JPP 2010, 62: 25–34 ß 2010 The Authors. Journal compilation ß 2010 Royal Pharmaceutical Society of Great Britain Received July 6, 2009 Accepted October 5, 2009 DOI 10.1211/jpp/62.01.0002 ISSN 0022-3573 Correspondence: Doaa Ahmed El-Setouhy, Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo 11562, Egypt. E-mail: doaaahmed@hotmail.com Research Paper Ketorolac trometamol topical formulations: release behaviour, physical characterization, skin permeation, efficacy and gastric safety Doaa Ahmed El-Setouhy a and Sahar Mohy Ahmed El-Ashmony b a Department of Pharmaceutics, Faculty of Pharmacy and b Department of Clinical Pharmacology, Faculty of Medicine, Cairo University, Cairo, Egypt Abstract Objectives The objective of this study was to improve systemic delivery of the highly analgesic ketorolac trometamol (ketorolac tromethamine) via the transdermal route, through cost-effective topical formulations, to avoid most of the problems associated with ketorolac trometamol therapy. Methods In-vitro release behaviour of the drug from different microemulsion and emulgel formulations was evaluated. E2 emulgel (based on isopropyl myristate as penetration enhancer) and E7 emulgel (based on Brij 92 as penetration enhancer) were evaluated for their physical properties, rat skin permeation, in-vivo analgesic effect (hot- plate test and the paw pressure test), acute and chronic anti-inflammatory activity and gastric safety. Key findings Isopropyl myristate and the synergistic effect of the two known penetration enhancers (propylene glycol and Brij 92) significantly modulated drug permeation and may be a promising approach for the transdermal delivery of ketorolac trometamol and other drugs. Selected in-vivo tested formulae (E2 and E7) caused significantly less ulcer score and less gastric erosion compared with oral ketorolac trometamol. E7 showed significantly higher analgesic and anti-inflammatory activity compared with E2 with no significant difference compared with oral ketorolac trometamol. Conclusions The developed ketorolac trometamol E7 emulgel appeared promising for dermal and transdermal delivery of ketorolac trometamol, which would circumvent most of the problems associated with drug therapy. Keywords analgesic; anti-inflammatory activity; ketorolac trometamol; transdermal delivery Introduction Ketorolac trometamol (ketorolac tromethamine) is one of the most potent non-steroidal anti-inflammatory drugs (NSAIDs) that is known to have potent analgesic and moderate anti-inflammatory effect. It is structurally and pharmacologically related to tolmetin and indometacin. Clinical studies have shown that a single dose of ketorolac is more effective than that of morphine, pethidine (meperidine) and pentazocine in severe to moderate postoperative pain. [1] It has been found effective in the treatment of trauma-related pain as well as pain associated with cancer. [2–4] Unlike narcotic analgesics, it has the advantage that it does not depress the respiratory and the central nervous system. It has no addiction potential associated with narcotic analgesics and hence it exhibits a more favourable safety profile. [5] The drug is currently administered intramuscularly and orally in a frequent dosing regimen (due to its short biological half-life; approximately 4–6 h) for the short- term management of postoperative pain. However, an injection is an invasive drug therapy, frequent dosing is inconvenient to the patient; and in addition ketorolac trometamol can cause gastrointestinal complaints associated with all NSAIDs such as gastrointestinal bleeding, perforation and peptic ulceration. [5,6] Transdermal drug delivery appears to be an attractive noninvasive mode of drug delivery; it maintains drug blood levels for an extended period of time, eliminating a frequent dosing regimen, and minimizes gastrointestinal side effects. [7] However, the low permeability of the skin due to the barrier properties of the stratum corneum limits 25 Downloaded from https://academic.oup.com/jpp/article/62/1/25/6135718 by guest on 14 January 2023