Pharmacokinetics of a new diclofenac sodium formulation developed for subcutaneous and intramuscular administration.
OBJECTIVE
To assess the relative bioavailability of diclofenac sodium hydroxypropyl β-cyclodextrin (HPβCD) administered via the subcutaneous (s.c.) and intramuscular (i.m.) route versus Voltaren® i.m. and to evaluate the dose linearity and pharmacokinetics of the s.c. formulation at three dose levels. Safety and local tolerability were also assessed.


METHODS
One single-dose, randomized, three-way, crossover relative bioavailability study and one linearity single escalating dose, randomized, three-way cross-over pharmacokinetic study were conducted at two different clinical sites. A total of 42 healthy male and female subjects participated in both studies. Subjects received 75 mg/ml diclofenac sodium HPβCD (i.m. and s.c.) and Voltaren® 75 mg/3 ml (i.m.) in Study 1 and 25, 50, or 75 mg/ml diclofenac sodium HPβCD (s.c.) in Study 2.


RESULTS
Study 1 demonstrated bioequivalence of the s.c. test formulation with Voltaren® i.m. with respect to Cmax and AUC. Bioequivalence of the test i.m. with Voltaren® i.m. was also demonstrated (except the upper limit of the 90% confidence interval (CI) for Cmax which marginally exceeded the 80 - 125% range (125.78%)). Study 2 demonstrated that after s.c. administration of the test formulation, both Cmax and AUC are linearly related to the tested diclofenac doses. All tested doses were safe and locally well-tolerated with no serious adverse events reported.


CONCLUSIONS
Bioequivalence of diclofenac HPβCD 75 mg/ml after s.c. and i.m. administration with Voltaren® i.m. was demonstrated, except for the marginal deviation in Cmax when comparing the i.m. test and Voltaren®. Linearity was also demonstrated for the three doses intended for marketing.
Medical University of Vienna, Vienna, Austria.
Markus
M
Zeitlinger
Antonio
A
Rusca
Alhan Z
AZ
Oraha
Barbara
B
Gugliotta
Markus
M
Müller
Murray P
MP
Ducharme
D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics*; D002626:Chemistry, Pharmaceutical; D018592:Cross-Over Studies; D004008:Diclofenac / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007273:Injections, Intramuscular; D007279:Injections, Subcutaneous; D008297:Male; D047392:beta-Cyclodextrins / Q000008:administration & dosage
D000894:Anti-Inflammatory Agents, Non-Steroidal; D047392:beta-Cyclodextrins; D004008:Diclofenac; D000073738:2-Hydroxypropyl-beta-cyclodextrin