U.S. patent application number 14/036828 was filed with the patent office on 2014-01-23 for compositions comprising tramadol and celecoxib in the treatment of pain.
This patent application is currently assigned to LABORATORIOS DEL DR. ESTEVE, S.A.. The applicant listed for this patent is LABORATORIOS DEL DR. ESTEVE, S.A.. Invention is credited to Enrique PORTILLO SALIDO, Sebastia VIDELA CES.
Application Number | 20140024622 14/036828 |
Document ID | / |
Family ID | 41566149 |
Filed Date | 2014-01-23 |
United States Patent
Application |
20140024622 |
Kind Code |
A1 |
PORTILLO SALIDO; Enrique ;
et al. |
January 23, 2014 |
COMPOSITIONS COMPRISING TRAMADOL AND CELECOXIB IN THE TREATMENT OF
PAIN
Abstract
The present invention relates to pharmaceutical compositions
comprising tramadol and celecoxib and their uses as medicaments or
analgesics, more particularly for the treatment of severe to
moderate pain with an inflammation component.
Inventors: |
PORTILLO SALIDO; Enrique;
(Barcelona, ES) ; VIDELA CES; Sebastia;
(Barcelona, ES) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
LABORATORIOS DEL DR. ESTEVE, S.A. |
Barcelona |
|
ES |
|
|
Assignee: |
LABORATORIOS DEL DR. ESTEVE,
S.A.
Barcelona
ES
|
Family ID: |
41566149 |
Appl. No.: |
14/036828 |
Filed: |
September 25, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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13394995 |
Mar 8, 2012 |
8569271 |
|
|
PCT/EP2010/006317 |
Oct 15, 2010 |
|
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14036828 |
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Current U.S.
Class: |
514/158 |
Current CPC
Class: |
A61K 31/135 20130101;
A61P 19/08 20180101; A61K 31/635 20130101; A61P 25/04 20180101;
A61K 31/415 20130101; A61P 29/00 20180101; A61K 45/06 20130101;
A61P 25/00 20180101; A61K 31/137 20130101; A61P 21/00 20180101;
A61P 19/02 20180101; A61P 25/02 20180101; A61K 31/135 20130101;
A61K 2300/00 20130101; A61K 31/415 20130101; A61K 2300/00
20130101 |
Class at
Publication: |
514/158 |
International
Class: |
A61K 31/635 20060101
A61K031/635; A61K 31/137 20060101 A61K031/137 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 16, 2009 |
EP |
09384004.9 |
Claims
1. A pharmaceutical composition comprising a synergistic
combination of (rac)-tramadol.HCl and celecoxib or a
pharmaceutically acceptable salt or hydrate thereof, wherein the
molecular ratio of the (rac)-tramadol.HCl to the celecoxib is a
molar ratio of from about 1:1 to about 1:3 or from about 1:1 to
about 3:1.
2. A pharmaceutical composition according to claim 1, wherein the
molecular ratio of the (rac)-tramadol.HCl to the celecoxib is a
molar ratio of about 3:1.
3. A pharmaceutical composition according to claim 1, wherein the
molecular ratio of the (rac)-tramadol.HCl to the celecoxib is a
molar ratio of about 1:3.
4. A pharmaceutical composition according to claim 1, wherein the
molecular ratio of the (rac)-tramadol.HCl to the celecoxib is a
molar ratio of about 1:1.
5. A pharmaceutical composition according to claim 1, wherein the
celecoxib is in neutral form.
6. A pharmaceutical composition according to claim 1, wherein the
composition is a liquid composition.
7. A method for the treatment of pain comprising administering to a
subject in need thereof a therapeutically effective amount of at
least one pharmaceutical composition according to claim 1.
8. A method according to claim 7, wherein said pain is selected
from acute pain, chronic pain, neuropathic pain, nociceptive pain,
mild and severe to moderate pain, hyperalgesia, pain related to
central sensitization, allodynia or cancer pain, diabetic
neuropathy, diabetic peripheral neuropathy, osteoarthritis,
fibromyalgia, rheumatoid arthritis, ankylosing spondylitis, frozen
shoulder and sciatica.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 13/394,995, filed Mar. 8, 2012, now allowed.
U.S. patent application Ser. No. 13/394,995 is a U.S. National
Phase filing under 35 U.S.C. .sctn.371 of International Application
PCT/EP2010/006317, filed Oct. 15, 2010, and published as WO
2011/045075 on Apr. 21, 2011. PCT/EP2010/006317 claimed benefit of
priority from European Patent Application No. EP 09384004.9, filed
Oct. 16, 2009. The entire contents of each of the prior
applications are incorporated herein by reference.
[0002] The present invention relates to pharmaceutical compositions
comprising tramadol and celecoxib and their uses as medicaments or
analgesics, more particularly for the treatment of severe to
moderate pain.
[0003] Pain is a complex response that has been functionally
categorized into sensory, autonomic, motor, and affective
components. The sensory aspect includes information about stimulus
location and intensity while the adaptive component may be
considered to be the activation of endogenous pain modulation and
motor planning for escape responses. The affective component
appears to include evaluation of pain unpleasantness and stimulus
threat as well as negative emotions triggered by memory and context
of the painful stimulus.
[0004] In general, pain conditions can be divided into chronic and
acute. Chronic pain includes neuropathic pain and chronic
inflammatory pain, for example arthritis, or pain of unknown
origin, as fibromyalgia. Acute pain usually follows non-neural
tissue injury, for example tissue damage from surgery or
inflammation, or migraine. Pain may also be divided into different
levels of severity starting from severe through moderate to light
pain.
[0005] There are many drugs that are known to be useful in the
treatment or management of pain. Opioids are frequently used as
analgesics in pain. Derivatives of morphine are indicated for the
treatment of moderate to acute pain in human. The analgesic effect
is obtained through their action on morphinic receptors, preferably
the p-receptors. Among these derivatives of morphine, morphine,
codeine, pethidine, dextropropoxyphenemethadone, lenefopan may be
mentioned.
[0006] One of the morphinic derivatives that has shown very good
results when orally administrated, and which is extensively
marketed, is tramadol, also available as a physiologically
acceptable salt, particularly as a chlorohydrate. Tramadol is a
central acting analgesic drug that exerts its effects by activating
opioid receptors and enhancing neuronal monoamine synaptic
concentration. Tramadol, whose chemical name is
2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol, has the
following formula:
##STR00001##
[0007] This structure shows two different chiral centers and thus
the molecule may exist in different diastereoisomers among which
the tramadol is the cis-diastereoisomer. The enantiomers (1R,2R),
or (1S,2S), are also known as (+)-tramadol and (-)-tramadol with
both of them contributing in different ways to the overall activity
of racemic tramadol.
[0008] "(rac)" is according to this invention defined as the
abbreviation of "racemate" and thus "(rac)-tramadol" or
"(rac)tramadol" means racemic tramadol (the cis-diastereoisomer) as
described in the paragraph above.
[0009] Accordingly, "(rac)-tramadol.HCl" or "(rac)tramadol.HCl" is
defined as the hydrochloride salt of racemic tramadol (the
cis-diastereoisomer) as described above.
[0010] From the art it appears that this compound is neither fully
opioid-like, nor non-opioid-like. Some studies have demonstrate
that tramadol is an opioid agonist, whereas clinical experience
indicates that it lacks many of the typical side effects of opioids
agonist, for example respiratory depression, constipation or
tolerance.
[0011] Due to their drawbacks, opioids used as analgesics to treat
pain cannot always be given repeatedly or at higher doses. The
effects of opioids are reviewed for example by J. Jaffe in "Goodman
and Gilman's, The Pharmacological Basis of Therapeutics", 8th
edition; Gilman et al.; Pergamon Press, New York, 1990, Chapter 22,
pages 522-573.
[0012] Consequently it has been proposed to combine opioids with
other drugs that are not opioid analgesic agents, in order to lower
the amount of opioids needed to produce an equivalent degree of
analgesia. Among these combinations, the association of tramadol
with nonsteroidal anti-inflammatory drugs (NSAIDs) has been
reported to be of particular interest (EP-0 546 676).
[0013] U.S. Pat. No. 5,516,803 discloses combination of tramadol
with non-steroidal anti-inflammatory drugs (NSAIDs), specifically
ibuprofen and discloses the combination of tramadol.HCl with
non-steroidal anti-inflammatories, such as for example ibuprofen,
in a composition ratio of 1:1 to 1:200 producing a synergistically
enhanced analgesic action and reducing the undesired accompanying
symptoms
[0014] U.S. Pat. No. 6,558,701 patent discloses combination of
tramadol with diclofenac and "for the treatment of moderate to
severe pain, the World Health Organization (WHO) recommends
combining opioid analgesics with non-steroidal analgesics in order
to produce a more effective pain relief and possibly reduce amounts
of analgesic which are necessary to administer".
[0015] One interesting NSAIDs to be combined with tramadol is the
marketed drug celecoxib, whose chemical name is
4-[5-(4-methylphenyl)-3-(trifluoromethyl)-pyrazol-1-yl]-benzenesulfonamid-
e. Celecoxib is an anti-inflammatory and pain killer drug and it is
one of the most used treatments for chronic musculo-skeletal
inflammatory illnesses. It has an empirical formula of
C.sub.17H.sub.14F.sub.3N.sub.3O.sub.2S.
##STR00002##
[0016] Celecoxib is an oral, highly selective cyclooxygenase-2
(COX-2) inhibitor, and it is indicated for the treatment of
symptomatic relief in the treatment of osteoarthritis, rheumatoid
arthritis and ankylosing spondylitis (Goldenberg M M. Celecoxib, a
selective cyclooxygenase-2 inhibitor for the treatment of
rheumatoid arthritis and osteoarthritis. Clin. Ther. 1999, 21,
1497-513). This high selectivity allows celecoxib and other COX-2
inhibitors to reduce inflammation (and pain) while minimizing
gastrointestinal adverse drug reactions (e.g. stomach ulcers) that
are common with non-selective NSAIDs.
[0017] Cyclooxygenase is responsible for generation of
prostaglandins. Two isoforms, COX-1 and COX-2, have been
identified. COX-2 is the isoform of the enzyme that has been shown
to be induced by pro-inflammatory stimuli and has been postulated
to be primarily responsible for the synthesis of prostanoid
mediators of pain, inflammation, and fever. COX-2 is also involved
in ovulation, implantation and closure of the ductus arteriosus,
regulation of renal function, and central nervous system functions
(fever induction, pain perception and cognitive function). It may
also play a role in ulcer healing. COX-2 has been identified in
tissue around gastric ulcers in man but its relevance to ulcer
healing has not been established.
[0018] WO00/51685 describes pharmaceutical composition comprising
on one hand a tramadol material selected from: [0019] (+)- and
(-)-tramadol, racemic tramadol, the N-oxide of tramadol and
O-desmethyl-tramadol (both of them as isolated stereoisomers or
mixtures thereof including their racemates) either as free base or
as a salt, solvate or polymorph; and on the other hand a selective
COX-2 inhibitor with celecoxib being listed among the COX-2
inhibitor drugs. The focus of the application rests in the
exemplified combination of tramadol and JT-522.
[0020] The applicant has now found that tramadol, especially the
(rac)-tramadol hydrochloride salt, having the opioid activity, and
celecoxib (especially in its neutral form) can be combined in one
pharmaceutical composition achieving an additive effect, especially
in the treatment of severe to moderate pain, especially in pain
with an inflammatory element.
[0021] Thus the object of the present invention is a pharmaceutical
composition comprising a combination of (rac)tramadol.HCl and
celecoxib or a pharmaceutically acceptable salt or hydrate
thereof.
[0022] In general each separate active principle of the
pharmaceutical composition according to the invention, the tramadol
and the celecoxib, has its own disadvantages when used alone.
[0023] Thus, tramadol hydrochloride, which is often used orally,
displays a highly bitter taste, which makes the drugs often
difficult to swallow and lowers patient compliance. Also, as stated
before, the drawbacks associated with opioids--their side
effects--are limiting their use, so that they have to be given at
lower doses and often less frequent as their use as analgesics to
treat pain would normally require. On the other hand celecoxib is
well-known to be only slightly soluble in water and this is further
limiting its use in pharmaceutical formulations.
[0024] The object of the present invention is to provide a
pharmaceutical composition comprising an opioid like tramadol and
an NSAID like celecoxib having a level of efficacy similar to the
one achievable by each active substance used alone, but: [0025]
with a better safety profile at higher doses and/or [0026] --by
showing a synergistic effect--allowing a reduction of dose while
still delivering the desired activity using less of each ingredient
and, therefore, reducing the side effects associated with each
active principle; and/or [0027] providing a new more effective
method for treating acute or severe to moderate pain, especially in
pain with an inflammatory component.
[0028] Other desirable improvements/advantages of the new
pharmaceutical composition would include being active in diseases
or symptoms being or related to pain and its subtypes, especially
those in which current treatment is insufficient like sciatica or
frozen shoulder or pain related to central sensitization (central
pain syndrome).
[0029] Most desirably the pharmaceutical composition should combine
more than one, most preferably all of these advantages.
[0030] This pharmaceutical composition according to the invention
shows improved properties if compared to any of the active
principles alone.
[0031] In one preferred embodiment of the pharmaceutical
composition according to the invention the celecoxib is in neutral
form.
[0032] As celecoxib is weakly acidic with a pKa of 11.1 its
"neutral form" according to the invention is defined therefore as
the form in which celecoxib is free (not in form of a salt) but
is--depending on the pH--neutral or carrying a load.
[0033] In one further embodiment of the pharmaceutical composition
according to the invention the ratio of the (rac)-tramadol.HCl to
the celecoxib is a weight ratio of from about 1:1 to about 1:300 or
from about 1:1 to about 300:1.
[0034] In one further embodiment of the pharmaceutical composition
according to the invention the ratio of the (rac)-tramadol.HCl to
the celecoxib is a molar ratio of from about 1:1 to about 1:300 or
from about 1:1 to about 300:1.
[0035] In one further embodiment of the pharmaceutical composition
according to the invention the molecular ratio of the
(rac)-tramadol.HCl to the celecoxib is a weight ratio of from about
1:1 to about 1:30 or from about 1:1 to about 30:1.
[0036] In one further embodiment of the pharmaceutical composition
according to the invention the molecular ratio of the
(rac)-tramadol.HCl to the celecoxib is a molar ratio of from about
1:1 to about 1:30 or from about 1:1 to about 30:1.
[0037] In one further embodiment of the pharmaceutical composition
according to the invention the molecular ratio of the
(rac)-tramadol.HCl to the celecoxib is a molar ratio of from about
1:1 to about 1:5 or from about 1:1 to about 5:1.
[0038] Another advantage is that the association of the two active
principles into one unique species seems to allow for a better
Pharmacokinetic/Pharmacodynamic (PKPD) including also a better
penetration of the blood-brain barrier, which helps in the
treatment of pain.
[0039] Both parts of the pharmaceutical composition are well-known
drugs used for a long time worldwide. Due to the therapeutic
interest in tramadol in the treatment of pain symptoms and the
well-known properties of celecoxib in this field of medical
indication, a further object of the present invention is a
medicament containing a pharmaceutical composition comprising
(rac)-tramadol.HCl and celecoxib.
[0040] Thus, the invention also relates to a medicament containing
a pharmaceutical composition comprising (rac)-tramadol.HCl and
celecoxib according to the invention as described above and
optionally one or more pharmaceutically acceptable excipients.
[0041] The medicament or pharmaceutical composition according to
the present invention may be in any form suitable for the
application to humans and/or animals, preferably humans including
infants, children and adults and can be produced by standard
procedures known to those skilled in the art. The medicament can be
produced by standard procedures known to those skilled in the art,
e.g. from the table of contents of "Pharmaceutics: The Science of
Dosage Forms", Second Edition, Aulton, M. E. (ED. Churchill
Livingstone, Edinburgh (2002); "Encyclopedia of Pharmaceutical
Technology", Second Edition, Swarbrick, J. and Boylan J. C. (Eds.),
Marcel Dekker, Inc. New York (2002); "Modern Pharmaceutics", Fourth
Edition, Banker G. S. and Rhodes C. T. (Eds.) Marcel Dekker, Inc.
New York 2002 y "The Theory and Practice of Industrial Pharmacy",
Lachman L., Lieberman H. And Kanig J. (Eds.), Lea & Febiger,
Philadelphia (1986). The respective descriptions are hereby
incorporated by reference and form part of the disclosure. The
composition of the medicament may vary depending on the route of
administration.
[0042] The medicament or pharmaceutical composition of the present
invention may for example be administered parentally in combination
with conventional injectable liquid carriers, such as water or
suitable alcohols. Conventional pharmaceutical excipients for
injection, such as stabilizing agents, solubilizing agents, and
buffers, may be included in such injectable compositions. These
medicaments or pharmaceutical compositions may for example be
injected intramuscularly, intraperitoneally, or intravenously.
[0043] Medicaments or pharmaceutical compositions according to the
present invention may also be formulated into orally administrable
compositions containing one or more physiologically compatible
carriers or excipients, in solid or liquid form. These compositions
may contain conventional ingredients such as binding agents,
fillers, lubricants, and acceptable wetting agents. The
compositions may take any convenient form, such as tablets,
pellets, granules, capsules, lozenges, aqueous or oily solutions,
suspensions, emulsions, or dry powdered forms suitable for
reconstitution with water or other suitable liquid medium before
use, for immediate or controlled release. The multiparticulate
forms, such as pellets or granules, may e.g. be filled into a
capsule, compressed into tablets or suspended in a suitable
liquid.
[0044] Suitable controlled release formulations, materials and
methods for their preparation are known from the prior art, e.g.
from the table of contents of "Modified-Release Drug Delivery
Technology", Rathbone, M. J. Hadgraft, J. and Roberts, M. S.
(Eds.), Marcel Dekker, Inc., New York (2002); "Handbook of
Pharmaceutical Controlled Release Technology", Wise, D. L. (Ed.),
Marcel Dekker, Inc. New York, (2000); "Controlled Drug Delivery",
Vol, I, Basic Concepts, Bruck, S. D. (Ed.), CRD Press Inc., Boca
Raton (1983) y de Takada, K. and Yoshikawa, H., "Oral Drug
Delivery", Encyclopedia of Controlled Drug Delivery, Mathiowitz, E.
(Ed.), John Wiley & Sons, Inc., New York (1999), Vol. 2,
728-742; Fix, J., "Oral drug delivery, small intestine and colon",
Encyclopedia of Controlled Drug Delivery, Mathiowitz, E. (Ed.),
John Wiley & Sons, Inc., New York (1999), Vol. 2, 698-728. The
respective descriptions are hereby incorporated by reference and
form part of the disclosure.
[0045] Medicaments or pharmaceutical compositions according to the
present invention may also comprise an enteric coating, so that
their dissolution is dependent on pH-value. Due to said coating the
medicament may pass the stomach undissolved and the respective
pharmaceutical composition and its components is/are liberated in
the intestinal tract. Preferably the enteric coating is soluble at
a pH value of 5 to 7.5. Suitable materials and methods for the
preparation are known from the prior art.
[0046] Typically, the medicaments or pharmaceutical compositions
according to the present invention may contain 1-60% by weight of
the combination of (rac)-tramadol.HCl and celecoxib as defined
herein and 40-99% by weight of one or more auxiliary substances
(additives/excipients).
[0047] The compositions of the present invention may also be
administered topically or via a suppository.
[0048] The daily dosage for humans and animals may vary depending
on factors that have their basis in the respective species or other
factors, such as age, sex, weight or degree of illness and so
forth. The daily dosage for humans preferably is in the range of 10
to 2000 milligrams of active substance to be administered during
one or several intakes per day.
[0049] A further aspect of the invention relates to a
pharmaceutical composition according to the invention comprising
the combination of (rac)-tramadol.HCl and celecoxib according to
the invention for use as an analgesic for the treatment of pain,
preferably acute pain, chronic pain, neuropathic pain,
hyperalgesia, allodynia or cancer pain, including diabetic
neuropathy and osteoarthritis; as well as severe to moderate pain;
including also rheumatoid arthritis, ankylosing spondylitis,
sciatica and frozen shoulder. The use of the pharmaceutical
composition might especially be drawn to the treatment of severe to
moderate pain with an inflammatory component like e.g. rheumatoid
arthritis, ankylosing spondylitis, sciatica and frozen
shoulder.
[0050] A further aspect of the invention relates to a
pharmaceutical composition according to the invention comprising
the combination of (rac)-tramadol.HCl and celecoxib according to
the invention for use as an analgesic or for the treatment of pain,
preferably acute pain, chronic pain (acute and chronic pain),
neuropathic pain, nociceptive pain (visceral and/or somatic pain),
mild and severe to moderate pain, hyperalgesia, pain related to
central sensitization, allodynia or cancer pain, including diabetic
neuropathy or diabetic peripheral neuropathy and osteoarthritis,
fibromyalgia; rheumatoid arthritis, ankylosing spondylitis, frozen
shoulder or sciatica. A further aspect of the invention relates to
a pharmaceutical composition according to the invention comprising
the combination of (rac)-tramadol.HCl and celecoxib according to
the invention for the treatment of pain, preferably acute pain, or
preferably acute pain, chronic pain (acute and chronic pain),
neuropathic pain, nociceptive pain (visceral and/or somatic pain),
mild and severe to moderate pain, hyperalgesia, pain related to
central sensitization, allodynia or cancer pain, including diabetic
neuropathy or diabetic peripheral neuropathy and osteoarthritis,
fibromyalgia; rheumatoid arthritis, ankylosing spondylitis, frozen
shoulder or sciatica. The invention thus also relates to the use of
a co-crystal according to the invention as described above in the
production of a medicament for the treatment of pain, preferably
acute pain, chronic pain (acute and chronic pain), neuropathic
pain, nociceptive pain (visceral and/or somatic pain), mild and
severe to moderate pain, hyperalgesia, pain related to central
sensitization, allodynia or cancer pain, including diabetic
neuropathy or diabetic peripheral neuropathy and osteoarthritis,
fibromyalgia; rheumatoid arthritis, ankylosing spondylitis, frozen
shoulder or sciatica.
[0051] A related further aspect of the invention is aimed at the
use of a pharmaceutical composition according to the invention as
described above in the manufacture of a medicament for the
treatment of pain, preferably acute pain, chronic pain, neuropathic
pain, hyperalgesia, allodynia or cancer pain, including diabetic
neuropathy, fibromyalgia or osteoarthritis; as well as severe to
moderate pain; including also rheumatoid arthritis, ankylosing
spondylitis, sciatica and frozen shoulder. Preferably this use is
provided for in form of a medicament or a pharmaceutical
composition according to the invention as described above. This
medicament might especially be drawn to the treatment of severe to
moderate pain with an inflammatory component like e.g. rheumatoid
arthritis, ankylosing spondylitis, sciatica and frozen shoulder.
Another related further aspect of the invention is aimed at the use
of a pharmaceutical composition according to the invention as
described above in the manufacture of a medicament for the
treatment of pain, preferably acute pain, chronic pain (acute and
chronic pain), neuropathic pain, nociceptive pain (visceral and/or
somatic pain), mild and severe to moderate pain, hyperalgesia, pain
related to central sensitization, allodynia or cancer pain,
including diabetic neuropathy or diabetic peripheral neuropathy and
osteoarthritis, fibromyalgia; rheumatoid arthritis, ankylosing
spondylitis, frozen shoulder or sciatica.
[0052] Another object of the current invention is a method of
treatment of pain, preferably acute pain, chronic pain, neuropathic
pain, hyperalgesia, allodynia or cancer pain, including diabetic
neuropathy, fibromyalgia or osteoarthritis; as well as severe to
moderate pain; including also rheumatoid arthritis, ankylosing
spondylitis, sciatica and frozen shoulder, by providing to a
patient in need thereof a sufficient amount of the pharmaceutical
composition comprising the combination of (rac)-tramadol.HCl and
celecoxib according to the invention as described above. This
method of treatment might especially be relevant for the treatment
of severe to moderate pain with an inflammatory component like e.g.
rheumatoid arthritis, ankylosing spondylitis, sciatica and frozen
shoulder. Another related object of the invention is aimed at a
method of treatment of pain, preferably acute pain, chronic pain
(acute and chronic pain), neuropathic pain, nociceptive pain
(visceral and/or somatic pain), mild and severe to moderate pain,
hyperalgesia, pain related to central sensitization, allodynia or
cancer pain, including diabetic neuropathy or diabetic peripheral
neuropathy and osteoarthritis, fibromyalgia; rheumatoid arthritis,
ankylosing spondylitis, frozen shoulder or sciatica by providing to
a patient in need thereof a sufficient amount of the pharmaceutical
composition comprising the combination of (rac)-tramadol.HCl and
celecoxib according to the invention as described above.
[0053] "Pain" is defined by the International Association for the
Study of Pain (IASP) as "an unpleasant sensory and emotional
experience associated with actual or potential tissue damage, or
described in terms of such damage (IASP, Classification of chronic
pain, 2.sup.nd Edition, IASP Press (2002), 210). Even though pain
is always subjective its causes or syndromes can be classified. One
classification to denominate subtypes of pain would be to divide
the general pain syndrome into the subtypes of acute and chronic
pain or--according to the pain intensity--into mild, moderate and
severe pain. In other definitions the general pain syndrome is also
divided into "nociceptive" (caused by activation of nociceptors),
"neuropathic" (caused by damage to or malfunction of the nervous
system) and pain related to central sensitization (central pain
syndrome).
[0054] "Sciatica" or "sciatic neuritis" is defined herein as a set
of symptoms including pain that derive from irritation of the
sciatic nerve or its roots,
[0055] "Frozen shoulder" or "adhesive capsulitis" is defined herein
as a symptom wherein the connective tissue surrounding the shoulder
joint or the shoulder capsule itself is causing chronic pain,
becoming inflamed and stiff.
[0056] "Ankylosing spondylitis" or "Morbus Bechterew" is a chronic,
inflammatory arthritis and autoimmune disease. It mainly affects
joints in the spine and the sacroilium in the pelvis, causing
eventual fusion of the spine.
[0057] "Pain related to central sensitization"/"central pain
syndrome" is defined within this application as a neurological
condition caused by damage to or dysfunction of the central nervous
system (CNS), which includes the brain, brainstem, and spinal cord.
This syndrome can inter alia be caused by stroke, multiple
sclerosis, tumors, epilepsy, brain or spinal cord trauma, or
Parkinson's disease.
[0058] "Nociceptive pain " is defined as a type of pain caused by
activation of nociceptors. It can be divided into somatic and
visceral pain. "Visceral pain" is pain generally originating from
the organs, whereas "(deep) somatic pain" originates from
ligaments, tendons, bones, blood vessels, fasciae and muscles.
BRIEF DESCRIPTION OF THE FIGURES:
[0059] FIG. 1:
[0060] A: Dose response curves of antihyperalgesic effects of
tramadol, celecoxib and different combinations of racemic tramadol
hydrochloride with celecoxib at different ratios (1:1, 1:3 and 3:1)
in the rat paw incision model of postoperative pain.
[0061] B: Isobologram analysis showing significant (p<0.01)
synergistic interaction on thermal hyperalgesia. All data are
presented as means.+-.SEM (n=10-13 per dose group).
[0062] The present invention is illustrated below with the help of
the following examples. These illustrations are given solely by way
of example and do not limit the invention.
EXAMPLES
Example 1
Preparation of Composition Doses of Tramadol Hydrochloride and
Celecoxib
[0063] Combinations of a racemic tramadol hydrochloride and
celecoxib were prepared at different molar ratios of
(rac)-tramadol.HCl:celecoxib (1:1, 1:3 and 3:1). All drugs and
combinations were dissolved in 0.5% hydroxypropyl methylcellulose
in distilled water and administered in a volume of 10 ml/kg per rat
through the intraperitoneal (i.p.) route. In Table 1 are listed the
different ratios prepared at the various concentrations,
TABLE-US-00001 TABLE 1 Corresponding doses of each drug or
combinations administered intraperitoneally. Doses (mg/kg) Tramadol
2.5 10 40 Celecoxib 0.625 2.5 10 40 Ratio 1:1 0.3130 0.625 2.5 10
40 Ratio 1:3 2.5 10 40 Ratio 3:1 0.625 2.5 10 40
Effects on Thermal Hyperalgesia in a Postoperative Pain Model in
Rat
[0064] The aim of this study was to evaluate the analgesic efficacy
and potency of compositions comprising a combination of
tramadol/celecoxib, especially a combination of racemic tramadol
hydrochloride with celecoxib in different molar ratios (1:1, 1:3
and 3:1) in a rat model of postoperative pain after paw incision.
To assess the reliability of the efficacy and potency of the
compounds tested thermal hypersensitivity (hyperalgesia) was
performed using the plantar test assay (Hargreaves et al., Pain
1988, 32, 77).
Experimental Design
Animals
[0065] Male, Wistar rats (120-160 g, Harlan, Italy) were housed in
a climate-controlled room for at least 5 days prior to testing.
Food and water were available ad libitum up to test time.
Animal Dosing
[0066] The rats were all dosed intraperitoneally with compositions
comprising a combination of racemic tramadol hydrochloride and
celecoxib at different ratios, dissolved in a suspension of 0.5%
hydroxypropyl methylcellulose in distilled water. The dosing volume
was 10 ml/kg. The antihyperalgesic response of the animal was
subsequently evaluated 60 min after compositions
administration.
Surgery
[0067] Rats were anaesthetized with 3% isofluorane and a 1 cm
longitudinal incision was made through skin and fascia of the
plantar surface of the paw, starting 0.5 cm from the proximal edge
of the heel and extending toward the toes. Both superficial (skin)
and deep (muscle) tissues and nerves were injured. Finally, the
skin of the paw was stitched with a suturing stitch with breaded
silk (3.0).
Assessment of Analgesic Activity in Post-Operative Pain in Rats
[0068] The drugs were tested 4 hours after the surgery (plantar
incision); 60 minutes after the administration of the product,
Assessment of Thermal Hypersensitivity (Hyperalgesia) in
Post-Operative Pain in Rats
[0069] Thermal hypersensitivity or hyperalgesia was assessed by
measurement of a response to a thermal stimulus using a Hargreaves
apparatus (Ugo Basile plantar test) which selectively elevates the
temperature of an individual paw (Dirig, et al., J Neurosci
Methods, 1997, 76, 183). Animals were placed in the methacrylate
cages of said apparatus, having a crystal floor. The acclimation
period within the cages was about 10 minutes. The thermal stimulus
came from a lamp moving below the crystal floor and which was
applied to both paws, with a minimum interval of 1 minute between
both stimulations in order to avoid learning behaviours. The rat is
able to withdraw the paw freely when it feels discomfort (pain)
produced by the heat coming from the lamp; then it is switched off
and the latency time to the withdrawal response is recorded in
seconds. In order to avoid hurting the animal's paw, the lamp was
automatically switched off after 32 seconds. Hyperalgesia is
defined as an increased response to a painful stimulus and the
analgesic effect of the test compound is seen as a (partial)
restoration of the latency toward normal (Dirig, et al., J.
Pharmacol Expt Therap. 1998, 285, 1031).
Analysis of Synergistic Effect
[0070] The synergistic interaction between tramadol and celecoxib
was determined by isobologram analysis as discloses by R. J.
Tallarida, et al., Life Sci., 1989, 45, 947. This procedure
involves the determination of the total amount in the mixture that
is required to produce a specified synergistic anti-hyperalgesic
effect at the 50% dose level (that is, the ED.sub.50 or Zt) and the
corresponding total amount that would be expected under simple
additivity (ED.sub.50 add or Zadd). Where it is established that
Zt<Zadd for a specific fixed-ratio, then that composition has a
synergistic anti-hyperalgesic effect. Both ED.sub.50 t and
ED.sub.50 add values are random variables. ED.sub.50 t is
determined from the dose-response curve for a specific fixed-ratio
of the components; ED.sub.50 add is calculated from the ED.sub.50
values for the individual drugs. Zt is then compared to Zadd via a
Student's t-test.
Results
[0071] In this study, dose response curves of compositions
comprising a combination of racemic tramadol hydrochloride and
celecoxib at different ratios (1:1, 1:3 and 3:1) were obtained (see
FIG. 1A). All drugs induced full efficacy when thermal
hypersensitivity was evaluated.
[0072] All ratios of combination of racemic tramadol hydrochloride
with celecoxib resulted to act synergistically inhibiting thermal
hyperalgesia in postoperative pain rats. The ratios 1:1 and 3:1
improved significantly around 4 times the antihyperalgesic effects.
The ratio 1:3 improved around 1 time the antihyperalgesic effects
(see Table 2 and FIG. 1B).
TABLE-US-00002 TABLE 2 Statistic comparative analysis of Zt
(experimental) versus Zadd (additive) using a student's t-test.
Combination ratio Zt Zadd Ratio 1:1 2.26 .+-. 0.48** 9.41 .+-. 1.49
4.16 3:1 1.81 .+-. 0.41** 7.97 .+-. 1.2 4.40 1:3 11.07 .+-. 1.25
13.59 .+-. 1.67 1.23
Conclusion
[0073] Compositions comprising a combination of racemic tramadol
hydrochloride and celecoxib show synergistic interaction to inhibit
thermal hyperalgesia in the rat paw incision postoperative pain
model.
* * * * *