Title: Methods and compositions for treating generalized anxiety disorder
United States Patent: 6,358,944
Inventors: Lederman; Seth (New York, NY); Iglehart, III; Iredell W. (Baltimore, MD)Assignee: Vela Pharmaceuticals, Inc. (Lawrenceville, NJ)
Appl. No.: 638058Filed: August 11, 2000
The present invention relates to methods and compositions comprising a very low dose of cyclobenzaprine or metabolite thereof for preventing and treating Generalized Anxiety Disorder. The present invention further relates to methods and compositions for treating and preventing symptoms associated with Generalized Anxiety Disorder using a very low dose of cyclobenzaprine.
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, the terms "cyclobenzaprine or metabolite
thereof" or "cyclobenzaprine or a metabolite thereof"
includes cyclobenzaprine or a metabolite thereof, prodrugs of
cyclobenzaprine or a metabolite thereof, or a pharmaceutically acceptable
salt, hydrate, or solvate of cyclobenzaprine or a metabolite thereof.
A "very low dose" of cyclobenzaprine or metabolite thereof
according to this invention is an amount of cyclobenzaprine or metabolite
thereof that is less than 5 mgs.
Metabolites of cyclobenzaprine useful according to the methods of this
invention are metabolites that have substantially the same activity or
better as cyclobenzaprine in alleviating GAD or one of more of the
symptoms of his/her illness. Cyclobenzaprine metabolites that may be
useful according to this invention include CBP 10,11-trans-dihydriol,
N-desmethyl-2-hydroxycyclobenzaprine, 3-hydroxycyclobenzaprine, N-desmethylcyclobezaprine
cyclobenzaprine N-oxide or a chiral isomer of these metabolites.
Pharmaceutical salts of cyclobenzaprine useful according to the methods of
this invention are salts prepared from pharmaceutically acceptable
non-toxic acids including inorganic acids and organic acids. In one
preferred embodiment, the salt is a hydrochloride salt.
A prodrug of cyclobenzaprine is a derivative of cyclobenzaprine that is
metabolized in vivo into the active agent. Prodrugs useful according to
this invention are those that have substantially the same activity or
better than cyclobenzaprine in treating or preventing GAD or one or more
of the symptoms of this disorder. Methods for making prodrugs are readily
known in the art (e.g., Balant, L. P., "Prodrugs for the Improvement
of Drug Absorption Via Different Routes of Administration," Eur. J.
Drug Metab. Pharmacokinet. 15:143-153 (1990); and Bundgaard, H.,
"Novel Chemical Approaches in Prodrug Design," Drugs of the
Future 16:443-458 (1991); incorporated by reference herein).
A composition according the present invention comprises less than 5 mg of
cyclobenzaprine, a metabolite thereof or a pharmaceutically acceptable
salt of cyclobenzaprine or the metabolite, as a single unit, or as a unit
that is pre-prepared into separable portions, each portion of which
comprises a very low dose of cyclobenzaprine or the metabolite. In one
embodiment, the composition or each portion of the separable composition
comprises less than or equal to 2.5 mgs of cyclobenzaprine or the
metabolite. In another embodiment, the composition or each portion of the
separable composition comprises less than or equal to 1 mg of
cyclobenzaprine or the metabolite. For example, a separable composition is
a scored tablet.
A composition according the present invention may also comprise one or
more other therapeutic agents selected from the group consisting of
barbiturates, benzodiazipines, antihistamines, tricyclic antidepressants (TCAs),
serotonin reuptake inhibitors (SSRIs), atypical antidepressants,
antipsychotics and beta-blockers.
A human to be treated for Generalized Anxiety Disorder (GAD) according to
this invention will meet the diagnosis criteria and characteristics
described in DSM-IV (1994, supra, incorporated by reference herein). The
essential feature of GAD is excessive anxiety or worry (apprehensive
expectation), occurring more days than not for a period of at least 6
months, about a plurality of events or activities. The diagnostic criteria
for GAD comprises the following:
A. Excessive anxiety and worry, occurring more days than not for at least
6 months, about a plurality of events or activities (such as work or
school performance);
B. the patient finds it difficult to control the worry;
C. the anxiety and worry are associated with three (or more) of the
following six symptoms (with at least some symptoms present for more days
than not for the past 6 months) selected from the group consisting of:
(1) restlessness or feeling keyed up or on edge;
(2) being easily fatigued;
(3) difficulty concentrating or mind going blank;
(4) irritability;
(5) muscle tension; and
(6) sleep disturbance (difficulty falling or staying asleep, or restless
unsatisfying sleep).
D. The focus of anxiety is not confined to features of an Axis I disorder
(as described in the DSM-IV.TM.);
E. The anxiety, worry, or physical symptoms cause clinically significant
distress or impairment in social, occupational, or other important areas
of functioning; and
F. The disturbance is not due to the direct physiological effects of a
substance or a general medical condition and does not occur exclusively
during a Mood Disorder, a Psychotic Disorder, or a Pervasive Development
Disorder.
The human suffering from GAD according to this invention (i.e., the
patient) includes a child. The GAD may be accompanied or exacerbated by
another illness or disorder (secondary GAD). In one embodiment of this
invention, the GAD in the human to be treated is accerbated by the
inability to exercise during waking hours due to injury or other
extenuating circumstances, such as lack of time or venues for exercise.
Symptoms of GAD include anxiety (feelings of apprehension, foreboding, or
dread) or worry that is difficult to control, general emotional upset as
well as nonspecific physical symptoms like shortness of breath, stress,
gastrointestinal upset, palpitations, fatigue, muscle aches, tension,
sweating, light-headedness, hot or cold flashes, numbness and tingling,
feelings of unreality, or insomnia.
In a preferred embodiment, the patient will experience a reduction in
anxiety and/or non-specific physical symptoms selected from the group
consisting of shortness of breath, stress, gastrointestinal upset,
palpitations, fatigue, muscle tension, muscle aches and insomnia.
Barbiturates according to this invention include phenobarbital,
amobarbital, probarbital, butabarbital, mephobarbital, pentobarbital,
secobarbital, and talbutal.
Benzodiazepines according to this invention according to this invention
include chlordiazepoxide, clorazepate, diazepam, flurazepam, halazepam,
prazepam, alprazolam, chlonazepam, flunitrazepam, lorazepam, midazolam,
oxazepam, quazepam, temazepam, triazolam, estazolam, and troazolam.
Antihistamines according to this invention include diphenhydramine
hydrochloride, carbinoxamine maleate, clemastine fumarate, tripelennamine
citrate, tripelennamine hydrochloride, pyrilamine maleate,
chlorpheniramine maleate, brompheniramine maleate, dexchlorpheniramine
maleate, tripolidine hydrochloride, methdilazine, methdilazine
hydrochloride, promethazine hydrochloride, trimeprazine tartrate,
azatadine maleate, cyproheptadine hydrochloride, diphenylpyraline
hydrochloride, hyrdoxyzine hydrochloride, hydroxyzine pamoate,
phenindamine tartrate, terfenadine, astemizole, and acrivastine.
TCAs according to this invention may be selected from the group consisting
of imipramine, trimipramine, nortriptyline, amitriptyline (Elavil.TM.),
doxepin, protriptyline, clomipramine, amoxapine, or desipramine. In a
preferred embodiment, the TCA is nefazodone (Serzone.TM.).
SSRIs according to this invention may be selected from the group
consisting of fluoxetine (Prozac.TM.), fluvoxamine maleate (Luvox.TM.),
paroxetine (Paxil.TM., Seroxar.TM., or Aropax.TM.), sertraline (Zoloft.TM.),
acelexa, and citalopram (Celexa.TM.). In a preferred embodiment, the SSRI
is sertraline (Zoloft.TM.)
Atypical antidepressants are antidepressants which are not TCAs or SSRIs,
e.g., serotonin agonist and reuptake inhibitors (SARIs) such as nefazodone
(Serzone.TM.) or trazodone (Desyrel.TM.); Norepinephrine-Dopamine Reuptake
Inhibitors (NDRIs) such as bupropion (Wellbutrin.TM.); norepinephrine
reuptake inhibitors (NRIs) such as reboxetine (Edronax.TM. or Vestra.TM.)
and serotonin-norepinephrine reuptake inhibitors (SNRIs) such as
venlafaxine (Effexor.TM.), amoxapine and maprotiline; and tetracyclic
atypical antidepressants such as mirtazapine (Remeron.TM.).
Antipsychotics according to this invention are fluphenazine, haloperidol,
thiothixene, trifluoperazine, perphenazine, molindone, loxapine,
prochlorperazine, acetophenazine, triflupromazine, mesoridazine,
chlorpromazine, chlorprothixene, mesoridazine, clozapine, pimozide,
risperidone, quetiapine, olanzapine, and thioridazine.
Beta blockers according to this invention are sotalol, timolol, esmolol,
cartelol, propranolol, betaxolol, penbutolol, metaprolol, acebutolol,
atenolol, and bisoprolol.
Said therapeutic agent according to the methods of this invention may be
administered before, during or after the administration of cyclobenzaprine
or metabolite thereof.
According to the methods of this invention, very low dose cyclobenzaprine
or a metabolite thereof, may be administered sequentially or concurrently
with other standard treatments for somatic or psychological illnesses and
disorders.
The period of treatment should be carried out for as long as necessary to
alleviate one or more of the symptoms of the illness being treated, either
in a single, uninterrupted session of visits or in discrete sessions. For
example, if a symptom of GAD is being treated, the treatments will
preferably be carried out such that the patient achieves alleviation or
remission of such symptom. Alternatively, treatments may be carried out
until the patient feels generally relieved of all symptoms of GAD.
Generally, cyclobenzaprine therapy can be carried out indefinitely to
alleviate the symptoms of interest and frequency of dosage may be changed
to be taken as needed. In one embodiment, the patient suffering from GAD
is treated with less than 5 mgs of cyclobenzaprine or a metabolite
thereof/day.
Any suitable route of administration may be employed for providing the
patient with an effective dosage of cyclobenzaprine or metabolite thereof.
For example, oral, rectal, parenteral, transdermal, subcutaneous,
sublingual, intranasal, intramuscular, intrathecal and the like may be
employed as appropriate. The term parenteral as used herein includes
subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular,
intrasynovial, intrasternal, intrathecal, intralesional and intracranial
injection or infusion techniques.
Dosage forms include tablets, scored tablets, coated tablets, caplets,
capsules (e.g. hard gelatin capsules), troches, dragees, dispersions,
suspensions, solutions, patches and the like, including sustained release
formulations well known in the art. In one preferred embodiment, the
dosage form is a scored tablet.
The compositions and separable compositions useful according to this
invention include those suitable for oral, rectal, transdermal,
sublingual, and parenteral administration (including subcutaneous,
intramuscular, intrathecal and intravenous), although the most suitable
route in any given case will depend on the nature and/or severity of the
condition being treated. A preferred route of administration according to
the methods of the present invention is the oral route. The composition
may be conveniently presented in unit dosage form and prepared by any of
the methods well-known in the art of pharmacy.
The compositions or separable compositions of this invention may be orally
administered in any orally acceptable dosage form including, but not
limited to, capsules, tablets, and aqueous suspensions and solutions. In
the case of tablets for oral use, carriers which are commonly used include
lactose and corn starch. Lubricating agents, such as magnesium stearate,
are also typically added. For oral administration in a capsule form,
useful diluents include lactose and dried corn starch. When aqueous
suspensions are administered orally, the active ingredient is combined
with emulsifying and suspending agents. If desired, certain sweetening
and/or flavoring and/or coloring agents may be added.
The compositions according to this invention may be in the form of a
sterile injectable preparation, for example, as a sterile injectable
aqueous or oleaginous suspension. This suspension may be formulated
according to techniques known in the art using suitable dispersing or
wetting agents (such as, for example, Tween 80) and suspending agents. The
sterile injectable preparation may also be a sterile injectable solution
or suspension in a non-toxic parenterally-acceptable diluent or solvent,
for example, as a solution in 1,3-butanediol. Among the acceptable
vehicles and solvents that may be employed are mannitol, water, Ringer's
solution and isotonic sodium chloride solution. In addition, sterile,
fixed oils are conventionally employed as a solvent or suspending medium.
For this purpose, any bland fixed oil may be employed including synthetic
mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride
derivatives are useful in the preparation of injectables, as are natural
pharmaceutically-acceptable oils, such as olive oil or castor oil,
especially in their polyoxyethylated versions. These oil solutions or
suspensions may also contain a long-chain alcohol diluent or dispersant
such as Ph. Helv or a similar alcohol.
Compositions or separable compositions of this invention may also be
administered in the form of suppositories for rectal administration. These
compositions or separable compositions can be prepared by mixing a
compound of this invention with a suitable non-irritating excipient which
is solid at room temperature but liquid at the rectal temperature and
therefore will melt in the rectum to release the active components. Such
materials include, but are not limited to, cocoa butter, beeswax and
polyethylene glycols.
The composition of this invention may be administered by nasal aerosol or
inhalation. Such compositions are prepared according to techniques
well-known in the art of pharmaceutical formulation and may be prepared as
solutions in saline, employing benzyl alcohol or other suitable
preservatives, absorption promoters to enhance bioavailability,
fluorocarbons, and/or other solubilizing or dispersing agents known in the
art.
A typical oral formulation for coated tablets would consist of the
following:
Quantity per Tablet
Formula (mg.)
cyclobenzaprine 1.0
Lactose 74.0
Corn Starch 35.0
Water (per thousand Tablets) 30.0 ml*
Magnesium Stearate 1.0
Corn Starch 25.0
*The water evaporates during manufacture.
The active ingredient (cyclobenzaprine) is blended with the lactose until
a uniform blend is formed. The smaller quantity of corn starch is blended
with a suitable quantity of water to form a corn starch paste. This is
then mixed with said uniform blend until a uniform wet mass is formed. The
remaining corn starch is added to the resulting wet mass and mixed until
uniform granules are obtained. The granules are then screened through a
suitable milling machine, using a 1/4 inch stainless steel screen. The
milled granules are then dried in a suitable drying oven until the desired
moisture content is obtained. The dried granules are then milled through a
suitable milling machine using 1/4 mesh stainless steel screen. The
magnesium stearate is then blended and the resulting mixture is compressed
into tablets of desired shape, thickness, hardness and disintegration.Tablets are coated by standard aqueous or nonaqueous techniques. For example, 2.5 mg of hydroxypropymethylcellulose can be dissolved in 25 mg of deionized water. An aqueous (10 mg) suspension of 1.88 mg talc, 0.5 mg of titanium dioxide, 0.1 mg of yellow iron oxide, and 0.02 mg of red iron oxide is stirred into this solution. The coating suspension is sprayed on the tablets and the coated tablets are dried overnight at 45oC.
Quantification of improvement may be measured according to methods known in the art. For example, standardized instruments such as Zung Anxiety Self Assessment Scale, the Hamilton Anxiety and Depression Scale, the Cori Anxiety Scale, the Irritability-Depression-Anxiety Scale and the Crown-Crisp Experimental Index may be used to measure existence and levels of symptoms. In addition, a clinician or physician may use verbal interviews such as the Hopkins Symptoms Checklist in order to make such assessments. practitioner may reliably assess changes in condition by comparing the treatment results over a time span.
The magnitude of a prophylactic or therapeutic dose of the active ingredient (i.e., cyclobenzaprine or metabolite thereof) in the prevention or treatment of a human will vary with the type of affliction, the severity of the patient's affliction and the route of administration. The dose and dose frequency will also vary according to the age, weight and response of the individual patient. In a preferred embodiment, the dosage will not equal or exceed 5 mgs per day.
The treating physician will know how to increase, decrease or interrupt treatment based upon patient response. Generally, however, treatment or prevention of an illness treated according to the methods of this invention will be timed to coincide with exposure to biochemical or environmental stimuli likely to trigger illness and psychological disorder, and the symptoms thereof, treatable according to this invention or symptoms thereof.
The various terms described above such as "therapeutically effective amount," are encompassed by the above-described dosage amounts and dose frequency schedule.
Throughout this specification and claims, the word "comprise," or variations such as "comprises" or "comprising," will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.
The embodiments of the present invention described above are intended to be merely exemplary and those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures described herein. All such equivalents are considered to be within the scope of the present invention and are covered by the following claims.
The contents of the documents cited herein including U.S. application Ser. No. 60/148,881, are hereby incorporated by reference.
Claim 1 of 21 Claims
We claim:
1. A method for treating or preventing Generalized Anxiety Disorder (GAD)
comprising the step of administering to a human in need thereof, a
composition comprising cyclobenzaprine or a metabolite thereof in an
amount of less than 5 mg/day.
____________________________________________
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