Design of a silicone reservoir intravaginal ring for the delivery of oxybutynin.
Oxybutynin, a drug of choice in the treatment of urinary incontinence, has low oral bioavailability due to extensive first-pass metabolism. A toxic metabolite, N-desethyloxybutynin, has been linked to adverse reactions to oral oxybutynin. This study, therefore, reports on the design of an oxybutynin intravaginal ring (IVR) of reservoir design, comprising an oxybutynin silicone elastomer core encased in a non-medicated silicone sheath, manufactured by reaction injection moulding at 50 degrees C. An unusually high initial burst release of oxybutynin (42.7 mg in 24 h) was observed in vitro with a full length core (100 mg drug loading), with subsequent non-zero order drug release. Use of fractional segment cores substantially reduced the burst effect, yielding linear cumulative drug release versus time plots from days 2 to 14. Thus, a 1/8 fractional segment core gave a 24 h burst of 11.28 mg oxybutynin and, thereafter, zero order release at the target dose of 5 mg/day over 14 days. Two oxybutynin cores, each 1/16 of full length, gave a greater release than a single 1/8 core, due to core segment end effects resulting in an increased surface area for release. The burst release was investigated by determining drug solubilities in the propan-1-ol product of elastomer condensation cure (390 mg/ml) and in the elastomer itself (13.9-20.21 mg/ml, by direct extraction and indirect thermal methods). These high oxybutynin solubilities were considered the major contributors to the burst effect. It was concluded that use of a fractional segment core would allow development of a suitable oxybutynin reservoir IVR.
Woolfson
A D
AD
School of Pharmacy, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK. d.woolfson@qub.ac.uk
Malcolm
R K
RK
Gallagher
R J
RJ
D003274:Contraceptive Devices, Female; D016503:Drug Delivery Systems / Q000379:methods*; D008333:Mandelic Acids / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D012828:Silicones / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics
D008333:Mandelic Acids; D012828:Silicones; C005419:oxybutynin