Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-05-25
2003-06-17
Cook, Rebecca (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S263370, C514S282000, C514S317000
Reexamination Certificate
active
06579895
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to new uses of certain orally deliverable pharmaceutical formulations containing the selective cyclooxygenase-2 inhibitory drug celecoxib, for fast relief of pain, and for manufacture of medicaments useful in treatment of pain.
BACKGROUND OF THE INVENTION
Numerous compounds have been reported having therapeutically and/or prophylactically useful selective cyclooxygenase-2 inhibitory effect, and have been disclosed as having utility in treatment or prevention of specific cyclooxygenase-2 mediated disorders or of such disorders in general. Among such compounds are a large number of substituted pyrazolyl benzenesulfonamides as reported in U.S. Pat. No. 5,760,068 to Talley et al., including for example the compound
4-[5
-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-y1]benzenesulfonamide, also referred to herein as celecoxib. Celecoxib has the structure shown in formula (I):
A need for orally deliverable pharmaceutical compositions giving fast relief of pain exists. A particular need exists for such compositions giving fast relief of pain through selective inhibition of cyclooxygenase-2 (COX-2), without the undesirable side effects associated with inhibition of cyclooxygenase-1 (COX-1) that can occur with conventional non-steroidal anti-inflammatory drugs (NSAIDs). An especial need exists for such compositions giving fast relief of pain through selective inhibition of COX-2, yet exhibiting an onset of effective pain relief at least as rapid as standard NSAIDs used in the art, for example ibuprofen.
Celecoxib is well known as a highly effective selective COX-2 inhibitory drug and is widely prescribed for treatment of chronic inflammatory diseases such as rheumatoid arthritis and osteoarthritis. Celecoxib is available under the trademark Celebrex® of Pharmacia Corporation in capsule dosage forms containing 100 mg or 200 mg of the drug. Although these dosage forms can provide very effective relief of pain, they can, at least in some acute pain situations, exhibit a slower onset of pain relief than a standard NSAID such as ibuprofen.
A suspension of particulate celecoxib in a vehicle of apple juice is disclosed in Ecuador Patent Application No. 98-2761 (“EC 98-2761” which corresponds to WO 00/32189, Jun. 8, 2000). See in particular Example 13 therein, which describes preparation of such a suspension by dissolving celecoxib in ethanol containing 5% polysorbate 80 and adding the resulting mixture to apple juice prior to oral administration to 10 healthy male subjects. The dose administered was 300 mg celecoxib. An equal 300 mg dose was administered for comparison, in the form of three 100 mg capsules containing formulated celecoxib having a D
90
particle size of about 37 &mgr;m (i.e., 90% by weight of celecoxib particles in the formulation were smaller, in their longest dimension, than about 37 &mgr;m). Pharmacokinetic parameters disclosed indicate that the suspension gave a higher C
max
, shorter T
max
and shorter T
½
than the capsules as indicated in Table 1 below, where C
max
is the average maximum blood plasma concentration of celecoxib following administration, T
max
is the average length of time from administration until C
max
is reached, and T
½
is the average terminal half-life of blood plasma concentration of celecoxib following T
max
.
TABLE 1
Pharmacokinetics of celecoxib suspension and capsule formulations
(from Ecuador Patent Application No. 98-2761)
300 mg celecoxib
300 mg celecoxib
as suspension
as capsules
C
max
(ng/ml
1526.5
1076.5
plasma)
T
max
(h)
1.42
1.94
T
1/2
(h)
11.53
15.57
Ibuprofen in a typical acute pain relief dose of 400 mg normally provides an adequate level of suppression of pain, for example post-surgical pain, by about 1 hour after administration. Celecoxib in capsule form normally takes longer, for example about 2 hours, to achieve a similar level of pain suppression. No suggestion is made in above-cited EC 98-2761 that the apparently modest reduction in T
max
exhibited by the disclosed suspension by comparison with the capsule formulation, when administered in a 300 mg dose, could be associated with a major improvement in onset of pain relief, or that the suspension formulation of celecoxib could be at least comparable with ibuprofen in onset of pain relief.
Above-cited EC 98-2761 merely discloses in general terms that compositions of the invention disclosed therein, i.e., including the disclosed capsule formulations as well as the suspension composition of Example 13 thereof, are effective “for pain management generally (particularly post-oral surgery pain, post-general surgery pain, post-orthopedic surgery pain, and acute flares of osteoarthritis)”. Nevertheless, this reference contains no suggestion that the suspension composition might provide an effective pain relieving amount of celecoxib nor was it appreciated by this reference that an effective pain-relieving concentration of 250 nm/ml plasma or greater could be achieved in a rapidly bioavailable formulation. This is particularly in view of the extensive binding of celecoxib to plasma albumin which was known to occur following oral administration (Davies et al.,
Clin. Pharmacokinet.
38:225-242, 2000). Thus, one could not have predicted that a particular plasma concentration would produce analgesia.
Australian Patent Applications No. 200042711, No. 200043730 and No. 200043736 disclose compositions comprising a selective COX-2 inhibitory drug, a 5HT
1
receptor agonist and caffeine, said to be useful for treating migraine.
Although objectives of the present invention are not limited to any particular measure of analgesic response, a method of providing analgesia with an onset time of 60 minutes or less, especially 30 minutes or less and ideally 15 minutes or less, by oral administration of a celecoxib composition would be an important advance in the art.
SUMMARY OF THE INVENTION
It has now surprisingly been discovered that celecoxib can provide acceptable relief of acute pain within about 60 minutes or less after oral administration, in some cases much less than 60 minutes, for example as little as about 15 to about 45 minutes, after oral administration, if it is formulated and administered in such a way as to give a particular pharmacokinetic profile as defined below.
Accordingly, there is now provided a therapeutic method comprising orally administering to a mammalian, preferably human, subject in need of analgesia an effective pain-relieving amount of a composition comprising celecoxib (herein also referred to as a celecoxib composition) formulated in such a way as to provide, when tested in fasting humans in accordance with standard pharmacokinetic practice, a blood plasma concentration profile of celecoxib in which a concentration of about 250 ng/ml is attained not later than about 30 minutes after oral administration. The plasma concentrations of 250 ng/ml or greater achieved by the compositions and methods of the present invention at or before 30 minutes after oral administration and, more preferably, at or before 15 minutes after oral administration, are effective pain-relieving plasma concentrations.
It has not previously been known that fast absorption of celecoxib, as indicated by such a blood plasma concentration profile, is important in achieving fast onset of analgesic response. As noted above, celecoxib is known to be extensively bound to plasma albumin following oral administration (Davies et al., supra) such that one could not have predicted that a particular plasma concentration would produce analgesia.
There is also provided a method of use of celecoxib, formulated in such a way as to provide, when tested in an effective pain-relieving amount in fasting humans in accordance with standard pharmacokinetic practice, a blood plasma concentration profile of celecoxib in which a concentration of about 250 ng/ml is attained not later than about 30 minutes after oral administration, in preparation of a medicament for rapid relief of pain in a mammalian, preferably human, subject.
The phrase
Brugger Andrew M.
Forbes James C.
Gao Ping
Hassan Fred
Karim Aziz
Cook Rebecca
Harness Dickey & Pierce
Pharmacia Corporation
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