Tra N S Mucosal Permeation of to P I C a L Ly Applied Diclofenac and Pirox I C a M
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VANDERBIJLJARFall03REP 12/29/03 3:08 PM Page 505 Tra n s mucosal Permeation of To p i c a l ly Applied Diclofenac and Pirox i c a m Pieter van der Bijl, BChD, BSc (Hons) (Pharmacol), PhD, DSc Armorel D. van Eyk, PhD Heiner I. Seifart, Dr rer nat Ianda Viljoen, BSc (Hons) (Pharmacol) Marli Jooste, BSc (Hons) (Pharmacol) Department of Pharmacology, Faculty of Health Sciences, University of Stellenbosch, Ty ge r b e rg, South A f r i c a KEY WO R D S : Diclofenac, pirox i c a m , n i f i c a n t ly higher than those from the gels. human mucosa, permeability studies Steady-state flux rates of the 5 mg/mL diclofenac solution were approx i m a t e ly half ABSTRACT that of the 10 mg/mL solution, whereas max- Nonsteroidal antiinflammatory dru g s imal p a rtitioning to the mucosa from the (NSAIDs) are frequently used for the treat- vehicle and/or saturable diffusion kinetics ment of acute myalgias, orthopedic injuries, was achieved at concentrations of 5 mg/mL p o s t o p e r a t ive pain, chronic rheumatoid or less for the piroxicam solutions under the a r thritis, and osteoarthritis. This study experimental conditions used. The diff u s i o n i nvo l ves the permeation of 2 NSAIDs, of diclofenac and piroxicam across mucosal diclofenac and piroxicam, from topically s u r f aces appears to be more efficient wh e n applied solutions and gels through human aqueous solutions of these compounds are vaginal mucosa as a model of bu c c a l used as opposed to gel formulations. T h i s mucosa. Pe r meation of diclofenac and must be considered when vehicles for both p i r oxicam from the solutions and gels these NSAIDs are chosen. There also through human vaginal mucosa was deter- appeared to be a limit to the release of mined using a flow-through diffusion appa- p i r oxicam from the vehicle and/or its flux ratus. Vaginal specimens were obtained rate across mucosal tissues. from 8 postmenopausal patients aged 57 ± 16 years (mean ± standard deviation [SD]; INTRODUCTION range, 32–76 y) after vaginal hy s t e r e c- Nonsteroidal antiinflammatory dru g s tomies. Experiments were conducted at (NSAIDs) belong to the most frequently 20˚C and over a time period of 24 hours. used drugs worldwide, with as many as 8% High-pressure liguid chromatogr a p hy of the global adult population taking pre- (HPLC) analysis was used as a detection scribed forms of these agents at any give n method. Statistical tests used included t i m e . 1 H oweve r, it is estimated that they are a n a lysis of variance (ANOVA) and Duncan’s also responsible for approx i m a t e ly 25% of multiple range test for determination of all adverse drug reaction report s . 2 In this steady state and an unpaired t test with respect, NSAID-related gastrointestinal tox i- We l c h ’s correction for comparing diff e r- city is the most frequently observed adve r s e ences between the mean flux values at each event, and it is a significant cause of mor- time point. Flux rates of both diclofenac and bidity and mort a l i t y.3 The ingestion of p i r oxicam from aqueous solutions were sig- NSAIDs increases the relative risk of upper The Journal of Applied Research • Vol. 3, No. 4, Fall 2003 505 VANDERBIJLJARFall03REP 12/29/03 3:08 PM Page 506 gastrointestinal tract bleeding 5-fold,4 is ele- mucosa, to aqueous and commercially ava i l- vated in the elderly,5 and might be eve n a ble gel forms of diclofenac and pirox i c a m . higher for certain NSAIDs.6 , 7 The NSAIDs are often the first choice of treatment for MATERIALS AND METHODS patients with acute myalgias, ort h o p e d i c Vaginal Mucosa injuries, postoperative pain, chronic rheuma- Specimens were obtained from excess tissue toid arthritis, and osteoart h r i t i s . 8 r e m oved from 8 postmenopausal patients In an attempt to reduce the relative ly aged 57 ± 16 years (mean ± standard dev i a- high incidence of serious adverse eff e c t s tion [SD]; range, 32–76 y) after vaginal hy s- associated with the systemic use of terectomies at the Louis Leipoldt and NSAIDs, a gr owing number of topical for- Panorama Mediclinic Hospitals, Bellville, mulations of these drugs have become com- South Africa. Surgical specimens we r e m e r c i a l ly ava i l a ble. These topical i m m e d i a t e ly placed in a transport fluid, pre- f o r mulations, either on their own or as pared as prev i o u s ly described,1 6 – 2 1 and trans- adjuncts to reduced dosages of systemic f e rre d to our laboratory within 1 hour. Excess agents, have proven to be useful in the man- c o n n e c t ive tissue was trimmed away and all agement of a variety of musculoskeletal and specimens were snap-frozen in liquid nitro- rheumatic diseases.2 , 9 Although the topical gen and stored at -85˚C for periods up to 6 NSAIDs have mainly been studied rega r d i n g m o n t h s . 2 2 No specimens were obtained in their transdermal diffusion kinetics, these which there was clinical evidence of any dis- agents might also have useful applications ease that might have influenced the perm e- when topically applied to mucous mem- ability characteristics of the vaginal mucosa. branes. In this respect, piroxicam, benzy- The study was approved by the Ethics damine, ketoprofen, flunoxaprofen, and Committee of the University of Stellenbosch diclofenac have all been topically applied to and the Ty g e r b e rg Hospital. mucosal membranes for a variety of condi- tions ranging from pain to inflammation.1 0 – 1 5 Permeability Experiments H oweve r, the majority of the topically ava i l- Before each permeability experiment tissue a ble NSAIDs on the market have been for- specimens were thawed at room temperature mulated for cutaneous application and hence in phosphate-bu ffered saline (PBS, pH 7.4). contain components and enhancers suitabl e Thereafter the specimens were cut into for improving skin, but not necessarily 5 - m m 2 sections and mounted in flow - mucosal, absorp t i o n . through diffusion cells (exposed areas 0.039 We have prev i o u s ly shown that human c m 2) as prev i o u s ly described,1 6 – 2 1 and perm e- vaginal mucosa can be used as a model for ation studies performed on 7 tissue repli- the buccal mucosa for in vitro perm e a b i l i t y cates for each patient. Before beg i n n i n g studies of a wide variety of chemical com- each permeability experiment, tissue disks p o u n d s . 1 6 – 2 1 F u rt h e rmo re, we have demon- were equilibrated for 10 minutes with PBS strated that both these tissues can be (pH 7.4) at 200C in both the donor and snap-frozen in liquid nitrogen and stored at r e c e iver compartments of the diffusion cells. –85˚C for many months and thereafter used After equilibration, the PBS was remove d for permeability experiments without signifi- from the donor compartment and replaced cant changes in permeability characteristics.2 2 with either 1 mL of 10 mg/mL or 5 mg/mL In view of the fact that the therapeutic diclofenac solution in PBS containing 10% e ffi c a cy of NSAIDs depends on their pene- ethanol or 0.5 mL of 10 mg/g diclofenac gel tration into the mucosal and underlying tis- ( Voltaren Emulgel‚, Nova r tis SA [Pty] Ltd, sues, it was the objective of the present study R ivonia, South Africa). A l t e rn a t ive ly, 1 mL to inve s t i gate the permeability of human of 5 mg/mL, 10 mg/mL of piroxicam solu- vaginal mucosa, as a model of bu c c a l tion, or 0.5 mL of the 5 mg/g piroxicam gel 506 Vol. 3, No. 4, Fall 2003 • The Journal of Applied Research VANDERBIJLJARFall03REP 12/29/03 3:08 PM Page 507 (Rheugesic gel‚, Cipla-Medro [Pty] Ltd, an Agilent Chem Station (Agilent Bellville, South Africa) was used. The gels Te c h n o l ogies, Waldbronn, Germ a ny ) . were covered with a Teflon disk and 1 mL S p i ked standards over the expected concen- of PBS. PBS at 37˚C was pumped through tration range (0.5–20 mg/mL) were random- the receiving chambers at a rate of 1.5 mL/h ly included in each batch. and collected, by means of a fraction collec- Calculation of Flux Values t o r, at 2-hour intervals for 24 hours. T h e Flux (J) values across vaginal tissue we r e p e r meability study was performed under calculated by means of the relationship sink conditions, ie, at the completion of each run the concentration of diclofenac or J = Q / A ¥ t (µg x cm- 2 x min- 1 ) p i r oxicam in the acceptor chamber neve r reached 10% of that in the donor compart- where Q = quantity of substance crossing ment.