Sustained Delivery of Commensal Bacteria from Pod-Intravaginal Rings

Abstract

Topical administration of live commensal bacteria to the vaginal tract holds significant potential as a cost-effective strategy for the treatment of sexually transmitted infections and the delivery of mucosal vaccines. Probiotic-releasing intravaginal rings (IVRs) embody significant theoretical advantages over traditional daily-dosage forms, such as sustained and controlled delivery leading to improved adherence to therapy compared to that of frequent dosing. The conventional IVR designs, however, are not amenable to the delivery of live bacteria. We have developed a novel pod-IVR technology where polymer-coated tablets ("pods") of Lactobacillus gasseri strain ATCC 33323, a commensal microorganism of human origin, are embedded in silicone IVRs. The release rate of bacterial cells is controlled by the diameter of a delivery channel that exposes a portion of the pod to external fluids. In vitro studies demonstrated that the prototype devices released between 1.1 ؋ 10 7 and 14 ؋ 10 7 cells per day for up to 21 days in a controlled sustained fashion with stable burst-free release kinetics. The daily release rates were correlated with the cross-sectional area of the delivery channel. Bacteria in the IVR pods remained viable throughout the in vitro studies and formed biofilms on the surfaces of the devices. This proof-of-principle study represents the first demonstration of a prolonged, sustained release of bacteria from an intravaginal device and warrants further investigation of this device as a nonchemotherapeutic agent for the restoration and maintenance of normal urogenital flora.

Vaginal rings with exposed cores for sustained delivery of the HIV CCR5 inhibitor 5P12-RANTES

“…For example, the leuprolide-releasing ethylene vinyl acetate (EVA) ring described by Kimball et al comprises ten distinct manufacturing steps: (i) washing of EVA beads to remove monomeric vinyl acetate; (ii) vacuum drying of beads; (iii) cryogenic milling of EVA granules to powder; (iv) preparation of ethanolic solution of EVA and leuprolide; (v) solvent casting of the ethanolic mixture; (vi) solvent evaporation; (vii) milling of the EVA/drug mixtures to form a powder; (viii) extrusion of the leuprolide acetate/EVA granulation mixture; (ix) pelletization of the mixtures; and finally (x) manufacture of the rings by injection molding [ 25 ]. The widely reported pod-insert vaginal rings [ 17 , 19 , 21 , 23 , 30 , [34] , [35] , [36] ] – comprising multiple individual polymer-coated drug cores embedded in a ring body, each core connected to the external environment through a preformed delivery channel – are similarly complex and time-consuming to manufacture, involving at least nine distinct steps: (i) compaction of drug powder to form a core; (ii) drop-coating of cores using a polylactic acid solution; (iii) fabrication of silicone elastomer ring bodies via injection molding; (iv) creation of delivery channels by mechanical punching; (v) trimming of sprue material and flashing; (vi) cleaning of silicone with ethanol to remove debris from the molding process; (vii) manual placement of a drug-loaded pod into each cavity; (viii) backfilling of the pod cavity with non-medicated silicone elastomer; (ix) filling of any unused pod cavities [ 17 ]. There is, therefore, a need for new vaginal ring designs for sustained/controlled release of hydrophilic or macromolecular drugs that can be easily manufactured using more conventional and scalable processes.…”

Comparative phase I randomized open-label pilot clinical trial of Gynophilus® (Lcr regenerans®) immediate release capsules versus slow release muco-adhesive tablets

“…Moreover, this new dosage form ultimately improved the comfort and ease of use, as the controlled muco-adhesive vaginal formulation affords a prolonged residence time of the LBM at efficacious concentrations with less frequent administration. Slow release delivery strategies have been successfully developed for antifungal and antibacterial drugs and for other vaginal LBPs using different muco-adhesive tablets or vaginal rings [ 33 – 37 ].…”

An intravaginal ring for real-time evaluation of adherence to therapy

“…The pod-IVR has been applied to delivery of small molecule ARV drugs for HIV [18, 19, 23–25] and HSV [18, 26] prevention as well as to vaginal delivery of monoclonal antibodies [27] and bacterial probiotics [28]. The pod-IVR consists of a silicone elastomer scaffold containing individual embedded drug pods that act as independent delivery devices.…”