U.S. patent application number 10/106845 was filed with the patent office on 2002-11-28 for method of treating migraines and pharmaceutical compositions.
This patent application is currently assigned to Merck & Co., Inc.. Invention is credited to Hargreaves, Richard, Khannna, Deepak K., McKinney, Errol, Reines, Scott A., Sandquist, Eric J., Simitchieva, Kremena.
Application Number | 20020177617 10/106845 |
Document ID | / |
Family ID | 22312313 |
Filed Date | 2002-11-28 |
United States Patent
Application |
20020177617 |
Kind Code |
A1 |
Simitchieva, Kremena ; et
al. |
November 28, 2002 |
Method of treating migraines and pharmaceutical compositions
Abstract
A combination of a 5HT.sub.1B/1D agonist and a COX-2 selective
inhibitor is useful in the treatment and or prevention of
migraine.
Inventors: |
Simitchieva, Kremena;
(Basking Ridge, NJ) ; Reines, Scott A.; (New Hope,
PA) ; McKinney, Errol; (Doylestown, PA) ;
Sandquist, Eric J.; (Doylestown, PA) ; Khannna,
Deepak K.; (Furlong, PA) ; Hargreaves, Richard;
(Terlings Park, GB) |
Correspondence
Address: |
MERCK AND CO INC
P O BOX 2000
RAHWAY
NJ
070650907
|
Assignee: |
Merck & Co., Inc.
|
Family ID: |
22312313 |
Appl. No.: |
10/106845 |
Filed: |
March 26, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10106845 |
Mar 26, 2002 |
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09934823 |
Aug 22, 2001 |
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6384034 |
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09934823 |
Aug 22, 2001 |
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09429274 |
Oct 29, 1999 |
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60106605 |
Nov 2, 1998 |
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Current U.S.
Class: |
514/374 ;
514/406 |
Current CPC
Class: |
A61K 45/06 20130101;
A61P 25/06 20180101; A61K 31/42 20130101; A61K 31/54 20130101; A61K
31/415 20130101; A61K 2300/00 20130101; A61K 31/41 20130101; A61K
31/42 20130101; A61K 31/40 20130101; A61K 31/42 20130101 |
Class at
Publication: |
514/374 ;
514/406 |
International
Class: |
A61K 031/421; A61K
031/415 |
Claims
What is claimed is:
1. A method of treating or preventing migraine in a mammalian
patient in need of such treatment, which comprises administering to
the patient a COX-2 selective inhibiting compound and a
5HT.sub.1B/1D agonist, or salts or hydrates thereof, in amounts
that are effective for treating or preventing migraines.
2. The method according to claim 1 wherein the 5HT.sub.1B/1D
agonist is selected from the group consisting of: sumitriptan,
naratriptan, zolmitriptan, eleptriptan, almatriptan and rizatriptan
and the COX-2 selective inhibiting compound is selected from the
group consisting of: meloxicam, MK-663, VIOXX.RTM., RS 57067,
celecoxib, valdecoxib and a compound of structure: 4
3. The method according to claim 2 wherein the COX-2 selective
inhibitor is VIOXX.RTM. and the 5HT.sub.1B/1D agonist is
rizatriptan.
4. The method of claim 1 wherein the 5HT.sub.1B/1D agonist and
COX-2 inhibitor are administered combined in a single dosage
form.
5. The method of claim 1 wherein the 5HT.sub.1B/1D agonist and
COX-2 inhibitor are administered as separate dosage forms
substantially concurrently.
6. A pharmaceutical composition which is comprised of a
5HT.sub.1B/1D agonist and a COX-2 selective inhibiting compound, or
salts or hydrates thereof, in combination with a pharmaceutically
acceptable carrier.
7. The composition of claim 6 wherein the 5HT.sub.1B/1D agonist is
selected from sumitriptan, naratriptan, zolmitriptan, eleptriptan,
almatriptan and rizatriptan, and the COX-2 inhibitor is selected
from MK-663, VIOXX.RTM., meloxicam, RS57067, celoxib, valdecoxib
and a compound of structure: 5
8. The composition of claim 7 wherein the 5HT.sub.1B/1D agonist is
rizatriptan or a salt thereof, and the COX-2 inhibitor is
VIOXX.RTM..
9. A composition in accordance with claim 7 wherein rizatriptan or
a salt thereof, is present in an amount ranging from about 1 to
about 10 mg, and VIOXX.RTM. is present in an amount ranging from
about 10 mg to about 100 mg.
10. A composition in accordance with claim 8 wherein the
rizatriptan is present in the form of the benzoate salt.
Description
BACKGROUND OF THE INVENTION
[0001] Migraines are recurrent, often familial, symptom complexes
of periodic attacks of vascular headache. Migraines affect
approximately 17% of adult women and 6% of adult men (Stewart et
al., Neurology, 1994, 44 (suppl. 4), 517-523).
[0002] It has been known for some time that sumatriptan, which
causes constriction of cranial blood vessels, is an effective
treatment for migraine (see, for example, Doenicke et al., Lancet,
1988, Vol. 1, 1309-11; and Feniuk & Humphrey, Drug Development
Research, 1992, 26, 235-40). As such, it is the prototypical
example of a class of compounds, including rizatriptan, which have
recently been classified (Hartig et al., TIPS, 1996, 17, 103-105)
as 5-HT.sub.1B/1D receptor agonists.
[0003] Activation of 5-HT.sub.1B and/or 5-HT.sub.1D receptors leads
to (1) selective vasoconstriction of certain cranial extracerebral
blood vessel segments; (2) pre-junctional inhibition of the release
of proinflammatory neuropeptides from sensory nerve terminals in
the meninges; and (3) attenuation of central nociceptive
neurotransmission by inhibition of neurotransmitter release within
the trigeminal nucleus caudalis. It is believed that one or more of
these three mechanisms is involved in the anti-migraine action of
5-HT.sub.1B/1D receptor agonists such as rizatriptan.
[0004] Cyclooxygenase (COX), also known as prostaglandin H
synthase, is an enzyme implicated in the mediation of pain, fever
and inflammation. It catalyzes the oxidative conversion of
arachidonic acid into prostaglandin H.sub.2, a key intermediate in
the biosynthetic pathway of prostaglandins, prostacyclins and
thromboxanes, which in turn mediate a variety of physiological
effects both beneficial and pathological. Recently it was
discovered that two COX isoforms exist: COX-1, expressed
constitutively in many tissues, and COX-2, an induced isoform
having elevated levels of expression in inflamed tissues. COX-1 is
thought to be involved in ongoing "housekeeping" functions, for
example, gastric cytoprotection, while COX-2 is implicated in the
pathological effects mentioned above.
[0005] Current cyclooxygenase inhibitors such as aspirin, ibuprofen
and indomethacin, used as non-steroidal anti-inflammatory drugs
(NSAIDs), inhibit both COX-1 and COX-2 and have associated side
effects, such as gastrotoxicity, which may be manifested as ulcer
formation. COX-2 selective inhibitors act as effective NSAIDs
without substantial gastrotoxic side effects. For purposes of this
disclosure only, a COX-2 selective inhibitor is defined as a COX
inhibitor having a selectivity for the COX-2 isoform relative to
the COX-1 isoform.
[0006] The treatment of migraines by coadministration of a 5HT
agonist and a traditional analgesic, including a NSAID has been
described in international patent application WO98/06392.
[0007] It has now been found that migraines can be more effectively
treated and/or controlled by the co-administration of a
5-HT.sub.1B/1D receptor agonist in combination with a COX-2
selective inhibitor, than with a 5HT.sub.1B/1D agonist alone, and
more safely than with a traditional analgesic in combination with a
5HT agonist.
SUMMARY OF THE INVENTION
[0008] The present invention relates to a method of treating or
preventing migraines in a mammalian patient in need thereof, which
comprises administering to said patient an anti-migraine effective
amount of a combination of a COX-2 selective inhibitor and a
5-HT.sub.1B/1D receptor agonist.
[0009] The invention also relates to a pharmaceutical composition
comprising a COX-2 selective inhibitor, a 5-HT.sub.1B/1D receptor
agonist and a pharmaceutically acceptable carrier therefore.
DETAILED DESCRIPTION
[0010] One embodiment of the present invention is a method of
treating or preventing migraine with an anti-migraine effective
amount of a combination of a 5HT.sub.1B/1D agonist and a COX-2
selective inhibitor. Another embodiment of the invention is a
pharmaceutical composition comprising a combination of a
5HT.sub.1B/1D agonist and a COX-2 selective inhibitor and a
pharmaceutically acceptable carrier.
[0011] In these two embodiments, examples of the 5HT.sub.1B/1D
agonist can be selected from rizatriptan (EP 0,497,512),
sumatriptan (GB 2,162,522), naratriptan (GB 2,208,646),
zolmitriptan (WO91/18897), eleptriptan (WO92/06973), and
almotriptan (WO94/02460).
[0012] The preferred 5HT.sub.1B/1D agonist for use in this
invention is rizatriptan, which is
N,N-dimethyl-2-[5-(1,2,4-triazol-1-ylmethyl)-1H-ind-
ol-3-yl]ethylamine, the benzoate salt thereof being particularly
preferred.
[0013] Examples of COX-2 inhibitors useful in the methods and
compositions described herein include Celebrex.RTM. (celecoxib),
VIOXX.RTM., MK-663 (WO98/03484), compounds disclosed in WO07/14691,
meloxicam, RS 57067, valdecoxib (U.S. Pat. No. 5,663,272) and a
compound of the structure: 1
[0014] In the novel method of treatment described herein, the two
active ingredients can be administered combined in a single dosage
form such as described as one embodiment of this invention, or as
two separate dosage forms, each containing one of the active
ingredients, the two being administered substantially
concurrently.
[0015] In one aspect of the invention, a method of treating or
preventing migraine is disclosed in a mammalian patient in need of
such treatment, which comprises administering to the patient a
COX-2 selective inhibiting compound and a 5HT.sub.1B/1D agonist, or
salts or hydrates thereof, in amounts that are effective for
treating or preventing migraines.
[0016] More particularly, a method is disclosed wherein the
5HT.sub.1B/1D agonist is selected from the group consisting of:
sumitriptan, naratriptan, zolmitriptan, eleptriptan, almatriptan
and rizatriptan and the COX-2 selective inhibiting compound is
selected from the group consisting of: meloxicam,
2-(6-methylpyrid-3-yl)-3-(4-methylsulfonylpheny-
l)-5-chloropyridine (MK-663), VIOXX.RTM. (valdecoxib), RS 57067,
Celebrex.RTM. (celecoxib), and a compound of structure: 2
[0017] Even more particularly, a methodis disclosed wherein the
COX-2 selective inhibitor is VIOXX.RTM. and the 5HT.sub.1B/1D
agonist is rizatriptan or a salt or hydrate thereof.
[0018] In one aspect, the method is described wherein the
5HT.sub.1B/1D agonist and COX-2 inhibitor are administered combined
in a single dosage form.
[0019] In another aspect, the method is described wherein the
5HT.sub.1B/1D agonist and COX-2 inhibitor are administered as
separate dosage forms substantially concurrently.
[0020] In a different aspect, a pharmaceutical composition is
included herein which is comprised of a 5HT.sub.1B/1D agonist and a
COX-2 selective inhibiting compound, or salts or hydrates thereof,
in combination with a pharmaceutically acceptable carrier.
[0021] More particularly, the composition is described wherein the
5HT.sub.1B/1D agonist is selected from sumitriptan, naratriptan,
zolmitriptan, eleptriptan, almatriptan and rizatriptan, and the
COX-2 inhibitor is selected from MK-663, VIOXX.RTM., meloxicam,
RS57067, celoxib, valdecoxib and a compound of structure: 3
[0022] Even more particularly, the composition is described wherein
the 5HT.sub.1B/1D agonist is rizatriptan or a salt thereof, and the
COX-2 inhibitor is VIOXX.RTM..
[0023] In a preferred combination, a composition is described
wherein rizatriptan or a salt thereof, is present in an amount
ranging from about 1 to about 10 mg, and VIOXX.RTM. is present in
an amount ranging from about 10 mg to about 100 mg. More
particularly, the rizatriptan is present as the benzoate salt, and
VIOXX.
[0024] An anti-migraine effective amount of the combination is that
amount that will relieve the subject being treated of the symptoms
of the migraine attack and the specific dose level and frequency of
dosage may vary and will depend upon a variety of factors including
the activity of the specific compounds used in combination, the
metabolic stability and length of action of the compounds, the age,
body weight, general health, sex diet, mode and time of
administration, rate of excretion, the severity of the particular
condition and the host undergoing therapy. However, dosage levels
of the 5HT.sub.1B/1D on the order of about 0.001 mg/kg to about 250
mg/kg of body weight per day, typically about 0.005 to about 100
mg/kg, more particularly about 0.01 to about 50 mg/kg and
especially about 0.05 to about 10 mg/kg per day are useful in the
novel method of treatment. Dosage levels of the COX-2 inhibitor of
about 0.1 to 500 mg/kg of body weight per day, typically about 0.5
to about 250 mg/kg, more particularly about 5 to about 100 mg/kg
and especially about 10 to about 50 mg/kg of body weight per day
are useful in the novel method of this invention.
[0025] For the treatment of a migraine attack, the active
ingredients, separately or in combination, may be administered
orally, topically, parenterally, by inhalation, spray, rectally or
intravaginally in formulations containing pharmaceutically
acceptable carriers.
[0026] The term parenteral as used herein includes subcutaneous
injections, intravenous, intramuscular, intrasisternal injection or
infusion techniques.
[0027] The separate active agents or the novel composition of this
invention may be in a form suitable for oral use, for example,
tablets, troches, lozenges, aqueous or oily suspensions,
dispersible powders or granules, emulsions, hard or soft capsules,
solutions, syrups and elixirs. Compositions intended for oral use
may be prepared according to any method known to the art for the
manufacture of pharmaceutical compositions and typically such
compositions contain one or more agents selected from the group
consisting of sweetening agents, flavouring agents, colouring
agents and preservatives in order to provide pharmaceutically
elegant and palatable preparations. These excipients may be for
example, diluents such as lactose, calcium carbonate, sodium
carbonate, calcium phosphate or sodium phosphate; granulating and
disintegrating agents, for example, corn starch or alginic acid;
binding agents, for example starch, gelatin or acacia, and
lubricating agents, for example, magnesium stearate, stearic acid
or talc.
[0028] The tablets may be uncoated or they may be coated. Coating
can be included to delay disintegration and absorption in the
gastrointestinal tract and thereby provide a sustained action over
a longer period. For example, a time delay material such as
glyceryl monostearate or glyceryl distearate may be employed. They
may also be coated by the technique described in the U.S. Pat. Nos.
4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic
tablets for control release.
[0029] Formulations for oral use may also be presented as hard
gelatin capsules wherein the active ingredient is mixed with an
inert solid diluent, for example, calcium carbonate, calcium
phosphate or kaolin, or as soft gelatin capsules wherein the active
ingredient is mixed with water or miscible solvents such as
propylene glycol, PEGs and ethanol, or an oil medium, for example
peanut oil, liquid paraffin or olive oil.
[0030] Aqueous suspensions contain the active material in admixture
with excipients suitable for the manufacture of aqueous
suspensions. Such excipients are suspending agents, for example
sodium carboxymethylcellulose, methylcellulose,
hydroxy-propylmethycellulose, sodium alginate,
polyvinyl-pyrrolidone, tragacanth and acacia; dispersing or wetting
agents may be a naturally-occurring phosphatide, for example
lecithin, or condensation products of an alkylene oxide with fatty
acids, for example polyoxyethylene stearate, or condensation
products of ethylene oxide with long chain aliphatic alcohols, for
example heptadecaethyleneoxycetanol, or condensation products of
ethylene oxide with partial esters derived from fatty acids and a
hexitol such as polyoxyethylene sorbitol monooleate, or
condensation products of ethylene oxide with partial esters derived
from fatty acids and hexitol anhydrides, for example polyethylene
sorbitan monooleate. The aqueous suspensions may also contain one
or more preservatives, for example ethyl or n-propyl
p-hydroxybenzoate, one or more colouring agents, one or more
flavouring agents, and one or more sweetening agents, such as
sucrose, saccharin or aspartame.
[0031] Oily suspensions may be formulated by suspending the active
ingredient in a vegetable oil, for example arachis oil, olive oil,
sesame oil or coconut oil, or in mineral oil such as liquid
paraffin. The oily suspensions may contain a thickening agent, for
example beeswax, hard paraffin or cetyl alcohol. Sweetening agents
such as those set forth above, and flavouring agents may be added
to provide a palatable oral preparation. These compositions may be
preserved by the addition of an anti-oxidant such as ascorbic
acid.
[0032] Dispersible powders and granules suitable for preparation of
an aqueous suspension by the addition of water provide the active
ingredient in admixture with a dispersing or wetting agent,
suspending agent and one or more preservatives. Suitable dispersing
or wetting agents and suspending agents are exemplified by those
already mentioned above. Additional excipients, for example
sweetening, flavouring and colouring agents, may also be
present.
[0033] The individual agents or the pharmaceutical compositions of
the invention may also be in the form of oil-in-water emulsions.
The oily phase may be a vegetable oil, for example olive oil or
arachis oil, or a mineral oil, for example liquid paraffin or
mixtures of these. Suitable emulsifying agents may be
naturally-occurring phosphatides, for example soy bean, lecithin,
and esters or partial esters derived from fatty acids and hexitol
anhydrides, for example sorbitan monooleate, and condensation
products of the said partial esters with ethylene oxide, for
example polyoxy-ethylene sorbitan monooleate. The emulsions may
also contain sweetening and flavouring agents.
[0034] Syrups and elixirs may be formulated with sweetening agents,
for example glycerol, propylene glycol, sorbitol or sucrose. Such
formulations may also contain demulcents, preservatives,
flavourants and colouring agents.
[0035] The pharmaceutical compositions may be in the form of a
sterile injectable aqueous or oleagenous suspension. This
suspension may be formulated according to the known art using those
suitable dispersing or wetting agents and suspending agents which
have been mentioned above.
[0036] Injectable compositions are typically in the form of sterile
solutions or suspensions, which include the active ingredient in a
parenterally-acceptable diluent. Among these are sterile water,
dextrose 5% in water (D5W), Ringer's solution and isotonic saline,
as well as mixtures thereof. Cosolvents such as ethanol, propylene
glycol or polyethylene glycols may also be used. Sterile,
injectable oil is occasionally employed as a solvent or suspending
medium in intramuscular preparations. A representative example is
peanut oil. In addition, fatty acids such as oleic acid,
preservatives, buffers and local anesthetics find use in the
preparation of intramuscular injectables.
[0037] The combination of active ingredients may also be
administered rectally or intravaginally as suppositories. These can
be prepared by mixing the drug with a suitable non-irritating
excipient which is solid at ordinary room temperature but molten at
normal or elevated body temperature. Examples of such materials
include cocoa butter and polyethylene glycols.
[0038] For topical use, creams, ointments, gels, solutions,
suspensions and the like containing the compound are employed. (For
purposes of this application, topical application includes mouth
washes and gargles, as well as transdermal applications.) Topical
formulations are comprised of a pharmaceutical carrier, which may
include, e.g., cosolvents, emulsifiers, penetration enhancers,
preservatives or emollients.
[0039] The active ingredients are combined with the carrier to
produce the dosage form. For example, a formulation intended for
oral administration may contain from as low as about 0.1 mg of the
novel combination to as high as about 5 g of combination per dose,
compounded with an appropriate and convenient amount of carrier
material which may vary from about 5 to about 95 percent of the
total composition.
EXAMPLES 1 AND 2
[0040] Tablet Preparation
[0041] Tablets containing 5 mg and 10 mg of rizatriptan benzoate
and 10 mg of Vioxx were prepared as follows:
1 Example 1 Example 2 Rizatriptan benzoate 5.0 mg 10.0 mg Vioxx
10.0 mg 10.0 mg Microcrystalline cellulose 42.0 mg 39.5 mg Modified
food corn starch 42.0 mg 39.5 mg Magnesium stearate 1.0 mg 1.0
mg
[0042] All of the active ingredients, cellulose, and a portion of
the corn starch are mixed and granulated to 10% corn starch paste.
The resulting granulation is sieved, dried and blended with the
remainder of the corn starch and magnesium stearate. The resulting
granulation is then compressed into tablets.
* * * * *