Nano-Formulated NSAIDs: A New Dawn for Safe Use

Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used for acute or temporary pain and various chronic disorders. Nevertheless, NSAID use carries an increased risk of gastric, cardiovascular, and renal events.^1,2,3

As the aging population continues to expand, so too does the prevalence of NSAID use among an ever-increasing cohort of chronic pain patients who present with comorbid conditions (kidney disease, heart failure, increased bleeding) and commensurate elevated risk for NSAID toxicity.⁴

While NSAIDs are effective in treating various pain conditions and generally have opioid-sparing attributes, their long-term toxicity and risks frequently preclude safe chronic use in many patients. ¹⁶

In July, the FDA strengthened the existing warning that NSAIDs can increase the risk for heart attacks and strokes. The warning further described how the risk “appears greater at higher doses,” and advised using the “lowest effective amount for the shortest possible time.”⁵

There is strong evidence demonstrating that these NSAID-related risks are dose dependent, but using lower doses of traditional NSAIDs may blunt their acceptable analgesic efficacy.⁶

Nanotechnology has been used in various drug delivery systems to manipulate the pharmacokinetic profile of certain medications and optimize pharmacodynamics at lower doses.^8,9 Low-dose micronized NSAIDs have been developed using nanotechnology to increase drug surface area and enhance absorption, thereby achieving comparable efficacy to conventional formulations at minimal doses with reduced adverse event risks.^8,9,17

Iroko Pharmaceuticals is at the forefront of developing low-dose NSAIDs using iCeutica’s SoluMatrix Technology, which produces submicron-sized drug particles that are approximately 10 to 20 times smaller than the original size.⁷ This particle size reduction results in increased surface area, allowing faster dissolution and absorption.^8,9,17

FDA-approved micronized NSAIDs currently include indomethacin (Tivorbex) and diclofenac (Zorvolex) for the treatment of mild-moderate pain in adults. Zorvolex received an additional FDA approval in August for osteoarthritis management.

At doses below their conventional counterparts, submicron NSAIDs have been shown to achieve comparable peak plasma levels (Cmax), shorter time to peak plasma concentration (Tmax), and lower overall extent of systemic exposure (AUC). Cmax is thought to correlate closely with efficacy, while AUC is thought to correlate with safety. ²⁰

In phase 1 clinical trials for the submicron formulations of indomethacin, diclofenac, and meloxicam under fasting conditions, a comparable Cmax was observed with shorter Tmax and lower AUC compared with conventional formulations (Table 1).^8,9

Table 1: Pharmacokinetic Parameters for Micronized NSAIDs Compared with Conventional Formulations Under Fasting Conditions

Indomethacin⁸

Diclofenac⁹

Meloxicam ¹⁷

Dose equivalency

Micronized

Conventional

Micronized

Conventional

Micronized

Conventional

Dose equivalency

40 mg

50 mg

35 mg

50 mg

10 mg

15 mg

Cmax (ng/mL)

3115±900

2759±936

1347±764

1316±577

1.25±0.25

1.29±0.42

Tmax

(hours)

1.25±0.60

1.97±0.81

0.59±0.20

0.80±0.50

2.0 (1.0-5.0)

4.0 (2.0-8.0)

AUC

(h*ng/mL)

6861±1585

9306±2234

1204±324

1493±388

29.2±11

40.9±11.7

T ½

(hours)

7.73±2.07

8.45±3.16

1.85±0.45

1.92±0.38

22.0±10.1

23.6±10.0

Tivorbex 40 mg PO TID, and Zorvolex 35 mg PO TID have both shown similar efficacy to celecoxib 200 mg PO BID and superior efficacy to placebo in pain relief following orthopedic procedure (bunionectomy).^11,13 Zorvolex has also demonstrated efficacy in osteoarthritis management in a 12-month, open-label safety study in 602 patients compared with placebo.

The aforementioned SoluMatrix NSAIDs have demonstrated reduced use of rescue medication compared with placebo. SoluMatrix meloxicam has also demonstrated significant analgesia compared with placebo in rheumatoid arthritis and osteoarthritis of the knee.¹⁴

NSAIDs have demonstrated synergistic effects when used in combination with opioids for various inflammatory pain conditions such as rheumatoid arthritis, ankylosing spondylitis, other spondyloarthritis disorders.¹⁵ Furthermore, NSAIDs may have opioid-sparing effects, allowing for lower opioid dose when used for chronic or acute pain, including in the postoperative pain setting.^15,16

More SoluMatrix agents are in the pipeline. For instance, meloxicam phase 3 clinical data has been submitted to the FDA and its New Drug Application is currently undergoing review.^14,17 Naproxen is in phase 3 clinical trials, and 2 additional submicron NSAIDs, celecoxib and ibuprofen, are currently undergoing preclinical development.⁹

Developing micronized NSAIDs represents a promising approach toward improving the overall safety and mitigating the risks associated with NSAID use in both acute and chronic settings. Current data demonstrates their favorable pharmacokinetic profile, comparable efficacy, and potential for lower complications compared with their traditional NSAID counterparts.

It is important to note that just prior to 2000, there was a huge surge in NSAID use with the exciting introduction of COX-2 selective inhibitors, presumably as a result of anticipated superior gastrointestinal safety.²¹ But, as Newton’s third law states, “For every action, there is an equal and opposite reaction,” and unfortunately, many patients experienced the reaction of increased cardiac risks associated with COX-2 selective inhibitors.

This occurred because of enhanced thromboembolic events from unanticipated effects on the prostaglandin/prostacyclin cascade. Fortunately, a new dawn has emerged from nano-formulations that could cast a far-reaching safety net devoid of any new or unanticipated biological negative feedback loops previously seen with COX-2 selective inhibitors.

Pharmacists should keep a watchful eye and consider discussing these new options with prescribers for higher-risk patients that may benefit from this technology.

This article was collaboratively written with Mena Raouf, a 2016 PharmD Candidate at the Albany College of Pharmacy and Health Sciences, with a concentration in Nephrology. He hopes to complete PGY1 and PGY2 Pharmacy Residency and practice as a clinical pharmacist specialist. He is currently under the mentorship of Dr. Fudin studying pain management.

References

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16. Wong I, St John-Green C, Walker SM. Opioid-sparing effects of perioperative paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs) in children. Paediatr Anaesth. 2013 Jun;23(6):475-95.

17. Altman R, Hochberg M, Gibofsky A et al. Low-Dose Solumatrix Meloxicam Demonstrates Low Systemic Exposure And Efficacy In Patients In Clinical Studies. Poster Presentation for 2014 European League Against Rheumatism (EULAR) Annual European Congress of Rheumatology. Ann Rheum Dis. 2014;73(Suppl2):1089.

18. Safety of Lower-Dose Diclofenac Submicron Particle Capsules Dosed Up To 12 Weeks in Patients with Osteoarthritis. Poster at ACR.

19. Edgar Online: IPO Alerts. Company Profile: Iroko Pharmaceuticals Inc. Available at: http://ipoalerts .edgar-online.com/ipo/textSection.asp?cikid=909043 &fnid=72836&IPO=1&sec=bd&coname=IROKO+ PHARMACEUTICALS+INC (accessed September 11, 2014).

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21. Atkinson TJ, Cronin K, Jahn HL, Kubotera N, Rennick A, Fudin J. What’s New in NSAID Pharmacotherapy? Pain Medicine. NSAID Supplement. Volume 14, Issue Supplement S1, pages S11—S17, December 2013.