Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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SINGLE-DOSE ANTIHISTAMINE/DECONGESTANT FORMULATIONS
FOR TREATING RHINITIS
1. Field of the Invention
The present invention relates to treatments for rhinitis, more particularly,
to
combinations of decongestant and non-sedating antihistamine that avoid
2. Description of the Prior Art
Rhinitis refers to an inflammatory disorder of the nasal passages. The
symptoms of rhinitis typically consist of sneezing, rhinorrhea, nasal
congestion,
Decongestants commonly used to treat rhinitis include the adrenaline-like
agents pseudoephedrine and phenylpropanolamine. These agents act to
constrict vessels in the nasal mucus membranes and thereby decrease tissue
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if taken when sleep is desired. This can be a source of confusion for
individuals,
who mistakenly attribute their inability to sleep to the malaise that may
accompany other rhinitis symptoms, rather than to the decongestant medication.
Histamine is a mediator released from cells that line the walls of the nasal
mucous membranes (mast cells). When released, histamine binds to local
histamine receptors causing sneezing, nasal itching, swelling of the nasal
membranes, and increased nasal secretions. Antihistamines relieve these
effects, albeit by a different mechanism than decongestants. Antihistamines
block the binding of histamines to the histamine receptors by preemptively
binding to the receptors. Consequently they are effective only if given prior
to
histamine release since once histamine is released and binds to the receptors,
it
is too late. Although individuals typically take antihistamines after symptoms
occur, it is more desirable to dose antihistamines so as to effect therapeutic
availability in anticipation of histamine release. Antihistamines are
generally
sedating. However, newer antihistamines with no or little sedation have been
developed in the last twenty years.
Combining decongestants and antihistamines utilizes both mechanistic
approaches, and has been shown to offer more complete relief of rhinitis
symptoms than therapy with either component alone. Consequently, many
products have been formulated so that their dosage units contain both. The
incorporation of decongestant and sedating antihistamine into a single dosage
unit attempts a balance between the stimulating and sedating side effects of
these components.
However, individuals are known to vary in their susceptibility to these side
effects. Consequently, some individuals experience stimulation and insomnia
when taking these combinations at night. More recently, formulations have been
commercialized which incorporate a decongestant and a non-sedating
antihistamine into a single dosage unit for the purpose of avoiding daytime
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sedation. Such combinations might be expected to provoke a greater incidence
of nighttime irritability and insomnia because the stimulating side effects of
decongestant are not attenuated by concomitant sedation by antihistamine.
Indeed, a 25% incidence of insomnia has been disclosed among users of a
commercialized combination of the non-sedating antihistamine terfenadine and
the decongestant pseudoephedrine. Examples of such formulations include:
SELDANE-D Extended-Release Tablets which contains 60 mg
terfenadine (non-sedating antihistamine) and 120 mg pseudoephedrine
hydrochloride (stimulating decongestant), and which is recommended to be taken
every 12 hours (adults and children over 12 years of age).
ALLEGRA-D contains 60 mg fexofenadine (non-sedating antihistamine)
and 120 mg pseudoephedrine hydrochloride (stimulating decongestant), and
which is recommended to be taken every 12 hours (adults and children over 12
years of age).
CLARITIN-D 24-HOUR Extended-Release Tablets which contains 10 mg
loratidine (non-sedating antihistamine) and 240 mg pseudoephedrine
hydrochloride (stimulating decongestant), and which is recommended to be taken
every 24 hours (adults and children over 12 years of age).
These and all currently marketed single entity combinations, which are
formulated with decongestant and non-sedating antihistamine, fail to address
the
problem of nighttime irritability and insomnia, a problem that is increased by
combining non-sedating, rather than sedating antihistamine. Note is made of
prior art which is directed toward reducing the side effects of antihistamines
and
decongestants. U.S. Patent No. 4,295,567, issued to Knudsen, teaches a
regimen for employing separate day and night dosage units for the purpose of
avoiding daytime sedation from sedating antihistamines. This patent does not
anticipate the advent of non-sedating antihistamine and overlooks the side
effect
of nighttime stimulation from decongestants. A regimen, commercialized as SYN-
,
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RXTm also employs separate day and night dosage units. SYNRXTM contains a
daytime
formulation of 600 mg guaifenesin, which is non-stimulating, and 60 mg
pseudoephedrine,
which is stimulating, and a nighttime formulation of 600 mg of guaifenesin
alone. SYNRXTM
does not contain an antihistamine. In failing to contain any medication that
would be effective
for the symptoms of rhinitis at night, SYNRXTM does not constitute a treatment
for rhinitis. The
use of multi-dosage unit regimens of such prior art is less convenient for a
user than a single
dose, once-per-day formulation, and more complex to follow, adding the
potential for a user to
confuse dosage units.
Individuals with rhinitis utilize antihistamines and decongestants together
many of millions of
times a year. Professional as well as consumer confusion is widely encountered
with the use of
these medications together, and unnecessarily negative consequences occur both
by self-
selection and prescription. In particular, individuals treated with
decongestants at night not only
¨5 risk insomnia, but also daytime irritability, fatigue, and malaise from
lack of rest. It is known
that these side effects are sometimes mistakenly ascribed to rhinitis rather
than to the medication
causing them. There is a present need for formulations which circumvent this
confusion and
which avoid nighttime stimulation.
SUMMARY OF THE INVENTION
In one aspect of the present invention, there is provided a once-per-day oral
dosage unit for
treatment of rhinitis over a 24-hour period, said oral dosage unit comprising:
(a) an
antihistamine; (b) a decongestant; and (c) a time release component that
allows for extended
release of the decongestant wherein: i) the antihistamine has antihistamine
activity of more than
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the first 22 hours; and ii) the decongestant has stimulatory activity for less
than the first 16 hours,
with the proviso that the oral dosage unit excludes ibuprofen.
In another aspect of the present invention, there is provided a once-per-day
oral dosage unit for
treatment of rhinitis over a 24-hour period, said oral dosage unit comprising:
(a) 10 mg of
loratadine; (b) 120 mg of pseudoephedrine; and (c) a time release component
that allows for
extended release of the pseudoephedrine over a period of 10 to 12 hours,
wherein: i) the
loratadine has antihistamine activity of more than the first 22 hours; ii) the
pseudoephedrine has
stimulatory activity for less than the first 16 hours; and iii) the time
release component comprises
hydroxypropyl methylcellulose; with the proviso that the oral dosage unit
excludes ibuprofen.
In a further aspect of the present invention, there is provided a once-per-day
oral dosage unit for
treatment of rhinitis over a 24-hour period, said oral dosage unit comprising:
(a) 10 mg of
cetirizine; (b) 75 mg of phenylpropanolamine; and (c) a time release component
that allows for
extended release of the phenylpropanolamine over a period of 10 hours,
wherein: i) the cetirizine
has antihistamine activity of more than the first 22 hours; and ii) the
phenylpropanolamine has
stimulatory activity for less than the first 16 hours; with the proviso that
the oral dosage unit
excludes ibuprofen.
In yet a further aspect of the present invention, there is provided a once-per-
day oral dosage unit
for treatment of rhinitis over a 24-hour period, said oral dosage unit
comprising: a0 120 mg of
fexofenadine; b) 75 mg of phenylpropanolamine; and c) a time release component
that allows
for extended release of the phenylpropanolamine over a period of 10 hours,
wherein: i) the
fexofenadine has antihistamine activity of more than the first 22 hours; and
ii) the
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phenylpropanolamine has stimulatory activity for less than the first 16 hours;
with the proviso
that the oral dosage unit excludes ibuprofen.
It is an object of the present invention to simplify the combined use of
antihistamine and nasal
decongestant medications for a user for the purpose of enhancing the
convenience of utilizing
these medications, reducing error in taking these medications, and reducing
the side effects of
these medications. Another object is to formulate antihistamines and
decongestants together for
the treatment of rhinitis so as to avoid stimulation at night. Yet another
object is to provide a
formulation for a user which incorporates antihistamines and decongestants
together as a single
dosage unit for the treatment of rhinitis in a manner so as not to cause
stimulation at night and
which can be taken once per day. A further object is to provide a user with a
single dosage unit
that provides an operational
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combination of decongestant and antihistamine during the day and antihistamine
without decongestant at night.
The single dosage unit of the present invention for treating the symptoms
of rhinitis is expertly formulated with a combination of medications,
including a
nasal decongestant, antihistamine, and optionally, other medications, such as
an
analgesic. The dosage unit is for oral ingestion. The dosage unit preferably
contains a non-sedating antihistamine, such as loratidine, cetirizine, or
fexofenadine. Examples of decongestants include pseudoephedrine and
phenylpropanolamine.
lo Other objects of the present invention will become apparent in light of
the
following detailed description of the invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
The single dosage unit of the present invention for treating the symptoms
of rhinitis contains a combination of medications that include nasal
decongestants
and antihistamines. The dosage unit s may be in the form of tablets, pills,
capsules, caplets, or other recognized oral form of medication. The dosage
unit
may be formulated to contain sedating or, preferably, non-sedating
antihistamine.
The components are formulated so as to produce the pharmacokinetic and
therapeutic characteristics desired. The devising of such formulations
requires
pharmaceutical expertise and requires understanding of the actions, side
effects,
and pharmacokinetics of antihistamines, decongestants, components which affect
the bioavailability of the medications, and other formulated components.
The terms "day" and "night" used herein are intended to be synonymous
with the period of wakefulness, when stimulation might be acceptable, and the
period of sleeping, when stimulation would be undesired, respectively. Such
times vary in accordance with the schedule of individuals.
Examples of the preferred single dosage units of the present invention
include:
Example 1. A single dosage unit consisting of 120 mg pseudoephedrine, a
stimulating decongestant, prepared so as to be released over a 10-12 hour
time,
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and 10 mg loratidine, a non-sedating antihistamine, formulated so as to be
released immediately. When taken at the start of the day (a time anticipating
a
desire to be awake for 12 to 16 hours), this dosage unit provides immediate
dosing with loratidine, which is known to exert an antihistaminic effect 1 to
3
hours after dosing, reach a maximum at 8 to 12 hours, and last in excess of 24
hours.
This dosage unit preferably provides immediate and delayed action of
pseudoephedrine so as to exert an effect during daytime hours, when the
stimulation of pseudoephedrine is best tolerated, but not at night. Once
released,
pseudoephedrine has a 4 to 6 hour half-life, considerably shorter than that of
loratidine. The comparatively short decongestant effect of pseudoephedrine may
be prolonged by release over time so as to achieve efficacy through the waking
hours, but not during the time when stimulation is undesired. One such time-
release method involves the additional formulation of cellulose ether base
materials such as hydroxypropyl methylcellulose to bond to the therapeutic
agent
and delay its bioavailability. Such time-release methods may be utilized to
delay
the bioavailability of all or only a portion of the ingested dose, and for
varying
lengths of time.
The antihistamine and decongestant components of this formulation are
similar to that of CLARITIN-D 24-HOUR Extended-Release Tablets which
contains 10 mg loratidine (antihistamine) and 240 mg pseudoephedrine
hydrochloride (decongestant), and which is recommended to be taken every 24
hours in adults. The present invention formulation differs, however, in that
it
contains a lesser dose of pseudoephedrine, and that it limits the duration of
action of pseudoephedrine to the daytime hours, thus avoiding the stimulation
of
pseudoephedrine at night.
Example 2. A single dosage unit consisting of 75 mg
phenylpropanolamine, a stimulating decongestant, prepared so as to be released
over a 10-hour time period, and 10 mg cetirizine, a non-sedating
antihistamine,
prepared so as to be released immediately. When taken at the start of the day,
this formulation provides immediate dosing with cetirizine, which is known to
exert
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an antihistaminic effect within one hour after dosing and to persist for at
least 22
hours. This formulation also preferably provides immediate and delayed action
of
phenylpropanolamine over a period not to exceed 16 hours after administration
so as to exert effect during daytime hours, when stimulation is best
tolerated, but
exerts no effect at night. Like pseudoephedrine, the comparatively short half-
life
and decongestant effect of phenylpropanolamine, is prolonged in this
formulation
by incorporating a prolonged release of phenylpropanolamine over time so as to
achieve efficacy through the waking hours, but not so long as to provide
phenylpropanolamine activity during the time when stimulation is undesired.
Example 3. A single dosage unit consisting of 75 mg
phenylpropanolamine, a stimulating decongestant prepared so as to be released
over a 10-hour time period, and 120 mg of fexofenadine, a non-sedating
antihistamine, prepared so as to be active over a 24-hour period.
Fexofenadine,
when given alone, exhibits antihistaminic effect within one hour, achieves a
maximum effect at 12 hours, and still has a visible effect at 24 hours. This
formulation preferably provides immediate and delayed activity of fexofenadine
over a 24-hour span. This formulation also preferably provides immediate and
delayed action of phenylpropanolamine over a period not in excess of 16 hours
after administration so as to exert an effect during daytime hours, when
stimulation is best tolerated, but not so long as to provide an effect during
the
time when stimulation is undesired, as at night.
In addition to antihistamines and decongestants, additional therapeutic
ingredients for the treatment of rhinitis may be formulated if desired. For
example, analgesics such as salicylates and acetaminophen may be considered
for inclusion in such dosage units and are within the scope of this invention.
These examples do not constitute an exhaustive list of potential
combinations, and variations and modifications may be made by those of
ordinary
skill in the art. Those of skill in the art may also recognize modifications
to these
presently disclosed embodiments. One such modification might involve a time-
release of decongestant over periods other than those exemplified, but not so
as
to allow stimulation at night. These variations and modifications are meant to
be
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covered by the scope of the present claims.
Thus it has been shown and described antihistamine/decongestant formulations
for treating
rhinitis that satisfies the objects set forth above.
Since certain changes may be made in the present disclosure without departing
from the scope of
the present invention, it is intended that all matter described in the
foregoing specification be
interpreted as illustrative and not in a limiting sense
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