Research paper In vitro/in vivo characterization of melt-molded gabapentin-loaded poly(epsilon-caprolactone) implants for sustained release in animal studies Ángel M. Carcaboso a , Diego A. Chiappetta b,c , Christian Höcht a , Mariano G. Blake a , Mariano M. Boccia a,c , Carlos M. Baratti a,c , Alejandro Sosnik b,c, * a Department of Pharmacology, University of Buenos Aires, Buenos Aires, Argentina b Department of Pharmaceutical Technology, University of Buenos Aires, Buenos Aires, Argentina c National Science Research Council (CONICET), Buenos Aires, Argentina article info Article history: Received 28 January 2008 Accepted in revised form 20 May 2008 Available online 12 June 2008 Keywords: Poly(epsilon-caprolactone) implants Melt-molding/compression method Gabapentin in vitro release In vivo pharmacokinetics towards memory studies abstract Gabapentin (GBP) is a water soluble low molecular weight drug with anticonvulsivant and antinocicep- tive activity. In animal models, systemic administration regimes resembling chronic exposure to this drug (50 mg/kg, twice a day during one week), induce memory impairment. Aiming to gain further insight on the mechanisms involved in this process, a monolithic implant that releases constant plasma levels dur- ing one-week was designed. GBP-loaded poly(epsilon-caprolactone) matrices were produced by means of a simple and reproducible melt-molding/compression procedure. In vitro release studies firstly com- prised uncoated implants that displayed release profiles according to a pseudo-first order model. In order to further regulate the release, two-sided coated implants where drug-free layers would perform as membranes controlling the delivery rate were prepared. A more moderated burst effect and a relatively linear (zero-order) release between days 1 and 7 were apparent. Implants were investigated in vivo and the plasma levels monitored during 10 days. Findings indicated that after a more pronounced release dur- ing day 1 and the achievement of the levels in blood comparable to a twice-a-day intraperitoneal man- agement, relatively constant levels were attained until day 7. Overall results support the usefulness of this manufacturing method for the production of implants to attain more prolonged GBP release profiles in memory animal studies. Ó 2008 Elsevier B.V. All rights reserved. 1. Introduction Long-term pharmacotherapy employed in the treatment of dif- ferent pathologies may affect the memory and learning processes [1]. In this context, aiming to characterize the cognitive effects associated with the chronic exposure to newly developed or al- ready commercialized drugs, a number of preclinical studies are usually conducted [2,3]. Most of this work comprises the adminis- tration of a single or limited number of doses (administered at dif- ferent time points) and the latter evaluation of the effect they have on certain behavior. However, in the case of drugs involved in the treatment of chronic diseases, these studies are of partial rele- vance. Having expressed this, only a few preclinical studies that evaluate the effect of chronic treatments on the cognitive aspects are available in the literature [4,5]. This is probably due to time- consuming administration schedules and the large number of ani- mals required in this kind of experiment. Epilepsy is a very common and complex pathology character- ized by anomalous neuronal discharges [6]. Chronic treatment with antiepileptic drugs aims to minimize the recurrence of con- vulsions by reducing the neuronal activity and excitability. At the same time, their inherent mechanism of action can eventually af- fect different neurobiological systems related to the cognitive pro- cess. From this perspective, both the disease and its treatment trigger cognitive impairment [7,8] that could be especially critical in the earlier stages of the learning process [4]. Some clinical stud- ies evidenced the negative influence of gabapentin (GBP), a well- known add-on antiepileptic drug used under chronic management, on memory performance after standard administration regimes [9–12]. In contrast, other scientists proclaimed that this agent had minimal effects on cognitive functions and improved memory and attention in different tests [13]. GBP was approved for use in the US in the early nineties [14,15]. Due to a relatively fast renal clearance it is administered several times a day [16] in epilepsy, neuropathic pain and also in off-label treatments [17,18], being all these chronic regimes. In the recent years, the potential contribution of GBP to memory deficit or enhancement has been a matter of comprehensive inves- tigations by research groups worldwide. We previously evaluated 0939-6411/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.ejpb.2008.05.031 * Corresponding author. Address: Department of Pharmaceutical Technology, Faculty of Pharmacy and Biochemistry, University of Buenos Aires, 956 Junín St., Buenos Aires CP1113, Argentina. Tel.: +54 11 4964 8252. E-mail address: alesosnik@gmail.com (A. Sosnik). European Journal of Pharmaceutics and Biopharmaceutics 70 (2008) 666–673 Contents lists available at ScienceDirect European Journal of Pharmaceutics and Biopharmaceutics journal homepage: www.elsevier.com/locate/ejpb