An intravaginal ring for the simultaneous delivery of multiple drugs

Abstract

Intravaginal delivery of microbicide combinations is a promising approach for the prevention of sexually transmitted infections, but requires a method of providing simultaneous, independent release of multiple agents into the vaginal compartment. A novel intravaginal ring (IVR) platform has been developed for simultaneous delivery of the reverse-transcriptase inhibitor tenofovir (TFV) and the guanosine analogue antiviral acyclovir (ACV) with independent control of release rate for each drug. The IVR is based on a pod design, with up to 10 individual polymer-coated drug cores embedded in the ring releasing through preformed delivery channels. The release rate from each pod is controlled independently of the others by the drug properties, polymer coating, and size and number of delivery channels. Pseudo-zero-order in vitro release of TFV (144 ± 10 µg day) and ACV (120 ± 19 µg day⁻¹) from an IVR containing both drugs was sustained for 28 days. The mechanical properties of the pod IVR were evaluated and compared with the commercially available Estring® (Pfizer, NY, NY). The pod-IVR design enables the vaginal delivery of multiple microbicides with differing physicochemical properties, and is an attractive approach for the sustained intravaginal delivery of relatively hydrophilic drugs that are difficult to deliver using conventional matrix IVR technology.

Figure 1

Photographs of (a) human ring with two TFV and two ACV pods and one delivery channel per pod; (b) macaque ring with four TFV pods and three delivery channels per pod (arrows denote the three delivery windows for one of the four pods); (c) rabbit ring segment with one TFV and one ACV pod, one delivery channel per pod; and (d) close-up of delivery channel and ACV pod in human ring.

Figure 2

(a) Cross-sectional view of a blank silicone pod-IVR, 1, showing an empty pod cavity, 2, and delivery channel, 3. The delivery channel length is 1.8 mm and the diameter, d, can be varied from 0.3 to 2.0 mm; (b) Cross-sectional view of assembled pod IVR showing polymer-coated pod, 4, placed in the pod cavity and abutting the delivery channel. The pod is sealed in place with a silicone backfill, 5.

Figure 3

Plot of average cumulative release of TFV (circles) and ACV (squares) into VFS from single-drug IVRs containing five drug pods each. The pods were PLA coated, and the delivery channels for TFV are 1.0 mm and for ACV 1.5 mm. The daily release rate (mean ± SD) for the TFV rings is 115 ± 14 µg day⁻¹ (N= 4, linear fit R²= 0.999) and for ACV is 133 ± 15 µg day⁻¹(N= 3, linear fit R²= 0.998).

Figure 4

Plot of average cumulative release of TFV (circles) and ACV (squares) into VFS from multiple-drug IVRs containing five pods of ACV and five pods of TFV in a single ring. The pods were PLA coated, and the delivery channels for TFV are 1.0 mm and for ACV 1.5 mm. The daily release rate (mean ± SD) for TFV is 144 ± 10 µg day⁻¹ (N= 4, linear fit R²= 0.999) and for ACV is 120 ± 19 µg day⁻¹ (N= 4, linear fit R²= 0.998).

Figure 5

Average daily release rate versus delivery channel area for TFV (circles) and ACV (squares). Release of TFV or ACV from IVR segments containing a single PLA-coated pod per ring and single delivery channel per pod into VFS was measured over 14 days, and the release rate calculated from the slope of the linear fit to the cumulative release data (N = 4 IVRs per delivery channel size).

Figure 6

Daily in vitro release rate as a function of number of TFV pods per ring. For all rings, 16 mg TFV drug cores were coated with PLA and had a single 1.0 mm delivery channel per pod. Release of TFV into VFS was measured over 15 days (one, three, and 10 pods per ring) or 28 days (five pods per ring), and the release rate calculated from the slope of the linear fit to the cumulative release data (N = 5 IVRs per # pods per ring).