(336c) Miniaturized Formulation and Processability Screening for the Rational Design of Ethylene Vinyl Acetate Based Co-Extrudates

Authors: 
Koutsamanis, I., University of Graz
Eder, S., Research Center Pharmaceutical Engineering GmbH
Mohr, S., RCPE
Beretta, M., European Consortium for Continuous Pharmaceutical Manufacturing (ECCPM)
Paudel, A., European Consortium on Continuous Pharmaceutical Manufacturing (ECCPM)
Nickisch, K., Evestra Inc.
Friedrich, M., Evestra Inc.
Roblegg, E., University of Graz
Intra-vaginal rings (IVRs) present an alternative strategy for the sustained release of estradiol (E2) in the vaginal tract. The currently marketed IVRs comprising E2 are reservoir-type silicon-based systems. One of the disadvantages of silicon elastomers is the requirement of additional curing and post-curing steps during the manufacturing process. Ethylene vinyl-acetate (EVA) copolymers represent a versatile polymeric carrier and they have been successfully used in a marketed IVR for contraception (NuvaRing®). EVA-based reservoir-type IVRs do not require additional curing steps and are manufactured via co-extrusion. A rapid, material-sparing and predictive screening methodology for IVR product development is, therefore, desirable for the rational (pre) formulation assessment and early feasibility studies.

The first aim of this study is to implement and evaluate a recently developed screening procedure (i.e., vacuum compression molding, VCM) to facilitate formulation development of EVA-based co-extrudates. The VCM screening procedure enables the manufacturing of small-scale reservoir systems (referred here as VCM systems) which can predict the rate and mechanism of release of full-scale IVRs. The second aim is to investigate the feasibility of EVA-based reservoir-type IVRs with broad daily in-vitro release rates of E2, considering the effect of the EVA copolymer type and drug loading. The equilibrium solubility of E2 in various EVA copolymers at low temperatures (i.e., 25 and 37 °C) was determined using polymer films immersed in an E2-saturated aqueous solution until equilibrium was reached. The drug-saturated polymer films were subsequently analyzed via HPLC. Additionally, the metastable solubility of E2 in the same copolymers was estimated via hot-stage microscopy (HSM) in samples produced with the VCM tool. Small-scale reservoir systems (VCM systems) with different drug loadings and different core-skin EVA copolymer combinations were produced. To evaluate the predictability of the screening procedure, full-scale IVRs were prepared with hot-melt co-extrusion to elucidate the impact of process parameters (e.g., shear forces) on the E2 drug release. The average daily E2 amount release (per cm2) from the IVR was higher by a factor of 1.154 ± 0.160 compared to the corresponding VCM systems, dependent on the drug core loading. This fact can be explained by the enhanced E2 solubility in the core polymer, due to the high shear forces during co-extrusion. Still, the average release rates per cm2 were in the same order of magnitude. All formulations showed near zero-order release (R2 > 0.99) over 28 days. It is well known that drug release from a reservoir-type system is a function of the core and skin polymer type, the drug loading and the solubility of the drug in the core polymer. Adaptation of these parameters, based on the outcome of the rational screening approach, resulted in average E2 release rates between 1.87 ± 0.65 and 21.01 ± 3.84 µg/day/cm2.

The generated data show that the applied screening method can be used as a time- and cost saving procedure to predict and facilitate formulation design of IVRs prior to co-extrusion. Moreover, it was shown that a broad and constant E2 release from EVA-based reservoir-type systems can be achieved by optimizing formulation parameters, such as the polymer type and drug loading. IVR formulations with broad release rates of E2 could present a versatile strategy for sustained vaginal drug delivery expanding from topical and systematic menopausal symptoms treatment to contraception purposes.

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