{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T01:41:44Z","timestamp":1787794904787,"version":"build-2784847793"},"reference-count":45,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2020,1,28]],"date-time":"2020-01-28T00:00:00Z","timestamp":1580169600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Reservoir systems (drug-loaded core surrounded by drug-free membrane) provide long-term controlled drug release. This is especially beneficial for drug delivery to specific body regions including the vagina. In this study, we investigated the potential of reservoir systems to provide high drug release rates over several weeks. The considered model system was an intra-vaginal ring (IVR) delivering progesterone (P4) in the mg\/day range using ethylene-vinyl acetate (EVA) as release rate-controlling polymers. To circumvent the high material needs associated with IVR manufacturing, we implemented a small-scale screening procedure that predicts the drug release from IVRs. Formulations were designed based on the solubility and diffusivity of P4 in EVAs with varying vinyl acetate content. High in-vitro P4 release was achieved by (i) high P4 solubility in the core polymer; (ii) high P4 partition coefficient between the membrane and the core; and\/or (iii) low membrane thicknesses. It was challenging for systems designed to release comparatively high fractions of P4 at early times to retain a constant drug release over a long time. P4 crystal dissolution in the core could not counterbalance drug diffusion through the membrane and drug crystal dissolution was found to be the rate-limiting step. Overall, high P4 release rates can be achieved from EVA-based reservoir systems<\/jats:p>","DOI":"10.3390\/pharmaceutics12020103","type":"journal-article","created":{"date-parts":[[2020,1,29]],"date-time":"2020-01-29T10:51:07Z","timestamp":1580295067000},"page":"103","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Controlled-Release from High-Loaded Reservoir-Type Systems\u2014A Case Study of Ethylene-Vinyl Acetate and Progesterone"],"prefix":"10.3390","volume":"12","author":[{"given":"Ioannis","family":"Koutsamanis","sequence":"first","affiliation":[{"name":"Research Center Pharmaceutical Engineering GmbH, Inffeldgasse 13, 8010 Graz, Austria"},{"name":"Institute of Pharmaceutical Sciences, Department Pharmaceutical Technology and Biopharmacy, University of Graz, Universitaetsplatz 1, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amrit","family":"Paudel","sequence":"additional","affiliation":[{"name":"Research Center Pharmaceutical Engineering GmbH, Inffeldgasse 13, 8010 Graz, Austria"},{"name":"Institute of Process and Particle Engineering, Graz University of Technology, Inffeldgasse 13, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus","family":"Nickisch","sequence":"additional","affiliation":[{"name":"Evestra Inc., 6410 Tri County Parkway, Schertz, TX 78154, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin","family":"Eggenreich","sequence":"additional","affiliation":[{"name":"Evestra Inc., 6410 Tri County Parkway, Schertz, TX 78154, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Roblegg","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Sciences, Department Pharmaceutical Technology and Biopharmacy, University of Graz, Universitaetsplatz 1, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Eder","sequence":"additional","affiliation":[{"name":"Research Center Pharmaceutical Engineering GmbH, Inffeldgasse 13, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,1,28]]},"reference":[{"key":"ref_1","unstructured":"Jones, D. (2004). Pharmaceutical Applications of Polymers for Drug Delivery (Rapra Review Reports), Smithers Rapra Press. [1st ed.]."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1177\/2211068211428189","article-title":"Reservoir-based polymer drug delivery systems","volume":"17","author":"Yang","year":"2012","journal-title":"J. Lab. Autom."},{"key":"ref_3","unstructured":"Cantow, H.-J., Harwood, H.J., Kennedy, J.P., Ledwith, A., Meissner, J., Okamura, S., Henrici-Olive, G., and Olive, S. (1989). Controlled Release A Quantitative Treatment, Springer. First."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Siepmann, J., Siegel, R.A., and Rathbone, M.J. (2012). Diffusion Controlled Drug Delivery Systems. Fundamentals and Applications of Controlled Release Drug Delivery, Springer.","DOI":"10.1007\/978-1-4614-0881-9"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1097\/QAI.0b013e3181acb536","article-title":"Safety and pharmacokinetics of dapivirine delivery from matrix and reservoir intravaginal rings to HIV-negative women","volume":"51","author":"Nel","year":"2009","journal-title":"J. Acquir. Immune Defic. Syndr."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Clark, J.T., Clark, M.R., Shelke, N.B., Johnson, T.J., Smith, E.M., Andreasen, A.K., Nebeker, J.S., Fabian, J., Friend, D.R., and Kiser, P.F. (2014). Engineering a segmented dual-reservoir polyurethane intravaginal ring for simultaneous prevention of HIV transmission and unwanted pregnancy. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0088509"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/j.contraception.2012.08.037","article-title":"Current status of contraceptive vaginal rings","volume":"87","author":"Brache","year":"2013","journal-title":"Contraception"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"6272","DOI":"10.1128\/AAC.01431-12","article-title":"A 90-day tenofovir reservoir intravaginal ring for mucosal HIV prophylaxis","volume":"56","author":"Johnson","year":"2012","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/0378-5122(89)90120-5","article-title":"Vaginal rings for continuous low-dose release of oestradiol in the treatment of urogenital atrophy","volume":"11","author":"Holmgren","year":"1989","journal-title":"Maturitas"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1016\/S0039-128X(00)00124-0","article-title":"Progestin implants","volume":"65","author":"Croxatto","year":"2000","journal-title":"Steroids"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.contraception.2004.08.010","article-title":"Contraceptive vaginal rings releasing Nestorone\u00ae and ethinylestradiol: A 1-year dose-finding trial","volume":"71","author":"Sivin","year":"2005","journal-title":"Contraception"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/j.jconrel.2017.08.004","article-title":"Applications of ethylene vinyl acetate copolymers (EVA) in drug delivery systems","volume":"262","author":"Schneider","year":"2017","journal-title":"J. Control. Release"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/j.ejpb.2010.12.004","article-title":"Ethylene vinyl acetate as matrix for oral sustained release dosage forms produced via hot-melt extrusion","volume":"77","author":"Almeida","year":"2011","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/0168-3659(95)00119-0","article-title":"Diffusion of benzocaine in poly(ethylene-vinyl acetate) membranes: Effects of vehicle ethanol concentration and membrane vinyl acetate content","volume":"38","author":"Chen","year":"1996","journal-title":"J. Control. Release"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1080\/gye.17.3.247.254","article-title":"Estradiol\/progesterone-releasing vaginal rings for hormone replacement therapy in postmenopausal women","volume":"17","author":"Hamada","year":"2003","journal-title":"Gynecol. Endocrinol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/0010-7824(92)90055-X","article-title":"Progesterone-Releasing Vaginal Rings for Use in Postpartum Contraception","volume":"45","author":"Matlin","year":"1992","journal-title":"Contraception"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2971","DOI":"10.1208\/s12249-017-0788-z","article-title":"Establishment of a Molding Procedure to Facilitate Formulation Development for Co-extrudates","volume":"18","author":"Eder","year":"2017","journal-title":"AAPS PharmSciTech"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.ijpharm.2019.04.041","article-title":"Formulation and processability screening for the rational design of ethylene-vinyl acetate based intra-vaginal rings","volume":"564","author":"Koutsamanis","year":"2019","journal-title":"Int. J. Pharm."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1021\/ma60059a006","article-title":"A Study of Equilibrium Melting of Polyethylene","volume":"10","author":"Wunderlich","year":"1977","journal-title":"Macromolecules"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1007\/s11095-013-1201-6","article-title":"The optimization of an intravaginal ring releasing progesterone using a mathematical model","volume":"31","author":"Helbling","year":"2014","journal-title":"Pharm. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3419","DOI":"10.1002\/jps.20983","article-title":"The Polymorphism of Progesterone: Stabilization of a \u2018Disappearing\u2019 Polymorph by Co-Crystallization","volume":"96","author":"Lancaster","year":"2007","journal-title":"J. Pharm. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/S0168-3659(99)00093-0","article-title":"Diffusion-controlled drug delivery systems: Calculation of the required composition to achieve desired release profiles","volume":"60","author":"Siepmann","year":"1999","journal-title":"J. Control. Release"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/S0378-5173(01)00900-0","article-title":"In vitro release properties of etonogestrel and ethinyl estradiol from a contraceptive vaginal ring","volume":"232","author":"Kruft","year":"2002","journal-title":"Int. J. Pharm."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/S0010-7824(98)00145-0","article-title":"Clinical acceptability of an ethylene-vinyl-acetate nonmedicated vaginal ring","volume":"59","author":"Roumen","year":"1999","journal-title":"Contraception"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.ijpharm.2013.09.040","article-title":"PAT tools for the control of co-extrusion implants manufacturing process","volume":"458","author":"Krier","year":"2013","journal-title":"Int. J. Pharm."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/nmeth.2089","article-title":"NIH Image to ImageJ: 25 years of image analysis","volume":"9","author":"Schneider","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ejpb.2016.10.012","article-title":"Development and evaluation of accelerated drug release testing methods for a matrix-type intravaginal ring","volume":"110","author":"Externbrink","year":"2017","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_28","unstructured":"(2019, February 07). LOCTITE\u00ae 4011TM Technical Data Sheet. Available online: https:\/\/tdsna.henkel.com\/NA\/UT\/HNAUTTDS.nsf\/web\/40B3DBCA6D797572882571870000D75F\/$File\/4011-EN.pdf."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1869","DOI":"10.1007\/BF01912217","article-title":"Polymorphism of progesterone - Influence of the carrier and of the solid dispersion manufacturing processes. A calorimetric and radiocrystallographic study","volume":"37","author":"Duclos","year":"1991","journal-title":"J. Therm. Anal."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1021\/op000210w","article-title":"An Investigation of Solvent-Mediated Polymorphic Transformation of Progesterone Using in Situ Raman Spectroscopy","volume":"4","author":"Wang","year":"2000","journal-title":"Org. Proc. Res. Dev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/S0040-6031(02)00492-6","article-title":"Importance of heat capacity determination in homogeneous nucleation: Application to progesterone","volume":"400","author":"Legendre","year":"2003","journal-title":"Thermochim. Acta"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4574","DOI":"10.1021\/cg5006727","article-title":"Polymorphism of progesterone: A new approach for the formation of form II and the relative stabilities of form i and form II","volume":"14","author":"Sarkar","year":"2014","journal-title":"Cryst. Growth Des."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2864","DOI":"10.1002\/polb.20917","article-title":"Solid-State NMR Characterizations on Phase Structures and Molecular Dynamics of Poly(ethylene-co-vinyl acetate)","volume":"44","author":"Wang","year":"2004","journal-title":"J. Polym. Sci. Part B Polym. Phys."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"623","DOI":"10.3144\/expresspolymlett.2008.75","article-title":"Non-isothermal crystallization and melting of ethylene-vinyl acetate copolymers with different vinyl acetate contents","volume":"2","author":"Shi","year":"2008","journal-title":"Express Polym. Lett."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1007\/BF01216751","article-title":"Zur mikroskopischen Identitaetspruefung und zur Polymorphie der Sexualhormone","volume":"47","author":"Kofler","year":"1959","journal-title":"Microchim. Acta"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1016\/0371-1951(66)80119-4","article-title":"The infra-red spectra of steroids in the solid state","volume":"22","author":"Mesley","year":"1966","journal-title":"Spectrochmica Acta"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"779","DOI":"10.3109\/10837450.2013.829096","article-title":"Dissolution properties, solid-state transformation and polymorphic crystallization: Progesterone case study","volume":"19","author":"Paulino","year":"2014","journal-title":"Pharm. Dev. Technol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1208\/s12248-016-9914-1","article-title":"The Use of Cellulose Membrane to Eliminate Burst Release from Intravaginal Rings","volume":"18","author":"Helbling","year":"2016","journal-title":"AAPS J."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/S0168-3659(01)00248-6","article-title":"On the importance and mechanisms of burst release in matrix-controlled drug delivery systems","volume":"73","author":"Huang","year":"2001","journal-title":"J. Control. Release"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1002\/jps.2600810116","article-title":"Mechanism of diffusion of monosubstituted benzoic acids through ethylene-vinyl acetate copolymers","volume":"81","author":"Maurin","year":"1992","journal-title":"J. Pharm. Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"990","DOI":"10.1021\/ma9906027","article-title":"Local free volume in ethylene-vinyl acetate copolymers: A positron lifetime study","volume":"33","author":"Dlubek","year":"2000","journal-title":"Macromolecules"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/S0168-3659(02)00139-6","article-title":"Effect of supersaturation and crystallization phenomena on the release properties of a controlled release device based on EVA copolymer","volume":"82","author":"Kruft","year":"2002","journal-title":"J. Control. Release"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1016\/j.ejpb.2014.08.002","article-title":"Development of disulfiram-loaded vaginal rings for the localised treatment of cervical cancer","volume":"88","author":"Boyd","year":"2014","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1126\/scitranslmed.3003936","article-title":"An Intravaginal Ring That Releases the NNRTI MIV-150 Reduces SHIV Transmission in Macaques","volume":"4","author":"Singer","year":"2012","journal-title":"Sci. Transl. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/j.jconrel.2011.10.006","article-title":"Modeling of diffusion-controlled drug delivery","volume":"161","author":"Siepmann","year":"2012","journal-title":"J. Control. 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