Use of a celecoxib composition for fast pain relief

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An “effective pain-relieving concentration” or “effective pain-relieving plasma concentration” as used herein is intended to mean a plasma level in a patient which when tested in a standardized test involving patient scoring of the severity of pain, achieves a mean score indicating pain relief. In one such test as described hereinbelow, patients score pain on a scale of from 0 (no reduction in severity of pain) to 4 (complete relief of pain) and a mean score equal to or greater than a given value is deemed to constitute effective pain-relief. A mean score of 0.5 or greater and, more preferably, 1.0 or greater in such a test, as exemplified herein, is deemed to constitute effective pain relief. The skilled artisan will appreciate, however, that other approaches can be used to assess the severity of pain and relief from such pain.

Thus, one aspect of the present invention involves a therapeutic method for analgesia in which a composition comprising celecoxib is administered orally to a subject, in a formulation which provides detectable pain relief not later than about 30 minutes after oral administration. By “detectable pain relief”, it is meant that the formulation produces effective pain relief which is measurable by a standard method such as described above. For example, a formulation, which achieves a mean score of 0.5 or greater and, more preferably, 1.0 or greater on a scale of from 0 to 4 in a testing system as described above, is deemed to provide detectable pain relief. The invention is not limited to use of any particular type of formulation, so long as it exhibits the pharmacokinetic profile defined herein. Examples of suitable formulation types are described below.

Protocols for conducting human pharmacokinetic studies are well known in the art and any standard protocol can be used to determine whether a particular celecoxib formulation satisfies the pharmacokinetic criteria set out herein. An example of a suitable protocol is described below.

An advantage of the present invention is that relief of pain, even intense pain as can occur, for example, following oral, general or orthopedic surgery, is achieved significantly faster, i.e., in a significantly shorter time after administration, than is achievable with standard formulations of celecoxib.

A further advantage is that, by contrast with pain relief methods involving NSAIDs lacking selectivity for inhibition of COX-2, rapid relief of pain can be obtained without the side-effects commonly associated with COX-1 inhibition. Thus the method of the present invention is especially suitable where NSAIDs are contraindicated, for example in patients with peptic ulcers, gastritis, regional enteritis, ulcerative colitis or diverticulitis, patients with a recurrent history of gastrointestinal lesions, patients with gastrointestinal bleeding, coagulation disorders including anemia such as hypothrombinemia, hemophilia and other bleeding problems, or kidney disease, patients prior to surgery, or patients taking anticoagulants.

Other features and advantages of the invention will be in part apparent and in part pointed out hereinafter.

The method of the invention can be used to relieve acute or chronic pain, but is particularly well-suited to acute pain indications such as post-surgical pain or post-traumatic pain. The method of the invention is useful for treatment of non-human mammalian subjects or patients, including domestic, farm and exotic animals, such as for example dogs horses, zoo animals and the like, but is primarily useful for treatment of human subjects or patients.

Celecoxib used in the method of the invention can be prepared by a process known per se, for example by processes described in U.S. Pat. No. 5,466,863 to Talley et al. or in U.S. Pat. No. 5,892,053 to Zhi & Newaz.

A suitable dose of celecoxib, administered according to the method of the invention, is typically in the range of about 1 to about 6 mg/kg body weight, preferably about 1.3 to about 5.3 mg/kg body weight and more preferably about 2 to about 3.5 mg/kg body weight, for example about 2.7 mg/kg body weight. Depending on the body weight of the subject, a suitable dosage amount of celecoxib is typically about 50 to about 400 mg, preferably about 100 to about 300 mg. Surprisingly good results can be obtained with dosage amounts less than 300 mg, such as about 100 to about 275 mg, or about 150 to about 250 mg, for example about 200 mg.

The doses set out above relate to a single administration, and can be repeated as needed. Generally no more than about 4 doses per day will be needed, and in most cases 1 or 2 doses per day will be found sufficient.

A key to the present invention is selecting a formulation that provides a pharmacokinetic profile wherein a threshold blood plasma concentration of celecoxib of at least about 250 ng/ml is attained not later than about 30 minutes after oral administration. This analgesically effective blood concentration is achieved in the present invention by utilizing a composition containing celecoxib in a rapidly bioavailable formulation, i.e. a “fast-acting formulation”. The celecoxib is present in the composition at dose levels as discussed above, which are typically used in formulations which do not achieve such plasma concentrations shortly after administration, i.e. within about 30 minutes and, more preferably, within about 15 minutes after oral administration.

In preferred methods, a formulation is selected providing a higher concentration than about 250 ng/ml within about 30 minutes. For example, a formulation can be expected to be particularly effective for relief of pain if a blood plasma concentration of at least about 300 ng/ml, more preferably at least about 400 ng/ml and most preferably at least about 500 ng/ml, is attained within about 30 minutes following oral administration of the formulation. There is no critical upper limit of blood plasma concentration so long as the dosage amounts set out above are not significantly exceeded; however it is likely that no significant incremental benefit will be obtained from blood plasma concentrations of celecoxib greatly in excess of about 500 ng/ml, for example in excess of about 1000 ng/ml, within the first 30 minutes.

Preferably, a threshold blood plasma concentration of celecoxib of about 250 ng/ml is attained not later than about 15 minutes after oral administration of the formulation.

In a particularly preferred embodiment the formulation provides a blood plasma concentration of celecoxib that attains about 300 ng/ml not later than about 30 minutes, most preferably not later than about 15 minutes, after oral administration.

In another particularly preferred embodiment the formulation exhibits a Tmax not greater than about 1.25 hours, most preferably not greater than about 1 hour.

In yet another particularly preferred embodiment the formulation exhibits, in comparative pharmacokinetic testing versus a standard commercial formulation of celecoxib, such as Celebrex® 200 mg capsules of Pharmacia Corporation, a Tmax not greater than about 50%, even more preferably not greater than about 33%, and most preferably not greater than about 25%, of the Tmax exhibited by said standard commercial formulation.

Any standard pharmacokinetic protocol can be used to determine blood plasma concentration profile in humans following oral administration of a celecoxib formulation, and thereby establish whether that formulation meets the pharmacokinetic criteria set out herein.