In this study, four PLGA microsphere formulations of Olanzapine were characterized on the basis of their in vitro behavior at 37°C, using a dialysis based method, with the goal of obtaining an IVIVC. In vivo profiles were determined by deconvolution (Nelson-Wagner method) and using fractional AUC. The in vitro and in vivo release profiles exhibited the same rank order of drug release. Further, in vivo profiles obtained with both approaches were nearly superimposable, suggesting that fractional AUC could be used as an alternative to the Nelson-Wagner method. A comparison of drug release profiles for the four formulations revealed that the in vitro profile lagged slightly behind in vivo release, but the results were not statistically significant ( ). Using the four formulations that exhibited different release rates, a Level A IVIVC was established using the deconvolution and fractional AUC approaches. A nearly 1？:？1 correlation ( ) between in vitro release and in vivo measurements confirmed the excellent relationship between in vitro drug release and the amount of drug absorbed in vivo. The results of this study suggest that proper selection of an in vitro method will greatly aid in establishing a Level A IVIVC for long acting injectables. 1. Introduction Establishing an IVIVC (in vitro in vivo correlation) remains a challenge for non-oral dosage forms like long acting injectables. One reason for the lack of IVIVC is the dearth of in vitro methods that are simple to set up and use, while suitably mimicking in vivo conditions. The benefits of establishing an in vitro in vivo correlation (IVIVC) have been enumerated in numerous pharmaceutical publications spanning the last three decades. Indeed, IVIVC has remained a topic of constant discussion with several dosage forms, especially solid orals, since the publication of an IVIVC guidance by the FDA in 1997 [1]. The goal of an IVIVC is to establish a relationship between the in vitro dissolution behavior and in vivo performance of a drug product. An IVIVC is generally described by a linear relationship between parameters derived from the in vitro and in vivo experiments as quantified by the Pearson correlation. As defined by the FDA guidance, these correlations have been classified under four categories.(i)Level A, the highest correlation, is a point to point correlation between in vitro dissolution and in vivo absorption over time. With a Level A correlation, the in vitro dissolution profiles are generally superimposable with in vivo absorption curves or may be made superimposable by use of an appropriate
References
[1]
FDA Guidance for Industry, “Extended Release Oral Dosage Forms: Development, Evaluation and Application of in vitro/in vivo Correlations,” 1997.
[2]
C. M. Negrín, A. Delgado, M. Llabrés, and C. évora, “In vivo-in vitro study of biodegradable methadone delivery systems,” Biomaterials, vol. 22, no. 6, pp. 563–570, 2001.
[3]
D.-F. Chu, X.-Q. Fu, W.-H. Liu, K. Liu, and Y.-X. Li, “Pharmacokinetics and in vitro and in vivo correlation of huperzine A loaded poly(lactic-co-glycolic acid) microspheres in dogs,” International Journal of Pharmaceutics, vol. 325, no. 1-2, pp. 116–123, 2006.
[4]
L. C. Amann, M. J. Gandal, R. Lin, Y. Liang, and S. J. Siegel, “In vitro-in vivo correlations of scalable plga-risperidone implants for the treatment of schizophrenia,” Pharmaceutical Research, vol. 27, no. 8, pp. 1730–1737, 2010.
[5]
S. D. 'Souza, J. A. Faraj, S. Giovagnoli, and P. P. DeLuca, “Preparation, characterization and in vivo evaluation of Olanzapine Poly(D, L-lactide-co-glycolide) (PLGA) microspheres,” Journal of Pharmaceutics, Article ID 831381, 2013.
[6]
E. J. Park, S. Amatya, M. S. Kim et al., “Long-acting injectable formulations of antipsychotic drugs for the treatment of schizophrenia,” Archives of Pharmacal Research, vol. 36, pp. 651–659, 2013.
[7]
S. S. D'Souza and P. P. DeLuca, “Methods to assess in vitro drug release from injectable polymeric particulate systems,” Pharmaceutical Research, vol. 23, no. 3, pp. 460–474, 2006.
[8]
J. C. Middleton and A. J. Tipton, “Synthetic biodegradable polymers as orthopedic devices,” Biomaterials, vol. 21, no. 23, pp. 2335–2346, 2000.
[9]
L. Wu and J. Ding, “In vitro degradation of three-dimensional porous poly(D,L-lactide-co- glycolide) scaffolds for tissue engineering,” Biomaterials, vol. 25, no. 27, pp. 5821–5830, 2004.
[10]
J. L. Cleland, “Protein delivery from biodegradable microspheres,” Pharmaceutical biotechnology, vol. 10, pp. 1–43, 1997.
[11]
T. Morita, Y. Sakamura, Y. Horikiri, T. Suzuki, and H. Yoshino, “Evaluation of in vivo release characteristics of protein-loaded biodegradable microspheres in rats and severe combined immunodeficiency disease mice,” Journal of Controlled Release, vol. 73, no. 2-3, pp. 213–221, 2001.
[12]
V. R. Sinha and A. Trehan, “Biodegradable microspheres for protein delivery,” Journal of Controlled Release, vol. 90, no. 3, pp. 261–280, 2003.
[13]
T. Heya, H. Okada, Y. Ogawa, and H. Toguchi, “Factors influencing the profiles of TRH release from copoly(d,l-lactic/glycolic acid) microspheres,” International Journal of Pharmaceutics, vol. 72, no. 3, pp. 199–205, 1991.
[14]
T. Heya, H. Okada, Y. Ogawa, and H. Toguchi, “In vitro and in vivo evaluation of thyrotrophin releasing hormone release from copoly(dl-lactic/glycolic acid) microspheres,” Journal of Pharmaceutical Sciences, vol. 83, no. 5, pp. 636–640, 1994.
[15]
M. Ramstack, G. Grandolfi, and E. Mannaert, “Long-acting Risperidone: prolonged release injectable delivery of Risperidone using Medisorb microsphere technology,” Biological Psychiatry, vol. 53, abstract 547, 2003.
[16]
B. H. Woo, K.-H. Na, B. A. Dani, G. Jiang, B. C. Thanoo, and P. P. DeLuca, “In vitro characterization and in vivo testosterone suppression of 6-month release poly(d,l-lactide) leuprolide microspheres,” Pharmaceutical Research, vol. 19, no. 4, pp. 546–550, 2002.
[17]
S. S. D'Souza, F. Selmin, S. B. Murty, W. Qiu, B. C. Thanoo, and P. P. DeLuca, “Assessment of fertility in male rats after extended chemical castration with a GnRH antagonist,” AAPS pharmSci, vol. 6, article 10, 2004.
[18]
S. D'Souza, J. Faraj, and P. DeLuca, “Microsphere delivery of Risperidone as an alternative to combination therapy,” European Journal of Pharmaceutics and Biopharmaceutics, vol. 85, no. 3, part A, pp. 631–639, 2013.
[19]
T. H. Kim, H. H. Jiang, C. W. Park et al., “PEGylated TNF-related apoptosis-inducing ligand (TRAIL)-loaded sustained release PLGA microspheres for enhanced stability and antitumor activity,” Journal of Controlled Release, vol. 150, no. 1, pp. 63–69, 2011.
[20]
W. W. Fleischhacker, M. Eerdekens, K. Karcher et al., “Treatment of Schizophrenia with long-acting injectable Risperidone: a 12-month open-label trial of the first long-acting second-generation antipsychotic,” Journal of Clinical Psychiatry, vol. 64, pp. 1250–1257, 2003.
[21]
B. Kim, S.-H. Lee, T. K. Choi et al., “Effectiveness of risperidone long-acting injection in first-episode schizophrenia: in naturalistic setting,” Progress in Neuro-Psychopharmacology and Biological Psychiatry, vol. 32, no. 5, pp. 1231–1235, 2008.
[22]
H. Okada, “One- and three-month release injectable microspheres of the LH-RH superagonist leuprorelin acetate,” Advanced Drug Delivery Reviews, vol. 28, no. 1, pp. 43–70, 1997.
[23]
E. David Crawford and J. M. Phillips, “Six-month gonadotropin releasing hormone (GnRH) agonist depots provide efficacy, safety, convenience, and comfort,” Cancer Management and Research, vol. 3, no. 1, pp. 201–209, 2011.
[24]
M. J. Blanco-Príeto, M. A. Campanero, K. Besseghir, F. Heimgatner, and B. Gander, “Importance of single or blended polymer types for controlled in vitro release and plasma levels of a somatostatin analogue entrapped in PLA/PLGA microspheres,” Journal of Controlled Release, vol. 96, no. 3, pp. 437–448, 2004.
[25]
S. S. D'Souza and P. P. DeLuca, “Development of a dialysis in vitro release method for biodegradable microspheres,” AAPS PharmSciTech, vol. 6, no. 2, article 42, 2005.
[26]
J. W. Kostanski and P. P. DeLuca, “A novel in vitro release technique for peptide containing biodegradable microspheres,” AAPS PharmSciTech, vol. 1, article E4, no. 1, 2000.
[27]
J. W. Kostanski, B. A. Dani, G. A. Reynolds, C. Y. Bowers, and P. P. DeLuca, “Evaluation of Orntide microspheres in a rat animal model and correlation to in vitro release profiles,” AAPS PharmSciTech, vol. 1, article 27, 2000.
[28]
J. G. Wagner and E. Nelson, “Per cent absorbed time plots derived from blood level and/or urinary excretion data,” Journal of pharmaceutical sciences, vol. 52, pp. 610–611, 1963.
[29]
B. H. Woo, J. W. Kostanski, S. Gebrekidan, B. A. Dani, B. C. Thanoo, and P. P. DeLuca, “Preparation, characterization and in vivo evaluation of 120-day poly(D,L-lactide) leuprolide microspheres,” Journal of Controlled Release, vol. 75, no. 3, pp. 307–315, 2001.
[30]
G. Reich, “Use of DSC to study the degradation behavior of PLA and PLGA microparticles,” Drug Development and Industrial Pharmacy, vol. 23, no. 12, pp. 1177–1189, 1997.
[31]
G. Jiang, W. Qiu, and P. P. DeLuca, “Preparation and in vitro/in vivo evaluation of insulin-loaded poly(acryloyl-hydroxyethyl starch)-PLGA composite microspheres,” Pharmaceutical Research, vol. 20, no. 3, pp. 452–459, 2003.
