U.S. patent application number 09/784640 was filed with the patent office on 2001-09-27 for antihistamine leukotriene combinations.
Invention is credited to Engel, Jurgen, Poppe, Hildegard, Szelenyi, Istvan.
Application Number | 20010025040 09/784640 |
Document ID | / |
Family ID | 7631276 |
Filed Date | 2001-09-27 |
United States Patent
Application |
20010025040 |
Kind Code |
A1 |
Poppe, Hildegard ; et
al. |
September 27, 2001 |
Antihistamine leukotriene combinations
Abstract
The invention relates to a pharmaceutical composition for the
treatment of allergic rhinitis, vasomotor rhinitis, and allergic
conjunctivitis, which comprises (a) a nonsedating antihistamine or
a pharmaceutically acceptable salt thereof, (b) a leukotriene
D.sub.4 antagonist, or a 5-lipoxygenase inhibitor, or a FLAP
antagonist, or a pharmaceutically acceptable salt thereof, and (c)
one or more of a conventional pharmaceutical vehicle, extender, and
excipient, and to its use for manufacturing a composition for the
treatment of allergic rhinitis, vasomotor rhinitis, and allergic
conjunctivitis.
Inventors: |
Poppe, Hildegard; (Dresden,
DE) ; Engel, Jurgen; (Alzenau, DE) ; Szelenyi,
Istvan; (Schwaig, DE) |
Correspondence
Address: |
Gabriel P. Katona L.L.P.
14th Floor
708 Third Avenue
New York
NY
10017
US
|
Family ID: |
7631276 |
Appl. No.: |
09/784640 |
Filed: |
February 15, 2001 |
Current U.S.
Class: |
514/217.05 ;
514/397 |
Current CPC
Class: |
A61P 37/08 20180101;
A61K 47/38 20130101; A61P 11/00 20180101; A61P 27/02 20180101; A61P
37/00 20180101; A61K 31/55 20130101; A61K 9/0043 20130101; A61K
31/4709 20130101; A61P 11/06 20180101; A61K 45/06 20130101; A61K
31/47 20130101; A61P 11/02 20180101; A61K 9/08 20130101; A61K 9/10
20130101; A61P 43/00 20180101; A61K 31/55 20130101; A61K 2300/00
20130101; A61K 31/47 20130101; A61K 2300/00 20130101; A61K 31/4709
20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/217.05 ;
514/397 |
International
Class: |
A61K 031/55 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 17, 2000 |
DE |
100 07 203.8 |
Claims
We claim:
1. A pharmaceutical composition for the treatment of allergic
rhinitis, vasomotor rhinitis, and allergic conjunctivitis, which
comprises (a) a nonsedating antihistamine or a pharmaceutically
acceptable salt thereof (b) a leukotriene D.sub.4 antagonist, or a
5-lipoxygenase inhibitor, or a FLAP antagonist, or a
pharmaceutically acceptable salt thereof, and (c) one or more of a
conventional pharmaceutical vehicle, extender, and excipient..
2. The pharmaceutical composition of claim 1, in which the
nonsedating antihistamine is azelastine, levocabastine, cetirizine,
fexofenadine, mizolastine, or astemizole..
3. The pharmaceutical composition of claim 1, wherein the
leukotriene D.sub.4 antagonist is montelukast, zafirlukast or
pranlukast.
4. The pharmaceutical composition of claim 1, wherein the
5-lipoxygenase inhibitor is zileuton, piriprost or AWD 23-115.
5. The pharmaceutical composition of claim 1, wherein the FLAP
antagonist is MK-591, MK-886 or Bay X 1005.
6. The pharmaceutical composition of claims 1, wherein the
concentration of the nonsedating antihistamine or salt is from
0.001 wt. % to 0.5 wt. % based on the composition..
7. The pharmaceutical composition of claim 1, wherein the
concentration of the leukotriene D.sub.4antagonist or salt is from
0.01 wt. % to 5 wt. % based on the composition..
8. The pharmaceutical composition of claim 1, wherein the
concentration of the 5-lipoxygenase inhibitor or salt is from 0.01
wt. % to 5 wt. % based on the composition..
9. The pharrmaceutical composition of claim 1, wherein the
concentration of the FLAP antagonist or salt is from 0.01 wt. % to
5 wt. % based on the composition.
10. The pharmaceutical composition of claim 1, wherein the
concentration of said leukotriene D.sub.4 antagonist,
5-lipoxygenase inhibitor, or FLAP antagonist, or a pharmaceutically
acce ptable salt is from 0.01 wt. % to 5 wt. % based on the
composition..
11. The pharmaceutical composition of claim 10 in a dosage form for
topical administration.
12. The pharmaceutical composition of claim 10 in a dosage form for
oral administration.
13. The pharmaceutical composition of claim 11, wherein the dosage
form for topical administration is a spray.
14. The pharmaceutical composition of claim 11, wherein the dosage
form for topical administration is a nasal or eye drop.
15. A process for preparing the pharmaceutical composition of claim
1, which comprises combining said antihistamine and said component
(b) with said component (c) and converting the resulting
combination into a dosage form for administration.
16. Use of a composition of (a) a nonsedating antihistamine or a
pharmaceutically acceptable salt thereof, (b) a leukotriene D.sub.4
antagonist, or a 5-lipoxygenase inhibitor, or a FLAP antagonist, or
a pharmaceutically acceptable salt thereof, for preparing a
pharmaceutical composition or pharmaceutical agents, for the
simultaneous or sequential treatment of allergic rhinitis,
vasomotor rhinitis, and allergic conjunctivitis.
17. Use of the pharmaceutical composition or ingredients of claim
16, wherein the nonsedating antihistamine is azelastine,
levocabastine, cetirizine, fexofenadine, mizolastine, or
astemizole.
18. Use of the pharmaceutical composdition or ingredients of claim
16, wherein the leukotriene D.sub.4 antagonist is zafirlukast,
montelukast or pranlukast, the 5-lipoxygenase inhibitor is
zileuton, piripost or AWD 23-115, and the FLAP antagonist is
MK-591, MK-886 or Bay 1005.
19. A pharmaceutical package containing the pharmaceutical
composition of claim 1, further containing instructions for its use
for the treatment of allergic rhinitis, vasomotor rhinitis, and
allergic conjuntivitis.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to pharmaceutical compositions
which contain a nonsedating antihistamine and a substance
influencing leukotriene action to improve the local therapy of
allergic and/or vasomotor rhinitis and of allergic
conjunctivitis.
BACKGROUND
[0002] The number of allergic disorders is greatly increasing
worldwide. Studies have shown that on average worldwide 7.5% of all
children and adolescents suffer from rhinoconjunctivitis which is
hay fever combined with an ocular symptomatology (Worldwide
variation in prevalence of symptoms of asthma, allergic
rhinoconjunctivitis and atopic eczema: ISAAC, Lancet, 351,
1225-1332, 1998). In West European countries, the prevalence, at
about 14%, is markedly higher (Annesi-Maesano, I. and Oryszczyn, M.
P.: Rhinitis in adolescents, Results of the ISAAC survey, Revue
Francaise d'Allergologie et d'Immunologie Clinique, 38, 283-289,
1998; Norrman, E., L. Nystrom, E. Jonsson and N. Stjernberg:
Prevalence and incidence of asthma and rhinoconjunctivitis in
Swedish teenagers, European Journal of Allergy and Clinical
Immunology, 53, 28-35, 1998).
[0003] Intensive research activities of recent years have led to
the recognition that allergic rhinoconjunctivitis is an
inflammatory process in the sense of a persistent inflammatory
reaction. While histamine is still regarded as the most important
mediator of the early phase and as the most important trigger of
the symptoms such as reddening, sneezing, itching and
hypersecretion (rhinorrhea and lacrimation), further mediators such
as the leukotrienes are involved in the nasal obstruction,
secretion and in the progression of the inflammation (e.g.
attraction of the proinflammatory cells, promotion of cellular
infiltration, etc.). Accordingly, the aims of the therapy have been
shifted from symptomatic therapy to an additional antiinflammatory
therapy with influencing of the inflammation underlying the
allergic disorders. Both histamine and leukotrienes (LTs) are
released in the allergic early phase and late phase.
[0004] The acute symptoms (itching, reddening, swelling, rhinorrhea
and lacrimation) of rhinoconjunctivitis can be readily controlled,
inter alia, with the aid of classical antihistamines of the first
and second generations. However, they hardly have a therapeutically
relevant influence on the inflammation which underlies the disorder
and is always progressive. Often, the allergic rhinitis
(rhinoconjunctivitis) is regarded both by patients and by the
physician as a trivial disorder and accordingly is only
inadequately treated. As a result, however, a so-called change of
stage can occur, i.e. bronchial asthma, which is to be taken very
seriously, develops from the relatively harmless rhinitis. For this
reason, it is indispensable to treat even allergic
rhinoconjunctivitis adequately and intensively. Only then can the
patients live symptom-free and only then can a change of stage,
which under certain circumstances is life-threatening, be
prevented.
[0005] Numerous animal experimental and clinical studies indicate
that both histamine and LTs can be detected in nasal secretion
(Yamasaki, U., T. Matsumoto, S. Fukuda, T. Natayama, H. Nagaya, Y.
Ashida. Involvement of thromboxane A.sub.2 and histamine in
experimental allergic rhinitis of guinea pigs. J. Pharmacol. Exp.
Ther. 82:1046, 1997; Pipkorn, U, G Karlsson, L Enerbeck. Cellular
response of the human allergic nasal mucosa to natural allergen
exposure. J. Allergy Clin. Immunol. 35:234, 1988; Volovitz, B., S.
L. Osur, M. Berstein, P. L. Ogra. Leukotriene C.sub.4 release in
upper respiratory mucosa during natural exposure to
ragweed-sensitive children. J. Allergy Clin. Immunol. 82:414,
1988). Owing to the blockade of the histamine H.sub.1 receptors,
certain symptoms such as sneezing, reddening, itching and nasal or
ocular hypersecretion (rhinorrhea, lacrimation) are significantly
reduced (Simons, F. E. R., K. J. Simons. Second generation
H.sub.1-receptor antagonists. Ann. Allergy 66:5, 1991). In the
acute phase of any allergic reaction--independently of the
location--degranulation and the emptying of the intracellular
stores of the mast cells or of the basophilic granulocytes are
prominent. This is a process which is controlled by the extra- or
intracellular calcium.
[0006] Histamine, however, does not only act as a mediator which
induces allergic symptoms, it also acts on the allergic
inflammation by influencing the release of cytokines. In a study on
human conjunctival epithelial cells (eye), it was shown that
histamine greatly increases the secretion of II-8 and GM-CSF
(granulocyte macrophage colony stimulating factor). This release
can be prevented by histamine H.sub.1 receptor antagonists, i.e.
this action is mediated via H.sub.1 receptors (Weimer, L. K., D. A.
Gamache, J. M. Yanni. Histamine-stimulated cytokine secretion from
human conjunctival epithelial cells: inhibition by histamine
H.sub.1-antagonist emedastine. Int. Arch. Allergy Immunol. 115:288,
1998). In addition, we know that allergic stimulation not only
releases the intracellularly stored histamine from the mast cells
and basophilic granulocytes, but also brings about the de novo
synthesis of other mediators such as leukotrienes.
[0007] Leukotrienes are mediators which belong to the group of
eicosanoids. They are derivatives of arachidonic acid, a fatty acid
which is a constituent of membrane phospholipids. The leukotrienes
are formed from arachidonic acid via 5-lipoxygenase (5-LOX). At the
present time, only the pathogenetically relevant role of the
so-called cysteinyl-leukotrienes, to which LTC.sub.4, LTD.sub.4 and
LTE.sub.4 belong, has been confirmed. The action of the
leukotrienes can take place due to occupation of their receptors or
by inhibition of their synthesis. In addition to the inhibition of
5-lipoxygenase, the inhibition of a 5-lipoxygenase-activating
protein (hereinafter also referred to as "FLAP") can also lead to
decreased synthesis of leukotrienes.
[0008] Among the numerous LT antagonists, a few, such as
zafirlukast, montelukast, pranlukast, etc. are employed
therapeutically in bronchial asthma.
[0009] Zileuton is on the market of the 5-LOX inhibitors. The
so-called FLAP inhibitors include, for example, MK-591, Bay 1005,
which are still in the clinical testing phase.
[0010] Numerous investigations confirm the importance of the
leukotrienes in allergic disorders. Thus after allergen provocation
a marked increase in the LT concentration in the nasal lavage fluid
of patients with allergic rhinitis was detected both in the early
phase and in the late phase (Creticos, P. S., S. P. Peters, N. F.
Adkinson. Peptide leukotriene release after antigen challenge in
patients sensitive to ragweed. N. Eng. J. Med. 310:1626, 1984).
Cysteinyl-LTs can induce hypersecretion (rhinorrhea or
lacrimation), but the leukotrienes appear to be far more important
for nasal obstruction.
[0011] The nasal obstruction induced by histamine is present in the
early phase of the allergic reaction and lasts only minutes, while
the obstruction due to leukotrienes can be observed up to the late
phase, which lasts 6-8 hours after the allergic provocation. In
contrast to histamine, sneezing and itching do not occur after LT
provocation (Okuda, M., T. Watase, A. Mazewa, C. M. Liu. The role
of leukotrine D.sub.4 in allergic rhinitis. Ann. Allergy 60:537,
1988). After provocation with LTD.sub.4, however, there is a
long-lasting infiltration of eosinophilic granulocytes, which for
the greatest part are responsible for the allergic inflammation
(Fujika, M. et al. see above).
[0012] These so-called late-phase reactions (e.g. nasal
obstruction) can be improved by LT antagonists such as zafirlukast
(Donnelly, A. L., M. Glass, M. C. Minkwitz, T. B. Casale. The
leukotriene D.sub.4-receptor antagonist ICI 204219 relieves
symptoms of acute seasonal allergic rhinitis. Am. J. Resp. Crit.
Care Med. 151:1734, 1995) (ICI 204219=Zafirlukast). The 5-LOX
inhibitors are also able markedly to reduce allergic reactions not
only in animal experiments, but also in human therapy (Liu, M. C.,
L. M. Dube, J. Lancaster, and the zileuton study group. Acute and
chronic effects of a 5-lipoxygenase inhibitor in asthma: a 6-month
randomized multicenter trial. J. Allergy Clin. Immunol. 98:859,
1996).
[0013] Azelastine is presently the only active compound among the
antihistamines which is available both systemically as a tablet,
and topically as nasal spray and eye drops. Accordingly, patients
even with very strongly pronounced allergic symptoms can be
successfully treated. Patients can be individually treated with
various pharmaceutical formulations of azelastine depending on the
nature and degree of severity of the symptoms and thus the
inflammation underlying the disorder can be suppressed.
[0014] Of the modern antihistamines, azelastine was the first in
which the inhibition of the synthesis of the leukotrienes important
for the allergic inflammatory reaction was observed in
therapeutically relevant doses or concentration
(Achterrath-Tuckermann, U., Th. Simmet, W. Luck, I. Szelenyi, B. A.
Peskar. Inhibition of cysteinyl-leukotriene production by
azelastine and its biological significance. Agents and Actions 24:
217, 1988). This antileukotriene effect of azelastine is also
detected in controlled clinical studies in allergics (Shin, M. H.,
F. M. Baroody, D. Proud, A. Kagey-Sobotka, L. M. Lichtenstein, M.
Naclerio. The effect of azelastine on the early allergic response.
Clin. Exp. Allergy 22:289, 1992). The clinical efficacy of
azelastine that is comparable with budesonide, a glucocorticoid,
can then also be explained as due to this action. (Wang, D. Y., J.
Smitz, M. De Waele, P. Clement. Effect of topical applications of
budesonide and azelastine on nasal symptoms, eosinophil counts and
mediator release in atopic patients after nasal allergen challenge
during the pollen season. Int. Arch. Allergy Immunol. 114:185,
1997; Gastpar, H., R. Aurich, U. Petzold. Intranasal treatment of
perennial rhinitis: Comparison of azelastine nasal spray and
budesonide nasal aerosol. Arzn. Forsch.--Drug Res. 43:475,
1993).
[0015] The action mechanism by which azelastine inhibits LT
synthesis and LT release is unique and is not described in the case
of other antihistamines. As is known, many release processes
proceed through an increased level of intracellular Ca.sup.2+,
which takes place due to allergic stimulation of the effector
cells, since intracellular Ca.sup.2+ initiates the decisive steps
for increased leukotriene synthesis and release. Azelastine
inhibits intracellular Ca.sup.2+ release (Takanaka, K. Effects of
azelastine on polymorphonuclear leukocytes: arachidonate cascade
inhibition mechanism. Progress Med. 275, 1987; Chand, N., et al.
Inhibition of allergic and non-allergic leukotriene formation and
histamine secretion by azelastine: Implication for its mechanism of
action. Int. Arch. Allergy Appl. Immunol. 90:67, 1989; Senn, N., et
al. Action of azelastine on intracellular Ca.sup.2+ in cultured
airway smooth muscle. Eur. J. Pharmacol. 205:29, 1991; Chand, N.,
R. D. Sofia. A novel in vivo inhibitor of leukotriene biosynthesis:
A possible mechanism of action: A mini review. J. Asthm. 32:227,
1995).
[0016] The mechanism of action of the LT receptor antagonists is
simple in that as receptor antagonists, they occupy the LT
receptors. Accordingly, the released leukotrienes can approach
their receptors and display their actions which can be mediated by
the receptor.
[0017] Combinations for intranasal application, which contain an
antihistamine having leukotriene-inhibiting properties together
with a glucocorticosteroid and, if appropriate, decongestants,
antiallergics, mucolytics, nonopioid analgesics, lipoxygenase
inhibitors and leukotriene receptor antagonists, are disclosed in
EP 0 780 127 A1 and are recommended for the treatment of allergic
rhinoconjunctivitis. The cooperation of the antihistamine with the
glucocorticosteroid is expected to increase the effectiveness of
the treatment.
[0018] For the topical treatment of rhinitis, WO 98/48839 also
discloses the application of an antiinflammatory agent in the form
of corticosteroids, with an efficacy increasing addition of, for
example, at least a vasoconstrictor, a leukotriene inhibitor, an
antihistamine, an antiallergic, a mucolytic, an anaesthetic, an
anticholinergic or a neuraminidase inhibitor.
[0019] As disclosed in WO 98/34611, for the topical treatment of
allergic asthma, combinations are proposed of
descarboethoxyloratadine, a metabolite of the nonsedating
antihistamine loratadine, and a leukotriene antagonist, which can
be a leukotriene D.sub.4 antagonist, a 5-lipoxygenase inhibitor or
a FLAP antagonist. The use of descarboethoxyloratadine should avoid
a large number of undesired side effects of loratadine and other
nonsedating antihistamines.
[0020] A. Roquet et al. (Combined antagonism of leukotrienes and
Histamine produces predominant inhibition of allergen-induced early
and late phase airway obstruction in asthmatics. Am. J. Respir.
Crit. Care Med., 1997, 155; 1856-1863) investigated the actions of
loratadine, the leukotriene antagonist zafirlukast and the
combination of both active compounds in allergen-induced airway
disorders of asthmatics on oral administration.
[0021] From investigations by Merck & Co., WO 97/28797, it is
also known to administer loratadine with five selected leukotriene
antagonists, monetlukast, zafirlukast, pranlukast, sodium
1-(((R)-3-(2-(6,7-difluoro-2-
-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methyl)cy-
clopropaneacetate, 1
-(((1(R)-3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-
-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)meth-
yl)cyclopropaneacetic acid orally or parenterally in asthma,
allergy and inflammations.
[0022] A lack of remedial success in the treatment of allergic
rhinitis/conjunctivitis, and on account of numerous side effects of
introduced preparations, and the nonspecific therapy in some cases,
a great need exists for combinations having high effectiveness and
safety.
Description of the Invention
[0023] It is an object of the present invention to provide novel
combinations for the treatment of allergic
rhinitis/conjunctivitis.
[0024] The present invention relates to pharmaceutical substance
combinations which can be topically administered but also orally in
allergic and/or vasomotor rhinitis or allergic conjunctivitis, and
containing a nonsedating antihistamine with the exception of
loratadine and loratadine metabolites, suitably azelastine, but,
for example, also levocabastine, cetirizine, fexofenadine,
mizolastine, astemizole, in combination with a leukotriene D.sub.4
antagonist which influences leukotriene action, such as
montelukast, zafirlukast or pranlukast or with a 5-lipoxygenase
inhibitor, such as zileuton, piriprost or AWD 23-115
(1-[4-(quinolin-2-ylmethoxy)benzyl]-5-methoxy-1H-indazol-3-ol
dihydrochloride) or with a FLAP antagonist, such as MK-591, MK-886,
Bay 1005 respectively, and, if desired, further pharmaceutically
acceptable vehicles and/or extenders or excipients therefor.
[0025] The present invention furthermore relates to the provision
of a process for the prophylaxis and treatment of allergic and/or
vasomotor rhinitis or allergic conjunctivitis in a mammalian body,
by administering topically or orally to a patient in need therefor
a combination of a nonsedating antihistamine with the exception of
loratadine or loratadine metabolites, suitably azelastine, and also
for example, levocabastine, cetirizine, fexofenadine, mizolastine,
astemizole, with a leukotriene D.sub.4 antagonist which influences
leukotriene action, such as montelukast, zafirlukast or pranlukast
or with a 5-lipoxygenase inhibitor, such as zileuton, piriprost or
AWD 23-115 or with a FLAP antagonist, such as MK-591, MK-886, Bay
1005 topically or orally. Administration can be carried out
simultaneously, sequentially or separately. Therefore, as used
throughout the disclosure and claims the term "nonsedating
antihistamine" does not include loratadine and loratadine
metabolites.
[0026] The present invention also relates to suitable individual
dosage forms of a nonsedating antihistamine, suitably azelastine
but also for example, levocabastine, cetirizine, fexofenadine,
mizolastine, astemizole, in combination with a leukotriene D.sub.4
antagonist which influences leukotriene action, such as
montelukast, zafirlukast or pranlukast or with a 5-lipoxygenase
inhibitor, such as zileuton, piriprost or AWD 23-115 or with a FLAP
antagonist, such as MK-591, MK-886, Bay 1005, which are suitable
for easy topical or oral administration, for example in the form of
sprays or drops or tablets.
[0027] The novel combination of a nonsedating antihistamine (with
the exception of compounds of the loratadine type), suitably
azelastine, but also for example, levocabastine, cetirizine,
fexofenadine, mizolastine, astemizole and a leukotriene D.sub.4
antagonist which influences leukotriene action, such as
montelukast, zafirlukast or pranlukast or a 5-lipoxygenase
inhibitor, such as zileuton, piriprost or AWD 23-115 or a FLAP
antagonist, such as MK-591, MK-886 or Bay 1005, which can also be
present as pharmaceutically acceptable salts, can be given,
according to the invention, simultaneously, successively or
independently of one another, topically (intranasally or
intraocularly), or orally as a fixed combination or in individual
substances. If separate formulations are present, then these are
tailored to one another and contain the respective active compounds
in the dosage unit in the same amounts and corresponding weight
ratios in which they can be present in the combination.
[0028] As a result of the combination, there is not only a rapid
onset of action, but also a high therapeutic efficacy, which is
accompanied by a strong antiinflammatory action, since the modes of
action of the active compounds mentioned are mutually complementary
and also behave pharmacokinetically in a similar manner. The long
duration of action makes twice daily administration possible. If
the active components are present in the form of a fixed
combination, administration is simpler for the patient, because
both active compounds are contained in one tablet or one container.
The concentration of the antihistamine components according to the
present invention can be in the range from 0.001% to 0.5%.
[0029] The concentration of the leukotriene antagonists in the
combination can be in the range from 0.01% to 5%.
[0030] Suitable concentrations are 0.05% to 0.2% for the
antihistamine component and 0.5% to 2% for leukotriene
antagonists.
[0031] The intended dosage takes place once to twice daily. The
individual dose of the antihistamine is from 50 to 500 .mu.g,
suitably from 200 to 400 .mu.g administered topically.
[0032] On topical application, the dose of the leukotriene D.sub.4
antagonist is between from 100 to 2000 .mu.g, suitably from 200 to
1000 .mu.g.
[0033] 5-LOX or FLAP inhibitors are administered in a dose range
from 50 to 2000 .mu.g, suitably from 200 to 1000 .mu.g.
[0034] The dose of the antihistamine (for example azelastine) is
between 0.5 and 16 mg/day, suitably 2 and 8 mg/day.
[0035] In the case of the leukotriene D.sub.4 antagonists (for
example montelukast), the individual dose is from 1 to 50 mg/day,
suitably from 5 to 10 mg/day.
[0036] The oral dose of 5-LOX inhibitors such as zileuton is
between 1 and 6 g/day, suitably 0.6 and 2 g/day.
[0037] In the case of FLAP inhibitors, the dose is from 50 to 2000
mg/day, suitably from 100 to 500 mg/day.
[0038] The specific individual antihistamine and leukotriene
antagonist compounds mentioned above, and processes for their
preparation are known.
[0039] The preparation of the pharmaceutical combinations of the
present invention can take place according to customary methods,
suitably by mixing the antihistamine and the leukotriene antagonist
individually or together, if desired with vehicles and/or extenders
or excipients, and converting the mixture thus obtained into
suitable forms of administration.
[0040] The active compounds are administered orally or topically in
the form of a mixture, which contains customary pharmaceutical
extenders, excipients or vehicles for pharmaceutical purposes.
[0041] The compositions for oral or topical administration can be
formulated as different, pharmaceutically acceptable forms of
administration, e.g. nasal sprays, nasal drops, eye drops, tablets,
capsules or granules. Apart from the active compounds, the
compositions according to the present invention can also contain
various typical pharmaceutical additives such as antimicrobial
preservatives, osmotics, thickening agents, excipients for pH
adjustment or buffer systems.
[0042] Antimicrobial preservative substances include, for example,
benzalkonium chloride, cetylpyridinium chloride/bromide,
chlorobutanol, chlorhexidine acetate, chlorhexidine HCl,
chlorhexidine digluconate, chlorocresol, methylparaben,
propylparaben, phenoxyethanol, phenylmercury salts, sorbic acid,
thiomersal.
[0043] A combination of sodium edetate and benzalkonium chloride
can be suitably used as a preservative. Sodium edetate is used in
concentrations of from 0.05 to 0.1%, and benzalkonium chloride in
concentrations of from 0.005 to 0.05% wt., based on the
composition.
[0044] Suitable excipients for adjusting the tonicity or
osmolality, sodium chloride, potassium chloride, mannitol, glucose,
sorbitol, glycerol or propylene glycol in concentrations of from
about 0.1 to about 10% wt. can be used.
[0045] The compositions frequently contain thickeners to increase
the viscosity and to prolong and to improve the contact between the
pharmaceutical ingredient and body tissue. Suitable thickeners
include methylcellulose, hydroxypropylmethylcellulose,
hydroxyethylcellulose, sodium carboxymethylcellulose, polyvinyl
alcohol, polyvinyl-pyrrolidone, polyacrylates, polyacrylamide,
dextran, gellan gum, poloxamer or cellulose acetate phthalate.
[0046] Moreover, the compositions according to the present
invention comprise pharmaceutically acceptable buffers to adjust pH
in a range from about 4 to about 8, suitably from about 5.5 to
about 7.5. Buffers of this type include citrate, phosphate,
tromethamine, glycine, borate or acetate salts. These buffers can
also be derived from substances of the type such as citric acid,
primary or secondary sodium phosphate, glycine, boric acid, sodium
tetraborate, acetic acid and sodium acetate. Moreover, further
excipients such as hydrochloric acid or sodium hydroxide can also
be used for pH adjustment.
[0047] The present invention is further illustrated by the
following examples:
Example 1
[0048]
1 Nasal spray or nasal drops comprising azelastine hydrochloride
(0.1%) Azelastine hydrochloride 0.1000 g
Hydroxypropylmethylcellulose 0.1000 g Sodium edetate 0.0500 g
Benzalkonium chloride 0.0125 g Sodium hydroxide q.s. pH 6.0
Sorbitol solution 70% 6.6666 g Purified water to 100 ml
[0049] Preparation of the Solution:
[0050] Introduce about 45 kg of purified water into a suitable
stirrer-equipped container.
[0051] Add the azelastine HCl, hydroxypropylmethylcellulose, sodium
edetate, benzalkonium chloride and sorbitol solution successively
thereto and dissolve with stirring. Make up the resulting solution
to a volume of 49.5 liters with purified water. Adjust the pH of
the solution to pH 6.0 using 1N sodium hydroxide solution. Make up
to the final volume of 50.0 liters using purified water and stir.
Filter the solution through a membrane filter having a pore size of
0.2 .mu.m and dispense into bottles.
Example 2
[0052]
2 Nasal spray or nasal drop suspension containing montelukast (1%)
Montelukast 1.0000 g Avicel RC 591 1.1000 g Polysorbate 80 0.1000 g
Sorbitol solution 70% 6.0000 g Sodium edetate 0.0500 g Benzalkonium
chloride 0.0200 g Purified water to 100 ml
[0053] Preparation:
[0054] Introduce 45 kg of purified water into a suitable
stirrer-equipped container having a homogenizing device and
homogenize Avicel RC 591 therein at high speed. Then successively
dissolve the substances Polysorbate 80, sorbitol solution, sodium
edetate and benzalkonium chloride with stirring. Then homogenize in
the active compound montelukast at high speed until a uniform
suspension results. Then make up to the final volume of 50 liters
with purified water and homogenize further. Then evacuate the
suspension in order to remove the resulting air bubbles. The
resulting suspension is then dispensed into bottles.
Example 3
[0055]
3 Nasal spray or nasal drops comprising azelastine hydrochloride
(0.1% dissolved) and montelukast (1% suspended) Montelukast 1.0000
g Azelastine hydrochloride 0.1000 g Avicel RC 591 1.1000 g
Polysorbate 80 0.1000 g Sorbitol solution 70% 6.0000 g Sodium
edetate 0.0500 g Benzalkonium chloride 0.0200 g Purified water to
100 ml
[0056] Preparation:
[0057] Introduce 45 kg of purified water into a suitable
stirrer-equipped container having a homogenizing device and
homogenize Avicel RC 591 therein at high speed. Then successively
dissolve the azelastine hydrochloride active and the excipients
Polysorbate 80, sorbitol solution, sodium edetate and benzalkonium
chloride with stirring. Then homogenize in the montelukast active
at high speed until a uniform suspension results. Then make up to
the final volume of 50 liters with purified water and homogenize
further. Then evacuate the suspension in order to remove the
resulting air bubbles. The resulting suspension is then dispensed
into bottles.
[0058] From the spectra of action of some antihistamines and also
of LT antagonists or 5-LOX and FLAP inhibitors, it can be derived
that a combination of both substances displays a synergistic action
on the symptoms of allergic rhinoconjunctivitis.
[0059] The following pharmacological investigation describes the
action of azelastine and montelukast on their own and in
combination on a rhinitis model on brown Norway rats. The brown
Norway rats were actively sensitized by double i.p. injection of a
suspension of ovalbumin and aluminum hydroxide in physiological
saline solution on two successive days. Three weeks after
sensitization, a catheter was tied into the trachea of the animals
in orthograde manner under sodium thiopental anesthesia to maintain
the respiration of the animals and a further catheter was advanced
in a retrograde manner through the trachea up to the internal
opening of the choanas for the perfusion of the nasal cavities and
fixed. The nasal perfusate can thus trickle out through the nasal
cavities and be accepted by a fraction collector. The test
substances were either suspended in Tylose (montelukast) or
dissolved in physiological saline solution (azelastine) and
injected intraperitoneally 60 min before allergen provocation. PBS
was perfused through the nasal cavity for 30 min using a roller
pump (perfusion rate 0.5 ml/min) to rinse mucus away from the nose.
In the case of topical application, the test substances are added
to the perfusate in molar concentration and the solution is
perfused through the nose for 30 min before allergen provocation.
The plasma marker Evans Blue (1 ml/animal each of a 1% strength
solution in PBS) was then injected into the jugular vein. The
perfusion was collected during a 15 min break. The allergen
provocation (challenge) was then carried out by perfusion of the
nasal cavity with a solution of ovalbumin in PBS (10 mg/ml of
ovalbumin in PBS) for 60 min, during which the perfusate was
collected in the fraction collector in 15 min fractions. The total
amount of the samples/animal was 5. The samples were centrifuged
and then applied to microtiter plates and measured at a wavelength
of 620 nm using the Digiscan photometer. The blank values were
automatically subtracted. The course of action over 60 min was
calculated using an AUC program. The substance action of the
preparation group was calculated in % against vehicle controls.
[0060] An increased mucosal permeability after allergen provocation
is to be assessed as a sign of the release of messengers such as
histamine and leukotrienes. After antigen contact, this phenomenon
occurs even in allergic people and is manifested by increased fluid
secretion and nasal blockage.
4TABLE 1 Action of azelastine and montelukast alone and in
combination (intraperitoneal administration) on the nasal mucosal
permeability in actively sensitized and topically provoked brown
Norway rats Dose Inhibitory action Substance (mg/kg, i.p.) in %
Azelastine 0.01 11 0.1 39 0.3 42 1 47 Montelukast 0.1 7 1 26 3 39
10 44 30 58 Azelastine 0.01 + + 40* montelukast 0.1 *p <
0.05
[0061] The administration of azelastine alone in a dose of 0.01
mg/kg i.p. causes a small inhibition of the vascular permeability
of 11%. Montelukast is likewise slightly active in a dose of 0.1
mg/kg i.p. with 7% inhibition. The combinatory administration of
azelastine in a dose of 0.01 mg/kg i.p. and montelukast in a dose
of 0.1 mg/kg i.p. caused a superadditive inhibition of the mucosal
plasma extravasation of 40% (p<0.05).
[0062] Addition of the FLAP inhibitor Bay X 1005 inhibited the
nasal mucosal permeability in a dose of 0.1 mg/kg i.p. by 31%. AWD
23-115, and a 5-LOX inhibitor, in a dose range of 0.03 to 10 mg/kg
i.p. caused a dose-dependent inhibition (37-54%) of the vascular
permeability.
5TABLE 2 Action of azelastine and AWD 23-115 alone and in
combination (topical application in the perfusate) on the nasal
mucosal permeability in actively sensitized and topically provoked
brown Norway rats Dose Inhibitory action Substance (mmol/l) in %
Azelastine 0.003 3 0.01 40 0.03 60 AWD 23-115 0.1 12 0.3 32 1 49
Azelastine 0.003 + + 31* AWD 23-115 0.1 *p < 0.05
[0063] On topical application, the histamine H.sub.1 blocker
azelastine exhibits a strong inhibition of the mucosal plasma
extravasation even in concentrations of 0.003 to 0.03 .mu.mol/l.
The 5-LOX inhibitor AWD 23-115 inhibits the vascular permeability
at 0.3 and 1 .mu.mol/l in a dose-dependent manner by 32% and 49%
respectively.
[0064] If azelastine is given at a concentration of 0.003 .mu.mol/l
in combination with AWD 23-115 (0.1 .mu.mol/l), the inhibition of
the mucosal extravasation is 31% (p<0.05).
* * * * *