Penetration and efficacy of transdermal NSAIDs in a model of acute joint inflammation

Abstract

Purpose: Prescription and OTC non-steroidal anti-inflammatory drugs (NSAIDs) are ubiquitous treatments for pain and inflammation; however, oral administration of these drugs may produce gastrointestinal (GI) side effects. Transdermal (TD) administration of NSAIDs circumvents these adverse events by avoiding the GI tract and, presumably, achieves regional drug levels of therapeutic effect and thereby, fewer off-target complications.

Methods: A drug quantification method was developed for ibuprofen and celecoxib in canine plasma and synovial fluid using liquid chromatography and mass spectrometry. This method was employed to evaluate the penetrance of ibuprofen and celecoxib topical formulations in dogs. Effectiveness of these topical NSAID formulations was compared to the equivalent oral drug concentration in a canine sodium-urate model of acute joint inflammation. In this model, pain was quantified using a modified Canine Brief Pain Inventory questionnaire and regional inflammation using joint caliper measurements; the significance of intervention was evaluated using linear mixed models for repeated measures along with Bonferroni corrections.

Results: After seven days of chronic topical administration, Delivra™ (DEL) formulations of ibuprofen and celecoxib generated serum levels of 2.9µg/mL and 220ng/mL and synovial fluid levels of 1.8 µg/mL and 203 ng/mL (respectively). In the canine model of acute inflammation, the overall treatment effects as well as the treatment by time interactions were strongly significant (P<0.001) for both drugs. Oral ibuprofen proved uniquely effective at the earliest time point, while all ibuprofen formulations were effective at treating pain at 8.5 and 24.5 hours post-induction. Similarly, all celecoxib formulations (oral and topical) were equally effective at 8.5 and 24.5 hours post-induction.

Conclusion: DEL formulations of ibuprofen and celecoxib successfully introduced these NSAIDs into synovial fluid at concentrations similar to those observed in circulation. Furthermore, these formulations reduced symptoms of pain associated with acute inflammation. Oral and transdermally delivered NSAIDs have similar pain relief effects; therefore, a replacement or combinatorial treatment may provide a more stable pain relief profile. In conclusion, this work supports further investigation of TD products in the treatment of regional inflammatory events.

Keywords: canine model; celecoxib; ibuprofen; osteoarthritis; pain.

Figure 1

Serum and synovial fluid ibuprofen concentration after chronic topical administration and washout. Notes: Aged beagles received 1 g cream per shoulder joint twice/day, either 4% ibuprofen formulated in Delivra™ SR or vehicle only (Delivra™ SR) for 7 days. Serum (A) and synovial fluid (B) were collected 60 minutes post final administration. The same bio-fluids were sampled again after a seven-day washout period. Ibuprofen concentrations measured by LC-MS/MS were 2,910±544.2 ng/mL (mean ±SEM), 67.6±13.2 ng/mL (mean ±SEM), 5.3±2.1 ng/mL (mean ±SEM) for BLQ in serum (A) for Delivra™-ibuprofen (n=6), Delivra™-ibuprofen washout, Delivra™ SR (n=2) and Delivra™ SR washout, respectively. Ibuprofen concentration in synovial fluid (B) was 1,817±262.0 ng/mL (mean ±SEM), 37.8±10.0 ng/mL (mean ±SEM), BLQ, and 4.9±0.1 ng/mL (mean ±SEM) for Delivra™-ibuprofen, Delivra™-ibuprofen washout, Delivra™ SR and Delivra™ SR washout, respectively. Paired t-tests demonstrated a significant reduction in ibuprofen levels between chronic treatment and washout periods for (A) serum (^*P=0.008) and (B) synovial fluid (^**P=0.004). Abbreviations: DEL, Delivra™; DEL-SR, Delivra™ slow release; SEM, standard error of the mean; BLQ, below the limit of quantification; LC-MS/MS, liquid chromatography tandem mass spectrometry.

Figure 2

Serum and synovial fluid celecoxib concentrations after chronic topical administration and washout. Notes: Aged beagles received 1 g cream per shoulder joint twice/day, either 3% celecoxib formulated in Delivra™ SR (Delivra™ celecoxib) or vehicle (Delivra™ SR) for 7 days. Serum (A) and synovial fluid (B) were collected 60 minutes post final administration. The same bio-fluids were sampled again after a seven-day washout period. Celecoxib concentrations were measured by LC-MS/MS and were 220.9±92.7 ng/mL (mean ±SEM), 4.2±2.2 ng/mL (mean ±SEM), 7.0±2.5 ng/mL (mean ±SEM), below the limit of quantification (BLQ) in (A) serum for Delivra™-celecoxib (n=6), Delivra™-celecoxib washout, Delivra SR (n=3) and Delivra™ SR washout, respectively. Celecoxib concentration in (B) synovial fluid was 203.0±67.3 ng/mL (mean±SEM), 16.8±15.5 ng/mL (mean±SEM), BLQ and BLQ for Delivra™-celecoxib, Delivra™-celecoxib washout, Delivra™ SR and Delivra™ SR washout, respectively. Paired t-tests demonstrated that the reduction in celecoxib levels between chronic treatment and washout periods for (A) serum (P=0.07) and (B) synovial fluid (P=0.09) were not significant. Abbreviations: DEL, Delivra™; DEL-SR, Delivra™ slow release; LC-MS/MS, liquid chromatography tandem mass; BLQ, below the limit of quantification; SEM, standard error of the mean.

Figure 3

A comparison of oral and TD ibuprofen to alter pain and swelling in a model of acute joint synovitis. Notes: A study design involving beagle dogs (N=8 per group) involved baseline (0.0) and post-synovitis measures at 4.5, 8.5, 24.5, and 30.5 hours for (A) pain levels using the CBPI and (B) swelling using stifle width (mm) for the ipsilateral and contralateral joints. Inflammatory synovitis was induced by injection of 1.0 mL of 20 mg/mL sodium urate (under anesthesia). Animals received no intervention (■), vehicle Delivra™ SR (100 mg/kg;), or equimolar interventions consisting of oral ibuprofen (4 mg/kg;), PLO-ibuprofen (4% at 100 mg/kg;), or Delivra™-ibuprofen (4% at 100 mg/kg). Results are graphically represented as the average CBPI score, average joint width along with SEM error bars for each group. Linear mixed models for repeated measures and Bonferroni adjustment for multiple comparisons demonstrated significant pain reduction (A) for oral ibuprofen (^*P<0.001) at 4.5 hours with all interventions yielding significant (^**P<0.02) and indistinguishable effects at 8.5 and 24.5 hours. Abbreviations: PLO, pluronic lecithin organogel; DEL, Delivra™; DEL-SR, Delivra™ slow release; CBPI, canine brief pain inventory; TD, transdermal.

Figure 4

A comparison of oral and TD celecoxib to alter pain and swelling in a model of acute joint synovitis. Notes: A study design involving beagle dogs (N=8 per group) involved baseline (0.0) and post-synovitis measurements at 4.5, 8.5, 24.5, and 30.5 hours for (A) pain levels using the CBPI and (B) swelling using stifle width (mm) for the ipsilateral and contralateral joints. Inflammatory synovitis was induced by injection of 1.0 mL of 20 mg/mL sodium urate (under anesthesia). Animals received no intervention (■), vehicle Delivra™ SR (100 mg/kg;), or equimolar interventions consisting of oral celecoxib (3 mg/kg;), PLO-ibuprofen (8% at 37.5 mg/kg;), or Delivra™-ibuprofen (8% at 37.5 mg/kg). Results are graphically represented as the average CBPI score and average joint width along with SEM error bars for each group. Linear mixed models for repeated measures and Bonferroni adjustment for multiple comparisons demonstrated all interventions yielding significant (^*P<0.02) and indistinguishable pain reduction (A) at 8.5 and 24.5 hours. Abbreviations: PLO, pluronic lecithin organogel; DEL, Delivra™; DEL-SR, Delivra™ slow release; CBPI, canine brief pain inventory; SEM, standard error of the mean; TD, transdermal; ipsi, ipsilateral; contra, contralateral.