U.S. patent application number 14/679754 was filed with the patent office on 2015-07-30 for escalating dosing regimen for effecting weight loss and treating obesity.
The applicant listed for this patent is Vivus, Inc.. Invention is credited to Thomas Najarian, Peter Y. Tam, Leland F. Wilson.
Application Number | 20150209325 14/679754 |
Document ID | / |
Family ID | 40863844 |
Filed Date | 2015-07-30 |
United States Patent
Application |
20150209325 |
Kind Code |
A1 |
Najarian; Thomas ; et
al. |
July 30, 2015 |
Escalating Dosing Regimen for Effecting Weight Loss and Treating
Obesity
Abstract
The present invention is drawn to novel topiramate compositions
as well as methods for effecting weight loss, e.g., in the
treatment of obesity and related conditions, including conditions
associated with and/or caused by obesity per se. The present
invention features an escalating dosing regimen adapted for the
administration of topiramate and optionally a sympathomimetic agent
such as phentermine or bupropion, in the treatment of obesity and
related conditions.
Inventors: |
Najarian; Thomas; (Los Osos,
CA) ; Tam; Peter Y.; (Redwood City, CA) ;
Wilson; Leland F.; (Menlo Park, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Vivus, Inc. |
Mountain View |
CA |
US |
|
|
Family ID: |
40863844 |
Appl. No.: |
14/679754 |
Filed: |
April 6, 2015 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
14495250 |
Sep 24, 2014 |
9011906 |
|
|
14679754 |
|
|
|
|
14048416 |
Oct 8, 2013 |
8895057 |
|
|
14495250 |
|
|
|
|
12481548 |
Jun 9, 2009 |
8580299 |
|
|
14048416 |
|
|
|
|
12135953 |
Jun 9, 2008 |
|
|
|
12481548 |
|
|
|
|
Current U.S.
Class: |
514/454 |
Current CPC
Class: |
A61P 11/00 20180101;
A61K 9/4866 20130101; A61P 15/00 20180101; A61P 9/12 20180101; A61P
3/04 20180101; A61K 31/00 20130101; A61K 31/35 20130101; A61K
9/5047 20130101; A61K 31/135 20130101; A61P 3/10 20180101; A61K
31/357 20130101; A61K 31/7048 20130101; A61P 9/10 20180101; A61K
9/1629 20130101; A61P 25/02 20180101; A61K 9/1676 20130101; A61P
3/06 20180101; A61P 31/04 20180101; A61K 9/167 20130101; A61P 25/06
20180101; A61K 9/5084 20130101; A61K 31/137 20130101; A61K 9/5026
20130101; A61P 19/02 20180101; A61P 21/00 20180101; A61P 25/00
20180101; A61K 47/38 20130101; A61P 1/08 20180101; A61P 19/06
20180101; A61P 25/20 20180101; A61P 35/00 20180101; A61K 9/5073
20130101; A61P 11/06 20180101; A61K 9/1623 20130101; A61P 43/00
20180101; A61K 31/00 20130101; A61K 2300/00 20130101; A61K 31/135
20130101; A61K 2300/00 20130101; A61K 31/137 20130101; A61K 2300/00
20130101 |
International
Class: |
A61K 31/357 20060101
A61K031/357; A61K 9/16 20060101 A61K009/16; A61K 9/48 20060101
A61K009/48; A61K 31/137 20060101 A61K031/137; A61K 9/50 20060101
A61K009/50 |
Claims
1. A controlled release composition for treating obesity, diabetes,
sleep apnea, or a related condition in a subject comprising: an
effective amount of topiramate and phentermine.
2. A method for effecting weight loss in a subject, comprising
administering to the subject continually over a significant period
of time a daily dose of phentermine in combination therewith a
daily dose of topiramate selected to prevent the loss of
effectiveness of phentermine alone.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. Ser. No.
14/495,250, filed Sep. 24, 2014, which is a continuation of U.S.
Ser. No. 14/048,416, filed Oct. 8, 2013, now U.S. Pat. No.
8,895,057, which is a continuation of U.S. Ser. No. 12/481,548,
filed Jun. 9, 2009, now U.S. Pat. No. 8,580,299, which is a
continuation-in-part of U.S. Ser. No. 12/135,953, filed Jun. 9,
2008. The contents of each of these applications are incorporated
by reference in their entirety.
BACKGROUND OF THE INVENTION
[0002] The prevalence of obesity in both children and adults is on
the rise in first world countries, especially in the United States,
as well as in many developing countries such as China and India.
Many aspects of a person's life are affected by obesity, from
physical problems such as knee and ankle joint deterioration, to
emotional problems resulting from self-esteem issues and society's
attitude towards heavy people. The medical problems caused by
obesity can be serious and often life-threatening and include
diabetes, shortness of breath and other respiratory problems such
as asthma and pulmonary hypertension, gallbladder disease,
dyslipidemia (for example, high cholesterol or high levels of
triglycerides) and dyslipidemic hypertension, osteoarthritis and
other orthopedic problems, reflux esophagitis (heartburn), snoring,
sleep apnea, menstrual irregularities, infertility, problems
associated with pregnancy, gout, cardiovascular problems such as
coronary artery disease and other heart trouble, muscular
dystrophy, and metabolic disorders such as
hypoalphalipoproteinemia, familial combined hyperlipidemia, and
Syndrome X, including insulin-resistant Syndrome X. In addition,
obesity has been associated with an increased incidence of certain
cancers, notably cancers of the colon, rectum, prostate, breast,
uterus, and cervix.
[0003] Obesity substantially increases the risk of morbidity from
hypertension, dyslipidemia, type II diabetes, coronary heart
disease, stroke, gallbladder disease, osteoarthritis and
endometrial, breast, prostate, and colon cancers. Higher body
weights are also associated with increases in all-cause mortality.
Many of these problems are relieved or improved when the afflicted
individual undergoes permanent significant weight loss. Weight loss
in these individuals can also promote a significant increase in
longevity.
[0004] Strategies for treating obesity and related disorders have
included dietary restriction, increased physical activity,
pharmacological approaches, and even surgery, with the choice
depending, at least in part, on the degree of weight loss one is
attempting to achieve as well as on the severity of obesity
exhibited by the subject. For example, treatments such as a
low-calorie, low-fat diet and/or regular exercise are often
adequate with individuals who are only mildly overweight. The
difficulty in maintaining long-term weight loss through diet and
behavior modification, however, has led to an increasing interest
in other avenues for treatment, particularly pharmacotherapy.
[0005] Traditional pharmacological interventions typically induce a
weight loss of between five and fifteen kilograms; if the
medication is discontinued, renewed weight gain often ensues.
Surgical treatments are comparatively successful and are reserved
for patients with extreme obesity and/or with serious medical
complications.
[0006] The above treatments can be enhanced by controlled use of
over-the-counter appetite suppressants including caffeine,
ephedrine and phenylpropanolamine (Acutrim.RTM., Dexatrim.RTM.).
Moreover, prescription medications including amphetamine,
diethylpropion (Tenuate.RTM.), mazindol (Mazanor.RTM.,
Sanorex.RTM.), phentermine (Fastin.RTM., Ionamin.RTM.),
phenmetrazine (Preludin.RTM.), phendimetrazine (Bontrol.RTM.,
Plegine.RTM., Adipost.RTM., Dital.RTM., Dyrexan.RTM., Melfiat.RTM.,
Prelu-2.RTM., Rexigen Forte.RTM.), benzphetamine (Didrex.RTM.) and
fluoxetine (Prozac.RTM.) are often used in the treatment of
seriously overweight and/or obese subjects or patients.
[0007] While society has seen tremendous advances in the field of
pharmaceuticals, there are, of course, drawbacks to the
administration of any given pharmaceutical agent. Sometimes, the
disadvantages, or "side effects," are so severe as to preclude
administration of a particular agent at a therapeutically effective
dose. Furthermore, many agents in the same therapeutic class
display similar side effect profiles, meaning that patients either
have to forego therapy or suffer from varying degrees of side
effects associated with the medication of choice.
[0008] The present invention is directed to an escalating dosing
regimen for administering topiramate alone or in combination with a
second therapeutic agent that directly or indirectly reduces the
side effects associated with one or both of the agents
administered. By "indirectly" reducing side effects is meant that
the second therapeutic agent allows the first pharmaceutical agent
to be administered at a lower dose without compromising therapeutic
efficacy, thus resulting dose-dependent unwanted effects.
[0009] Topiramate
(2,3,4,5-bis-O-(1-methylethylidene)-.beta.-D-fructopyranose
sulfamate) is a broad-spectrum neurotherapeutic agent approved by
the FDA and the regulatory agencies of many other countries for the
treatment of certain seizure disorders and the prevention of
migraine headaches. E. Faught et al. (1996) Neurology 46:1684-90;
Karim et al. (1995) Epilepsia 36 (S4):33; S. K. Sachdeo et al.
(1995) Epilepsia 36(S4):33; T. A. Glauser (1999) Epilepsia 40
(S5):S71-80; R. C. Sachdeo (1998) Clin. Pharmacokinet 34:335-346).
There has also been evidence that topiramate is effective in the
treatment of diabetes (U.S. Pat. Nos. 7,109,174 and 6,362,220),
neurological disorders (U.S. Pat. No. 6,908,902), depression (U.S.
Pat. No. 6,627,653), psychosis (U.S. Pat. No. 6,620,819), headaches
(U.S. Pat. No. 6,319,903) and hypertension (U.S. Pat. No.
6,201,010). However there have been adverse effects associated with
the use of topiramate in humans, such as cognitive dulling and word
finding difficulties, which can discourage many obese patients from
taking this drug.
[0010] As such, there is considerable interest in the development
of additional methods and compositions for treating obesity and
related conditions in which the therapeutic efficacy of known
therapeutic agents and compositions are improved. In addition,
combination therapy, wherein two or more active agents are
administered in combination, may be employed to decrease the dose
of each individual active agent administered and mitigate one or
more side effects of the other active agent or agents. Given that
the incidence of obesity and conditions caused by or related to
obesity has reached epidemic proportions, there is an urgent need
for effective methods for the treatment of obesity and/or a related
condition, including combination treatments that result in
reduction of toxicity, decreased side effects and effective
treatment.
SUMMARY OF THE INVENTION
[0011] The present invention provides novel topiramate compositions
and methods for effecting weight loss, treating obesity, and
treating conditions caused by or associated with excess weight or
obesity. The compositions can contain topiramate as a single active
agent but more typically contain topiramate in combination with at
least one sympathomimetic agent. The term "sympathomimetic agent"
is a term of art and refers to agents or compounds that mimic or
alter stimulation of the sympathetic nervous system. Exemplary
sympathomimetic agents include phentermine and bupropion.
Optimally, the topiramate and the sympathomimetic agent are
contained in a single dosage form, which provides for immediate
release of the sympathomimetic agent and controlled release, e.g.,
sustained release, delayed release, or both sustained release and
delayed release, of the topiramate.
[0012] In another aspect of the invention, a controlled release
topiramate composition is provided that is composed of an effective
amount of topiramate, microcrystalline cellulose, and
methylcellulose. Such a composition will provide for sustained
release of the topiramate. The composition, in the form of, for
instance, a bead or tablet, may be coated with ethyl cellulose,
polyvinyl pyrrolidone, or the like, to provide for delayed release
of the topiramate as well. A sympathomimetic agent is preferably
although not necessarily included, and, if present, is preferably
in immediate release form.
[0013] The present invention features an escalating dosing regimen
for administering topiramate alone or in combination with a
sympathomimetic agent, wherein the dosing regimen is in the context
of a method for effecting weight loss, e.g., in a method for
treating obesity, overweight, or a condition associated with
obesity, or in an alternative method, e.g., a method for treating
epilepsy, a method for treating an impulse control disorder, or the
like. The method involves administration of a topiramate
composition as described above, wherein the topiramate is generally
although not necessarily administered in a controlled release
composition and/or in combination with a sympathomimetic agent. The
escalating dosing regimen involves administration of an initial
daily dosage to an individual for a specific time period and
incrementally increasing the dosage at various designated time
points.
[0014] The invention also provides a packaged pharmaceutical
preparation comprising topiramate, optionally a sympathomimetic
agent as well, and instructions for administering, e.g.,
self-administering, the active agent(s). Generally, the
instructions for administration include reference to an escalating
dosing regimen wherein a lower daily dosage of topiramate is
administered initially, with incremental increases at various
designated time points thereafter. Ideally, a titration card is
provided that sets forth the recommended dosages for at least four
weeks.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] FIG. 1 provides a summary of the plasma concentration of
controlled release topiramate according to the present invention
versus topiramate (Topamax.RTM.) in normal obese subjects.
[0016] FIG. 2 depicts the mean plasma phentermine concentrations
versus time for subjects administered phentermine in combination
with controlled release topiramate and phentermine in combination
with immediate release topiramate (Topamax.RTM.).
DETAILED DESCRIPTION OF THE INVENTION
Definitions and Nomenclature
[0017] It must be noted that, as used in this specification and the
appended claims, the singular forms "a," "an" and "the" include
plural referents unless the context clearly dictates otherwise.
Thus, for example, "an active agent" refers not only to a single
active agent but also to a combination of two or more different
active agents, "a dosage form" refers to a combination of dosage
forms as well as to a single dosage form, and the like.
[0018] Unless defined otherwise, all technical and scientific terms
used herein have the meaning commonly understood by one of ordinary
skill in the art to which the invention pertains. Specific
terminology of particular importance to the description of the
present invention is defined below.
[0019] When referring to an active agent, applicants intend the
term "active agent" to encompass not only the specified molecular
entity but also its pharmaceutically acceptable, pharmacologically
active analogs, including, but not limited to, salts, esters,
amides, prodrugs, conjugates, active metabolites, and other such
derivatives, analogs, and related compounds as will be discussed
infra. Therefore, reference to "phentermine," for example, or
"bupropion," encompasses not only phentermine and bupropion per se
but also salts and other derivatives of phentermine and bupropion,
e.g., phentermine hydrochloride and bupropion hydrochloride,
respectively. It is to be understood that when amounts or doses are
specified, that those amounts or doses refer to the amount or dose
of active agent per se and not to a salt or the like. For example,
when it is indicated that a dose or amount of phentermine is 7.5
mg, that would correspond to 9.84 phentermine hydrochloride and not
7.5 phentermine hydrochloride.
[0020] The terms "treating" and "treatment" as used herein refer to
reduction in severity and/or frequency of symptoms, elimination of
symptoms and/or underlying cause, and improvement or remediation of
damage. In certain aspects, the term "treating" and "treatment" as
used herein refer to the prevention of the occurrence of symptoms.
In other aspects, the term "treating" and "treatment" as used
herein refer to the prevention of the underlying cause of symptoms
associated with obesity, excess weight, and/or a related condition.
The phrase "administering to a subject" refers to the process of
introducing a composition or dosage form of the invention into the
subject (e.g., a human or other mammalian subject) via an
art-recognized means of introduction
[0021] By the terms "effective amount" and "therapeutically
effective amount" of an agent, compound, drug, composition or
combination of the invention which is nontoxic and effective for
producing some desired therapeutic effect upon administration to a
subject or patient (e.g., a human subject or patient).
[0022] The term "dosage form" denotes any form of a pharmaceutical
composition that contains an amount of active agent sufficient to
achieve a therapeutic effect with a single administration. When the
formulation is a tablet or capsule, the dosage form is usually one
such tablet or capsule. The frequency of administration that will
provide the most effective results in an efficient manner without
overdosing will vary with the characteristics of the particular
active agent, including both its pharmacological characteristics
and its physical characteristics, such as hydrophilicity.
[0023] The term "controlled release" refers to a drug-containing
formulation or fraction thereof in which release of the drug is not
immediate, i.e., with a "controlled release" formulation,
administration does not result in immediate release of the drug
into an absorption pool. The term is used interchangeably with
"nonimmediate release" as defined in Remington: The Science and
Practice of Pharmacy, Nineteenth Ed. (Easton, Pa.: Mack Publishing
Company, 1995). In general, the term "controlled release" as used
herein includes sustained release, modified release, and delayed
release formulations.
[0024] The term "sustained release" (synonymous with "extended
release") is used in its conventional sense to refer to a drug
formulation that provides for gradual release of a drug over an
extended period of time, and that preferably, although not
necessarily, results in substantially constant blood levels of a
drug over an extended time period. The term "delayed release" is
also used in its conventional sense, to refer to a drug formulation
which, following administration to a patient provides a measurable
time delay before drug is released from the formulation into the
patient's body.
[0025] By "pharmaceutically acceptable" is meant a material that is
not biologically or otherwise undesirable, i.e., the material may
be incorporated into a pharmaceutical composition administered to a
patient without causing any undesirable biological effects or
interacting in a deleterious manner with any of the other
components of the composition in which it is contained. When the
term "pharmaceutically acceptable" is used to refer to a
pharmaceutical carrier or excipient, it is implied that the carrier
or excipient has met the required standards of toxicological and
manufacturing testing or that it is included on the Inactive
Ingredient Guide prepared by the U.S. Food and Drug administration.
"Pharmacologically active" (or simply "active") as in a
"pharmacologically active" (or "active") derivative or analog,
refers to a derivative or analog having the same type of
pharmacological activity as the parent compound and approximately
equivalent in degree. The term "pharmaceutically acceptable salts"
include acid addition salts which are formed with inorganic acids
such as, for example, hydrochloric or phosphoric acids, or such
organic acids as acetic, oxalic, tartaric, mandelic, and the like.
Salts formed with the free carboxyl groups can also be derived from
inorganic bases such as, for example, sodium, potassium, ammonium,
calcium, or ferric hydroxides, and such organic bases as
isopropylamine, trimethylamine, histidine, procaine and the
like.
[0026] As used herein, "subject" or "individual" or "patient"
refers to any subject for whom or which therapy is desired, and
generally refers to the recipient of the therapy to be practiced
according to the invention. The subject can be any vertebrate, but
will typically be a mammal. If a mammal, the subject will in many
embodiments be a human, but may also be a domestic livestock,
laboratory subject, or pet animal.
[0027] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention belongs. Although
any methods and materials similar or equivalent to those described
herein can also be used in the practice or testing of the present
invention, the preferred methods and materials are now described.
All publications mentioned herein are incorporated herein by
reference to disclose and describe the methods and/or materials in
connection with which the publications are cited.
[0028] Where a range of values is provided, it is understood that
each intervening value, to the tenth of the unit of the lower limit
unless the context clearly dictates otherwise, between the upper
and lower limit of that range and any other stated or intervening
value in that stated range, is encompassed within the invention.
The upper and lower limits of these smaller ranges may
independently be included in the smaller ranges, and are also
encompassed within the invention, subject to any specifically
excluded limit in the stated range. Where the stated range includes
one or both of the limits, ranges excluding either or both of those
included limits are also included in the invention.
[0029] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention belongs. Although
any methods and materials similar or equivalent to those described
herein can also be used in the practice or testing of the present
invention, the preferred methods and materials are now described.
All publications mentioned herein are incorporated herein by
reference to disclose and describe the methods and/or materials in
connection with which the publications are cited.
[0030] The publications discussed herein are provided solely for
their disclosure prior to the filing date of the present
application. Nothing herein is to be construed as an admission that
the present invention is not entitled to antedate such publication
by virtue of prior invention. Further, the dates of publication
provided may be different from the actual publication dates which
may need to be independently confirmed.
Methods and Formulations of the Invention:
[0031] The present invention provides novel methods and
compositions to effect weight loss and treat obesity, conditions
related to excess weight or obesity, diabetes (whether or not
related to obesity), and other conditions and disorders as will be
explained infra. According to the U.S. Centers for Disease Control,
the clinical definition of being overweight (the term being used
synonymously herein with the term "excess weight") is having a body
mass index (BMI) between 25.0 and 29.9 kg/m; BMI is calculated by
multiplying an individual's weight, in kilograms, by height, in
meters. The CDC defines obesity as having a BMI of 30 or higher. In
one embodiment, the invention provides a method for effecting
weight loss and treating overweight, obesity, and conditions
associated with excess weight and obesity, and involves
administration of a combination of the sympathomimetic agent
phentermine and the anti-convulsant agent topiramate.
[0032] Topiramate is an anticonvulsant sulfamate compound that is
sold in the United States under the trade name Topamax.RTM.
(Ortho-McNeil Pharmaceutical, Inc., Raritan, N.J., U.S.A).
Topiramate has been approved for use as an antiepileptic agent as
an adjuvant therapy for patients with partial onset seizures or
primary generalized tonic-clonic seizures, and for the prevention
of migraine headache. See Physician's Desk Reference, 56th ed.
(2002); see also U.S. Pat. No. 4,513,006 to Maryanoff et al. and
U.S. Pat. No. 7,351,695 to Almarssoo et al.
[0033] "Topiramate" generally refers to the sulfamate-substituted
monosaccharide having the chemical name
2,3,4,5-bis-O-(1-methylethylidene)-.beta.-D-fructopyranose
sulfamate and the molecular formula C12H21NO8S. The structure of
the compound is represented by Formula (I)
##STR00001##
As used herein, the term "topiramate" encompasses
2,3,4,5-bis-(O)-(1-methylethylidene)-.beta.-D-fructopyranose
sulfamate as well as individual enantiomers, individual
diastereomers, or mixtures thereof. The term "topiramate" as used
herein also encompasses topiramate salts as well as polymorphs,
solvates (including hydrates and mixed solvates, as well as
hydrates of salts), co-crystals (for instance, with other compounds
or other forms of topiramate), amorphous, and anhydrous forms of
the compound of Formula (I). Topiramate salts useful in conjunction
with the present invention, as will be appreciated from the fact
that the compound is a sulfamic acid derivative, are
pharmaceutically acceptable basic addition salts. Such salts are
prepared from bases that provide a pharmaceutically acceptable
cation that associates with the sulfamic acid group of the compound
of Formula (I). Suitable pharmaceutically acceptable cations
include both organic and inorganic cations, including, without
limitation, sodium, sodium, potassium, lithium, magnesium, calcium,
aluminum, zinc, procaine, benzathine, chloroprocaine, choline,
diethylamine, ethylenediamine, N-methylglucamine, benethamine,
clemizole, diethylamine, piperazine, tromethamine, triethylamine,
ethanolamine, triethanolamine, arginine, lysine, histidine,
tributylamine, 2-amino-2-pentylpropanol,
2-amino-2-methyl-1,3-propanediol, tris(hydroxymethyl)aminomethane,
benzylamine, 2-(dimethylamino)ethanol, barium or bismuth counter
ions. Particularly preferred cations are sodium, lithium, and
potassium. Other forms of topiramate referenced above may be
prepared using methods known in the art; see, e.g., U.S. Pat. No.
7,351,695. The subject methods include a dosing regimen for the
administration of topiramate alone or, more preferably, in
combination with a sympathomimetic agent. In certain aspects, the
present invention provides a dosing regimen for the administration
of a pharmaceutical composition that includes, e.g., topiramate in
combination with bupropion or phentermine.
[0034] In one embodiment of the invention, directed to an
escalating dosage regimen, the dosing strategy involves
administering to a patient a lower daily dosage of topiramate alone
or in combination with a sympathomimetic agent for a specific
period of time and then incrementally increasing the dosage at
various designated time points.
[0035] For example, when treating a patient who is overweight or
obese, and who may suffer from a condition associated with or
caused by excess weight or obesity, the patient receives a dosage
of 15 mg/day to 30 mg/day, e.g., 23 mg/day, of topiramate for 1
week. Next, the patient receives a dosage of 35 mg/day to 55
mg/day, e.g., 46 mg/day, of topiramate for a second week.
Thereafter, the patient receives a dosage of 60 mg/day to 80
mg/day, e.g., 69 mg/day, of topiramate for a third week, which is
followed by a final dosage of 85 mg to 125 mg/day, e.g., 92 mg/day
of topiramate for a fourth week.
[0036] In another example, when treating a patient for obesity
and/or a related condition, the patient receives a dosage of 15
mg/day to 30 mg/day, e.g., 23 mg/day, of topiramate in combination
with a dosage of 3.75 mg/day of phentermine for 1 week. The patient
next receives a dosage of 35 mg/day to 55 mg/day, e.g., 46 mg/day,
of topiramate in combination with a dosage of 7.5 mg/day of
phentermine for a second week. Thereafter, the patient receives a
dosage of 60 mg/day to 80 mg/day, e.g., 69 mg/day, of topiramate in
combination with a dosage of 11.25 mg/day of phentermine for a
third week which is followed by a final dosage of 85 mg to 125
mg/day, e.g., 92 mg/day, topiramate in combination with a dosage of
15 mg/day of phentermine for a fourth week.
[0037] After the fourth week of administration, the further
administration of topiramate alone or topiramate in combination
with phentermine is carried on indefinitely or, more typically,
until a sufficient reduction of symptoms has been achieved. In
certain aspects, the final dose of 92 mg/day of topiramate alone or
in combination with a dosage of 15 mg/day of phentermine
indefinitely or until a sufficient reduction of symptoms has been
achieved. In other aspects, the final dose of topiramate alone or
topiramate in combination with phentermine is decreased to the
initial starting dose of the regimen and maintained indefinitely or
until a sufficient reduction of symptoms has been achieved. In a
weight loss regimen, the dosage regimen generally involves
continual, i.e., ongoing, administration, over a significant period
of time, e.g., in the range of about 4 weeks to about 67 weeks,
depending on the severity of an individual's weight problem, the
amount of weight that should be lost, and the rate at which weight
is lost.
[0038] In another embodiment of the invention, topiramate is
administered on an ongoing basis, i.e., generally following the
escalating dosage regimen described above. In either of these
methods, i.e., the escalating dosage regimen or an ongoing
maintenance dosage regimen, pharmaceutical compositions are
administered that include an effective amount of topiramate as the
active agent, wherein an "effective amount" of topiramate is
generally an amount that results in a reduction of at least one
pathological parameter associated with obesity, excess weight,
and/or a related disorder. In the methods of the invention, e.g.,
in a method for effecting weight loss such as in the treatment of
obesity and/or a condition related to obesity, an effective amount
of topiramate is an amount that is effective to achieve a reduction
of at least about 10%, at least about 15%, at least about 20%, or
at least about 25%, at least about 30%, at least about 35%, at
least about 40%, at least about 45%, at least about 50%, at least
about 55%, at least about 60%, at least about 65%, at least about
70%, at least about 75%, at least about 80%, at least about 85%, at
least about 90%, or at least about 95%, compared to the expected
reduction in the parameter, e.g., loss of weight, in an individual
suffering from obesity, excess weight, and/or a related disorder
and not treated with the topiramate compositions.
[0039] A suitable daily dose of topiramate is in the range of 10 mg
to 1500 mg. For example, 10 mg, 20 mg, 30 mg, 60 mg, 90 mg, 120 mg,
150 mg, 180 mg, 210 mg, 240 mg, 270 mg, 300 mg, 330 mg, 360 mg, 390
mg, 420 mg, 450 mg, 480 mg, 500 mg, 600 mg, 800 mg, 1000 mg, 1200
mg, 1500 mg or the like is administered to a patient as a daily
dosage. In another example, 23 mg, 46 mg, 69 mg and 92 mg or the
like is administered to a patient as a daily dosage. In some
embodiments, the daily dosage of topiramate is in the range of 10
mg to 150. In certain embodiments, the daily dosage of topiramate
is in the range of 10 mg to 100 mg. Each of the aforementioned
"daily dosages" is generally although not necessarily administered
as a single daily dose.
[0040] The patient may receive a specific dosage of topiramate over
a period of weeks, months, or years, e.g., 1 week, 2 weeks, 3
weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7
months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years,
3 years, 4 years, 5 years, and the like.
[0041] Aspects of the invention provide a topiramate monotherapy or
combination therapy in which the subject topiramate formulation is
effective when administered at an initial dose as low as 10-23 mg.
In certain aspects, the topiramate formulation is effective at a
dose of approximately 20 mg. The novel topiramate formulations of
the present invention have a lower maximum concentration (Cmax)
without decreasing total drug exposure defined by the area under
the concentration-time curve (AUC). Further, the novel topiramate
formulations of the present invention have a delay in time after
administration of a drug when the maximum plasma concentration is
reached (Tmax) by six to eight hours. As depicted in FIG. 1, drug
exposure as measured by AUC for the control release (CR)
formulation capsule is the same as the 100 mg of immediate release
topiramate (Topamax.RTM.) tablet despite a 20% reduction in the
Cmax. Therefore, this formulation is capable of reducing the Cmax
which would reduce side effects without compromising the efficacy
of the treatment, since the AUC is the same. This reduction in Cmax
is preferred as topiramate can be sedating and a delay in the time
to reach maximum plasma concentration to the late afternoon or
evening time would improve the tolerability of the drug.
[0042] As such, the effective amount of topiramate is decreased,
thereby further reducing any toxicity or harmful side effects in
the patient. The amount of topiramate administered to the patient
is less than an amount that would cause toxicity in the patient. In
certain embodiments, the amount of the compound that is
administered to the patient is less than the amount that causes a
concentration of the compound in the patient's plasma to equal or
exceed the toxic level of the compound. The optimal amount of the
compound that should be administered to the patient in the practice
of the present invention will depend on the individual as well as
the severity of the individual's symptoms.
[0043] Depending on the intended mode of administration, the
pharmaceutical formulation may be a solid, semi-solid or liquid,
such as, for example, a tablet, a capsule, a caplet, a liquid, a
suspension, an emulsion, a suppository, granules, pellets, beads, a
powder, or the like, preferably in unit dosage form suitable for
single administration of a precise dosage. Suitable pharmaceutical
compositions and dosage forms may be prepared using conventional
methods known to those in the field of pharmaceutical formulation
and described in the pertinent texts and literature, e.g., in
Remington: The Science and Practice of Pharmacy (Easton, Pa.: Mack
Publishing Co., 1995). Oral administration and therefore oral
dosage forms are generally preferred, and include tablets,
capsules, caplets, solutions, suspensions and syrups, and may also
comprise a plurality of granules, beads, powders, or pellets that
may or may not be encapsulated. Preferred oral dosage forms are
capsules and tablets, particularly controlled release capsules and
tablets, as noted above.
[0044] As noted above, it is especially advantageous to formulate
compositions of the invention in unit dosage form for ease of
administration and uniformity of dosage. The term "unit dosage
forms" as used herein refers to physically discrete units suited as
unitary dosages for the individuals to be treated. That is, the
compositions are formulated into discrete dosage units each
containing a predetermined, "unit dosage" quantity of an active
agent calculated to produce the desired therapeutic effect in
association with the required pharmaceutical carrier. The
specifications of unit dosage forms of the invention are dependent
on the unique characteristics of the active agent to be delivered.
Dosages can further be determined by reference to the usual dose
and manner of administration of the ingredients. It should be noted
that, in some cases, two or more individual dosage units in
combination provide a therapeutically effective amount of the
active agent, e.g., two tablets or capsules taken together may
provide a therapeutically effective dosage of topiramate, such that
the unit dosage in each tablet or capsule is approximately 50% of
the therapeutically effective amount.
[0045] Tablets may be manufactured using standard tablet processing
procedures and equipment. Direct compression and granulation
techniques are preferred. In addition to the active agent, tablets
will generally contain inactive, pharmaceutically acceptable
carrier materials such as binders, lubricants, disintegrants,
fillers, stabilizers, surfactants, coloring agents, and the
like.
[0046] Capsules are also preferred oral dosage forms, in which case
the active agent-containing composition may be encapsulated in the
form of a liquid or solid (including particulates such as granules,
beads, powders or pellets). Suitable capsules may be either hard or
soft, and are generally made of gelatin, starch, or a cellulosic
material, with gelatin capsules preferred. Two-piece hard gelatin
capsules are preferably sealed, such as with gelatin bands or the
like. See, for example, Remington: The Science and Practice of
Pharmacy, cited earlier herein, which describes materials and
methods for preparing encapsulated pharmaceuticals.
[0047] Oral dosage forms, whether tablets, capsules, caplets, or
particulates, can, if desired, be formulated so as to provide for
controlled release of topiramate, and in a preferred embodiment,
the present formulations are controlled release oral dosage forms.
Generally, the dosage forms provide for sustained release, i.e.,
gradual, release of topiramate, from the dosage form to the
patient's body over an extended time period, typically providing
for a substantially constant blood level of the agent over a time
period in the range of about 4 to about 12 hours, typically in the
range of about 6 to about 10 hours or 6 to about 8 hours. Release
of the topiramate may also be delayed; that is, there is a time lag
between administration and the start of topiramate release. In this
way, for instance, an individual will not experience sleepiness or
other side effects of topiramate during the school or work day.
Preferred dosage forms thus involve sustained release of the
topiramate, delayed release of the topiramate, or both sustained
and delayed release of the topiramate.
[0048] Generally, as will be appreciated by those of ordinary skill
in the art, sustained release dosage forms are formulated by
dispersing the active agent within a matrix of a gradually
hydrolyzable material such as a hydrophilic polymer, or by coating
a solid, drug-containing dosage form with such a material.
Hydrophilic polymers useful for providing a sustained release
coating or matrix include, by way of example: cellulosic polymers
such as hydroxypropyl cellulose, hydroxyethyl cellulose,
hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose,
cellulose acetate, and carboxymethylcellulose sodium; acrylic acid
polymers and copolymers, preferably formed from acrylic acid,
methacrylic acid, acrylic acid alkyl esters, methacrylic acid alkyl
esters, and the like, e.g. copolymers of acrylic acid, methacrylic
acid, methyl acrylate, ethyl acrylate, methyl methacrylate and/or
ethyl methacrylate; and vinyl polymers and copolymers such as
polyvinyl pyrrolidone e.g., Povidone K30, polyvinyl acetate, and
ethylene-vinyl acetate copolymer. Preferred sustained release
polymers herein include those available as "Methocel" polymers from
Dow Chemical, particularly the methylcellulose ether polymers in
the Methocel.TM. A group, having a viscosity grade of about 4,000
cps and a methoxyl content of about 27.5% to 31.5%, e.g.,
Methocel.TM. A15LV, Methocel.TM. A15C, and Methocel.TM. A4M.
[0049] When sustained release preparations are prepared, tablets,
granules, powder, capsules, and the like can be produced according
to a conventional method after adding excipient, and as necessary,
binder, disintegrating agent, lubricant, coloring agent,
taste-modifying agent, flavoring agent, and the like. These
additives may be ones generally used in the field, and for example,
lactose, sodium chloride, glucose, starch, microcrystalline
cellulose, and silicic acid as the excipient, water, ethanol,
propanol, simple syrup, gelatin solution, hydroxypropyl cellulose,
methyl cellulose, ethyl cellulose, shellac, calcium phosphate, and
polyvinylpyrrolidone as the binder, agar powder, sodium hydrogen
carbonate, sodium lauryl sulfate, and stearic acid monoglyceride as
the disintegrating agent, purified talc, stearic acid salt, borax,
and polyethylene glycol as the lubricant, .beta.-carotene, yellow
iron sesquioxide, and caramel as the coloring agent, and saccharose
and orange peel as the taste-modifying agent can be listed as
examples. It should be noted that various grades of
microcrystalline cellulose are preferred fillers herein, e.g.,
Avicel.RTM. PH101, Avicel.RTM. PH102, and Avicel.RTM. PH200 (FMC),
with particle sizes of about 50 microns, 100 microns, and 190
microns, respectively. Microcrystalline cellulose having a particle
size in the range of about 50 microns to 200 microns is preferred
herein.
[0050] The dosage forms may also be provided with a delayed release
coating, e.g., composed of an acrylate and/or methacrylate
copolymers. Examples of such polymers are those available under the
trade name "Eudragit" from Rohm Pharma (Germany). The Eudragit
series E, L, S, RL, RS, and NE copolymers are available as
solubilized in organic solvent, in an aqueous dispersion, or as a
dry powder. Preferred acrylate polymers are copolymers of
methacrylic acid and methyl methacrylate, such as the Eudragit L
and Eudragit S series polymers. Other preferred Eudragit polymers
are cationic, such as the Eudragit E, RS, and RL series polymers.
Eudragit E100 and E PO are cationic copolymers of
dimethylaminoethyl methacrylate and neutral methacrylates (e.g.,
methyl methacrylate), while Eudragit RS and Eudragit RL polymers
are analogous polymers, composed of neutral methacrylic acid esters
and a small proportion of trimethylammonioethyl methacrylate.
[0051] In a specific embodiment, controlled release topiramate
beads for oral administration, e.g., by incorporation in an orally
administrable capsule or compaction into an orally administrable
tablet, are made using an extrusion spheronization process to
produce a matrix core comprised of: topiramate, 40.0% w/w;
microcrystalline cellulose, e.g., Avicel.RTM. PH102, 56.5% w/w; and
methylcellulose, e.g., Methocel.TM. A15 LV, 3.5% w/w. The
topiramate cores are then coated with ethyl cellulose, 5.47% w/w
and Povidone K30: 2.39% w/w. As will be described in detail infra,
beads of a second active agent, e.g., a sympathomimetic agent, may
also be prepared and incorporated into the capsule. For instance,
phentermine or bupropion beads having an immediate release drug
coating on sugar spheres or analogous non-active cores may be
employed. Both sets of beads may then be encapsulated into one
capsule.
[0052] Preparations according to this invention for parenteral
administration include sterile aqueous and nonaqueous solutions,
suspensions, and emulsions. Injectable aqueous solutions contain
the active agent in water-soluble form. Examples of nonaqueous
solvents or vehicles include fatty oils, such as olive oil and corn
oil, synthetic fatty acid esters, such as ethyl oleate or
triglycerides, low molecular weight alcohols such as propylene
glycol, synthetic hydrophilic polymers such as polyethylene glycol,
liposomes, and the like. Parenteral formulations may also contain
adjuvants such as solubilizers, preservatives, wetting agents,
emulsifiers, dispersants, and stabilizers, and aqueous suspensions
may contain substances that increase the viscosity of the
suspension, such as sodium carboxymethyl cellulose, sorbitol, and
dextran. Injectable formulations are rendered sterile by
incorporation of a sterilizing agent, filtration through a
bacteria-retaining filter, irradiation, or heat. They can also be
manufactured using a sterile injectable medium. The active agent
may also be in dried, e.g., lyophilized, form that may be
rehydrated with a suitable vehicle immediately prior to
administration via injection.
[0053] The active agents may also be administered through the skin
using conventional transdermal drug delivery systems, wherein the
active agent is contained within a laminated structure that serves
as a drug delivery device to be affixed to the skin. In such a
structure, the drug composition is contained in a layer, or
"reservoir," underlying an upper backing layer. The laminated
structure may contain a single reservoir, or it may contain
multiple reservoirs. In one embodiment, the reservoir comprises a
polymeric matrix of a pharmaceutically acceptable contact adhesive
material that serves to affix the system to the skin during drug
delivery. Alternatively, the drug-containing reservoir and skin
contact adhesive are present as separate and distinct layers, with
the adhesive underlying the reservoir which, in this case, may be
either a polymeric matrix as described above, or it may be a liquid
or hydrogel reservoir, or may take some other form. Transdermal
drug delivery systems may in addition contain a skin permeation
enhancer.
[0054] In addition to the formulations described previously, the
active agent may be formulated as a depot preparation for
controlled release of the active agent, preferably sustained
release over an extended time period. These sustained release
dosage forms are generally administered by implantation (e.g.,
subcutaneously or intramuscularly or by intramuscular
injection).
[0055] Although the present compositions will generally be
administered orally, parenterally, transdermally, or via an
implanted depot, other modes of administration are suitable as
well. For example, administration may be transmucosal, e.g., rectal
or vaginal, preferably using a suppository that contains, in
addition to the active agent, excipients such as a suppository wax.
Formulations for nasal or sublingual administration are also
prepared with standard excipients well known in the art. The
pharmaceutical compositions of the invention may also be formulated
for inhalation, e.g., as a solution in saline, as a dry powder, or
as an aerosol.
[0056] In another embodiment, the methods of the invention, i.e.,
the escalating dosage regimen or ongoing maintenance dosing,
involve administration of a combination of topiramate and a
sympathomimetic agent.
[0057] Sympathomimetic agents for use in the present invention and
their general clinical uses or effects are set forth in Table
1.
TABLE-US-00001 TABLE 1 Sympathomimetic Agents and Clinical Uses
Thereof General structure: Main Clinical Uses Ring Receptor .RTM.
Receptor Agent name substituent(s) R.sup..alpha. R.sup..beta.
R.sup..gamma. A N P V B C CNS, 0 Bupropion 3-Cl .dbd.O CH.sub.3
C(CH.sub.3).sub.3 Phenylethylamine H H H Epinephrine 3-OH, 4-OH OH
H CH.sub.3 A, P, V B, C Norepinephrine 3-OH, 4-OH OH H H P Epinine
3-OH, 4-OH H H CH.sub.3 Dopamine 3-OH, 4-OH H H H P Dobutamine
3-OH, 4-OH H H 1* C Nordefrin 3-OH, 4-OH OH CH.sub.3 H V
Ethylnorepinephrine 3-OH, 4-OH OH CH.sub.2CH.sub.3 H B
Isoproterenol 3-OH, 4-OH OH H CH(CH.sub.3).sub.2 B, C Protokylol
3-OH, 4-OH OH H 2* B Isoetharine 3-OH, 4-OH OH CH.sub.2CH.sub.3
CH(CH.sub.3).sub.2 B Metaproterenol 3-OH, 5-OH OH H
CH(CH.sub.3).sub.2 B Terbutaline 3-OH, 5-OH OH H C(CH.sub.3).sub.3
B Metaraminol 3-OH OH CH.sub.3 H P Phenylephrine 3-OH OH H CH.sub.3
N, P Tyramine 4-OH H H H Hydroxyamphetamine 4-OH H CH.sub.3 H N, P
C Methoxyphenamine 2-OCH.sub.3 H CH.sub.3 CH.sub.3 B Methoxamine
2-OCH.sub.3, 5-OCH.sub.3 OH CH.sub.3 H P Albuterol 3-CH.sub.2OH,
4-OH OH H C(CH.sub.3).sub.3 B Amphetamine H CH.sub.3 H CNS, 0
Methamphetamine H CH.sub.3 CH.sub.3 P CNS, 0 Benzphetamine H
CH.sub.3 --NHR.sup..gamma. 0 is replaced with 3* Ephedrine OH
CH.sub.3 CH.sub.3 N, P B, C Phenylpropanolamine OH CH.sub.3 H N
Mephentermine H --CHR.sup..beta.-- CH.sub.3 N, P is replaced with
4* Phentermine H " H 0 Chlorphentermine 4-Cl H " H 0 Fenfluramine
3-CF.sub.3 H CH.sub.3 C.sub.2H.sub.5 0 Propylhexedrine 5*: phenyl
ring H CH.sub.3 CH.sub.3 N is replaced with cyclohexyl
Diethylpropion 6*: The substituent at the 1- 0 position is replaced
with 6, below. Phenmetrazine 7*: The substituent at the 1- 0
position is replaced with 7, below. Phendimetrazine 8*: The
substituent at the 1- 0 position is replaced with 8, below.
##STR00002## ##STR00003## ##STR00004## ##STR00005## ##STR00006##
*6: ##STR00007## Activity .RTM. Activity A = Allergic reactions
(includes .RTM. action) B = Bronchodilator CNS = Central nervous
system N = Nasal decongestion C= Cardiac 0 = Anorectic P= Pressor
(may include .RTM. action) V = Other local vacocontriction (e.g. in
local anesthesia) *Numbers bearing an asterisk refer to the
substituents numbered in the bottom rows of the table; substituent
5 replaces the phenyl rings, and 6, 7 and 8 are attached directly
to the phenyl ring, replacing the ethylamine side chain.
.dagger.The and .RTM. in the prototype formula refer to positions
of the C atoms in the ethylamine side chain.
[0058] In certain embodiments, the sympathomimetic agent is
phentermine or a phentermine-like compound. As defined herein, a
"phentermine-like compound" is a compound structurally related to
phentermine (e.g., an analog or derivative) which maintains an
anorectic activity similar to that of phentermine. One
phentermine-like compound is chlorphentermine. In yet another
embodiment, the sympathomimetic agent is amphetamine or an
amphetamine-like compound. As used herein, an "amphetamine-like
compound" is a compound structurally related to amphetamine (e.g.,
an analog or derivative) which maintains an anorectic effect of
amphetamine. In yet another embodiment, the sympathomimetic agent
is phenmetrazine or a phenmetrazine-like compound. As defined
herein, a "phenmetrazine-like compound" is a compound structurally
related to phenmetrazine (e.g., an analog or derivative) which
maintains an anorectic effect of phenmetrazine. One
phenmetrazine-like compound is phendimetrazine. Analogs and/or
derivatives of the compounds of the present invention can be tested
for their ability to suppress appetite (e.g., suppress food intake)
in a subject (e.g., a mammalian subject).
[0059] In other embodiments, the sympathomimetic agent is bupropion
or a bupropion-like compound. As defined herein, a "bupropion-like
compound" is a compound structurally related to bupropion (e.g., an
analog or derivative) which maintains an anti-depressive activity
similar to that of bupropion.
[0060] In an exemplary embodiment, the sympathomimetic agent is
selected from bupropion, amphetamine, methamphetamine,
benzphetamine, phenylpropanolamine, phentermine, chlorphentermine,
diethylpropion, phenmetrazine, and phendimetrazine (as set forth in
Table 1).
[0061] In one embodiment, the sympathomimetic agent is phentermine.
It is also within the scope of the present invention to utilize
other sympathomimetic agents including pseudoephedrine (a
stereoisomer of ephedrine), methylphenidate, dexmethylphenidate,
tuaminoheptane, and other CNS stimulants including, for example,
caffeine and bupropion.
[0062] The selection of appropriate dosages for the drugs used in
combination therapy according to the present invention can be
determined and optimized by the skilled artisan, e.g., by
observation of the patient, including the patient's overall health,
the response to the combination therapy, and the like. Optimization
may be necessary if it is determined that a patient is not
exhibiting the desired therapeutic effect or, conversely, if the
patient is experiencing undesirable or adverse side effects that
are too many in number or are of troublesome severity.
[0063] Although the dosage used will vary depending on the clinical
goals to be achieved, a suitable daily dose range for the
sympathomimetic agent is generally in the range of 2 mg to 1500 mg,
administered to a patient over an ongoing time period. For example,
2 mg, 4 mg, 10 mg, 20 mg, 30 mg, 60 mg, 90 mg, 120 mg, 150 mg, 180
mg, 210 mg, 240 mg, 270 mg, 300 mg, 330 mg, 360 mg, 390 mg, 420 mg,
450 mg, 480 mg, 500 mg, 600 mg, 800 mg, 1000 mg, 1200 mg, 1500 mg
or the like is administered to a patient as a daily dosage, which
may be a single daily dosage. In another example, 3.75 mg, 7.5 mg,
11.75 mg, 15 mg or the like is administered to a patient as a daily
dosage, which, again, may be a single daily dosage.
[0064] In one embodiment, each component of the combination (e.g.,
(i) topiramate, and (ii) a sympathomimetic drug) is prescribed at a
dose that is below the typically described dose for each component
as a monotherapy. The components may be prescribed separately or as
a combination dosage. In one embodiment, each component of the
combination (e.g., (i) topiramate, and (ii) a sympathomimetic drug)
is prescribed at a dose that is above the typically described dose
for each component as a monotherapy. The components may be
prescribed separately or as a combination dosage.
[0065] In another embodiment, the prescribed dosage of the
sympathomimetic drug is above the typically described dose for
monotherapy, and topiramate is prescribed at a dosage that is at or
below the typically described dose for monotherapy. In another
embodiment, the prescribed dosage of the sympathomimetic drug is at
or below the typically described dose for monotherapy, and
topiramate is prescribed at a dosage that is above the typically
described dose for monotherapy.
[0066] In certain embodiments, when phentermine is the
sympathomimetic agent, phentermine may be, for example,
administered at a daily dosage, e.g., a single daily dosage, in the
range of 2 mg to 60 mg. In one aspect, the phentermine is
administered at a daily dosage, e.g., a single daily dosage, in the
range of 2 mg to 30 mg. In another aspect, the phentermine is
administered at a daily dosage, e.g., a single daily dosage, in the
range of 2 mg to 15 mg.
[0067] In certain embodiments, when bupropion is the
sympathomimetic agent, bupropion may be, for example, administered
at a daily dosage, e.g., a single daily dosage, in the range of 50
mg to 400 mg, more typically in the range of 50 mg to 200 mg.
[0068] The method of administration of pharmaceutical combinations
of the invention will depend, in particular, on the type of
sympathomimetic agent used. Topiramate and the sympathomimetic
agent may be administered together in the same composition or
simultaneously or sequentially in two separate compositions. Also,
one or more sympathomimetic agents may be administered to a subject
or patient either in the form of a therapeutic composition or in
combination, e.g., in the form of one or more separate compositions
administered simultaneously or sequentially. The schedule of
administration will be dependent on the type of sympathomimetic
agent(s) chosen. For example, a sympathomimetic agent can have a
stimulant effect and the degree of the stimulant effect may vary
depending on the sympathomimetic agent chosen. A sympathomimetic
agent having a significant stimulant effect would preferably be
administered earlier in the day than would a sympathomimetic agent
having a lesser stimulant effect. Topiramate, which typically has
at least some sedative effect even at lower doses, may be
administered later in the day than administration of a compound
having a lesser sedative effect.
[0069] In one embodiment, topiramate is administered in a
controlled release form, i.e., in sustained release and/or delayed
release form, preferably both, and phentermine is administered in
an immediate release form. As such, the phentermine may be taken in
the morning because the drug is a stimulant as well as an appetite
suppressant. In this embodiment, topiramate may be taken later in
the day than the phentermine. Preferably, the patient takes the
topiramate just before dinner or later in the evening because the
drug is sedating.
[0070] In yet another embodiment, topiramate is administered in a
controlled release form, i.e., in sustained release and/or delayed
release form, and bupropion is administered in an immediate release
form. As such, the bupropion may be taken in the morning because
the drug is a stimulant as well as an appetite suppressant. In this
embodiment, topiramate may be taken later in the day than the
bupropion. Preferably, the patient takes the topiramate just before
dinner or later in the evening because the drug is sedating.
[0071] As described supra, a controlled release dosage form of the
invention wherein combination therapy is indicated can be a capsule
containing controlled release topiramate beads and immediate
release phentermine beads, bupropion beads, or the like. The
topiramate beads may be made using an extrusion spheronization
process to produce a matrix core comprised of: topiramate, 40.0%
w/w; microcrystalline cellulose, e.g., Avicel.RTM. PH102, 56.5%
w/w; and methylcellulose, e.g., Methocel.TM. A15 LV, 3.5% w/w. The
topiramate cores are then coated with ethyl cellulose, 5.47% w/w
and Povidone K30: 2.39% w/w. The phentermine beads, bupropion
beads, or the like, are composed of an immediate release drug
coating on sugar spheres or analogous non-active cores. Both sets
of beads are then encapsulated into one capsule.
[0072] In certain embodiments, the phentermine beads may be
provided with a controlled release drug coating on sugar spheres or
other non-active cores. In other aspects, the phentermine beads may
be coated onto the controlled release topiramate beads.
[0073] In combination therapy, then, a preferred method of
administration involves simultaneous administration of the two
active agents, in a single composition or in two discrete
compositions each containing one of the active agents. The method
of administration may also involve administration of the two active
agents at different times of day, with the sympathomimetic agent
generally administered earlier in the day and the topiramate
generally administered later in the day. Normally, however, the two
agents are administered simultaneously using one or more dosage
forms that provide for immediate release of the sympathomimetic
agent and controlled release of the topiramate. In an exemplary
embodiment, the sympathomimetic agent and the topiramate are
administered in a single dosage form that provides for immediate
release of the sympathomimetic agent and sustained release and/or
delayed release, preferably both sustained release and delayed
release, of the topiramate. Such dosage forms may be coated cores
or encapsulated beads, as described above, or they may be tablets,
wherein, for example, the tablets contain at least two discrete
segments, at least one of which contains the sympathomimetic agent
such as phentermine or bupropion in immediate release form, and
another of which contains topiramate in controlled release
form.
Indications:
[0074] Conditions of particular interest for which the invention
finds utility include overweight, obesity, and conditions often
associated with and/or caused by excess weight and obesity.
Topiramate compositions and combinations administered according to
the dosage regimens provided herein give rise to significant
therapeutic effects and reduced adverse effects, making these
pharmaceutical compositions extremely effective therapeutics,
especially in the treatment of overweight, obesity, and/or related
conditions, including conditions associated with and/or caused by
excess weight or obesity per se. Subjects suitable for treatment
with the subject combination therapy treatment regimen thus include
individuals suffering from conditions associated with obesity, such
conditions including, without limitation: [0075] diabetes, insulin
resistance, and impaired glucose tolerance; [0076] respiratory
problems such as pulmonary hypertension, asthma, and shortness of
breath; gallbladder disease; [0077] dyslipidemia, e.g., high
cholesterol, high levels of triglycerides, etc.; [0078]
osteoarthritis and other orthopedic problems; [0079] reflux
esophagitis; [0080] adverse conditions related to sleep, including
sleep apnea and loud snoring; [0081] menstrual irregularities,
infertility, and complications in pregnancy; [0082] gout; [0083]
high blood pressure, i.e., hypertension; [0084] cardiovascular
problems such as coronary artery disease and other heart trouble;
muscular dystrophy; [0085] stroke, particularly thrombotic stroke
and deep vein thrombosis (DVT); [0086] migraines; [0087] metabolic
disorders such as hypoalphalipoproteinemia, familial combined
hyperlipidemia, and Syndrome X, including insulin-resistant
Syndrome X; and [0088] colon, rectal, renal, esophageal,
gallbladder, pancreatic, prostate, breast, uterine, ovarian,
endometrial, and cervical cancers.
[0089] Higher body weights are also associated with increases in
all-cause mortality. Most or all of these problems are relieved or
improved by permanent significant weight loss. Longevity is
likewise significantly increased by permanent significant weight
loss.
[0090] Diabetes mellitus is very commonly seen in obese
individuals, and is associated with continuous and pathologically
elevated blood glucose concentration. It is one of the leading
causes of death in the United States and is responsible for about
5% of all mortality. Diabetes is divided into two major
sub-classes: Type I, also known as juvenile diabetes, or
Insulin-Dependent Diabetes Mellitus (IDDM); and Type II, also known
as adult onset diabetes, or Non-Insulin-Dependent Diabetes Mellitus
(NIDDM).
[0091] According to the American Diabetes Association, there are
over one million juvenile diabetics in the United States. Type I
Diabetes is a form of autoimmune disease. Autoantibodies produced
by the patients completely or partially destroy the insulin
producing cells of the pancreas. Juvenile diabetics must,
therefore, receive exogenous insulin during their lifetime. Without
treatment, excessive acidosis, dehydration, kidney damage, and
death may result. Even with treatment, complications such as
blindness, atherosclerosis, and impotence can Occur.
[0092] There are more than five million Type II (adult onset)
diabetics diagnosed in the United States. Type II disease usually
begins during middle age; the principal cause is now known to be
overweight and obesity. In Type II diabetics, rising blood glucose
levels after meals do not properly stimulate insulin production by
the pancreas. Additionally, peripheral tissues are generally
resistant to the effects of insulin. The resulting high blood
glucose levels (hyperglycemia) can cause extensive tissue damage.
Type II diabetics are often referred to as insulin resistant. They
often have higher than normal plasma insulin levels
(hyperinsulinemia) as the body attempts to overcome its insulin
resistance. Some researchers now believe that hyperinsulinemia may
be a causative factor in the development of high blood pressure,
high levels of circulating low density lipoproteins (LDLs), and
lower than normal levels of the beneficial high density
lipoproteins (HDLs). While moderate insulin resistance can be
compensated for in the early stages of Type II diabetes by
increased insulin secretion, in more advanced disease states
insulin secretion is also impaired.
[0093] Insulin resistance and hyperinsulinemia have also been
linked with two other metabolic disorders that pose considerable
health risks: impaired glucose tolerance and metabolic obesity.
Impaired glucose tolerance is characterized by normal glucose
levels before eating, with a tendency toward elevated levels
(hyperglycemia) following a meal. According to the World Health
Organization, approximately 11% of the U.S. population between the
ages of 20 and 74 are estimated to have impaired glucose tolerance.
These individuals are considered to be at higher risk for diabetes
and coronary artery disease.
[0094] Obesity may also be associated with insulin resistance. A
causal linkage among obesity, impaired glucose tolerance, and Type
II diabetes has been proposed, but a physiological basis has not
yet been established. Some researchers believe that impaired
glucose tolerance and diabetes are clinically observed and
diagnosed only later in the disease process after a person has
developed insulin resistance and hyperinsulinemia.
[0095] Insulin resistance is frequently associated with
hypertension, coronary artery disease (arteriosclerosis), and
lactic acidosis, as well as related disease states. The fundamental
relationship between these disease states, and a method of
treatment, has not been established.
[0096] Hypertension is another condition that is frequently seen in
obese individuals, and occurs when the blood pressure inside the
large arteries is chronically elevated. Hypertension affects about
50 million people in the United States alone. It is more common as
people grow older and is both more common and more serious in
African Americans. Most cases of hypertension are of unknown
etiology. It is known that the tendency to develop hypertension can
be inherited. Environment also plays a very important role in
hypertension. For example, hypertension may be avoided by keeping
body weight under control, keeping physically fit, eating a healthy
diet, limiting alcohol intake, and avoiding medications that might
increase blood pressure. Other less common causes of hypertension
include disorders of the kidneys or endocrine glands. Hypertension
has been called "the silent killer" because it has no specific
symptoms and yet can lead to death. People with untreated
hypertension are much more likely to die from or be disabled by
cardiovascular complications such as strokes, heart attacks, heart
failure, heart rhythm irregularities, and kidney failure, than
people who have normal blood pressure.
[0097] Current treatments for hypertension include lifestyle
changes (diet, exercise, nonsmoking, etc.) as well as drug therapy.
The major classes of medications currently used to treat
hypertension include adrenergic neuron antagonists (which are
peripherally acting), alpha adrenergic agonists (which are
centrally acting), alpha adrenergic blockers, alpha and beta
blockers, angiotensin II receptor blockers, angiotensin converting
enzyme (ACE) inhibitors, beta adrenergic blockers, calcium channel
blockers, thiazides (benzothiadiazine derivatives) and related
diuretics, and vasodilators (which act by direct relaxation of
vascular smooth muscles).
[0098] A particularly serious hypertensive disorder is primary
pulmonary hypertension, also known as idiopathic pulmonary
hypertension. This is a condition in which the blood pressure in
the pulmonary arteries is abnormally high in the absence of other
diseases of the heart or lungs. The cause of primary pulmonary
hypertension is unknown. Pulmonary hypertension develops in
response to increased resistance to blood flow. Narrowing of the
pulmonary arterioles occurs and the right side of the heart becomes
enlarged due to the increased work of pumping blood against the
resistance. Eventually, progressive heart failure develops.
Currently, there is no known cure for primary pulmonary
hypertension. Treatment is primarily directed towards controlling
the symptoms, although some success has occurred with the use of
vasodilators. Other medications used to treat the symptoms of
primary pulmonary hypertension include diuretics and calcium
channel blockers. Typically, as the disease progresses, oxygen is
often required. In certain cases, a heart-lung transplant may be
indicated for certain suitable candidates, although the
availability of donor organs continues to be extremely limited.
Unfortunately, primary pulmonary hypertension is a progressive
disease, usually leading to congestive heart failure and
respiratory failure.
[0099] Secondary pulmonary hypertension is a serious disorder that
arises as a complication of other conditions such as, for example,
scleroderma. Treatments are similar as those for primary pulmonary
hypertension and, unfortunately, the prognosis is the same as
well.
[0100] Other respiratory disorders that are frequently seen in
obese individuals include asthma and shortness of breath, both of
which conditions are often alleviated by weight loss.
[0101] With respect to adverse conditions and disorders associated
with sleep, sleep apnea is perhaps the most concerning. Sleep apnea
is classified as either obstructive sleep apnea, the more common
form that occurs when throat muscles relax, or central sleep apnea,
which occurs when the brain doesn't send proper signals to the
muscles that control breathing. Additionally, some people have
mixed sleep apnea, which is a combination of both obstructive and
central sleep apneas. Sleep apnea literally means "cessation of
breath." It is characterized by repetitive episodes of upper airway
obstruction that occur during sleep, usually associated with a
reduction in blood oxygen saturation. In other words, the airway
becomes obstructed at several possible sites. The upper airway can
be obstructed by excess tissue in the airway, large tonsils, and a
large tongue and usually includes the airway muscles relaxing and
collapsing when asleep. Another site of obstruction can be the
nasal passages. Sometimes the structure of the jaw and airway can
be a factor in sleep apnea.
[0102] The signs and symptoms of obstructive and central sleep
apneas overlap, sometimes making the type of sleep apnea more
difficult to determine. The most common signs and symptoms of
obstructive and central sleep apneas include: excessive daytime
sleepiness (hypersomnia); loud snoring; observed episodes of
breathing cessation during sleep; abrupt awakenings accompanied by
shortness of breath; awakening with a dry mouth or sore throat;
morning headache; and/or difficulty staying asleep (insomnia).
Disruptive snoring may be a more prominent characteristic of
obstructive sleep apnea, while awakening with shortness of breath
may be more common with central sleep apnea.
[0103] Sleep apnea is a progressive condition and can be very
serious; it is a potentially life-threatening condition that
requires immediate medical attention. The risks of undiagnosed
obstructive sleep apnea include heart attacks, strokes, high blood
pressure, heart disease, irregular heartbeat, and impotence. In
addition, obstructive sleep apnea causes daytime sleepiness that
can result in accidents, lost productivity and interpersonal
relationship problems. The severity of the symptoms may be mild,
moderate, or severe.
[0104] Sleep apnea is diagnosed utilizing a sleep test, called
polysomnography but treatment methodologies differ depending on the
severity of the disorder. Mild Sleep Apnea is usually treated by
some behavioral changes; losing weight and sleeping on one's side
are often recommended. There are oral mouth devices (that help keep
the airway open) that may help to reduce snoring in three different
ways. Some devices (1) bring the jaw forward or (2) elevate the
soft palate or (3) retain the tongue (from falling back in the
airway and blocking breathing).
[0105] Moderate to severe sleep apnea is usually treated with a
continuous positive airway pressure (C-PAP). C-PAP is a machine
that blows air into your nose via a nose mask, keeping the airway
open and unobstructed. For more severe apnea, there is a Bi-level
(Bi-PAP) machine. The Bi-level machine is different in that it
blows air at two different pressures. When a person inhales, the
pressure is higher and in exhaling, the pressure is lower.
[0106] Some people have facial deformities that may cause the sleep
apnea. It simply may be that their jaw is smaller than it should be
or they could have a smaller opening at the back of the throat.
Some people have enlarged tonsils, a large tongue, or some other
tissues partially blocking the airway. Fixing a deviated septum may
help to open the nasal passages. Removing the tonsils and adenoids
or polyps may help also. Children are much more likely to have
their tonsils and adenoids removed. Surgical procedures, such as
tracheostomy, uvulopalatopharyngoplasty (UPPP), laser assisted
uvuloplasty (LAUP), somnoplasty, and mandibular myotomy are often
required to effectively treat sleep apnea. Weight loss, however,
particularly in an obese person, can significantly alleviate sleep
apnea and other sleep-related adverse conditions such as loud
snoring and the like.
[0107] Relatively recently, a connection between obesity and the
occurrence or increased incidence of migraine headaches has been
noted. Migraine headaches begin with mild pain, which increases in
intensity over a short period of time. There are two major types of
migraines. The common migraine affects 80-85% of migraine sufferers
and classical migraine with aura affects 15% of migraine sufferers.
Symptoms associated with migraines include headaches, psychological
symptomology such as irritability, depression, fatigue, drowsiness,
restlessness; neurological symptoms such as photophobia,
phonophobia or gastrointestinal symptoms such as change in bowel
habit, change of food intake or urinary symptoms such as urinary
frequency, auras which are neurological deficits and can be a
variety of deficits for the migraine population but in the
individual is usually stereotyped. These deficits may be visual
scotoma or visual designs, hemiplegia, migrating paraesthesia,
dysarthria, dysphasia, or deja vu. The headache is usually
accompanied by light or sound sensitivity, photophobia or
phonophobia, irritability and impaired concentration. For those
individuals whose migraine headaches are caused by or exacerbated
by obesity, treatment according to the methodology of the present
invention can be effective.
[0108] Other indications for which the present invention is readily
adapted include epilepsy and certain psychiatric indications such
as impulse control disorders.
[0109] Topiramate has long been known as an anti-epileptic agent.
At dosages previously required or believed to be required for
efficacy, however, topiramate therapy resulted in significant side
effects, as noted elsewhere herein. The present invention,
according to which topiramate dosage may be reduced by concomitant
administration of phentermine, significantly reduces those side
effects of topiramate, most if not all of which are
dose-related.
[0110] Among psychiatric indications, depression is particularly
common. "Depression," as is well known, is manifested by a
combination of symptoms that interfere with the ability to work,
study, sleep, eat, and enjoy once pleasurable activities.
Depression includes major depression, especially refractory
depression, bipolar depression, and the degeneration associated
with depression. Symptoms of depression include persistent sad,
anxious, or "empty" mood, feelings of hopelessness, pessimism,
feelings of guilt, worthlessness, helplessness, loss of interest or
pleasure in hobbies and activities that were once enjoyed,
including sex, decreased energy, fatigue, being "slowed down",
difficulty concentrating, remembering, making decisions, insomnia,
early-morning awakening, or oversleeping, appetite and/or weight
loss or overeating and weight gain, thoughts of death or suicide;
suicide attempts, restlessness, irritability, persistent physical
symptoms that do not respond to treatment, such as headaches,
digestive disorders, and chronic pain.
[0111] Other psychiatric disorders may also be treated using the
compositions and methods of the invention. These disorders include
impulse control disorders, panic syndrome, general anxiety
disorder, phobic syndromes of all types, mania, manic depressive
illness, hypomania, unipolar depression, stress disorders, PTSD,
somatoform disorders, personality disorders, psychosis, and
schizophrenia.
[0112] "Impulse Control Disorders" are characterized by harmful
behaviors performed in response to irresistible impulses. The
essential feature of an impulse control disorder is the failure to
resist an impulse, drive, or temptation to perform an act that is
harmful to the person or to others. Symptoms include an increasing
sense of tension or arousal before committing an act, and then
experiences pleasure, gratification, or release at the time of
committing the act. After the act is performed, there may or may
not be regret or guilt. Numerous disorders can be characterized as
impulse control disorders including intermittent explosive
disorder, kleptomania, pathological gambling, pyromania,
trichotillomania, compulsive buying or shopping, repetitive
self-mutilation, nonparaphilic sexual addictions, severe nail
biting, compulsive skin picking, personality disorders with
impulsive features, attention deficit/hyperactivity disorder,
eating disorders characterized by binge eating, and substance abuse
disorders such as alcoholism and drug addiction. Binge eating
disorder and bulimia are also sometimes classified as impulse
control disorders.
Packaged Pharmaceutical Preparations:
[0113] Also provided are packaged pharmaceutical preparations for
practicing the subject methods. The packaged preparation contains a
composition of the invention in a sealed container, and typically
contains a plurality of individual dosage forms each in a sealed
housing, as in a blister pack, but could also contain one or more
dosage forms in a single sealed container. Optionally, dosage forms
with lower doses of one or both active agents can also be included,
for dose titration and dose escalation.
[0114] In certain embodiments, the packaged pharmaceutical
preparations include instructions for a patient to carry out drug
administration to achieve weight loss, treat obesity, treat
conditions associated with obesity, or treat other conditions as
explained earlier herein. For instance, the instructions may
include the daily dose of topiramate to be taken, the daily dose of
phentermine or other sympathomimetic agent to be taken, and/or the
dosing regimen for self-administration of a controlled release
dosage form containing topiramate and optionally the second active
agent. The instructions may be recorded on a suitable recording
medium or printed on a substrate such as paper or plastic. As such,
the instructions may be present as a package insert, in the
labeling of the package, container(s), or components thereof (i.e.,
associated with the packaging or sub-packaging), etc. In other
embodiments, the instructions are present as an electronic storage
data file present on a suitable computer readable storage medium,
e.g. CD-ROM, diskette, etc. In yet other embodiments, the actual
instructions are not present, but means for obtaining the
instructions from a remote source, e.g. via the internet, are
provided. As an example, a web address might be included to direct
patients to a website where the instructions can be viewed and/or
from which the instructions can be downloaded. As with the
instructions per se, this means for obtaining the instructions is
recorded on a suitable substrate.
[0115] Some or all of the included components may be packaged in
suitable packaging to maintain sterility. In many embodiments, the
components are packaged in a containment element to provide a
single, easily handled unit, where the containment element, e.g.,
box or analogous structure, may or may not be an airtight
container, e.g., to further preserve the sterility of some or all
of the components. In certain aspects, a sealed package of
controlled release dosage forms is provided wherein the dosage
forms contain phentermine in immediate release form and topiramate
in controlled release, e.g., sustained release and delayed release
form. Alternatively, separate phentermine-containing and
topiramate-containing dosage forms may be included.
EXAMPLES
[0116] The following examples are put forth so as to provide those
of ordinary skill in the art with a complete disclosure and
description of how to make and use the present invention, and are
not intended to limit the scope of what the inventors regard as
their invention nor are they intended to represent that the
experiments below are all or the only experiments performed.
Efforts have been made to ensure accuracy with respect to numbers
used (e.g. amounts, temperature, etc.) but some experimental errors
and deviations should be accounted for. Unless indicated otherwise,
parts are parts by weight, molecular weight is weight average
molecular weight, temperature is in degrees Celsius, and pressure
is at or near atmospheric.
Example 1
[0117] Controlled release topiramate beads are made using an
extrusion spheronization process to produce a matrix core comprised
of topiramate, 40.0% w/w; microcrystalline cellulose (Avicel.RTM.
PH102), 56.5% w/w; and Methocel.TM. A15 LV, 3.5% w/w. The
topiramate cores were then coated with ethyl cellulose, 5.47% w/w,
and Povidone K30, 2.39% w/w.
[0118] The composition of the topiramate beads so prepared is as
follows:
TABLE-US-00002 Component % w/w topiramate 36.85 microcrystalline
cellulose, 52.05 (Avicel .RTM. PH102) Methylcellulose 3.22
(Methocel .TM. A15 LV) ethylcellulose 5.47 Polyvinylpyrrolidone
2.39 (Povidone K30)
[0119] Phentermine hydrochloride was coated onto sugar spheres to
provide immediate release phentermine beads. Both sets of beads
were then encapsulated into each of a plurality of capsules.
Example 2
[0120] In a study comparing controlled-release formulation of
topiramate according to the present invention versus immediate
release topiramate (Topamax.RTM.) in combination with phentermine,
the controlled release formulation of the instant invention of
topiramate had a 10-15% lower effect on phentermine exposure (FIG.
2).
[0121] The mean and statistical comparisons for plasma phentermine
PK parameters at steady state in multiple dose administrations are
summarized in Table 2.
TABLE-US-00003 TABLE 2 Arithmetic Mean (SD) and Statistical
Comparison of Pharmacokinetic Parameters for Plasma Phentermine
Treatment 2 Versus Treatment 4 Pharmaco- Mean +/- SD 90% Con- %
kinetic Treatment 2 Treatment 4 fidence Mean Parameters (N = 13) (N
= 12) Intervals Ratio AUC.sub.0-tau 2250 +/- 563 2530 +/- 644
(75.6, 105.3) 89.2 (ng*hr/mL) AUC.sub.0-96 4640 +/- 1570 5550 +/-
1960 (67.1, 105.0) 84.0 (ng*hr/mL) AUC.sub.0-t 4640 +/- 1570 5550
+/- 1960 (67.1, 105.0) 84.0 (ng*hr/mL) C.sub.max, ss 114 +/- 23.6
127 +/- 27.6 (78.8, 104.5) 90.7 (ng*hr/mL) C.sub.min, ss 9.84 +/-
7.24 14.6 +/- 11.3 (42.5, 109.0) 68.1 (ng*hr/mL) t.sub.max (hr)
4.01 (1.04, 7.00) 4.54 (1.00, 10.0) T.sub.1/2 (hr) 23.3 +/- 6.17
26.3 +/- 7.43 CL.sub.ss/F 7.10 +/- 1.89 6.38 +/- 2.00 (L/hr)
V.sub.2/F (L/hr) 229 +/- 45.3 232 +/- 58.5 t.sub.max is presented
as median (minimum, maximum) Parameters were dose-normalized and
In-transformed prior to analysis. % Mean Ratio = 100* ex[(Treatment
2 - Treatment 4) for In-transformed parameters Treatment 1 (Test):
7.5 mg phentermine/50 mg topiramate (Formulation A) Treatment 2
(Test): 15 mg phentermine/100 mg topiramate (Formulation A)
Treatment 4 (Reference): 15 mg phentermine/100 mg topiramate
Source: Tables 14.2.1.8, 14.2.1.10, 14.2.1.12, and 14.2.1.17
[0122] These data indicate a lower maximum and extent of
phentermine exposure between tests versus reference treatments
after multiple-dose administration. As such, the controlled release
formulation of topiramate reduced drug interaction with phentermine
which in turn will reduce further side effects associated with
phentermine.
* * * * *