Talk: Application of Nanotechnology to Improve Non-Steroidal Anti-Inflammatory Drugs (2011 ACR/ARHP Annual Scientific Meeting)

Monday, November 7, 2011: 9:00 AM-6:00 PM

Hall F2 - Poster Hall (McCormick Place West)

Garen Manvelian, Iroko Pharmaceuticals, Poway, CA, Roy D. Altman, UCLA, Los Angeles, CA and Vibeke Strand, Stanford University, Palo Alto, CA

Presentation Number: 1282

Background/Purpose: Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed for various conditions involving both acute and long-term pain. However, concerns exist about the safety and tolerability associated with NSAIDs. We have completed 3 Phase 2 clinical trials in acute pain models to assess the analgesic efficacy and safety of investigational, nano-formulated, oral NSAIDs: diclofenac, indomethacin, and naproxen.

Method: All 3 Phase 2 trials were multi-center, randomized, double-blind, single-dose, parallel-group, active- and placebo-controlled studies. More than 200 subjects (N=202 [diclofenac], N=203 [indomethacin], and N=253 [naproxen]) were enrolled for each trial. Subjects were 18-50 years of age, had extraction of ≥2 third molars (at least one of which had to be a fully or partially impacted mandibular third molar), and experienced moderate to severe pain intensity within 6 hours after surgery. Subjects received nano-formulated diclofenac, indomethacin, or naproxen, an active comparator (parent compound or celecoxib), or placebo. The sum of total pain relief (TOTPAR) was assessed at 4, 8, and 12 hours. The primary efficacy endpoints were TOTPAR 0 to 12 hours (diclofenac and naproxen) and 0 to 8 hours (indomethacin). Higher scores indicated better pain relief.

Result: All active treatments resulted in significantly (P<0.001) better TOTPAR values compared with placebo (Table).

TOTPAR-12
Mean; SD

TOTPAR-8
Mean; SD

TOTPAR-4
Mean; SD

Nano-formulated Diclofenac 18 mg, N=49

17.8; 13.8^a

14.3; 9.4^a

8.2; 4.2^a

Nano-formulated Diclofenac 35 mg, N=51

16.8; 12.8^a

13.9; 8.8^a

7.9; 4.3^a

Celecoxib 400 mg, N=51

14.6; 15.1^a

11.2; 10.5^a

5.7; 5.0^a

Placebo, N=51

5.7; 11.5

3.9; 7.2

2.1; 3.3

Nano-formulated Naproxen 400 mg, N=51

31.9; 12.4^a

21.5; 7.6^a

10.1; 3.5^a

Standard Naproxen 500 mg, N=51

28.3; 13.0^a

19.8; 8.1^a

9.5; 3.8^a

Nano-formulated Naproxen 200 mg, N=50

25.7; 16.2^a

17.3; 9.8^a

8.2; 4.3^a

Standard Naproxen 250 mg, N=50

24.6; 15.3^a

16.9; 9.8^a

8.0; 4.5^a

Placebo, N=51

9.6; 13.6

6.8; 8.8

3.5; 3.9

Nano-formulated Indomethacin 20 mg, N=50

Not assessed

10.8; 10.5^a

5.5; 4.6^a

Nano-formulated Indomethacin 40 mg, N=51

Not assessed

12.6; 10.7^a

6.2; 4.8^a

Celecoxib 400 mg, N=51

Not assessed

14.9; 9.9^a

7.2; 4.2^a

Placebo, N=51

Not assessed

3.0; 6.6

1.6; 2.8

^aP<0.001 compared with placebo

SD=standard deviation

TOTPAR values for nano-formulated diclofenac and nano-formulated naproxen were numerically better than the active comparators, although the studies were not powered to assess this statistically. Additionally, visual analog scale pain intensity difference values for each treatment group were all significantly (P<0.001) better than placebo.

Conclusion: Investigational, nano-formulated, oral NSAIDs demonstrated efficacy in an acute pain model. These Phase 2 data indicate that nano-formulated diclofenac, indomethacin, and naproxen may offer efficacy at a lower dose and deserve further investigation in Phase 3 clinical trials. The aforementioned results are in line with the FDA directive to use the lowest effective NSAID dose.

Keywords: clinical trials, nanomedicine, nonsteroidal antiinflammatory drugs (NSAIDs) and pain

Disclosure: G. Manvelian, Consultant, 5 ; R. D. Altman, None; V. Strand, Consultant, 5 .

1282 - Application of Nanotechnology to Improve Non-Steroidal Anti-Inflammatory Drugs