Note: Descriptions are shown in the official language in which they were submitted.
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COMPOSITIONS AND METHODS FOR TREATING RESPIRATORY
DISORDERS
TECHNICAL FIE~,D
The present invention relates to compositions and methods for providing
improved treatment, management or mitigation of cold, cold-like, allergy,
sinus
and/or flu symptoms by administering a safe and effective amount of a
composition
comprising naproxen or a related compound along with cetirizine or a related
compound.
EACKGROUND OF THE INVENTION
The common cold, although not usually a serious illness, is a highly pre-
valent, discomforting and annoying affliction. The term "common cold" is
applied
to minor respiratory illnesses caused by a variety of different respiratory
viruses.
While rhinoviruses are the major known cause of common colds, accounting for
approximately 30 percent of colds in adults, viruses in several other groups
are also
important. While immune responses occur, and infection with some respiratory
tract viruses therefore could be prevented by a vaccine, development of a
polytypic
vaccine to cover all possible agents is impractical. Thus, the problem of
controlling acute upper respiratory disease presents complex challenges, and
the
long-desired discovery of a single cure for the common cold is an unrealistic
expectation.
Early symptoms may be minimal with only mild malaise, sore throat and
nasal complaints. With rhinovirus infection, symptoms of nasal discharge,
nasal
congestion, and sneezing usually commence on the first day of illness and
progress
to maximum severity by the second or third day. Along with nasal symptoms may
come sore, dry or scratchy throat and hoarseness and cough. Other symptoms may
include mild burning of the eyes, loss of smell and taste, a feeling of
pressure or
fullness in the sinuses or ears, headache, and vocal impairment. Fever can
occur,
but is uncommon. Influenza infection generally includes fever, often of sudden
onset and persisting for several days, and with great severity; generalized
aches and
pains; fatigue and weakness; and chest discomfort.
At present, only symptomatic treatment is available for the common cold.
The costs of treating colds with over-the-counter medications in the United
States
is estimated at an annual cost of over 1.5 billion dollars. The direct costs
of
treatment in outpatient clinics is estimated at almost four billion dollars.
Indirect
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- 2
costs, based on the amount of loss in wages because of restricted activity are
sub-
stantially higher.
- Exemplary prior art formulations for treatment of cough, cold, cold-like,
allergy, sinus and/or flu symptoms and the discomfort, pain, fever and general
malaise associated therewith generally contain an analgesic (aspirin or
acetaminophen) and one or more antihistaminics, decongestants, cough sup-
pressants, antitussives and expectorants.
The use of non-steroidal anti-inflammatory drugs to combat inflammation
and attendant pain is accepted medical practice. The non-steroidals are
commonly
employed to relieve pain and inflammation associated with, for example,
bursitis,
arthritis, headache and the like. Among the most commonly used drugs of the
non-narcotic analgesic class of drugs are aspirin, acetaminophen, ibuprofen,
ketoprofen, diclofenac and naproxen and their salts (e.g., lysine, arginine,
sodium
and potassium). Aspirin, acetaminophen and ibuprofen have heretofore been
included as the pain reliever and fever-reducing component in conventional
cough/cold multisymptom alleviating compositions. These commercially marketed
products generally contain in addition to aspirin, acetaminophen or ibuprofen,
one
or more antihistaminics, decongestants, cough-suppressants, antitussives and
expectorants.
The present inventors have found that selected compositions comprising
naproxen along with cetirizine provides improved treatment, management or miti-
gation of cold, cold-like, allergy, sinus and/or flu symptoms, including nasal
congestion.
It is therefore an object of the present invention to pmvide a method for the
treatment of cough, cold, cold-like, allergy, sinus and/or flu symptoms in a
mam-
malian organism in need of such treatment comprising administering to such
organism the compositions of the present invention. Such symptoms as used
herein
refer to coryza, nasal congestion, sinus congestion, sinus pain, upper
respiratory
infections, otitis, sinusitis, etc.
Sl;m~iMARY OF THE INVENTION
The present invention relates to compositions and methods for providing
improved treatment, management or mitigation of cold, cold-like, allergy,
sinus
and/or flu symptoms by administering a safe and effective amount of a
composition
comprising napmxen along with cetirizine.
All percentages and ratios used herein are by weight unless otherwise in-
dicated. Additionally, all measurements are made at 25°C unless
otherwise
specified.
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3
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to compositions and methods for providing
improved treatment, management or mitigation of cold, cold-like, allergy,
sinus
and/or flu symptoms by administering a safe and effective amount of a
composition
consisting essentially of naproxen along with cetirizine. -
'ri ' a
The present invention relates to the use of 2-[4-(diphenyl-methyl)-1-
piperazinyl]-acetic acids and the amides and non-toxic, pharmaceutically
acceptable salts thereof, in compositions also containing napmxen.
Cetirizine and related compounds have the general formula:
x
,o
~- ~N-'E (~zhro"Inr Q-1t- ~
Y
X
wherein
Y is hydroxyl group or an --NH2 group,
X and X' represents independently a hydrogen atom, a halogen atom, a straight
or
branched chain lower alkoxy radical or a trifluoromethyl radical,
m is 1 or 2, and
n is 1 or 2, preferably 2, as well as the non-toxic, pharmaceutically
acceptable salts
thereof. .
The term "lower alkoxy" as used herein means residues of both straight and
branched chain aliphatic alcohols having from 1 to 4 carbon atoms, such as
methoxy, ethoxy, propoxy and the like. The halogen atom is preferably a
chlorine
or fluorine atom. .
The expression "non-toxic, pharmaceutically acceptable salts" are used
herein means not only the addition salts of the acids and amides of formula
with
pharmaceutically acceptable acids, such as acetic, citric, succinic, ascorbic,
hydrochloric, hydrobromic, sulfuric and phosphoric acid, but also the
pharmaceutically acceptable salts of the acids or formula such as the metal
salts
(for example sodium or potassium salts), the ammonium salts, the amine salts
and
the aminoacid salts.
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4
The preferred compounds a~rding to the presets invention are:
2-[2-[4-[(4-chlomphenyl~henylmethyl]-1-Piperarinyl]ethoxy)-acetic acid and its
dihydrochloride;
potassium 2-[2-[4-[(4-chlorophenylYlmethyll-1-PiPerazinYllethoxY]-acetates
2-[2-[4-[(4-diphenylmethyl~ 1-pipa~azinYl]etlwxyJ-acetic acid and its
dihydrochloride;
2-[2-[4-[(4-fluorophe~rl~h~yl]-1-pipa~yl]ethoxy]ac~ic acid and its hydrate.
The cane compounds of formula possess intere~g pharmacological
properties. In particular, they are useful as antiallergic, antihistaminic,
bmnchodilatory
and antispasmodic agents and are used at a level of from about 5 to about 20
mg.
The preferred compounds are 3,4-dihydro-6-fluoro-2-naphthyl-oc-methylacetic
acid, the aklyl esters thereof wherein the alkyl moiety has 1 to 12 carbon
atoms, and the
pharmac~tically acceptable addition salts thereof. Particularly preferred are:
3,4-
dihydro-6-chloro-2-naphthyl-a,-methylacetic acid, the alkyl esters thereof
wherein the
alkyl moiety has 1 to 12 carbon atoms, and the pharmaceutically acceptabie
addition
salts thereof.
These compourxis are described in detail is U.S. Patent 4,525,358, June 25,
1985, incorporated herein by reference in its entirety.
Napmxen and similar compounds are derivatives of 2-naphthylacetic acid, a
compound which can be represented by the formula:
s ~ 1
~ Z~ COOH
6 ~ ~ 3
4
The arabic numerals and the alpha symbols indicate the positions used herein
in
the nomenclature of 2-naphthylacetic acid da~ivatives. This is a general
formula for
naproxen and its related compounds.
These are further described in U.S. Patent 3,896,157, incorporated herein by
reference in its entirety. Napmxen itself is (S~6-Methoxy-2-methyl-2-
napthaleneacetic
acid and preferably the sodium salt.
SUBSTITUTE SHEET tRULE 26)
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Naproxen and its related compounds are generally used in amounts of 50 to
660 mg, preferably from about l00 to 330 mg and more preferably from.about t50
to about 220 mg.
Additional Pharmaceutical Actives -
The compositions of the present invention can also include at least one
other pharmacological active selected from the following class: (a) a
decongestant,
(b) an expectorant (c) an additional antihistamine and (d) an antitussive. The
decongestants useful in the compositions of the present invention include
pseudoephedrine, phenylpropanolamine, phenylephrine and ephedrine, their
pharmaceutically acceptable salts, and mixtures thereof. The antitussives
useful in
the present invention include those such as dextromethorphan, chlophedianol,
car-
betapentane, caramiphen, noscapine, diphenhydramine, codeine, hydrocodone,
hydromorphone, fominoben, their pharmaceutically-acceptable salts, and
mixtures
thereof. The additional antihistamines useful in the present invention include
those such as chlorpheniramine, brompheniramine, dexchlorpheniramine,
dexbromphreniramine, triprolidine, azatadine, doxylamine, tripelennamine,
cypro-
heptadine, hydroxyzine, carbinoxamine, phenindamine, bromodiphenhydramine,
pyrilamine, their pharmaceutically acceptable salts, as well as the non-
sedating
antihistamines which include acrivastine, AHR-11325, astemizole, azatadine,
azelastine, ebastine, ketotifen, lodoxamide, loratidine, levocabastine,
mequitazine,
oxatomide, setastine, tazifylline, and temelastine, their pharmaceutically
acceptable salts and mixtures thereof. The expectorants (also known as
mucolytic
agents) useful in the present invention include glyceryl guaiacolate, tenpin
hydrate,
ammonium chloride, N-acetylcysteine and bromhexine, ambroxol, their
pharmaceutically acceptable salts, and mixtures thereof. AlI of these
components,
as well as their acceptable dosage ranges are described in the following: U.S.
Patent 4,783,465 to Sunshine et al., issued November 8, 1988, U.S. Patent
4,619,934 to Sunshine et al., issued October 28, 1986, which are incorporated
by
reference herein.
Additional agents which are found useful in the present compositions are a-
agonists such as those disclosed in U.S. Patent 5,478,858, issued December 26,
1995, incorporated herein by reference in its entirety.
Various oral dosage forms can be used, including such solid forms as tab-
lets, caplets, capsules, granules, lozenges and bulk powders and liquid forms
such
as syrups and suspensions. Controlled release dosage forms which pmvide a
controlled release of these actives) are also useful. These oral forms
comprise a
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safe and eff~tive amount, usually at least about 5% of the active components.
Solid oral dosage forms preferably contain from about 5% to about 95%, more
preferably from about 10% to about 95%, and most preferably from about 25% to
about 95% of the active components. Liquid oral dosage forms preferably
contain
from about 1% to about 50% and more preferably from about 1% to about 25% and
most preferably from about 3% to about 10% of the active components.
Tablets can be compressed, triturated, enteric-coated, sugar-coated,
film-coati or multiple compressed, containing suitable binders, lubricants,
dilu-
ents, disintegrating agents, coloring agents, flavoring agents, preservatives
and
flowinducing agents. Also useful are soft gelatin capsules.
Liquid oral dosage forms include aqueous and nonaqueous solutions, emul-
sions, pseudo emulsions, suspensions, and solutions and/or suspensions recons-
tituted from non-effervescent granules, containing suitable solvents,
preservatives,
emulsifying agents, suspending agents, diluents, sweeteners, taste-masking
agents,
coloring agents, and flavoring agents. Specific examples of pharmaceutically
ac-
ceptable carriers and excipients that may be used to formulate oral dosage
forms,
are described in U.S. Patent 3,903,297, Robert, issued September 2, 1975,
incorpo-
rated by reference herein. Techniques and compositions for making solid oral
dosage forms are described in Marshall, "Solid Oral Dosage Forms," Modern ~r-
maceutics. Vol. 7.7. (Banker and Rhodes, editors), 359-427 (1979),
incorporated by
reference herein. Techniques and compositions for making tablets {compressed
and molded), capsulcs (hard and soft gelatin) and pills are described in Remin
on's
Pharmaceutical i ces (Arthur Osol, editor), 1553-1593 (1980), incorporated
herein by reference.
An additional agent found useful in the present compositions is caffeine.
Caffeine has been found to lessen the minor sedating effect of the cetirizine.
The
level of caffeine use is generally from about 20 mg to about 500 mg,
preferably
from about 50 mg to about 200 mg, most preferably from about 65 mg to about
100
mg.
In preparing the liquid oral dosage forms, the active component is incor-
porated into an aqueous-based orally acceptable pharmaceutical carrier
consistent
with conventional pharmaceutical practices. An "aqueous-based orally
acceptable
pharmaceutical carrier" is one wherein the entire or predominant solvent
content is
water. Typical carriers include simple aqueous solutions, syrups, dispersions
and
suspensions, and aqueous based emulsions such as the oil-in-water type. The
most
preferred carrier is a suspension of the pharmaceutical composition in an
aqueous
vehicle containing a suitable suspending agent. Suitable suspending agents
include
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7
Avicel RC-591 (a microcrystalline-cellulose/sodium carboxymethyl cellulose mix-
ture available from FMC), guar gum and the like. Such suspending agents are
well
known to those skilled in the art. While the amount of water in the
compositions of
this invention can vary over quite a wide range depending upon the total
weight
and volume of the active component and other optional non-active ingredients,
the
total water content, based on the weight of the final composition, will
generally
range from about 20 to about 75%, and, preferably, from about 20 to about 40%,
by
weight/volume.
Although water itself may make up the entire carrier, typical liquid formu-
lations preferably contain a co-solvent, for example, propylene glycol,
glycerin,
sorbitol solution and the like, to assist solubilization and incorporation of
water-insoluble ingredients, such as flavoring oils and the like into the
composi-
tion. In general, therefore, the compositions of this invention preferably
contain
from about 5 to about 25 volume/volume percent and, most preferably, from
about
to about 25 volume) volume percent, of the co-solvent.
Other optional ingredients well known to the pharmacist's art may also be
included in amounts generally known for these ingredients, for example,
natural or
artificial sweeteners, flavoring agents, colorants and the Iike to provide a
palatable
and pleasant looking final product, antioxidants, for example, butylated
hydroxy
anisole or butylated hydroxy toluene, and preservatives, for example, methyl
or
propyl paraben or sodium benzoate, to prolong and enhance shelf life. A highly
preferred optional component is caffeine.
METHOD OF TREATMENT
The amount of the pharmaceutical composition administered dcpends upon
the percent of active ingredients within its formula, which is a function of
the
amount of cetirizine and naproxen and any optional components such as a de
congestant, cough suppressant, expectorant, caffeine and/or additional
antihistamine required per dose, stability, release characteristics and other
pharmaceutical parameters.
Usually from about 1 mg/kg to about 50 mg/kg per day, preferably from
about 2 mg/kg to about 30 mg/kg per day and most preferably from about 3 mg/kg
per day to about 20 mg/kg per day of the pharmaceutical composition is adminis-
tered as described herein. This amount can be given in a single dose, or,
preferably, in multiple (two to six) doses repeatedly or sustained release
dosages
over the course of treatment. Generally, each individual dosage of the pharma-
ceutical compositions of the present invention range from about 1 mg/kg to
about
25 mg/kg, preferably from about 2 mg/kg to about 15 mg/kg and most preferably
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from about 3 mg/kg to about 10 mg/kg. While dosages higher than the foregoing
are effective to provide relief from cough, cold-like, flu, flu-like and
allergic
rhinitis symptoms, care must be taken, as with any drug, in some individuals
to
prevent adverse side effects.
The following examples illustrate embodiments of the subject invention
wherein both essential and optional ingredients are combined.
EX~ LE I
A hard gelatin capsule composition for oral administration is prepared by
combining the following ingredients:
In i t Amount
Naproxen Sodium 220 - 440 mg:
Pseudoephedrine HCI 60 mg. (120 mg. sustained released)
Cetirizine * 5 mg.
Triturate active ingredients and q.s. with lactose to selected capsule size.
* Cetirizine is [2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]-
ethoxy]acetic acid.
Administration of one or two the above capsules every four to twelve hours
to a human in need of treatment provides improved relief from cough, cold-
like,
flu, flu-like and allergic rhinitis symptoms.
EXAM~'LE I~
A hard compressed caplet composition for oral administration is prepared
by combining the following ingredients:
ount
Naproxen Sodium 220 or 440 mg.
Cetirizine 5 mg.
Pregelatinized starch 20.0
mg.
Corn starch 80.0
mg.
Croscarmellose sodium 10.0
mg.
Silicone dioxide, colloidal1.5 mg.
Stearic acid, TP fine powder2.0 mg
Sodium lauryl sulfate 0.5 mg
Opadry clear / Colorcon 5.0 mg.
(containing
Hydroxypropylmethyl cellulose)
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Administration of two caplets every twelve hours to a human in need of
treatment provides improved relief from cough, cold-like, flu-like and
allergic
rhinitis symptoms.
EXAMPLE III
A hard compressed tablet composition for oral administration is prepal~d by
combining the following ingredients:
i n of t
Naproxen sodium 220 or 440 mg.
Cetirizine 5 mg.
Microcrystalline cellulose 110 mg.
Povidone 10 mg
Talc 12 mg
Magnesium stearate 2 mg
Opadry clear / Colorcon (containing 5.0 mg.
Hydroxypropylmethyl cellulose)
Administration of one
of the above tablets
every twelve hours
to a human in
need of treatment provides
improved relief from
cough, cold-like, flu,
flu-like and
allergic rhinitis symptoms.
EXAMPLE IV
A liquid composition
for oral administration
is prepared by combining
the
following ingredients:
In edi~'ent % WN
Naproxen sodium 2.200
Cetirizine 0.050
High Fructose corn syrup55%) 55.000
(
Polyethylene Glycol 10.000
400
Propylene Glycol 10.000
Alcohol (95%) 8.500
Sodium citrate dihydrate0.470
Citric Acid 0.180
Saccharin socium 0.700
Flavor 0.015
Color 0.005
Water, Purified QS QS to 100%
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The purified water (approximately 10% of the final batch volume) is poured
into a batch container equipped with a lightnin' mixer. The sodium citrate,
citric
acid, asodium saccharin, and actives other than naproxen sodium are added
sequen-
tially and dissolved with agitation. The high frucose is then added. In a
separate
container the colorants are added to purified water (approximately 0.5% of the-
final
batch volume). This colorant solution is then added to the first batch
container. In
a separate container the naproxen sodium is added to the alcohol while
stirring.
The propylene glycol, polyethylene glycol, and flavors are added to this
alcohol
premix and the resulting mixture is stirred until homogeneous and then added
to the
first container. The remaining purified water is added to the resulting
mixture and
stirred.
Administration of 10 ml to 20 ml (2 to 4 teaspoonsful) every twelve hours
to a human in need of treatment provides improved relief from cough, cold-
like,
flu, flu-like and allergic rhinitis symptoms.
Administration of 20 ml (4 teaspoonsful) every eight to twelve hours to a
human in need of treatment provides improved relief from cough, cold-like,
flu,
flu-like and allergic rhinitis symptoms.
