Abstract
In bovine estrus synchronization, intravaginal devices made of silicone are used to administer exogenous progesterone with the aim of maintain plasmatic levels above 2 ng ml−1 during the treatment. After their use, devices must be discarded. There is an important concern on the environmental impact of the disposal of these used products due mainly to the non-degradability of the silicone and to the residual content of the hormone. Different alternatives are being studied, and the use of ecological materials appears as the more important. The objective of the present contribution was to design and evaluate a recyclable intravaginal prototype using ethylene vinyl acetate copolymer (EVA). Devices were fabricated by an injection-molding technique and characterized in terms of dimensions, loading efficiency, release rate, and wing tension. An analysis was first conducted to compare three different matrices and two supports. Secondly, the best candidate prototype was assayed in both beef and dairy cattle. Finally, used matrices were recycled measuring the progesterone content in the resulting devices and testing them in vitro. According to release tests, no differences were observed between the three matrices both in vitro and in vivo. On the contrary, a better performance was achieved when a support with a more flexible Y shape was used in comparison with a rigid T geometry. Successful results were observed in non-lactating cows, with plasma concentrations above the threshold value defined for the synchronization therapy. However, lower progesterone levels resulted when devices were tested in animals with large milk production. By last, recycled matrices presented a similar initial content and in vitro release rate than original matrices. These findings could open the possibility to use recyclable EVA devices as an alternative to the non-degradable silicone intravaginal inserts. Future research must be carried out to optimize the performance of the recycled matrices in dairy cattle. Modifications of the release surface and/or the initial loading can give a solution to the lower values observed in these animals.
Similar content being viewed by others
Abbreviations
- DSC:
-
differential scanning calorimetry
- EDTA:
-
ethylenediaminetetraacetic acid
- EVA:
-
ethylene vinyl acetate copolymer
- FSH:
-
follicle stimulating hormone
- FTIR:
-
Fourier-transform infrared spectroscopy
- GC:
-
gas chromatography
- GnRH:
-
gonadotropin-releasing hormone
- HPLC:
-
High-performance liquid chromatography
- LH:
-
luteinizing hormone
- RIA:
-
radioimmunoassay
References
Crowe MA. Reproduction, events and management | estrous cycles: characteristics. In: W.F. Editor-in-Chief: John, Editor. Encyclopedia of Dairy Sciences. 2nd ed. San Diego: Academic Press; 2011. p. 428-433.
Rathbone MJ, Macmillan KL, Inskeep K, Burggraaf S, Bunt CR. Fertility regulation in cattle. J Control Release. 1998;54:117–48.
Knez R, Medina L, Dick A. Uso de un dispositivo intravaginal con 0,5 gramos de progesterona en un protocolo de IATF en vacas cíclicas y en anestro en producción. Tandil: Facultad de Ciencias Veterinarias, UNCPBA; 2010.
Larson RL. The bovine estrous cycle and estrous synchronization. USA: college of veterinary medicine, Kansas State University; 2008.
Perry, G.A., The bovine estrous cycle. 2004, USA: South Dakota State University, Cooperative Extension Service.
Baruselli PS, et al. The use of hormonal treatments to improve reproductive performance of anestrous beef cattle in tropical climates. Anim Reprod Sci. 2004;82–83:479–86.
Ferguson JD. Diet, production and reproduction in dairy cows. Anim Feed Sci Technol. 1996;59(1–3):173–84.
Mauleon P. New trends in the control of reproduction in the bovine. Livest Prod Sci. 1974;1(2):117–31.
de Graaff W, Grimard B. Progesterone-releasing devices for cattle estrus induction and synchronization: device optimization to anticipate shorter treatment durations and new device developments. Theriogenology. 2018;112:34–43.
Roche JF, Ireland JJ. Effect of exogenous progesterone on time of occurrence of the LH surge in heifers. J Anim Sci. 1981;52(3):580–6.
Roseman TJ. Release of steroids from a silicone polymer. J Pharm Sci. 1972;61:46–50.
Ali Channa A, et al. Inducing sub-luteal circulating concentrations of progesterone and persistent follicles in Holstein heifers and non-lactating cows using a modified CIDR device. Livest Sci. 2017;198:191–4.
Kajaysri J, et al. Comparison of estrus synchronization by controlled internal drug release device (CIDR) and adhesive transdermal progestin patch in postpartum beef cows. Theriogenology. 2017;100:66–71.
El-Tarabany MS. The efficiency of new CIDR and once-used CIDR to synchronize ovulation in primiparous and multiparous Holstein cows. Anim Reprod Sci. 2016;173:29–34.
Veneranda G, et al. Pregnancy rates in dairy cows treated with progesterone-releasing devices and different gonadotropin-releasing hormone or estradiol plus equine chorionic gonadotropin fixed time artificial insemination protocols. Reprod Fertil Dev. 2008;20(1):91.
Ramos M, et al. Effect of time or fixed-time IA on pregnancy rates in zebu cross-bred beef heifers treated with progesterone releasing devices and estradiol cypionate. Reprod Fertil Dev. 2009;22(1):177.
Maraña D, et al. Ovulation and pregnancy rates in postpartum bos indicus cows treated with progesterone vaginal devices and estradiol benzoate, with or without eCG and temporary weaning. Reprod Fertil Dev. 2006;18(2):116–7.
Pfeifer LF, et al. Effect of the ovulatory follicle diameter and progesterone concentration on the pregnancy rate of fixed-time inseminated lactating beef cows. R Bras Zootec. 2012;41:1004–8.
Martinez M, et al. Progesterone release patterns from Cue-Mate in comparison to other intravaginal progesterone-releasing devices in lactating dairy cows. Reprod Fertil Dev. 2007;19.
Xu ZZ. Reproduction, Events and Management. Control of Estrous Cycles: Synchronization of Estrus. In: W.F. Editor-in-Chief: John, editor. Encyclopedia of Dairy Sciences. 2nd ed. San Diego: Academic Press; 2011. p. 448–53.
Rathbone MJ, Burke CR. Controlled release intravaginal veterinary drug delivery. In: Rathbone MJ, McDowell A, editors. Long acting animal health drug products: fundamentals and applications. Boston: Springer US; 2013. p. 247–70.
Rathbone MJ, Bunt CR, Ogle CR, Burggraaf S, Macmillan KL, Burke CR, et al. Reengineering of a commercially available bovine intravaginal insert (CIDR insert) containing progesterone. J Control Release. 2002;85(1–3):105–15.
Colazo MG, Mapletoft RJ. A review of current timed-AI (TAI) programs for beef and dairy cattle. Can Vet J. 2014;55(8):772–80.
Islam R. Synchronization of estrus in cattle: a review. Vet World. 2011;4(3):136–41.
van Werven T, et al. Comparison of two intravaginal progesterone releasing devices (PRID-Delta vs CIDR) in dairy cows: blood progesterone profile and field fertility. Anim Reprod Sci. 2013;138(3):143–9.
Atanasov B, et al. Pathways of the dominant follicle after exposure to sub-luteal circulating progesterone concentrations are different in lactating dairy cows versus non-lactating heifers. Anim Reprod Sci. 2015;154:8–15.
Crabtree JR, et al. Investigation into the safety and clinical effects of a new progesterone releasing intra-vaginal device (PRID®Delta) in mares. J Equine Vet Sci. 2018;66:123.
Helbling I, Ibarra JD, Luna J. The optimization of an intravaginal ring releasing progesterone using a mathematical model. Pharm Res. 2014;31(3):795–808.
Helbling IM, Busatto CA, Fioramonti SA, Pesoa JI, Santiago L, Estenoz DA, et al. Preparation of TPP-crosslinked chitosan microparticles by spray drying for the controlled delivery of progesterone intended for estrus synchronization in cattle. Pharm Res. 2018;35(3):66.
Helbling IM, Ibarra JC, Luna JA. The use of cellulose membrane to eliminate burst release from intravaginal rings. AAPS J. 2016;18(4):960–71.
Helbling IM, Ibarra JCD, Luna JA. Evaluation and optimization of progesterone release from intravaginal rings using response surface methodology. J Drug Delivery Sci Technol. 2015;29:218–25.
Pereira GR, Marchetti JM, Bentley MVLB. A rapid method for determination of progesterone by reversed-phase liquid chromatography from aqueous media. Anal Lett. 2000;33:881–9.
Turino LN, Mariano RN, Cabrera MI, Scándolo DE, Maciel MG, Grau RJ. Pharmacokinetics of progesterone in lactating dairy cows: gaining some insights into the metabolism from kinetic modeling. J Dairy Sci. 2010;93(3):988–99.
Rathbone MJ, Bunt CR, Ogle CR, Burggraaf S, Macmillan KL, Pickering K. Development of an injection molded poly(ε-caprolactone) intravaginal insert for the delivery of progesterone to cattle. J Control Release. 2002;85(1–3):61–71.
Harrison RO, Ford SP, Young JW, Conley AJ, Freeman AE. Increased milk production versus reproductive and energy status of high producing dairy cows. J Dairy Sci. 1990;73(10):2749–58.
Rabiee AR, Macmillan KL, Schwarzenberger F. Excretion rate of progesterone in milk and faeces in lactating dairy cows with two levels of milk yield. Reprod Nutr Dev. 2001;41(4):309–19.
Williams AH, Cumming IA. Inverse relationship between concentration of progesterone and nutrition in ewes. J Agric Sci. 1982;98(03):517–22.
Parr RA, Davis IF, Miles MA, Squires TJ. Liver blood flow and metabolic clearance rate of progesterone in sheep. Res Vet Sci. 1993;55(3):311–6.
Prime GR, Symonds HW. Influence of plane of nutrition on portal blood flow and the metabolic clearance rate of progesterone in ovariectomized gilts. J Agric Sci. 1993;121(03):389–97.
Miller HM, Foxcroft GR, Squires J, Aherne FX. The effects of feed intake and body fatness on progesterone metabolism in ovariectomized gilts. J Anim Sci. 1999;77(12):3253–61.
Bedford CA, Harrison FA, Heap RB. In: Pierrepoint CG, editor. Kinetics of progesterone metabolism in the pregnant sheep. The endocrinology of pregnancy and parturition - experimental studies in sheep. Cardiff: Alpha Omega Alpha; 1973.
Freetly HC, Ferrell CL. Net uptakes of oestradiol-17 beta and progesterone across the portal-drained viscera and the liver of ewes. J Endocrinol. 1994;141(2):353–8.
Burrin DG, Ferrell CL, Eisemann JH, Britton RA, Nienaber JA. Effect of level of nutrition on splanchnic blood flow and oxygen consumption in sheep. Br J Nutr. 1989;62(1):23–34.
Symonds HW, Prime GR. The influence of volume of food intake by gilts on blood flow in the portal vein and clearance of progesterone from plasma. Anim Prod. 1989;48:620–1.
Sangsritavong S, Combs DK, Sartori R, Armentano LE, Wiltbank MC. High feed intake increases liver blood flow and metabolism of progesterone and estradiol-17beta in dairy cattle. J Dairy Sci. 2002;85(11):2831–42.
Funding
This study was financially supported by the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) and the Universidad Nacional del Litoral (UNL) of Argentina.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Helbling, I.M., Karp, F., Cappadoro, A. et al. Design and evaluation of a recyclable intravaginal device made of ethylene vinyl acetate copolymer for bovine estrus synchronization. Drug Deliv. and Transl. Res. 10, 1255–1266 (2020). https://doi.org/10.1007/s13346-020-00717-4
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13346-020-00717-4