Nano-Formulated Diclofenac Found Effective in Phase 2 Trial

Laird Harrison

May 21, 2012

May 21, 2012 (Honolulu, Hawaii) — Diclofenac in a fine powder relieves pain effectively at a lower dose than the standard formulation, researchers reported here at the American Pain Society (APS) 31st Annual Scientific Meeting.

When patients take diclofenac in a powder whose granules are one tenth the size of the standard formulation, they may absorb it faster and only need about 20% of a standard dose, Garen Manvelian, MD, a San Diego, California–based consultant to Iroko Pharmaceuticals told Medscape Medical News.

"It changes the absorption kinetics dramatically," said Dr. Manvelian, who presented the results of a phase 2 clinical trial.

Nonsteroidal antiinflammatory drugs can cause cardiovascular, gastrointestinal, and renal adverse reactions, and these effects are more likely with higher doses, Dr. Manvelian said.

To reduce the risk of these effects, Iroko Pharmaceuticals is looking for a way to reduce the dosages while maintaining the same benefits for pain relief.

So the company licensed from iCeutica a technique called SoluMatrix to mill the drug more finely.

To test this approach, the researchers recruited 202 patients experiencing moderate to severe pain within 6 hours of wisdom tooth extractions.

They randomly assigned 51 patients to a placebo, 49 patients to 18 mg of nano-formulated diclofenac, 51 patients to 35 mg of nano-formulated diclofenac, and 51 patients to 400 mg of celecoxib. All groups took a single dose of the assigned medication.

Celecoxib was included only to validate the study; it was not meant as a comparison, said Dr. Manvelian.

The patients rated their pain on the basis of total pain relief (TOTPAR) score, which is the sum of hourly pain relief scores weighted by the time interval between observations, and on a visual analogue scale.

At 12 hours, the TOTPAR score of the placebo patients was 5.49 +/- 1.87, whereas patients receiving 18 mg diclofenac scored 17.77 +/- 1.9, patients receiving 35 mg diclofenac scored 16.89 +/- 1.87, and patients receiving celecoxib scored 14.69 +/- 1.86. The differences between the scores of the placebo group and all 3 active treatment groups were statistically significant (P < .001).

The 3 active treatment groups also showed a significantly shorter time to analgesia (P < .001) and a larger improvement on the visual analogue scale than the placebo group.

The researchers did not compare nano-formulated diclofenac to standard diclofenac in this study because the study was designed to prove to the US Food and Drug Administration that the drug is safe and effective, rather than to show that it is superior to its parent drug, Dr. Manvelian explained.

Also, he said researchers would have to recruit and follow tens of thousands of participants to measure a difference in adverse reactions, he said.

However, he said that the 18 mg group experienced no severe treatment-emergent adverse events, whereas 2 particpants in the 35 mg group experienced dizziness, 1 had flushing, and 1 had pallor.

The statistics were similar for the placebo group, in which 1 patient had alveolar osteitis, 1 had a headache, 1 reported incision-site pain, 1 reported postprocedural swelling, and 1 vomited.

One of the patients on celecoxib reported alveolar osteitis.

The researchers are already in the midst of a phase 3 follow-up study, said Dr. Manvelian. "I can disclose that it's promising," he said. "In the phase 3 study, [the results] hold up," he said.

Although the results look promising, questions remain, said Subo Liao, PhD, a researcher with Covidien in St. Louis, Missouri. Grinding the drug into a finer powder is expensive, he pointed out. "In nano formulations, you increase the costs," he told Medscape Medical News. "What are the benefits vs the costs?"

Dr. Manvelian disclosed that he is a consultant to Iroko Pharmaceuticals. Dr. Liao disclosed that he is an employee of Covidien, which also makes pain relievers.

American Pain Society (APS) 31st Annual Meeting. Abstract #395. Presented May 17, 2012.


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