Human Insulin Injection (rDNA), insulin glargine,
insulin lispro, insulin aspart, as well as insulin mixed with other
ingredients such as zinc crystals or in a phosphate buffer. Insulin
may be from Saccharomyces cerevisiae or other sources. Examples
of meglitinides include nateglinide and repaglinide. Examples of
sulfonylureas include glimepiride, glyburide, glibenclamide, gliquidone,
gliclazide, chlorpropamide, tolbutamide, tolazamide and glipizide.
Examples of thiazolidinediones include rosiglitazone and pioglitazone.
Also included are extended release formulations of the above drugs,
as well as combinations of the above drugs and pharmaceutically
acceptable salts or prodrugs thereof. In certain embodiments, the
antidiabetic is metformin.
[0013] 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.
[0014] 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.
[0015] In some embodiments, the second compound is an anticonvulsant.
Examples of anticonvulsants include barbiturates, benzodiazepines,
GABA analogues, hydantoins, miscellaneous anticonvulsants, phenyltriazines,
and succinimides. An example of a barbiturate includes pentobarbital.
Examples of benzodiazepines include clonazepam, clorazepate, and
diazepam. Examples of GABA analogues include tiagabine, pregabalin
and gabapentin. Examples of hydantoins include fosphenytoin, phenytoin,
and 5,5-Diphenylhydantoin. Examples of miscellaneous anticonvulsants
include carbamazepine, oxcarbazepine, valproate, valproic acid,
divalproex, valrocemide, felbamate, levetiracetam, retigabine, lacosamide,
talampanel, topiramate, and zonisamide. An example of a phenyltriazine
is lamotrigine. Examples of succinimides include methsuximide and
ethosuximide. Also included are extended release formulation of
the above drugs, pharmaceutically acceptable salts, as well as combinations
of the above drugs. In certain embodiments, the anticonvulsant is
zonisamide, while in other embodiments, the anticonvulsant is topiramate.
[0016] 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 with an antidiabetic and
an anticonvulsant.
[0017] In certain embodiments, the individual has a body mass index
(BMD) 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.
[0018] 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 antidiabetic and
the second compound is a anticonvulsant.
[0019] 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.
[0020] 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.
[0021] 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 with a first
compound and a second compound, where the first compound is an antidiabetic
and the second compound is an anticonvulsant.
[0022] 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.
[0023] 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
by administering to the individual a first compound and a second
compound, where the first compound is an antidiabetic and the second
compound is a anticonvulsant.
[0024] 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.
[0025] 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 by administering
to the individual a first compound and a second compound, where
the first compound is an antidiabetic and the second compound is
a anticonvulsant.
[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 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.
[0028] In another aspect, the invention relates to a pharmaceutical
composition comprising a combination of an antidiabetic and an anticonvulsant,
as described above, or comprising a linked molecule, as described
herein, and a physiologically acceptable carrier, diluent, or excipient,
or a combination thereof.
[0029] 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.
[0030] 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.
[0031] 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.
[0032] The term "physiologically acceptable" defines
a carrier or diluent that does not abrogate the biological activity
and properties of the compound.
[0033] 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.
[0034] 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.
[0035] 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.
[0036] 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.
[0037] 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.
[0038] 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.
[0039] 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.
[0040] 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.
[0041] 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.
[0042] For buccal administration, the compositions may take the
form of tablets or lozenges formulated in conventional manner.
[0043] 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.
[0044] 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.
[0045] 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.
[0046] Alternatively, the active ingredient may be in powder form
for constitution with a suitable vehicle, e.g., sterile pyrogen-free
water, before use.
[0047] 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.
[0048] 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.
[0049] 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.
[0050] 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.
[0051] 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.
[0052] 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.
[0053] 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.
[0054] 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 or sublingual or by delivery through
a skin patch or intranasal of between 0.1 mg and 5000 mg of each
ingredient, preferably between 1 mg and 2500 mg, e.g. 25 to 2500
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 2500 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.
[0055] In one embodiment, the dosage range for metformin hydrochloride,
for an oral dose, will vary between about 500 mg to about 2500 mg
per day. In a preferred embodiment, the dosage range, for an oral
dose will vary from about 500 mg three times a day to about 2500
mg a day.
[0056] In one embodiment, the dosage range for Zonisamide, for
an oral dose, is in the range of about 25 to about 600 mg per day.
[0057] 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.
[0058] 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%.
[0059] In cases of local administration or selective uptake, the
effective local concentration of the drug may not be related to
plasma concentration.
[0060] 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.
[0061] 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.
[0062] 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
[0063] Some of the embodiments of the present invention are as
follows:
[0064] 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 antidiabetic and said
second compound is an anticonvulsant.
[0065] In the second embodiment, the invention relates to the composition
of the first embodiment, wherein said antidiabetic has antihyperglycemic
characteristics in a mammal.
[0066] In the third embodiment, the invention relates to the composition
of the first embodiment, wherein said antidiabetic is selected from
the group consisting of biguanides, glucosidase inhbitors, insulins,
meglitinides, sulfonylureas, thiazolidinediones, and pharmaceutically
acceptable salts or prodrugs thereof.
[0067] In the fourth embodiment, the invention relates to the composition
of the third embodiment, wherein the biguanide is metformin hydrochloride.
[0068] In the fifth embodiment, the invention relates to the composition
of the third embodiment, wherein the glucosidase inhibitor is selected
from the group consisting of acarbose, miglitol, and combinations
thereof.
[0069] In the sixth embodiment, the invention relates to the composition
of the third embodiment, wherein the insulin is selected from the
group consisting of human, pork, beef, and combinations thereof.
[0070] In the seventh embodiment, the invention relates to the
composition of the third embodiment, wherein the meglitinide is
selected from the group consisting of nateglinide, repaglinide,
and combinations thereof.
[0071] In the eighth embodiment, the invention relates to the composition
of the third embodiment, wherein the sulfonylurea is selected from
the group consisting of glimepiride, glyburide, glibenclamide, gliquidone,
gliclazide, chlorpropamide, tolbutamide, tolazamide and glipizide,
and combinations thereof.
[0072] In the ninth embodiment, the invention relates to the composition
of the third embodiment, wherein the thiazolidinedione is selected
from a group consisting of rosiglitazone and pioglitazone.
[0073] In the tenth embodiment, the invention relates to the composition
of the first embodiment, wherein said second compound is selected
from the group consisting of a barbiturate, a benzodiazepine, GABA
analogue, hydantoins, miscellaneous anticonvulsant, phenyltriazine,
a succinimide, pharmaceutically acceptable salts or prodrugs thereof,
and combinations thereof.
[0074] In the eleventh embodiment, the invention relates to the
composition of the tenth embodiment, wherein said barbiturate is
pentobarbital.
[0075] In the twelfth embodiment, the invention relates to the
composition of the tenth embodiment, wherein said benzodiazepine
is selected from the group consisting of clonazepam, clorazepate,
diazepam, and combinations thereof.
[0076] In the thirteenth embodiment, the invention relates to the
composition of the tenth embodiment, wherein said GABA analogue
is selected from the group consisting of tiagabine, pregabalin,
gabapentin, and combinations thereof.
[0077] In the fourteenth embodiment, the invention relates to the
composition of the tenth embodiment, wherein said hydantoin is selected
from the group consisting of fosphenytoin, phenytoin, 5,5-Diphenylhydantoin,
and combinations thereof.
[0078] In the fifteenth embodiment, the invention relates to the
composition of the tenth embodiment, wherein said miscellaneous
anticonvulsant is selected from the group consisting of carbamazepine,
oxcarbazepine, valproate, valproic acid, divalproex, valrocemide,
felbamate, lacosamide, talampanel, retigabine, levetiracetam, topiramate,
zonisamide, and combinations thereof.
[0079] In the sixteenth embodiment, the invention relates to the
composition of the tenth embodiment, wherein said phenyltriazine
is lamotrigine.
[0080] In the seventeenth embodiment, the invention relates to
the composition of the tenth embodiment, wherein said succinimide
is selected from the group consisting of methsuximide, ethosuximide,
and combinations thereof.
[0081] In the eighteenth embodiment, the invention relates to the
composition of the first embodiment, wherein said first compound
is an antihyperglycemic and said second compound is a zonisamide.
[0082] In the nineteenth embodiment, the invention relates to the
composition of the first embodiment, wherein said first compound
is metformin hydrochloride and said second compound is zonisamide.
[0083] In the twentieth embodiment, the invention relates to the
composition of the first embodiment, wherein said first compound
is topiramate and said second compound is zonisamide.
[0084] In the twenty first embodiment, the invention relates to
the composition of the nineteenth embodiment, wherein the zonisamide
is in a time-release formulation.
[0085] In the twenty second embodiment, the invention relates to
a method of affecting weight loss, comprising identifying an individual
in need thereof and treating that individual with an antidiabetic
and an anticonvulsant.
[0086] In the twenty third embodiment, the invention relates to
the method of the twenty second embodiment, wherein said individual
has a body mass index greater than 25.
[0087] In the twenty fourth embodiment, the invention relates to
the method of the twenty second embodiment, wherein the antidiabetic
is selected from biguanides, glucosidase inhibitors, insulins, meglitinides,
sulfonylureas, and pharmaceutically acceptable salts and prodrugs
thereof.
[0088] In the twenty fifth embodiment, the invention relates to
the method of the twenty second embodiment, wherein the antidiabetic
is selected from the group consisting of metformin hydrochloride,
acarbose, miglitol, human insulin, pork insulin, beef insulin, beef-pork
insulin, insulin glargine, insulin lispro, insulin aspart, nateglinide,
repaglinide, glimepiride, glyburide, chlorpropamide, tolazamide,
glibenclamide; gliclazide, gliquidone, tolbutamide, glibenclamide,
glipizide, extended release formulations of the above drugs, and
combinations of the above drugs.
[0089] In the twenty sixth embodiment, the invention relates to
the method of the twenty second embodiment, wherein the anticonvulsant
is selected from the group consisting of barbiturates, benzodiazepines,
GABA analogues, hydantoins phenyltriazines, and succinimides, and
pharmaceutically acceptable salts or prodrugs thereof.
[0090] In the twenty seventh embodiment, the invention relates
to the method of the twenty second embodiment, wherein the anticonvulsant
is selected from the group consisting of pentobarbital, clonazepam,
clorazepate, diazepam, tiagabine, gabapentin, pregabalin, fosphenytoin,
phenytoin, phenytoin, 5,5-Diphenylhydantoin, carbamazepine, oxcarbazepine,
valproate, valproic acid, divalproex, valrocemide, felbamate, levetiracetam,
topiramate, zonisamide, lamotrigine, methsuximide, ethosuximide,
retigabine, lacosamide, talampanel, extended release formulation
of the above drugs, and combinations of the above drugs.
[0091] In the twenty eighth embodiment, the invention relates to
the method of the twenty second embodiment, wherein said first compound
and said second compound are administered nearly simultaneously.
[0092] In the twenty ninth embodiment, the invention relates to
the method of the twenty second embodiment, wherein said first compound
is administered prior to said second compound.
[0093] In the thirtieth embodiment, the invention relates to the
method of the twenty second embodiment, wherein said first compound
is administered subsequent to said second compound.
[0094] In the thirty first 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 and a second compound, wherein said first compound
is an antidiabetic and said second compound is a anticonvulsant.
[0095] In the thirty second embodiment, the invention relates to
the method of the thirty first embodiment, wherein said first compound
and said second compound are administered nearly simultaneously.
[0096] In the thirty third embodiment, the invention relates to
the method of the thirty first embodiment, wherein said first compound
is administered prior to said second compound.
[0097] In the thirty fourth embodiment, the invention relates to
the method of the thirty first embodiment, wherein said first compound
is administered subsequent to said second compound.
[0098] In the thirty fifth 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
with a first compound and a second compound, wherein said first
compound is an antidiabetic and said second compound is an anticonvulsant.
[0099] In the thirty sixth embodiment, the invention relates to
the method of the thirty fifth embodiment, wherein said first compound
and said second compound are administered nearly simultaneously.
[0100] In the thirty seventh embodiment, the invention relates
to the method of the thirty fifth embodiment, wherein said first
compound is administered prior to said second compound.
[0101] In the thirty eighth embodiment, the invention relates to
the method of the thirty fifth embodiment, wherein said first compound
is administered subsequent to said second compound.
[0102] In the thirty ninth 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
with a first compound and a second compound, wherein said first
compound is an antidiabetic and said second compound is an anticonvulsant.
[0103] In the fortieth embodiment, the invention relates to the
method of the thirty ninth embodiment, wherein said first compound
and said second compound are administered nearly simultaneously.
[0104] In the forty first embodiment, the invention relates to
the method of the thirty ninth embodiment, wherein said first compound
is administered prior to said second compound.
[0105] In the forty second embodiment, the invention relates to
the method of the thirty ninth embodiment, wherein said first compound
is administered subsequent to said second compound.
[0106] In the forty third 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 metformin hydrochloride and zonisamide.
[0107] In the forty fourth embodiment, the invention relates to
the method of the forty third embodiment, wherein the individual
has a BMI greater than 30.
[0108] In the forty fifth embodiment, the invention relates to
the method of the forty third embodiment, wherein the individual
has a BMI greater than 25.
[0109] In the forty sixth embodiment, the invention relates to
the method of the forty third embodiment, wherein the metformin
is in a time-release formulation.
[0110] In the forty seventh embodiment, the invention relates to
the method of the forty sixth embodiment, wherein the plasma concentration
level of both metformin and zonisamide follow a similar concentration
profile.
[0111] In the forty eighth embodiment, the invention relates to
the method of the forty sixth embodiment, wherein the metformin
and the zonisamide are administered substantially simultaneously.
[0112] In the forty ninth embodiment, the invention relates to
the method of the forty sixth embodiment, wherein the metformin
is administered prior to the zonisamide.
[0113] In the fiftieth embodiment, the invention relates to the
method of the forty sixth embodiment, wherein the metformin is administered
subsequent to the zonisamide.
EXAMPLES
[0114] The examples below are non-limiting and are merely representative
of various aspects of the invention.
Example 1
Combination of Zonisamide and Metformin
[0115] Individuals having a BMI of greater than 25 and fasting
plasma glucose .gtoreq.100 mg/dL are identified. Each individual
is instructed to take one 25 mg tablet of zonisamide on a daily
basis, in addition to one 500 mg tablet of metformin hydrochloride
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 weight 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 zonisamide
dosage can be increased by approximately 20 mg per day, though never
exceeding 600 mg total per day. Alternatively, or concurrently,
the metformin hydrochloride dosage can be increased by 20 mg per
day, though never exceeding 2500 mg total per day. If the initial
dosage results in a more rapid weight loss than the above rate,
the dosage of each of zonisamide or metformin can be reduced.
[0118] In some cases, it is beneficial to administer one dose of
zonisamide per day in conjunction with two or three or more doses
of metformin throughout the day. Metformin may also be in a time-release
formulation where the dose is administered once a day, but metformin
gradually enters the blood stream throughout the day, or in the
course of a 12 hour period. |