Note: Descriptions are shown in the official language in which they were submitted.
wo 95/10278 2 1 7 2 9 6 ~ PCT~S94/11155
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TREATMENTO~ FR~ D~ORDERSW~TH ~3~NAD~ECARBOXXLATE
Terfenadine, ~-[4-(1,1-dimethylethyl)phenyl]-4-
(hydroxydiphenylmethyl)-l-piperidinebutanol, is a known
antihistaminic agent which is currently available
commercially under the name Seldane~ with a recommended
dosage of 60 mg b.i.d. (See PHYSICIAN ' S DESK REFERENCE,
47th Edition, 1993, Supplement A, pp. All9-A121, Medical
Economics Data, a division of Medical Economics Company,
Inc., Montvale, New Jersey. Terfenadine is disclosed in
the Carr et al. '217 patent [U.S. Patent No. 3,878,217;
issued April 15, 1975]. Sorken and Heel have provided a
review of the pharmacodynamic properties and therapeutic
efficacy of terfenadine ~Drugs 29, 34-56 (1985)].
Terfenadine undergoes extensive (99%) first pass
metabolism to two primary metabolites, an active acid
metabolite (Terfenadine carboxylate) and an inactive
dealkylated metabolite. Terfenadine carboxylate is 4-[1-
hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-
~ dimethyl-benzeneacetic acid and has been disclosed in
the Carr et al. '129 patent [U.S. Patent No. 4,254,129,
issued March 3, 1981] as an antihistaminic agent having
oral activity.
Antagonism of histamine-induced skin wheals has long
been accepted as a means for demonstrating the activity of
particular doses of histamine antagonists. Huther et al.
WOgS/10278 2 1 7 29 6 ~ - 2- PCT~S94/1115~
[Eur. J. Clin. Pharmaco~. 12, 195-99 (1977)] have described the
ef~ects of various doses of terfenadine on the antagonism
of histamine-induced skin wheals in studies carried out in
man. In a study described by Huther et al., the effects of
single oral doses of 20, 60, and 200 mg terfenadine tablets
on skin wheals induced by intradermal injections of 2~g
histamine were studied. The results of this study shows a
dose-dependent reduction in the size of the histamine wheal
with a maximal effect being reached at the 60 mg dose and
being maintained at the 200 mg dose. The effects of
multiple doses of terfenadine (20, 40 or 60 mg every 8
hours and 60 mg every 12 hours over 2 or 3 days) were also
studied by Huther et al. Again, maximal inhibition of
histamine-induced skin wheal was produced by 60 mg b.i.d.
and 60 mg t.i.d. with no difference being observed between
the 60 mg b.i.d. and t.i.d. dosage regimens. In the
studies described by Huther et al., doses of terfenadine
lower than 60 mg (single dose, b.i.d. or t.i.d.) showed
decreased inhibition of histamine-induced skin wheals.
Recently, it has been observed that patients with
significant hepatic dysfunction (alcoholic cirrhosis,
hepatitis), on ketoconazole, itraconazole, or erythromycin
therapy, having conditions leading to electrocardiographic
QT prolongation (e.g., hypokalemia, congenital QT
syndrome), may experience cardiac events of QT prolongation
and/or ventricular tachycardia at the recommended dose of
terfenadine [See Seldane~ Prescribing Information,
PHYSICIAN'S DESK REFERENCE, 47th Edition, 1993, Supplement
A, pp. Al19-Al21, Medical Economics Data, a division of
Medical Economics Company, Inc., Montvale, New Jersey].
SUMMARY OF THE INVENTION
The present invention provides a method of treating a
patient suffering from an allergic disorder comprising
WO95/10278 2 1 7 2 9 6 0 PCT~S94/11155
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administering daily to said patient an amount of
terfenadine carboxylate from about 10 mg to about 50 mg.
The present invention further provides a pharmaceutical
composition in solid unit dosage form comprising an amount
of terfenadine carboxylate from about 5 mg to about 50 mg
in admixture with a pharmaceutically acceptable carrier.
DETAILED DESCRIPTION OF THE INVENTION
Terfenadine carboxylate,4-[1-hydroxy-4-[4-
(hydroxydiphenylmethyl)-l-piperidinyl~butyl]~ -dimethyl-
benzeneacetic acid , may be prepared as described in the
Carr et al. '129 patent [U.S. Patent No. 4,254,129, issued
March 3, 1981].
Terfenadine carboxylate is used according to the
present invention as a histamine Hl-receptor antagonist and
as such will provide relief of symptoms associated with
histamine-mediated allergic disorders in patients suffering
therefrom. Histamine-mediated allergic disorders are
diseases or conditions which have a histamine-mediated
allergic component such as, for example, seasonal allergic
rhinitis, perennial rhinitis, idiopathic urticaria, asthma
and the like. Terfenadine carboxylate also is effective
according to the present invention in providing relief of
symptoms associated with non-histamine-mediated allergic
disorders such as tinnitus, motion sickness, common cold,
and the like. Relief of symptoms of an allergic disorder
by treatment according to the present invention refers to a
decrease in symptom severity over that expected in the
- absence of treatment and does not necessarily indicate a
total elimination or cure of the disease.
As used herein, the term "patient" refers to an adult
person who is suffering from a histamine-mediated allergic
disorder. It is understood that for purposes of the
WO95/10278 2 ~ 7 ~9 60 PCT~S94111155
present invention, the term "adult" refers to a person of
12 years of age or older who would typically be treated for
allergic disorders with an antihistamine dosage as
recommended for adults.
The identification of those patients who would benefit
from the present invention is well within the ability and
knowledge o~ one skilled in the art. A clinician skilled
in the art can readily identify, by the use of clinical
tests, physical examination and medical/family history,
those patients who are suffering from an allergic disorder,
either histamine-mediated or non-histamine-mediated.
According to the present invention, terfenadine
carboxylate is administered to a patient in a daily amount
of from about lO mg to about 50 mg. A preferred daily dose
is from about 20 mg to about 40 mg. The most preferred
daily dose is about 30 mg.
It is of course understood that the daily dose may be
administered to a patient according to a dosage regimen in
single or multiple dosage units. For example, a daily dose
may be administered in a regimen requiring one, two, three,
or four unit doses. Typically, these unit doses will be of
equal strength and will be administered on a time schedule
so that each dose is approximately equally spaced
throughout the day. For example, a daily dose requiring a
once a day dosage regimen may be administered about every
24 hours; a daily dose requiring a twice-a-day dosage
regimen may be administered about every 12 hours; a daily
dose requiring a three times-a-day dosage regimen may be
administered about every 8 hours; a daily dose requiring a
four times-a-day dosage regimen may be administered about
every 6 hours.
In a preferred embodiment of the present invention,
terfenadine carboxylate is administered to a patient in a
21 72~60
WO95/10278 PCT~S94/1l155
.
unit dose of from about 5 mg to about 25 mg taken twice
daily. More preferably, terfenadine carboxylate is
administered to a patient in a unit dose of from about 10
mg to about 20 mg taken twice daily. Most preferably,
~ 5 terfenadine carboxylate is administered to a patient in a
J unit dose of about 15 m~ taken twice daily (15 mg b.i.d.).
Terfenadine carboxylate can be administered according
to the present invention in any form or mode which makes
the compound bioavailable in effective amounts, including
oral and parenteral routes. For example, terfenadine
carboxylate can be administered orally, subcutaneously,
transdermally, intranasally, and the like. Oral
administration is preferred. One skilled in the art of
preparing formulations can readily select the proper form
and mode of administration depending upon the particular
characteristics of the compound selected the disease state
to be treated, the stage of the disease, and other relevant
circumstances.
The compounds can be administered alone or in the form
of a pharmaceutical composition in combination with
pharmaceutically acceptable carriers or excipients, the
proportion and nature of which are determined by the chosen
route of administration and standard pharmaceutical
practice. Terfenadine carboxylate, while effective itself,
may be formulated and administered in the form of its
pharmaceutically acceptable acid addition salt for purposes
of stability, convenience of crystallization, increased
solubility and the like. In addition, an individual
polymorph, solvate or individual optical isomer of
terfenadine carboxylate [i.e., (R)-4-[1-hydroxy-4-[4-
(hydroxydiphenylmethyl)-l-piperidinyl]butyl]-~,~-dimethyl-
benzeneacetic acid or (S)-4-[1-hydroxy-4-[4-
(hydroxydiphenylmethyl)-l-piperidinyl]butyl]-~ dimethyl-
benzeneacetic acid] may be used.
WO95/10278 ~ 7 ~9 60 -6- PCT~S94111155
The present invention contemplates compositions
comprising terfenadine carboxylate in admixture or
otherwise in association with one or more inert carriers.
These compositions are useful, for example, as assay
standards, as convenient means of making bulk shipments, or
as pharmaceutical compositions. An assayable amount of
terfenadine carboxylate is an amount which is readily
measurable by standard assay procedures and techniques as
are well known and appreciated by those skilled in the art.
Assayable amounts of terfenadine carboxylate will generally
vary from about 0.001% to about 75% of the composition by
weight. Inert carriers can be any material which does not
degrade or otherwise covalently react with terfenadine
carboxylate. Examples of suitable inert carriers are
water; aqueous buffers, such as those which are generally
useful in High Performance Liquid Chromatography (HPLC)
analysis; organic solvents, such as acetonitrile, ethyl
acetate, hexane and the like; and pharmaceutically
acceptable carriers or excipients.
More particularly, the present invention contemplates a
pharmaceutical composition in solid unit dosage form
comprising an amount of terfenadine carboxylate from about
5 mg to about 50 mg in admixture with a pharmaceutically
acceptable carrier. As used herein, the term "solid unit
dosage form" contemplates a solid dosage form for oral
administration such as a tablet, capsule, and the like, as
well as solid dosage forms for parenteral administration
such as a transdermal patch, and the like.
The pharmaceutical compositions are prepared in a
manner well known in the pharmaceutical art. The carrier
or excipient may be a solid, semi-solid, or liquid material
which can serve as a vehicle or medium for the active
ingredient. Suitable carriers or excipients are well known
in the art. The pharmaceutical composition may be adapted
for oral or parenteral use and may be administered to the
WO95/10278 /1 7 2 9 6 ~ PCT~S94/1115~
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7--
patient in the form of tablets, capsules, solutions,
suspensions, transdermal patch, and the like.
Terfenadine carboxylate may be administered orally, for
example, with an inert diluent or with an edible carrier.
It may be enclosed in gelatin capsules or compressed into
tablets. For the purpose of oral therapeutic
administration, terfenadine carboxylate may be incorporated
with excipients and used in the form of tablets, capsules,
elixirs, suspensions, syrups, wafers, chewing gums and the
like. These preparations should contain at least 4% of
the compound of the invention, the active ingredient, but
may be varied depending upon the particular form and may
conveniently be between about 4% to about 70% of the weight
of the unit. The amount of the compound present in
compositions is such that a suitable dosage will be
obtained upon administration. Preferred compositions and
preparations according to the present invention are
prepared so that an oral unit dosage form contains between
about 15 mg to about 30 mg. Most preferred unit doses for
oral administration are those which contain about 15 mg to
about 30 mg.
The tablets, pills, capsules, and the like may also
contain one or more of the following adjuvants: binders
such as microcrystalline cellulose, gum tragacanth or
gelatin; excipients such as starch or lactose,
disintegrating agents such as alginic acid, Primogel~, corn
starch, carbonate salts such as sodium bicarbonate or
calcium carbonate, and the like; lubricants such as
magnesium stearate or Sterotex~; glidants such as colloidal
silicon dioxide; and sweetening agents such as sucrose or
saccharin may be added or a flavoring agent such as
peppermint, methyl salicylate or orange flavoring. When
the dosage unit form is a capsule, it may contain, in
addition to materials of the above type, a liquid carrier
such as polyethylene glycol or a fatty oil. Other dosage
WO95/10278 ~1 7 ~ 9 6 0 - 8- PCT~S94/lllS5
unit forms may contain other various materials which modify
the physical form of the dosage unit, for example, as
coatings. Thus, tablets or pills may be coated with sugar,
shellac, or other enteric coating agents. A syrup may
contain, in addition to the present compounds, sucrose as a
sweetening agent and certain preservatives, dyes and
colorings and flavors. Materials used in preparing these
various compositions should be pharmaceutically pure and
non-toxic in the amounts used. Preferred excipients are
corn starch, gelatin, lactose, magnesium stearate and
sodium bicarbonate.
Oral unit dosage forms may be formulated to provide
immediate or sustained release characteristics. These
forms may be formulated according to conventional
techniques and procedures to give the desirable dissolution
and bioavailability characteristics.
In addition, terfenadine çarboxylate may be
incorporated into a solution or suspension for oral or
parenteral administration. These preparations should
contain at least 0.1% of terfenadine carboxylate, but may
be varied to be between 0.l and about 50% of the weight
thereof. The amount of terfenadine carboxylate in such
compositions is such that a suitable dosage will be
obtained upon oral or parenteral administration.
The solutions or suspensions may also include the one
or more of the following adjuvants: sterile diluents such
as water for injection, saline solution, fixed oils,
polyethylene glycols, glycerine, propylene glycol or other
synthetic solvents; antibacterial agents such as benzyl
alcohol or methyl paraben; antioxidants such as ascorbic
acid or sodium bisulfite; chelating agents such as ethylene
diaminetetraacetic acid; buffers such as acetates, citrates
or phosphates and agents for the adjustment of tonicity
such as sodium chloride or dextrose.
WO95/10278 2 ~ 7 ~ 9 6 0 PCT~S94/11155
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_g _
Transdermal dosage forms for administering terfenadine
carboxylate can be prepared by conventional techniques well
known in the art of pharmaceutical science such as by
incorporating terfenadine carboxylate into various
polymeric reservoir matrix materials. These polymeric
matrix materials may include pressure sensitive acrylic,
silicone, polyurethane, ethylene vinyl acetate copolymers,
polyolefins, and rubber adhesive matrices, medical grade
silicone fluids, and medical grade silicone elastamers,
which are well known in the art for forming reservoirs for
transdermal delivery of drugs.
It is further contemplated that terfenadine
carboxylate, according to the present invention, may be
formulated with a variety of other active ingredients which
are commonly combined with antihistamines, such as a
decongestant, including pseudoephedrine and the like;
analgesics such as acetaminophen and the like, non-
steroidal antiinflammatory agents such as ibuprofen and thelike.
