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.

Pharmacokinetics and Preliminary Safety Study of Pod-Intravaginal Rings Delivering Antiretroviral Combinations for HIV Prophylaxis in a Macaque Model

“…The delivery of two or more ARV drugs from conventional IVR designs involves significant technological and manufacturing hurdles. To meet these challenges, we have developed a novel IVR technology, the pod-IVR (13), that enables rapid development of devices capable of delivering multiple agents over a wide range of target delivery rates and aqueous solubilities (14)(15)(16). We recently published the design and 28-day pharmacokinetic (PK) evaluation in sheep of a five-drug pod-IVR as a proof-of-concept, advanced multipurpose prevention technology (MPT), combining three ARV drugs from different mechanistic classes (tenofovir [TFV], nevirapine, and saquinavir) with a proven estrogen-progestogen contraceptive for prevention of HIV infection and unintended pregnancy (17).…”

Pharmacokinetics and Preliminary Safety of Pod-Intravaginal Rings Delivering the Monoclonal Antibody VRC01-N for HIV Prophylaxis in a Macaque Model

“…The release rate from pod-IVRs is determined by the additive effect of the MAb solubility and three independently variable parameters: the composition and thickness of the pod's polymer membrane coating, the size and number of delivery channels through the ring exposing each individual pod to the vaginal fluid, and the number of pods in the ring. The pod-IVR design has been used for the delivery of relatively hydrophilic small-molecule antiretroviral drugs singly and in combination (43,44,48) and of ovine IgG as a model for human MAb (45). Formulation and in vitro release of VRC01-N.…”

“…Because each pod is a separate delivery device, pod-IVRs can deliver multiple MAbs simultaneously with the independent control of release rates. Pod-IVRs for macaques (48,49) are significantly smaller than those for humans (44,45) and limit the total drug loading and capacity to deliver multiple MAbs at efficacious rates. The macaque pod-IVRs used here accommodate a maximum of six 25-mg pods, providing a maximum MAb loading of 75 mg from a formulation that contains 50% MAb.…”

“…Intravaginal rings of the pod-IVR design containing VRC01 were prepared using methods previously reported (44). The IVR dimensions were identical to those used in previous macaque studies (48,49).…”

“…Intravaginal ring (IVR) formulations of Nicotiana-manufactured VRC01 using a pod-based design (pod-IVR) (43)(44)(45) were fabricated and evaluated in vitro for release characteristics and MAb stability. Preliminary local safety and pharmacokinetics were investigated in a rhesus macaque primate model, in which it was found that steady-state vaginal fluid levels of VRC01-N were sustained over 21 days and the gp120 binding activity of the VRC01-N in the pod-IVR was retained in vivo.…”