International Journal of Pharmaceutics 382 (2009) 98–103 Contents lists available at ScienceDirect International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm Polyisoprene matrix for progesterone release: In vitro and in vivo studies V. Heredia a , I.D. Bianco a,b,c,∗ , H. Tríbulo d , R. Tríbulo d , M. Ferro Seoane a , S. Faudone a , S.L. Cuffini a,b , N.A. Demichelis a , H. Schalliol a , D.M. Beltramo a,b,∗ a Centro de Excelencia en Productos y Procesos de Córdoba (CEPROCOR), Ministerio de Ciencia y Tecnología de Córdoba, Pabellón CEPROCOR, CP 5164, Santa María de Punilla, Córdoba, Argentina b Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina c Universidad Nacional de La Rioja, Argentina d Instituto de Reproducción Animal Córdoba (IRAC), Jerónimo Luis de Cabrera 106 1 ◦ piso, Barrio Alta Córdoba, CP 5000, Córdoba, Argentina article info Article history: Received 11 April 2009 Received in revised form 30 July 2009 Accepted 13 August 2009 Available online 20 August 2009 Keywords: Drug delivery systems Elastomer Estrous control Polymer matrix Polymorphism Progesterone abstract Latex, a polyisoprene (PI) hydrophobic elastomer, was evaluated in vitro and in vivo as a matrix for intravaginal steroid hormone delivery. Matrices containing hormone were prepared by swelling latex in chloroform that contained soluble progesterone (P4). In vitro studies demonstrate that P4 release from PI follows a zero order model during at least 100 h and depends on initial load up to 10 mg cm -2 . The release of P4 from a PI matrix was found to be two times faster than from a polydimethylsiloxane (PDMS) matrix. FT-IR and X-ray powder diffraction analysis of P4 polymorphs show that when nucleated in PDMS, the hormone crystallizes only in -form while in latex, crystallizes as a mixture of - and -form. In vivo studies show that devices with a PI matrix containing 0.5 g of P4 are effective to reach plasma levels above 1 ng ml -1 that are needed to synchronize estrous in cattle. Altogether, the results show that PI, a vulcanized polymer with a carbon–carbon backbone, can be used as a new matrix for the intravaginal administration of progesterone with improved release profile than silicone and that the matrix can influence the crystalline state of the hormone. © 2009 Elsevier B.V. All rights reserved. 1. Introduction Pharmacologic control of reproduction through the delivery of hormones is an area of intense research (Vernon et al., 2004; Biruss and Valenta, 2008). In humans it is mainly used as a contracep- tive method while in livestock it is widely used to synchronize estrous associated with artificial insemination for planned con- ception programs (Rathbone et al., 1997; Vernon et al., 2004). Estrous control can be achieved through the use of commercially available drug delivery systems characterized by a daily release of progesterone (P4) or a synthetic derivative (Rathbone et al., 1997). The best fertility results are obtained when the drug delivery sys- tem achieves a 7 or 8 days sustained progesterone delivery and plasma progesterone concentration above 1 ng ml -1 (Macmillan et al., 1991; Rathbone et al., 1998a). Silicones, in particular, lend themselves well to the release of steroid molecules (Malcolm et al., 2003). They are thermoset rubbers consisting of three-dimensional ∗ Corresponding authors at: Centro de Excelencia en Productos y Procesos de Córdoba (CEPROCOR), Ministerio de Ciencia y Tecnología de Córdoba, Pabellón CEPROCOR, CP 5164, Santa María de Punilla, Córdoba, Argentina. Tel.: +54 3541 489651/53x143; fax: +54 3541 488181. E-mail addresses: ibianco@ceprocor.uncor.edu (I.D. Bianco), dbeltramo@ceprocor.uncor.edu (D.M. Beltramo). polydimethylsiloxane (PDMS) networks held together by chemical bonds. The fabrication of intravaginal devices used to synchro- nize estrous in cattle consists of dispersing between 1 and 2 g micronized progesterone in a high temperature vulcanizing PDMS that requires a treatment at up to 190 ◦ C during the manufacturing process (Rathbone et al., 1997, 2002a). In a recent study, we charac- terized the in vitro and in vivo kinetics of a new intravaginal device consisting of a skin made with room temperature vulcanizing PDMS impregnated with P4, supported on a reusable spine (Heredia et al., 2008). This system was loaded with 6% (w/w) P4 (0.75 g total) and delivered the drug in such a way that the hormone plasma concen- tration required to synchronize estrous in cattle was achieved and sustained over the period of time needed (Heredia et al., 2008). Although a significant body of work has been published to date to understand the kinetic release of P4 from PDMS matrices (Rathbone et al., 1997, 2002a; Malcolm et al., 2003; Taghizadeh et al., 2003; Woolfson et al., 2003; Heredia et al., 2008) few attempts have been made to study other polymers as potential P4 carriers (Vernon et al., 2004; Biruss and Valenta, 2008; Wischke and Schwendeman, 2008). One of the few examples is poly(- caprolactone) (PCL) that has been used within the veterinary field to engineer a steroid intravaginal delivery system with a high reten- tion rate in the vagina of cows (Rathbone et al., 2002b). This system provided bioequivalent plasma levels to those attained with a com- mercially available product (CIDR intravaginal insert) (Rathbone et 0378-5173/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.ijpharm.2009.08.015