Intra vaginal rings have been made for many years in various polymer materials such as EVA, LSR and polyurethane elastomers and thermoplastics, to slowly release active pharmaceutical ingredients. This has been in the form of polymer “reservoir rings” (“core”) with a hollow core containing dissolved APIs, “sandwich” (“shell”) ring versions or solid “matrix” rings with one or more APIs incorporated within the polymer matrix.
Researchers at Queens University Belfast in Northern Ireland have observed that reservoir and sandwich rings involve complex production but release API at a low but constant rate, while matrix rings are easier to produce, but with a tendency of some API level depletion with time in the outer part of the material.
Results of clinical trials published in February 2016 by the non-profit organization IPM International Partnership for Microbicides in Silver Spring, Md., and MTN Microbiocide Trials Network found an LSR matrix ring containing 25 milligrams of the antiretroviral non-nucleoside reverse transcriptase inhibitor drug Dapivirine had reduced HIV infection rates by respectively 31 and 27 percent when used for 28 days.
QPharma AB in Malmö, Sweden, produced the platinum catalyzed LSR O-rings of outer diameter 56 millimeters, thickness 7.7 millimeters and weighing 8 grams used in the trials. The company has been producing this type of ring by static mixing micronized Dapivirine API dispersed with 30 percent silica in silicone oil in equal proportions into both LSR A and B components.
The LSR used by QPharma comes from Trelyst LLC, as subsidiary of NuSil Technology LLC, set up in Carpinteria, Calif., to focus on medical silicone applications.
The materials are mixed and dosed at QPharma with 0.001 mm precision,
using PFM Process Flow Mix equipment from 2 Komponenten Maschinenbau GmbH (2KM) in Marienheide‑Rodt, Germany. Injection molding takes place with 6.5 seconds injection time via a 232 gram injection unit and with 250 bar holding pressure in a 16-cavity mold from Rico Elastomere Projecting GmbH in Thalheim/Wels, Austria. The mold is equipped, as usual with LSR injection molding, with a cold runner system, preventing premature vulcanization outside the hot mold.
Rico talks with pride about low 0.145 mm outer diameter deviation and maximum 20 mg weight deviation across the 16 cavities. The low weight deviation and high mixing homogeneity are both crucial to ensure that the required amount of Dapivirine is available for HIV protection, within a range of 22.5 to 27.5 mg. QPharma controls this with Raman spectroscopic inspection equipment, along with optical dimension.
The mold has a seal around the cavity area and is mounted on a stainless steel-housed 150 metric ton electric drive Allrounder 520A 1,500‑400 injection press from Arburg GmbH + Co. KG in Lossburg, Germany. After one to two minutes vulcanization in the mold at 185° C, a six-axis articulated arm industry robot from Kuka AG in Augsburg, Germany, removes sets of 16 rings at a time, held with hangers on a stripper plate, and lays down the rings onto a conveyor belt by tilting the stripper plate. The robot is a key feature of the automation system designed by FPT Robotik GmbH & Co. KG in Amtzell, Germany, and it operates in an ISO Class 3 ionized clean room environment that also includes the mold area. Arburg says it had overall responsibility for the entire turnkey vaginal ring production cell at QPharma.