The objective of this study was to develop long-acting injectable dosage forms of Orntide, a peptide GnRH antagonist, to provide tailored release for 6-month duration. Using a polylactide homopolymer and the solvent extraction/evaporation method, three microsphere formulations (Formulations A, B, and C) were prepared at various drug loadings (11.85–15.79%). The microspheres were characterized for particle size by laser diffractometry, surface morphology by scanning electron microscopy (SEM), and bulk density by tapping, as well as long-term in vitro drug release, mass loss and hydration at 37°C, and short-term in vitro drug release at elevated temperatures (51–59°C). Experiments at 37°C revealed that drug release was triphasic and occurred due to slow degradation of the polylactide polymer. Short-term in vitro release results indicated that drug release was diffusional. Application of the Higuchi equation to short-term release confirmed the temperature dependency of the diffusional rate constant. Using the rate constant and the Arrhenius equation, an value of 45？kcal/mol (Formulation A) and approximately 25？kcal/mol (Formulations B and C) was obtained for diffusional release. Study results suggest that by selection of an appropriate biodegradable polymer, injectable dosing forms that release drug for 6 months or longer can be developed. 1. Introduction Several reports document the challenges faced by pharmaceutical researchers in the area of drug delivery of large molecules [1–5]. Undoubtedly, administration of large molecules like peptides and proteins in vivo is fraught with obstacles. Unlike most small molecules, peptides and proteins show poor oral absorption and bioavailability due to their large molecular weight and rapid degradation in the gastrointestinal (GI) tract [6]. Choosing an alternate route of administration (e.g., parenteral, nasal) to deliver these types of large molecules does not provide significant advantages over oral administration due to the fact that they are rapidly degraded in body fluids, resulting in a short-half life in vivo [7]. Since proteins and peptides are generally considered to be highly potent molecules requiring administration of small therapeutic doses, a frequent dosing regimen is needed to maintain constant and continuous blood levels over a period of time. Such type of dosing is neither suitable nor ideal and often results in nonadherence to therapy, patient compliance issues, and increased costs [8]. Peptide therapeutics like GnRH (gonadotropin receptor hormone) analogs have been a mainstay in the treatment of
References
[1]
J. Xuan, Y. Lin, J. Huang, et al., “Exenatide-loaded PLGA microspheres with improved glycemic control: in vitro bioactivity and in vivo pharmacokinetic profiles after subcutaneous administration to SD rats,” Peptides, vol. 46, pp. 172–179, 2013.
[2]
J. He, M. Feng, X. Zhou et al., “Stabilization and encapsulation of recombinant human erythropoietin into PLGA microspheres using human serum albumin as a stabilizer,” International Journal of Pharmaceutics, vol. 416, no. 1, pp. 69–76, 2011.
[3]
L. Sun, S. Zhou, W. Wang, X. Li, J. Wang, and J. Weng, “Preparation and characterization of porous biodegradable microspheres used for controlled protein delivery,” Colloids and Surfaces A: Physicochemical and Engineering Aspects, vol. 345, no. 1-3, pp. 173–181, 2009.
[4]
H. K. Kim and T. G. Park, “Comparative study on sustained release of human growth hormone from semi-crystalline poly(L-lactic acid) and amorphous poly(D,L-lactic-co-glycolic acid) microspheres: morphological effect on protein release,” Journal of Controlled Release, vol. 98, no. 1, pp. 115–125, 2004.
[5]
T. G. Park, H. Y. Lee, and Y. S. Nam, “A new preparation method for protein loaded poly(D,L-lactic-co-glycolic acid) microspheres and protein release mechanism study,” Journal of Controlled Release, vol. 55, no. 2-3, pp. 181–191, 1998.
[6]
A. K. Banga and Y. W. Chien, “Systemic delivery of therapeutic peptides and proteins,” International Journal of Pharmaceutics, vol. 48, no. 1–3, pp. 15–50, 1988.
[7]
H. Okada and H. Toguchi, “Biodegradable microspheres in drug delivery,” Critical Reviews in Therapeutic Drug Carrier Systems, vol. 12, no. 1, pp. 1–99, 1995.
[8]
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, pp. 631–639, 2013.
[9]
C. Garner, “Uses of GnRH agonists,” Journal of Obstetric, Gynecologic, and Neonatal Nursing, vol. 23, no. 7, pp. 563–570, 1994.
[10]
J. N. Pace, J. L. Miller, and L. I. Rose, “GnRH agonists: gonadorelin, leuprolide and nafarelin,” The American Family Physician, vol. 44, no. 5, pp. 1777–1782, 1991.
[11]
H. Lepor and N. D. Shore, “LHRH agonists for the treatment of prostate cancer: 2012,” Reviews in Urology, vol. 14, pp. 1–12, 2012.
[12]
P. M. Conn and W. F. Crowley Jr., “Gonadotropin-releasing hormone and its analogs,” Annual Review of Medicine, vol. 45, pp. 391–405, 1994.
[13]
E. Kienle and G. Lübben, “Efficacy and safety of leuprorelin acetate depot for prostate cancer,” Urologia Internationalis, vol. 56, no. 1, pp. 23–30, 1996.
[14]
A. B. Copperman and C. Benadiva, “Optimal usage of the GnRH antagonists: a review of the literature,” Reproductive Biology and Endocrinology, vol. 11, no. 1, article 20, 2013.
[15]
J. A. F. Huirne and C. B. Lambalk, “Gonadotropin-releasing-hormone-receptor antagonists,” The Lancet, vol. 358, no. 9295, pp. 1793–1803, 2001.
[16]
G. F. Weinbauer and E. Nieschlag, “LH-RH antagonists: state of the art and future perspectives,” Recent Results in Cancer Research, vol. 124, pp. 113–136, 1992.
[17]
L. A. Kiesel, A. Rody, R. R. Greb, and A. Szilágyi, “Clinical use of GnRH analogues,” Clinical Endocrinology, vol. 56, no. 6, pp. 677–687, 2002.
[18]
J. W. Kostanski, B. A. Dani, B. Schrier, and P. P. DeLuca, “Effect of the concurrent LHRH antagonist administration with a LHRH superagonist in rats,” Pharmaceutical Research, vol. 17, no. 4, pp. 445–450, 2000.
[19]
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.
[20]
R. Sharifi, L. D. Knoll, J. Smith, and E. Kramolowsky, “Leuprolide acetate (30-mg depot every four months) in the treatment of advanced prostate cancer,” Urology, vol. 51, no. 2, pp. 271–276, 1998.
[21]
S. L. Gupta, K. P. Rao, K. P. R. Choudary, and S. Pratima, “Preformulation studies of biodegradable drug implants of meloxicam for orthopedic patient care,” Journal of Pharmaceutical Science and Technology, vol. 3, pp. 494–498, 2011.
[22]
S. Takada, T. Kurokawa, K. Miyazaki, S. Iwasa, and Y. Ogawa, “Utilization of an amorphous form of a water-soluble GPIIb/IIIa antagonist for controlled release from biodegradable microspheres,” Pharmaceutical Research, vol. 14, no. 9, pp. 1146–1150, 1997.
[23]
J. M. Ramstack, G. P. Grandolfi, E. Mannaert, P. D'Hoore, and R. A. Lasser, “Risperdal Consta: Prolonged-Release Injectable Delivery of Risperidone using Medisorb Microsphere Technology,” Abstract AAPS, 2002.
[24]
E. Comets, F. Mentré, F. Nimmerfall et al., “Nonparametric analysis of the absorption profile of octreotide in rabbits from long-acting release formulation OncoLAR,” Journal of Controlled Release, vol. 59, no. 2, pp. 197–205, 1999.
[25]
G.-K. Zou, Y.-L. Song, W. Zhou et al., “Effects of local delivery of bFGF from PLGA microspheres on osseointegration around implants in diabetic rats,” Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology, vol. 114, no. 3, pp. 284–289, 2012.
[26]
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.
[27]
U. Seju, A. Kumar, and K. K. Sawant, “Development and evaluation of olanzapine-loaded PLGA nanoparticles for nose-to-brain delivery: in vitro and in vivo studies,” Acta Biomaterialia, vol. 7, no. 12, pp. 4169–4176, 2011.
[28]
S. D'Souza, J. A. Faraj, S. Giovagnoli, and P. P. DeLuca, “Development of risperidone PLGA microspheres,” Journal of Drug Delivery, vol. 2014, Article ID 620464, 11 pages, 2014.
[29]
J. Braunecker, M. Baba, G. E. Milroy, and R. E. Cameron, “The effects of molecular weight and porosity on the degradation and drug release from polyglycolide,” International Journal of Pharmaceutics, vol. 282, no. 1-2, pp. 19–34, 2004.
[30]
T. G. Park, “Degradation of poly(lactic-co-glycolic acid) microspheres: effect of copolymer composition,” Biomaterials, vol. 16, no. 15, pp. 1123–1130, 1995.
[31]
E. O. Akala, P. Wiriyacoonkasem, and G. Pan, “Studies on in vitro availability, degradation, and thermal properties of naltrexone-loaded biodegradable microspheres,” Drug Development and Industrial Pharmacy, vol. 37, no. 6, pp. 673–684, 2011.
[32]
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, vol. 2013, Article ID 831381, 9 pages, 2013.
[33]
J. W. Kostanski, B. C. Thanoo, and P. P. DeLuca, “Preparation, characterization, and in vitro evaluation of 1- and 4-month controlled release orntide PLA and PLGA microspheres,” Pharmaceutical Development and Technology, vol. 5, no. 4, pp. 585–596, 2000.
[34]
G. Ploussard and P. Mongiat-Artus, “Triptorelin in the management of prostate cancer,” Future Oncology, vol. 9, no. 1, pp. 93–102, 2013.
[35]
C.-C. Kao, Y.-H. Chang, T. Wu et al., “Open, multi-center, phase IV study to assess the efficacy and tolerability of triptorelin in Taiwanese patients with advanced prostate cancer,” Journal of the Chinese Medical Association, vol. 75, no. 6, pp. 255–261, 2012.
[36]
D. Fontana, M. Mari, A. Martinelli et al., “3-Month formulation of goserelin acetate (“Zoladex” 10.8-mg Depot) in advanced prostate cancer: results from an Italian, open, multicenter trial,” Urologia Internationalis, vol. 70, no. 4, pp. 316–320, 2003.
[37]
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.
[38]
U. W. Tunn, “A 6-month depot formulation of leuprolide acetate is safe and effective in daily clinical practice: a non-interventional prospective study in 1273 patients,” BMC Urology, vol. 11, article 15, 2011.
[39]
A. Spitz, J. M. Young, L. Larsen, C. Mattia-Goldberg, J. Donnelly, and K. Chwalisz, “Efficacy and safety of leuprolide acetate 6-month depot for suppression of testosterone in patients with prostate cancer,” Prostate Cancer and Prostatic Diseases, vol. 15, no. 1, pp. 93–99, 2012.
[40]
U. W. Tunn, D. Gruca, and P. Bacher, “Six-month leuprorelin acetate depot formulations in advanced prostate cancer: a clinical evaluation,” Clinical Interventions in Aging, vol. 8, pp. 457–464, 2013.
[41]
J. W. Kostanski and P. P. DeLuca, “A novel in vitro release technique for peptide containing biodegradable microspheres,” AAPS PharmSciTech, vol. 1, no. 1, article E4, 2000.
[42]
S. D'Souza, J. A. Faraj, S. Giovagnoli, and P. P. DeLuca, “IVIVC from long acting olanzapine microspheres,” International Journal of Biomaterials, vol. 2014, Article ID 407065, 11 pages, 2014.
[43]
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.
[44]
M. Shameem, H. Lee, and P. P. DeLuca, “A short-term (accelerated release) approach to evaluate peptide release from PLGA depot formulations,” AAPS PharmSci, vol. 1, no. 3, article 7, 1999.
[45]
S. D'Souza, J. A. Faraj, R. Dorati, and P. P. DeLuca, “A short term quality control tool for biodegradable microspheres,” AAPS PharmSciTech, vol. 15, no. 3, pp. 530–541, 2014.
[46]
S. S. D’Souza, J. A. Faraj, and P. P. DeLuca, “A model-dependent approach to correlate accelerated with real-time release from biodegradable microspheres,” AAPS PharmSciTech, vol. 6, no. 4, article 70, 2005.
[47]
T. Higuchi, “Rate of release of medicaments from ointment bases containing drugs in suspension,” Journal of pharmaceutical sciences, vol. 50, pp. 874–875, 1961.
