U.S. patent application number 10/084250 was filed with the patent office on 2002-07-04 for methods and compositions using norastemizole in combination with leukotriene inhibitors.
This patent application is currently assigned to Sepracor, Inc.. Invention is credited to Rubin, Paul D..
Application Number | 20020086854 10/084250 |
Document ID | / |
Family ID | 22023845 |
Filed Date | 2002-07-04 |
United States Patent
Application |
20020086854 |
Kind Code |
A1 |
Rubin, Paul D. |
July 4, 2002 |
Methods and compositions using norastemizole in combination with
leukotriene inhibitors
Abstract
Methods and pharmaceutical compositions employing norastemizole
and a leukotriene inhibitor for the treatment or prevention of
inflammation or allergic disorders, such as asthma or the symptoms
thereof. Also included are methods and compositions employing
norastemizole and a decongestant for the treatment or prevention of
inflammation or allergic disorders, such as asthma or the symptoms
thereof.
Inventors: |
Rubin, Paul D.; (Sudbury,
MA) |
Correspondence
Address: |
PENNIE & EDMONDS LLP
1667 K STREET NW
SUITE 1000
WASHINGTON
DC
20006
|
Assignee: |
Sepracor, Inc.
|
Family ID: |
22023845 |
Appl. No.: |
10/084250 |
Filed: |
February 28, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10084250 |
Feb 28, 2002 |
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09721668 |
Nov 27, 2000 |
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6372197 |
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09721668 |
Nov 27, 2000 |
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09059572 |
Apr 14, 1998 |
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6248308 |
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Current U.S.
Class: |
514/161 ;
514/322; 514/406 |
Current CPC
Class: |
Y10S 514/826 20130101;
A61K 31/445 20130101; A61P 11/06 20180101; A61P 27/16 20180101;
A61P 37/08 20180101; A61P 17/00 20180101; A61K 45/06 20130101; A61P
29/00 20180101 |
Class at
Publication: |
514/161 ;
514/322; 514/406 |
International
Class: |
A61K 031/454; A61K
031/415 |
Claims
What is claimed is:
1. A method of treating or preventing asthma or the symptoms
thereof in a human which comprises administering to a human a
therapeutically effective amount of norastemizole, or a
pharmaceutically acceptable salt thereof, and a therapeutically
effective amount of a leukotriene inhibitor, or a pharmaceutically
acceptable salt thereof.
2. A method of treating or preventing asthma or the symptoms
thereof in a human which comprises administering to a human a
composition, said composition comprising (i) a therapeutically
effective amount of norastemizole, or a pharmaceutically acceptable
salt thereof; (ii) a therapeutically effective amount of
leukotriene inhibitor, or a pharmaceutically acceptable salt
thereof, selected from the group consisting of 5-lipoxygenase
inhibitors, 5-lipoxygenase activating protein antagonists,
leukotriene receptor antagonists, and mixtures thereof; and a
pharmaceutically acceptable carrier or excipient.
3. The method of claim 1, wherein the administration of the amount
norastemizole, or a pharmaceutically acceptable salt thereof, and
the amount of leukotriene inhibitor, or a pharmaceutically
acceptable salt thereof, avoids the concomitant liability of
adverse effects associated with the administration of non-sedating
antihistamines.
4. The method of claim 2, wherein the administration of the amount
norastemizole, or a pharmaceutically acceptable salt thereof, and
the amount of leukotriene inhibitor, or a pharmaceutically
acceptable salt thereof, avoids the concomitant liability of
adverse effects associated with the administration of non-sedating
antihistamines.
5. The method of claim 1, 2, 3, or 4 wherein the administering
further comprises a therapeutically effective amount of a
decongestant, or a pharmaceutically acceptable salt thereof.
6. The method of claim 1 wherein said human has asthma.
7. A method of treating or preventing dermatitis in a human which
comprises administering to a human a therapeutically effective
amount of norastemizole, or a pharmaceutically acceptable salt
thereof, and a therapeutically effective amount of a leukotriene
inhibitor, or a pharmaceutically acceptable salt thereof.
8. A method of treating or preventing dermatitis in a human which
comprises administering to a human a composition, said composition
comprising (i) a therapeutically effective amount of norastemizole,
or a pharmaceutically acceptable salt thereof; (ii) a
therapeutically effective amount of leukotriene inhibitor, or a
pharmaceutically acceptable salt thereof, selected from the group
consisting of 5-lipoxygenase inhibitors, 5-lipoxygenase activating
protein antagonists, leukotriene receptor antagonists, and mixtures
thereof; and a pharmaceutically acceptable carrier or
excipient.
9. The method of claim 7 wherein the administration of the amount
norastemizole, or a pharmaceutically acceptable salt thereof, and
the amount of leukotriene inhibitor, or a pharmaceutically
acceptable salt thereof, avoids the concomitant liability of
adverse effects associated with the administration of non-sedating
antihistamines.
10. The method of claim 8 wherein the administration of the amount
norastemizole, or a pharmaceutically acceptable salt thereof, and
the amount of leukotriene inhibitor, or a pharmaceutically
acceptable salt thereof, avoids the concomitant liability of
adverse effects associated with the administration of non-sedating
antihistamines.
11. The method of claim 7, 8, 9, or 10 wherein the administering
further comprises a therapeutically effective amount of a
decongestant, or a pharmaceutically acceptable salt thereof.
12. A method of treating or preventing allergic rhinitis in a human
which comprises administering to a human a therapeutically
effective amount of norastemizole, or a pharmaceutically acceptable
salt thereof, and a therapeutically effective amount of a
leukotriene inhibitor, or a pharmaceutically acceptable salt
thereof.
13. A method of treating or preventing allergic rhinitis in a human
which comprises administering to a human a composition, said
composition comprising (i) a therapeutically effective amount of
norastemizole, or a pharmaceutically acceptable salt thereof; (ii)
a therapeutically effective amount of leukotriene inhibitor, or a
pharmaceutically acceptable salt thereof, selected from the group
consisting of 5-lipoxygenase inhibitors, 5-lipoxygenase activating
protein antagonists, leukotriene receptor antagonists, and mixtures
thereof; and a pharmaceutically acceptable carrier or
excipient.
14. The method of claim 12 wherein the administration of the amount
norastemizole, or a pharmaceutically acceptable salt thereof, and
the amount of leukotriene inhibitor, or a pharmaceutically
acceptable salt thereof, avoids the concomitant liability of
adverse effects associated with the administration of non-sedating
antihistamines.
15. The method of claim 13, wherein the administration of the
amount norastemizole, or a pharmaceutically acceptable salt
thereof, and the amount of leukotriene inhibitor, or a
pharmaceutically acceptable salt thereof, avoids the concomitant
liability of adverse effects associated with the administration of
non-sedating antihistamines.
16. The method of claim 12, 13, 14, or 15 wherein the administering
further comprises a therapeutically effective amount of a
decongestant, or a pharmaceutically acceptable salt thereof.
17. A method of treating or preventing inflammation in a human
which comprises administering to a human a therapeutically
effective amount of norastemizole, or a pharmaceutically acceptable
salt thereof, and a therapeutically effective amount of a
leukotriene inhibitor, or a pharmaceutically acceptable salt
thereof.
18. A method of treating or preventing inflammation in a human
which comprises administering to a human a composition, said
composition comprising (i) a therapeutically effective amount of
norastemizole, or a pharmaceutically acceptable salt thereof; (ii)
a therapeutically effective amount of leukotriene inhibitor, or a
pharmaceutically acceptable salt thereof, selected from the group
consisting of 5-lipoxygenase inhibitors, 5-lipoxygenase activating
protein antagonists, leukotriene receptor antagonists, and mixtures
thereof; and a pharmaceutically acceptable carrier or
excipient.
19. The method of claim 17 wherein the administration of the amount
norastemizole, or a pharmaceutically acceptable salt thereof, and
the amount of leukotriene inhibitor, or a pharmaceutically
acceptable salt thereof, avoids the concomitant liability of
adverse effects associated with the administration of non-sedating
antihistamines.
20. The method of claim 18, wherein the administration of the
amount norastemizole, or a pharmaceutically acceptable salt
thereof, and the amount of leukotriene inhibitor, or a
pharmaceutically acceptable salt thereof, avoids the concomitant
liability of adverse effects associated with the administration of
non-sedating antihistamines.
21. The method of claim 17, 18, 19, or 20 wherein the administering
further comprises a therapeutically effective amount of a
decongestant, or a pharmaceutically acceptable salt thereof.
22. A method for treating or preventing a condition responsive to
leukotriene inhibition which comprises administering a
therapeutically effective amount of norastemizole, or a
pharmaceutically acceptable salt thereof, and a therapeutically
effective amount of a leukotriene inhibitor, or a pharmaceutically
acceptable salt thereof.
23. A method of treating or preventing a condition responsive to
leukotriene inhibition which comprises administering to a human a
composition, said composition comprising (i) a therapeutically
effective amount of norastemizole, or a pharmaceutically acceptable
salt thereof; (ii) a therapeutically effective amount of
leukotriene inhibitor, or a pharmaceutically acceptable salt
thereof, selected from the group consisting of 5-lipoxygenase
inhibitors, 5-lipoxygenase activating protein antagonists,
leukotriene receptor antagonists, and mixtures thereof; and (iii) a
pharmaceutically acceptable carrier or excipient.
24. The method of claim 22 wherein the administration of the amount
norastemizole, or a pharmaceutically acceptable salt thereof, and
the amount of leukotriene inhibitor, or a pharmaceutically
acceptable salt thereof, avoids the concomitant liability of
adverse effects associated with the administration of non-sedating
antihistamines.
25. The method of claim 23, wherein the administration of the
amount norastemizole, or a pharmaceutically acceptable salt
thereof, and the amount of leukotriene inhibitor, or a
pharmaceutically acceptable salt thereof, avoids the concomitant
liability of adverse effects associated with the administration of
non-sedating antihistamines.
26. The method of claim 22, 23, 24, or 25 wherein the administering
further comprises a therapeutically effective amount of a
decongestant, or a pharmaceutically acceptable salt thereof.
27. The method of claim 22 wherein the condition responsive to
leukotriene inhibition comprises asthma or a symptom thereof.
28. The method of claim 22 wherein the condition responsive to
leukotriene inhibition comprises an allergic condition.
29. The method of claim 22 wherein the condition responsive to
leukotriene inhibition comprises inflammation.
30. The method of claim 1, 2, 7, 8, 12, 13, 17, 18, 22, or 23
wherein the amount of norastemizole administered is from about 1 mg
to about 200 mg per day.
31. The method of claim 30 wherein the amount of norastemizole
administered is from about 10 mg to about 100 mg per day.
32. The method of claim 1, 2, 7, 8, 12, 13, 17, 18, 22, or 23
wherein the compositions are administered as a nasal or oral
spray.
33. The method of claim 1, 2, 7, 8, 12, 13, 17, 18, 22, or 23
wherein at least one of the norastemizole and the leukotriene
inhibitor is administered as a nasal or oral spray.
34. The method of claim 1, 2, 7, 8, 12, 13, 17, 18, 22, or 23
wherein at least one of the norastemizole and the leukotriene
inhibitor is administered in an oral solid dosage form.
35. The method of claim 3, 9, 14, 19, or 24 wherein the
norastemizole is administered as a nasal or oral spray.
36. The method of claim 1, 2, 7, 8, 12, 13, 17, 18, 22, or 23
wherein the leukotriene inhibitor is a 5-lipoxygenase
inhibitor.
37. The method of claim 36, wherein the 5-lipoxygenase inhibitor is
selected from the group consisting of zileuton, docebenone,
piripost, ICI-D2318, and mixtures thereof.
38. The method of claim 1, 2, 7, 8, 12, 13, 17, 18, 22, or 23
wherein the leukotriene inhibitor is a 5-lipoxygenase activating
protein.
39. The method of claim 38, wherein the 5-lipoxygenase activating
protein is selected from the group consisting of MK-591, MK-886,
and mixtures thereof.
40. The method of claim 1, 2, 7, 8, 12, 13, 17, 18, 22, or 23
wherein the leukotriene inhibitor is a leukotriene receptor
antagonist.
41. The method of claim 40, wherein the leukotriene receptor
antagonist is selected from the group consisting of zafirlukast,
montelukast, pranlukast, sodium
1(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethynyl)phenyl-
)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methyl)cyclopropaneacetate;
1-(((1(R)-(3-(2-(2,3-dichlorothieno[3,2-b
]pyridin-5-yl)-(E)ethenyl)pheny-
l)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneace-
tic acid, and salts and mixtures thereof.
42. A pharmaceutical composition which comprises a therapeutically
effective amount of norastemizole, or a pharmaceutically acceptable
salt thereof; a therapeutically effective amount of a leukotriene
inhibitor, or a pharmaceutically acceptable salt thereof; and a
pharmaceutically acceptable carrier or excipient.
43. The pharmaceutical composition of claim 42 which further
comprises a therapeutically effective amount of a decongestant, or
a pharmaceutically acceptable salt thereof.
44. A pharmaceutical composition which comprises from about 1 mg to
about 200 mg of norastemizole, or a pharmaceutically acceptable
salt thereof, and from about 20 mg to about 2,500 mg of
5-lipoxygenase inhibitor, or a pharmaceutically acceptable salt
thereof.
45. A pharmaceutical composition which comprises from about 1 mg to
about 200 mg of norastemizole, or a pharmaceutically acceptable
salt thereof, and from about 20 mg to about 2500 mg of
5-lipoxygenase activating protein antagonist, or a pharmaceutically
acceptable salt thereof.
46. A pharmaceutical composition which comprises from about 1 mg to
about 200 mg of norastemizole, or a pharmaceutically acceptable
salt thereof, and from about 2 mg to about 200 mg of leukotriene
receptor antagonist, or a pharmaceutically acceptable salt
thereof.
47. The composition of claim 42, 43, 44, 45, or 46 administered as
a nasal or oral spray.
48. The composition of claim 42, 43, 44, 45, or 46 wherein at least
one of the norastemizole and the leukotriene inhibitor is
administered as a nasal or oral spray.
49. The composition of claim 42, 43, 44, 45, or 46 wherein at least
one of the norastemizole and the leukotriene inhibitor is
administered in an oral solid dosage form.
Description
1. FIELD OF THE INVENTION
[0001] The invention relates to methods of treating asthma,
inflammation, and allergic conditions. In another aspect, this
invention relates to the use of antihistamines and leukotriene
inhibitors, and compositions containing them.
2. BACKGROUND OF THE INVENTION
[0002] Astemizole is an antagonist of the H-1 histamine receptor
protein, which mediates the response antagonized by conventional
antihistamines. Astemizole is well absorbed but is extensively
metabolized. See Uchiyama et al., Pharmacometrics, 40:7793 (1990).
Three main metabolites have been identified, all of which are
reported to have some antihistaminic activity. See Kamei et al.,
Arzneimittel-Forschung/Drug Research, 41:932-36 (1991).
[0003] Weintraub et al., Hosp. Formul., 22:918-27 (1987) describes
clinical efficacy of astemizole in the treatment of both seasonal
and perennial allergies. It has also been suggested that astemizole
would be useful for the treatment of asthma.
[0004] Astemizole is sold commercially as a prescription
antihistamine (HISMANAL.RTM.), however, the use of astemizole is
believed to have a potential for serious cardiotoxicity in certain
patients. Norastemizole, one of the metabolites of astemizole, is
said to have the beneficial effects of astemizole while having a
reduced risk of cardiotoxicity. The preparation of norastemizole is
described, e.g., in WO 94/07495, published Apr. 14, 1994.
[0005] Leukotrienes augment neutrophil and eosinophil migration,
neutrophil and monocyte aggregation, leukocyte adhesion, increase
capillary permeability, and smooth muscle contraction, all of which
contribute to inflammation, edema, mucus secretion, and
bronchoconstriction. For example, zileuton, sold commercially as
ZYFLO.RTM., is a specific inhibitor of 5-lipoxygenase having the
chemical name (.+-.)-1-(1-Benso[b]thien-2-ylethyl)-1-hydroxyurea.
Zileuton is known to inhibit leukotriene (LTH.sub.4, LTC.sub.4,
LTD.sub.4, and LTE.sub.4) formation in vitro. Zileuton is an
inhibitor ex vivo of LTB.sub.4 formation in several species and
inhibits leukotriene-dependent smooth muscle contractions in vitro
in guinea pig and human airways. One study of 373 patients
indicated that 600 mg of zileuton four times daily were required to
provide efficacy, while 400 mg failed to do so. In some patients,
zileuton was reported to cause headache, pain, asthenia, dyspepsia,
nausea, and myalgia. [Physician's Desk Reference, 52 ed., Medical
Economics Co., Inc., 474-76 (1998)].
[0006] Zafirlukast, sold commercially as ACCOLATE.RTM., is another
type of leukotriene inhibitor. This leukotriene inhibitor is a
leukotriene receptor antagonist (LTRA) of leukotriene D.sub.4 and
E.sub.4, and has the chemical name
4-(5-cyclopentyloxy-carbonylamino-1-methyl-indol-8-ylme-
thyl)-3-methoxy-N-o-tolylsulfonylbenzamide. Cysteinyl leukotriene
production and receptor occupation have been correlated with the
pathophysiology of asthma. In vitro studies indicated that
zafirlukast antagonized the contractile activity of three
leukotrienes in conducting airway smooth muscle from laboratory
animals and humans; prevented intradermal LTD.sub.4induced
increases in cutaneous vascular permeability; and inhibited inhaled
LTD.sub.4-induced influx of eosinophils into animal lungs. In some
patients, zafirlukast has been reported to cause headache,
infection, nausea, diarrhea, pain, asthenia, abdominal pain,
dizziness, myalgia, fever, vomiting, SGPT elevation, and dyspepsia.
[Physician's Desk Reference, 52 ed., Medical Economics Co., Inc.,
3148-49 (1998)].
3. SUMMARY OF THE INVENTION
[0007] The present invention represents an improvement over the
astemizole and norastemizole, as well as the leukotriene inhibitor,
technology presently available.
[0008] This invention relates to novel pharmaceutical compositions
containing (a) norastemizole, or a pharmaceutically acceptable salt
thereof, and (b) a leukotriene inhibitor, or a pharmaceutically
acceptable salt thereof, and optionally (c) a decongestant, and a
pharmaceutically acceptable carrier or excipient.
[0009] The compositions of the invention employing norastemizole
and a leukotriene inhibitor, and optionally a decongestant, possess
potent antihistaminic activity and are useful in treating,
preventing, or managing asthma, asthma symptoms, inflammation,
allergic rhinitis, and other allergic disorders, as well as
dermatitis. The compositions employing norastemizole and a
leukotriene inhibitor provide an improved overall therapy relative
to either norastemizole or the leukotriene inhibitor alone.
Additionally, the novel pharmaceutical compositions of the
invention are useful in treating, preventing, or managing motion
sickness, vertigo, diabetic retinopathy, small vessel complications
due to diabetes and such other conditions as may be related to the
activity of the norastemizole as an antagonist of the H-1 histamine
receptor. The compositions of the invention are also useful in
combination with non-steroidal anti-inflammatory agents or other
non-narcotic analgesics, and are useful for the treatment of cough,
cold, cold-like, and/or flu symptoms and the discomfort, headache,
pain, fever, and general malaise associated therewith. The
aforementioned combinations (e.g., norastemizole and a leukotriene
inhibitor) may optionally include one or more other active
components including a decongestant, cough suppressant/antitussive,
or expectorant.
[0010] The compositions of the invention can be used to treat,
prevent, or manage the disorders described herein while reducing or
avoiding adverse effects associated with administration of other
non-sedating antihistamines, such as astemizole.
[0011] In one embodiment, this invention provides a method of
preventing or treating asthma or the symptoms of asthma in a human
which comprises administering to a human a therapeutically
effective amount of norastemizole, or a pharmaceutically acceptable
salt thereof, and a therapeutically effective amount of a
leukotriene inhibitor, or a pharmaceutically acceptable salt
thereof.
[0012] The invention also provides a method of treating or
preventing asthma or the symptoms of asthma in a human which
comprises administering to a human a composition, said composition
comprising (i) a therapeutically effective amount of norastemizole
or a pharmaceutically acceptable salt thereof; (ii) a leukotriene
inhibitor selected from the group consisting of 5-lipoxygenase
inhibitors, 5-lipoxygenase activating protein antagonists, and
leukotriene receptor antagonists, or a pharmaceutically acceptable
salt thereof; (iii) optionally a therapeutically effective amount
of a decongestant; and a pharmaceutically acceptable carrier or
excipient.
[0013] This invention also includes a method of preventing or
treating asthma or the symptoms of asthma in a human which
comprises administering to a human a therapeutically effective
amount of norastemizole, or a pharmaceutically acceptable salt
thereof, a therapeutically effective amount of a leukotriene
inhibitor, or a pharmaceutically acceptable salt thereof, and a
therapeutically effective amount of a decongestant.
[0014] In a second embodiment, the invention also provides for a
method of preventing or treating allergic rhinitis in a human which
comprises administering to a human a therapeutically effective
amount of norastemizole, or a pharmaceutically acceptable salt
thereof, and either a leukotriene inhibitor or a decongestant, or
both, such that all three active ingredients are used.
[0015] In a third embodiment, the invention also provides for a
method of preventing or treating dermatitis in a human which
comprises administering to a human a therapeutically effective
amount of norastemizole, or a pharmaceutically acceptable salt
thereof, and either a leukotriene inhibitor or a decongestant, or
both, such that all three active ingredients are used.
[0016] In a fourth embodiment, the invention also provides for a
method of preventing or treating inflammation in a human which
comprises administering to a human a therapeutically effective
amount of norastemizole, or a pharmaceutically acceptable salt
thereof, and a leukotriene inhibitor, or a pharmaceutically
acceptable salt thereof.
[0017] The invention also provides a method of preventing or
treating inflammation in a human which comprises administering to a
human a composition, said composition comprising (i) a
therapeutically effective amount of norastemizole or a
pharmaceutically acceptable salt thereof; (ii) a leukotriene
inhibitor selected from the group consisting of 5-lipoxygenase
inhibitors, 5-lipoxygenase activating protein antagonists, and
leukotriene receptor antagonists, or a pharmaceutically acceptable
salt thereof; (iii) optionally a therapeutically effective amount
of a decongestant; and a pharmaceutically acceptable carrier or
excipient.
[0018] This invention also includes a method of preventing or
treating inflammation in a human which comprises administering to a
human a therapeutically effective amount of norastemizole, or a
pharmaceutically acceptable salt thereof, a therapeutically
effective amount of a leukotriene inhibitor, or a pharmaceutically
acceptable salt thereof, and a therapeutically effective amount of
a decongestant.
[0019] In a fifth embodiment, the invention also provides for a
method of preventing or treating a condition responsive to
leukotriene inhibition in a human which comprises administering to
a human a therapeutically effective amount of norastemizole, or a
pharmaceutically acceptable salt thereof, and either a leukotriene
inhibitor or a decongestant, or both, such that all three active
ingredients are used.
[0020] The invention encompasses the treatment, prevention and/or
management of asthma or the symptoms of asthma, allergic rhinitis,
inflammation, or dermatitis using a metabolite of astemizole,
preferably norastemizole, and a leukotriene inhibitor. The
invention also encompasses the treatment, prevention, and/or
management of these disorders with norastemizole and a
decongestant. Further, the invention encompasses the treatment,
prevention and/or management of these disorders using
norastemizole, a leukotriene inhibitor, and a decongestant. The
invention encompasses the treatment, prevention, and/or management
of these disorders using a single unit dosage form (solid or
liquid; preferably a solid) that contains norastemizole and either
a leukotriene inhibitor or a decongestant, or all three active
ingredients. However, it should be recognized that combination
therapy by separate administration of each active ingredient is
also contemplated. The methods and compositions of this invention
are believed to reduce or avoid adverse effects associated with
administration of non-sedating antihistamines, such as astemizole.
The methods and compositions described herein are believed to
provide superior or improved therapy over prior art methods and
compositions involving norastemizole in the absence of a
leukotriene inhibitor, or a leukotriene inhibitor in the absence of
norastemizole. Without being limited by theory, it is believed that
the combination of norastemizole, a leukotriene inhibitor, and
optionally a decongestant, provides superior, improved, and
synergistic effects unachievable by any of these compounds
alone.
4. DETAILED DESCRIPTION OF THE INVENTION
[0021] The administration of norastemizole, a leukotriene
inhibitor, and optionally a decongestant, in the methods of the
present invention may be made either concurrently or sequentially,
i.e., norastemizole, a leukotriene inhibitor, and an optional
decongestant may be administered as a combination, concurrently but
separately, or by the sequential administration, e.g., of
norastemizole, leukotriene inhibitor, and decongestant, or the
sequential administration of a leukotriene inhibitor, decongestant,
and norastemizole. The compositions administered in each of these
methods may be concurrent, sequential, or in any combination of
concurrent and/or sequential.
[0022] The major adverse effects to be avoided by the methods and
compositions of the present invention include, but are not limited
to, cardiotoxicity, such as cardiac arrythmia.
[0023] Astemizole and other non-sedating antihistamines have
antihistaminic activity and provide therapy and a reduction of
symptoms for a variety of conditions and disorders related to
allergic rhinitis and other allergic disorders, diabetes mellitus,
and other conditions; however, such drugs, while offering the
expectation of efficacy, may cause adverse effects. Utilizing
norastemizole in combination with a leukotriene inhibitor, and
optionally with a decongestant, results in clearer dose-related
definitions of efficacy, diminished adverse effects, a superior
therapy due to synergistic activity, and accordingly, an improved
therapeutic index. It is, therefore, more desirable to use the
compositions and methods of the invention than to use astemizole,
or norastemizole, itself or other non-sedating antihistamines.
Norastemizole and its salts can be synthesized, for example, as
described in U.S. Pat. Nos. 4,835,161, 4,556,660, and 4,219,559,
which are expressly incorporated herein by reference thereto for
this purpose.
[0024] The term "adverse effects" as used herein includes, but is
not limited to, cardiac arrhythmias, cardiac conduction
disturbances, appetite stimulation, weight gain, sedation,
gastrointestinal distress, headache, dry mouth, constipation, and
diarrhea. The term "cardiac arrhythmias" includes, but is not
limited to, ventricular tachyarrhythmias, torsades de pointes, and
ventricular fibrillation.
[0025] The phrase "therapeutically effective amount of
norastemizole" as used herein means that amount of norastemizole
which provides a therapeutic benefit in the treatment, management,
or prevention of conditions that are responsive to histamine
antagonists, such as urticaria, allergic rhinitis, inflammation,
symptomatic dermographism, dermatitis, asthma, allergic asthma,
retinopathy or other small vessel disorders associated with
diabetes mellitus, and the symptoms associated with asthma or
allergic rhinitis such as cough, cold, cold-like, wheezing,
dyspnea, and/or flu symptoms including, but not limited to,
sneezing, rhinorrhea, lacrimation, and dermal irritation.
[0026] The phrase "therapeutically effective amount" with respect
to leukotriene inhibitor as used herein means that amount of
leukotriene inhibitor that provides a therapeutic benefit in the
treatment, prevention, or management of conditions that are
responsive to leukotriene inhibitors, such as urticaria, allergic
rhinitis, inflammation, symptomatic dermographism, dermatitis,
asthma, allergic asthma, retinopathy or other small vessel
disorders associated with diabetes mellitus, and the symptoms
associated with asthma or allergic rhinitis such as cough, cold,
cold-like, wheezing, dyspnea, and/or flu symptoms including, but
not limited to, sneezing, rhinorrhea, lacrimation, and dermal
irritation.
[0027] The phrase "therapeutically effective amount" with respect
to decongestant as used herein means that amount of decongestant
alone, or in combination with other drugs, that provides a
therapeutic benefit in the treatment, prevention, or management of
any condition that is responsive to decongestants, such as
congestion of the respiratory tract and/or the sinuses, and the
symptoms associated with congestion, such as cough, cold,
cold-like, wheezing, dyspnea, and/or flu symptoms including, but
not limited to, sneezing, rhinorrhea, lacrimation, and dermal
irritation.
[0028] The term "asthma" as used herein is defined as a disorder
characterized by increased responsiveness of the trachea and
bronchi to various stimuli, which results in symptoms that include,
but are not limited to, wheezing, cough, shortness of breath,
dyspnea, and the like. Asthma includes, for example, allergic
asthma.
[0029] The term "dermatitis" as used herein is that disorder caused
by inflammation to the skin including endogenous and contact
dermatitis such as, but not limited to: actinic dermatitis (or
photodermatitis), atopic dermatitis, chemical dermatitis, cosmetic
dermatitis, dermatitis aestivalis, and seborrheic dermatitis.
[0030] The term "inflammation" as used herein is a fundamental
pathologic process of a dynamic complex of cytologic and chemical
reactions that occur in the affected blood vessels and adjacent
tissues in response to an injury or abnormal stimulation caused by
a physical, chemical, or biologic agent, including: the local
reactions and resulting morphologic changes; the destruction or
removal of the injurious material; and the responses that lead to
repair and healing. The typical signs of inflammation are redness,
heat or warmth, swelling, pain, and occasionally inhibited or lost
function. All of the signs may be observed in certain instances,
although any particular sign is not necessarily always present.
[0031] The term "leukotriene inhibitor" as used herein includes any
agent or compound that inhibits, restrains, retards or otherwise
interacts with the action or activity of leukotrienes, such as, but
not limited to, 5-lipoxygenase ("5-LO") inhibitors, 5-lipoxygenase
activating protein ("FLAP") antagonists, and leukotriene receptor
antagonists ("LTRAs"). An exemplary LTRA is leukotriene D.sub.4
("LTD.sub.4") receptor antagonist.
[0032] The term "5-lipoxygenase inhibitor" or "5-LO inhibitor" as
used herein includes any agent or compound that inhibits,
restrains, retards or otherwise interacts with the enzymatic action
of 5-lipoxygenase, such as, but not limited to, zileuton,
docebenone, piripost, and ICI-D2318
[0033] The term "5-lipoxygenase activating protein antagonist" or
"FLAP antagonist" as used herein includes any agent or compound
that inhibits, restrains, retards or otherwise interacts with the
action or activity of 5-lipoxygenase activating protein, such as,
but not limited to, MK-591 and MK-886.
[0034] The term "leukotriene receptor antagonist" or "LTRA" as used
herein includes any agent or compound that inhibits, restrains,
retards or otherwise antagonizes the activity of receptors that are
responsive to leukotrienes, including those responsive to
leukotriene D.sub.4. Exemplary LTRAs include, but are not limited
to, sodium
1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethynyl)phenyl)-3-(2-.(2-hydroxy-
-2-propyl)phenyl)thio)methyl)cyclopropaneacetate;
1-(((1(R)-(3(2-(2,3-dich-
lorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methy-
lethyl)phenyl)propyl),thio)methyl)cyclopropaneacetic acid or sodium
or other salts thereof, pranlukast, zafirlukast (ICI-204219), and
montelukast (MK-476), the latter of which is sold commercially as
SINGULAIR.RTM..
[0035] The magnitude of a prophylactic or therapeutic dose of
norastemizole or leukotriene inhibitor in the acute or chronic
management of a disorder or condition will vary with the severity
of the condition to be treated and the route of administration. The
dose, and perhaps the dose frequency, will also vary according to
the age, body weight, and response of the individual patient.
Suitable total daily dose ranges can be readily determined by those
skilled in the art. In general, the total daily dose range for
norastemizole, for the conditions described herein, is from about 1
mg to about 200 mg administered in single or divided doses orally,
topically, transdermally, or locally by inhalation. For example, a
preferred oral daily dose range should be from about 10 mg to about
100 mg. A preferred oral daily dose range of decongestant, such as
pseudoephedrine, should be from about 50 mg to about 300 mg, more
preferably, about 150 mg to about 250 mg. In addition, suitable
oral daily dosage ranges of leukotriene inhibitor can be readily
determined by those skilled in the art. For example, see the
Physician's Desk Reference.RTM. 1998 for suitable dosages presently
used for known leukotriene inhibitors. For example, for
5-lipoxygenase inhibitors, the oral daily dose range should be from
about 20 mg to 2,500 mg, preferably from about 20 mg to 800 mg. For
leukotriene receptor antagonists, the oral daily dose range should
be from about 2 mg to 100 mg, preferably from about 5 mg to 20
mg.
[0036] It is further recommended that children, patients aged over
65 years, and those with impaired renal or hepatic function
initially receive low doses, and that they then be titrated based
on individual response(s) or blood level(s). It may be necessary to
use dosages outside these ranges in some cases as will be apparent
to those skilled in the art. Further, it is noted that the
clinician or treating physician will know how and when to adjust,
interrupt, or terminate therapy in conjunction with individual
patient response.
[0037] The term "therapeutically effective amount of norastemizole
or a pharmaceutically acceptable salt thereof" is encompassed by
the above-described dosage amounts. In addition, the terms "said
composition comprising (i) a therapeutically effective amount of
norastemizole or a pharmaceutically acceptable salt thereof; and
(ii) "a therapeutically effective amount of a decongestant"; "said
composition comprising (i) a therapeutically effective amount of
norastemizole or a pharmaceutically acceptable salt thereof; and
(ii) a therapeutically effective amount of a leukotriene
inhibitor"; and "said composition comprising (i) a therapeutically
effective amount of norastemizole or a pharmaceutically acceptable
salt thereof; (ii) a therapeutically effective amount of a
leukotriene inhibitor; and (iii) a therapeutically effective amount
of decongestant" are also encompassed by the above-described dosage
amounts and dose frequency schedule.
[0038] Any suitable route of administration may be employed for
providing the patient with an effective dosage of norastemizole
according to the methods of the present invention. For example,
oral, intraoral, rectal, parenteral, epicutaneous, transdermal,
subcutaneous, intramuscular, intranasal, sublingual, buccal,
intradural, intraocular, intrarespiratory, or nasal inhalation and
like forms of administration may be employed. Oral administration
is generally preferred. For the methods to treat dermatitis,
however, topical administration is preferred.
[0039] The pharmaceutical compositions used in the methods of the
present invention, which are sterile and stable, include
norastemizole, the metabolic derivative of astemizole, and either a
leukotriene inhibitor, or a decongestant, or both, as the active
ingredients, or pharmaceutically acceptable salts thereof. The
compositions may also contain a pharmaceutically acceptable carrier
or excipient, and optionally, other therapeutic ingredients. The
compositions are preferably single solid unit doses, e.g.,
capsules, tablets, or the like.
[0040] The term "pharmaceutically acceptable salt" refers to a salt
prepared from pharmaceutically acceptable non-toxic acids or bases
including inorganic acids or bases or organic acids or bases.
Examples of such inorganic acids are hydrochloric, hydrobromic,
hydroiodic, sulfuric, and phosphoric. Appropriate organic acids may
be selected, for example, from aliphatic, aromatic, carboxylic and
sulfonic classes of organic acids, examples of which are formic,
acetic, propionic, succinic, glycolic, glucuronic, maleic, furoic,
glutamic, benzoic, anthranilic, salicylic, phenylacetic, mandelic,
embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic,
benzenesulfonic, stearic, sulfanilic, algenic, and galacturonic.
Examples of such inorganic bases include metallic salts made from
aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc.
Appropriate organic bases may be selected, for example, from
N,N-dibenzylethylenediamine, chloroprocaine, choline,
diethanolamine, ethylenediamine, meglumaine
(N-methylglucamine),lysine and procaine.
[0041] The compositions for use in the methods of the present
invention can include suitable excipients or carriers such as
starches, sugars, microcrystalline cellulose, diluents, granulating
agents, lubricants, binders, disintegrating agents, and the
like.
[0042] Dosage forms include tablets, troches, dispersions,
suspensions, solutions, capsules, patches, gel caps, syrups,
elixirs, gels, powders, magmas, lozenges, ointments, creams,
pastes, plasters, lotions, discs, suppositories, nasal or oral
sprays, aerosols, and the like.
[0043] Because of their ease of administration, tablets and
capsules represent the most advantageous oral dosage unit form, in
which case solid pharmaceutical carriers are employed. If desired,
tablets may be coated by standard aqueous or nonaqueous
techniques.
[0044] In addition to the common dosage forms set out above, the
compound for use in the methods of the present invention may also
be administered by controlled release means and/or delivery devices
such as those described in U.S. Pat. Nos. 3,845,770; 3,916,899;
3,536,809; 3,598,123; and 4,008,719, the disclosures of which are
incorporated herein by reference thereto.
[0045] Preferred compositions containing norastemizole are lactose
free solid oral compositions. Additional preferred suitable
compositions containing norastemizole for use according to the
invention include non-hygroscopic and anhydrous norastemizole solid
oral compositions.
[0046] Pharmaceutical compositions for use in the methods of the
present invention may be prepared by any of the methods of
pharmacy, but all methods include the step of bringing into
association the active ingredient(s) with the carrier, which
constitutes one or more necessary ingredients. In general, the
compositions are prepared by uniformly and intimately admixing the
active ingredient with liquid carriers or finely divided solid
carriers or both, and then, if necessary, shaping the product into
the desired presentation.
[0047] For example, a tablet may be prepared by compression or
molding, optionally, with one or more accessory ingredients.
Compressed tablets may be prepared by compressing in a suitable
machine the active ingredient in a free-flowing form such as powder
or granules, optionally mixed with a binder, lubricant, inert
diluent, surface active or dispersing agent. Molded tablets may be
made by molding, in a suitable machine, a mixture of the powdered
compound moistened with an inert liquid diluent. Preferably, the
tablet, cachet or capsule contains either of the following dosages:
15 mg, 30 mg, or 45 mg of norastemizole, in combination with the
leukotriene inhibitor and/or decongestant.
[0048] The invention is further defined by reference to the
following example describing in detail the preparation of the
composition and the compositions used in the methods of the present
invention, as well as their utility. It will be apparent to those
skilled in the art that many modifications, both to materials and
methods, may be practiced which are within the scope of this
invention.
5. EXAMPLES
5.1 Example 1
Preparation of Norastemizole
[0049] Norastemizole may be synthesized, for example, by the
methods disclosed in U.S. Pat. Nos. 4,219,559 and 4,835,161, which
are hereby incorporated herein by express reference thereto.
Norastemizole may also be prepared by the reaction steps disclosed
in WO 94/07495, published Apr. 14, 1994. Reaction of an
isothiocyanate with phenylenediamine gives a corresponding
thiourea. N-Alkylation with p-fluorobenzylbromide gives a secondary
amine which, upon cyclization, yields a substituted benzimidazole.
Treatment of the benzimidazole with base hydrolyzes the urethane
moiety to give norastemizole. N-Alkylation of norastemizole with
p-methoxyphenethyl bromide yields astemizole. Astemizole can be
converted to desmethylastemizole by demethylation using, for
example, a Lewis acid, such as boron trifluoride, boron
trichloride, aluminum trichloride, and the like.
[0050] Various modifications of the invention in addition to those
shown and described herein will be apparent to those skilled in the
art from the foregoing description. Such modifications are also
intended to fall within the scope of the appended claims.
[0051] The foregoing disclosure includes all the information deemed
essential to enable those skilled in the art to practice the
claimed invention. Because the cited patents or publications may
provide further useful information these cited materials are
incorporated herein in their entireties by reference thereto.
* * * * *