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A Short Term Quality Control Tool for Biodegradable Microspheres

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Abstract

Accelerated in vitro release testing methodology has been developed as an indicator of product performance to be used as a discriminatory quality control (QC) technique for the release of clinical and commercial batches of biodegradable microspheres. While product performance of biodegradable microspheres can be verified by in vivo and/or in vitro experiments, such evaluation can be particularly challenging because of slow polymer degradation, resulting in extended study times, labor, and expense. Three batches of Leuprolide poly(lactic-co-glycolic acid) (PLGA) microspheres having varying morphology (process variants having different particle size and specific surface area) were manufactured by the solvent extraction/evaporation technique. Tests involving in vitro release, polymer degradation and hydration of the microspheres were performed on the three batches at 55°C. In vitro peptide release at 55°C was analyzed using a previously derived modification of the Weibull function termed the modified Weibull equation (MWE). Experimental observations and data analysis confirm excellent reproducibility studies within and between batches of the microsphere formulations demonstrating the predictability of the accelerated experiments at 55°C. The accelerated test method was also successfully able to distinguish the in vitro product performance between the three batches having varying morphology (process variants), indicating that it is a suitable QC tool to discriminate product or process variants in clinical or commercial batches of microspheres. Additionally, data analysis utilized the MWE to further quantify the differences obtained from the accelerated in vitro product performance test between process variants, thereby enhancing the discriminatory power of the accelerated methodology at 55°C.

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REFERENCES

  1. Han B, Wang H-T, Liu H-Y, Hong H, Lv W, Shang Z-H. Preparation of pingyangmycin PLGA microspheres and related in vitro/in vivo studies. Int J Pharm. 2010;398(1–2):130–6.

    Article  CAS  PubMed  Google Scholar 

  2. Sun F, Sui C, Teng L, Liu X, Teng L, Meng Q, et al. Studies on the preparation, characterization and pharmacological evaluation of tolterodine PLGA microspheres. Int J Pharm. 2010;397(1–2):44–9.

    Article  CAS  PubMed  Google Scholar 

  3. Kim TH, Jiang HH, Park CW, Youn YS, Lee S, Chen X, et al. PEGylated TNF-related apoptosis-inducing ligand (TRAIL)-loaded sustained release PLGA microspheres for enhanced stability and antitumor activity. J Control Release. 2011;150(1):63–9.

    Article  CAS  PubMed  Google Scholar 

  4. He J, Feng M, Zhou X, Ma S, Jiang Y, Wang Y, et al. Stabilization and encapsulation of recombinant human erythropoietin into PLGA microspheres using human serum albumin as a stabilizer. Int J Pharm. 2011;416(1):69–76.

    Article  CAS  PubMed  Google Scholar 

  5. Ratajczak-Enselme M, Estebe J-P, Dollo G, Chevanne F, Bec D, Malinovsky J-M, et al. Epidural, intrathecal and plasma pharmacokinetic study of epidural ropivacaine in PLGA-microspheres in sheep model. Eur J Pharm Biopharm. 2009;72(1):54–61.

    Article  CAS  PubMed  Google Scholar 

  6. Umeki N, Sato T, Harada M, Takeda J, Saito S, Iwao Y, et al. Preparation and evaluation of biodegradable microspheres containing a new potent osteogenic compound and new synthetic polymers for sustained release. Int J Pharm. 2010;392(1–2):42–50.

    Article  CAS  PubMed  Google Scholar 

  7. Sun L, Zhou S, Wang W, Li X, Wang J, Weng J. Preparation and characterization of porous biodegradable microspheres used for controlled protein delivery. Colloids Surf A Physicochem Eng Asp. 2009;345(1–3):173–81.

    Article  CAS  Google Scholar 

  8. Jiang W, Gupta RK, Deshpande MC, Schwendeman SP. Biodegradable poly(lactic-co-glycolic acid) microparticles for injectable delivery of vaccine antigens. Adv Drug Deliv Rev. 2005;57(3):391–410.

    Article  CAS  PubMed  Google Scholar 

  9. D’Souza S, Faraj JA, Giovagnoli S, DeLuca PP. Preparation, characterization and in vivo evaluation of Olanzapine Poly(D,L-lactide-co-glycolide) (PLGA) microspheres. J Pharm. 2013:article 831381.

  10. Tice TR, Gilley RM. Preparation of injectable controlled-release microcapsules by a solvent-evaporation process. J Control Release. 1985;2:343–52.

    Article  CAS  Google Scholar 

  11. Yang Y-Y, Chung T-S, Bai X-L, Chan W-K. Effect of preparation conditions on morphology and release profiles of biodegradable polymeric microspheres containing protein fabricated by double-emulsion method. Chem Eng Sci. 2000;55(12):2223–36.

    Article  CAS  Google Scholar 

  12. Jeyanthi R, Thanoo BC, Mehta RC, DeLuca PP. Effect of solvent removal technique on the matrix characteristics of polylactide/glycolide microspheres for peptide delivery. J Control Release. 1996;38(2–3):235–44.

    Article  CAS  Google Scholar 

  13. Li W-I, Anderson KW, Mehta RC, Deluca PP. Prediction of solvent removal profile and effect on properties for peptide-loaded PLGA microspheres prepared by solvent extraction/ evaporation method. J Control Release. 1995;37(3):199–214.

    Article  CAS  Google Scholar 

  14. Li W-I, Anderson KW, Deluca PP. Kinetic and thermodynamic modeling of the formation of polymeric microspheres using solvent extraction/evaporation method. J Control Release. 1995;37(3):187–98.

    Article  CAS  Google Scholar 

  15. Chung T-W, Huang Y-Y, Tsai Y-L, Liu Y-Z. Effects of solvent evaporation rate on the properties of protein-loaded PLLA and PDLLA microspheres fabricated by emulsion-solvent evaporation process. J Microencapsul. 2002;19(4):463–71.

    Article  CAS  PubMed  Google Scholar 

  16. Crotts G, Park TG. Preparation of porous and nonporous biodegradable polymeric hollow microspheres. J Control Release. 1995;35(2–3):91–105.

    Article  CAS  Google Scholar 

  17. Mehta RC, Jeyanthi R, Calis S, Thanoo BC, Burton KW, DeLuca PP. Biodegradable microspheres as depot system for parenteral delivery of peptide drugs. J Control Release. 1994;29(3):375–84.

    Article  CAS  Google Scholar 

  18. Ehtezazi T, Washington C. Controlled release of macromolecules from PLA microspheres: using porous structure topology. J Control Release. 2000;68(3):361–72.

    Article  CAS  PubMed  Google Scholar 

  19. O’Donnell PB, McGinity JW. Preparation of microspheres by the solvent evaporation technique. Adv Drug Deliv Rev. 1997;28(1):25–42.

    Article  PubMed  Google Scholar 

  20. Bodmeier R, McGinity JW. The preparation and evaluation of drug-containing poly(dl-lactide) microspheres formed by the solvent evaporation method. Pharm Res. 1987;4(6):465–71.

    Article  CAS  PubMed  Google Scholar 

  21. Berkland C, Kipper MJ, Narasimhan B, Kim KK, Pack DW. Microsphere size, precipitation kinetics and drug distribution control drug release from biodegradable polyanhydride microspheres. J Control Release. 2004;94(1):129–41.

    Article  CAS  PubMed  Google Scholar 

  22. Berkland C, Kim KK, Pack DW. PLG microsphere size controls drug release rate through several competing factors. Pharm Res. 2003;20(7):1055–62.

    Article  CAS  PubMed  Google Scholar 

  23. Berkland C, King M, Cox A, Kim KK, Pack DW. Precise control of PLG microsphere size provides enhanced control of drug release rate. J Control Release. 2002;82(1):137–47.

    Article  CAS  PubMed  Google Scholar 

  24. Liggins RT, Burt HM. Paclitaxel loaded poly(l-lactic acid) (PLLA) microspheres: II. The effect of processing parameters on microsphere morphology and drug release kinetics. Int J Pharm. 2004;281(1–2):103–6.

    Article  CAS  PubMed  Google Scholar 

  25. Uppoor VRS. Regulatory perspectives on in vitro (dissolution)/in vivo (bioavailability) correlations. J Control Release. 2001;72(1–3):127–32.

    Article  CAS  PubMed  Google Scholar 

  26. Ramstack M, Grandolfi G, Mannaert E. Long-acting Risperidone: prolonged release injectable delivery of Risperidone using Medisorb microsphere technology. Biol Psychiatry. 2003;53(8 Suppl 1):Abstract 547.

  27. Woo BH, Na K-H, Dani BA, Jiang G, Thanoo BC, DeLuca PP. In vitro characterization and in vivo testosterone suppression of 6-month release poly(D, L-Lactide) leuprolide microspheres. Pharm Res. 2002;19(4):546–50.

    Article  CAS  PubMed  Google Scholar 

  28. D’Souza SS, Selmin F, Murty SB, Qiu W, Thanoo BC, DeLuca PP. Assessment of fertility in male rats after extended chemical castration with a GnRH antagonist. AAPS PharmSci. 2004;6(1):94–9.

    Google Scholar 

  29. Burgess DJ, Hussain AS, Ingallinera TS, Chen ML. Assuring quality and performance of sustained and controlled release parenterals: workshop report. AAPS PharmSci. 2002;4(2):E7.

    Article  PubMed  Google Scholar 

  30. Okada H. One- and three-month release injectable microspheres of the LH-RH superagonist leuprorelin acetate. Adv Drug Deliv Rev. 1997;28(1):43–70.

    Article  CAS  PubMed  Google Scholar 

  31. D’Souza SS, DeLuca PP. Methods to assess in vitro drug release from injectable polymeric particulate systems. Pharm Res. 2006;23(3):460–74.

    Article  PubMed  Google Scholar 

  32. Burgess DJ, Crommelin DJA, Hussain AS, Chen M-L. Assuring quality and performance of sustained and controlled release parenterals. Eur J Pharm Sci. 2004;21(5):679–90.

    Article  CAS  PubMed  Google Scholar 

  33. Shameem M, Lee H, DeLuca PP. A short term (accelerated release) approach to evaluate peptide release from PLGA depot-formulations. AAPS PharmSci. 1999;1(3):E7.

  34. D’Souza SS, Faraj JA, DeLuca PP. A model-dependent approach to correlate accelerated with real-time release from biodegradable microspheres. AAPS PharmSciTech. 2005;6(4):E553–64.

    Google Scholar 

  35. Makino K, Arakawa M, Kondo T. Preparation and in vitro degradation properties of polylactide microcapsules. Chem Pharm Bull. 1985;33(3):1195–201.

    Article  CAS  PubMed  Google Scholar 

  36. Park EJ, Na DH, Lee KC. In vitro release study of mono-PEGylated growth hormone-releasing peptide-6 from PLGA microspheres. Int J Pharm. 2007;343(1–2):281–3.

    Article  CAS  PubMed  Google Scholar 

  37. Aso Y, Yoshioka S, Li Wan Po A, Terao T. Effect of temperature on mechanisms of drug release and matrix degradation of poly(D, L-lactide) microspheres. J Control Release. 1994;31(1):33–9.

    Article  CAS  Google Scholar 

  38. Bergsma JE, Rozema FR, Bos RRM, Boering G, de Bruijn WC, Pennings AJ. In vivo degradation and biocompatibility study of in vitro pre-degraded as-polymerized polylactide particles. Biomaterials. 1995;16(4):267–74.

    Article  CAS  PubMed  Google Scholar 

  39. Buchholz B. Accelerated degradation test on resorbable polymers. Degradation phenomena of polymeric biomaterials. New York: Springer; 1992. p. 67.

    Book  Google Scholar 

  40. Zackrisson G, Ostling G, Skagerberg B, Anfalt T. Accelerated dissolution rate analysis (ACDRA) for controlled release drugs. Application to Roxiam(R). J Pharm Biomed Anal. 1995;13(4–5):377–83.

    Article  CAS  PubMed  Google Scholar 

  41. Quist P-O, Ostling G. Accelerated dissolution testing for improved quality assurance. J Pharm Biomed Anal. 2002;28(6):1081–9.

    Article  CAS  PubMed  Google Scholar 

  42. Ertan G, Karasulu E, Özgüney I, Karasulu Y, Apaydın Ş, Kantarcı G, et al. Acceleration of in vitro dissolution studies of sustained release dosage form of theophylline and in vitro–in vivo evaluations in terms of correlations. Eur J Drug Metab Pharmacokinet. 2011;36(4):243–8.

    Article  CAS  PubMed  Google Scholar 

  43. Hall SC, Tan MM, Leonard JJ, Stevenson CL. Characterization and comparison of leuprolide degradation profiles in water and dimethyl sulfoxide. J Pept Res. 1999;53(4):432–41.

    Article  CAS  PubMed  Google Scholar 

  44. D’Aurizio E, van Nostrum CF, van Steenbergen MJ, Sozio P, Siepmann F, Siepmann J, et al. Preparation and characterization of poly(lactic-co-glycolic acid) microspheres loaded with a labile antiparkinson prodrug. Int J Pharm. 2011;409(1–2):289–96.

    Article  PubMed  Google Scholar 

  45. Aubert-Pouessel A, Bibby DC, Venier-Julienne M-C, Hindre F, Benoit J-P. A novel in vitro delivery system for assessing the biological integrity of protein upon release from PLGA microspheres. Pharm Res. 2002;19(7):1046–51.

    Article  CAS  PubMed  Google Scholar 

  46. Rawat A, Stippler E, Shah VP, Burgess DJ. Validation of USP apparatus 4 method for microsphere in vitro release testing using Risperdal® Consta®. Int J Pharm. 2011;420(2):198–205.

    Article  CAS  PubMed  Google Scholar 

  47. D’Souza SS, DeLuca PP. Development of a dialysis in vitro release method for biodegradable microspheres. AAPS PharmSciTech. 2005;6(2):E323–8.

    Google Scholar 

  48. Gray V. An interview with Professor Patrick DeLuca and Dr. Susan D’Souza on a novel in vitro technique. Dissolution Technol. 2006;13:21–3.

    Google Scholar 

  49. Siewert M, Dressman J, Brown CK, Shah VP. FIP/AAPS guidelines to dissolution/in vitro release testing of novel/special dosage forms. AAPS PharmSciTech. 2003;4(1):E7.

    Google Scholar 

  50. Sathe PM, Tsong Y, Shah VP. In vitro dissolution profile comparison: statistics and analysis, model dependent approach. Pharm Res. 1996;13(12):1799–803.

    Article  CAS  PubMed  Google Scholar 

  51. Braunecker J, Baba M, Milroy GE, Cameron RE. The effects of molecular weight and porosity on the degradation and drug release from polyglycolide. Int J Pharm. 2004;282(1–2):19–34.

    Article  CAS  PubMed  Google Scholar 

  52. Klose D, Siepmann F, Elkharraz K, Krenzlin S, Siepmann J. How porosity and size affect the drug release mechanisms from PLGA-based microparticles. Int J Pharm. 2006;314(2):198–206.

    Article  CAS  PubMed  Google Scholar 

  53. Woo BH, Kostanski JW, Gebrekidan S, Dani BA, Thanoo BC, DeLuca PP. Preparation, characterization and in vivo evaluation of 120-day poly(D, L-lactide) leuprolide microspheres. J Control Release. 2001;75(3):307–15.

    Article  CAS  PubMed  Google Scholar 

  54. Costa P, Sousa Lobo JM. Modeling and comparison of dissolution profiles. Eur J Pharm Sci. 2001;13(2):123–33.

    Article  CAS  PubMed  Google Scholar 

  55. Polli JE, Rekhi GS, Augsburger LL, Shah VP. Methods to compare dissolution profiles and a rational for wide dissolution specifications for metoprolol tartrate tablets. J Pharm Sci. 1997;86(6):690–700.

    Article  CAS  PubMed  Google Scholar 

  56. Blasi P, D’Souza SS, Selmin F, DeLuca PP. Plasticizing effect of water on poly(lactide-co-glycolide). J Control Release. 2005;108(1):1–9.

    Article  CAS  PubMed  Google Scholar 

  57. Fu K, Pack DW, Klibanov AM, Langer R. Visual evidence of acidic environment within degrading poly(lactic-co-glycolic acid) (PLGA) microspheres. Pharm Res. 2000;17(1):100–6.

    Article  CAS  PubMed  Google Scholar 

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ACKNOWLEDGMENTS

The research described in this manuscript was performed while the authors were affiliated with the University of Kentucky, Lexington, KY, USA. The authors wish to thank Oakwood Labs, Oakwood, OH, USA, and the Graduate School, University of Kentucky, Lexington, KY, USA, for their financial support.

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Author notes

  1. Susan D’Souza

    Present address: Sunovion Pharmaceuticals Inc, Marlborough, Massachusetts, 01752, USA

  2. Jabar A. Faraj

    Present address: Fresenius Kabi USA, Skokie, Illinois, 60077, USA

  3. Rossella Dorati

    Present address: Dipartimento di Chimica Farmaceutica, Università degli Studi di Pavia, V.le Taramelli 12, 27100, Pavia, Italy

Authors and Affiliations

  1. University of Kentucky College of Pharmacy, Lexington, Kentucky, 40536, USA

    Susan D’Souza, Jabar A. Faraj, Rossella Dorati & Patrick P. DeLuca

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  1. Susan D’Souza
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  2. Jabar A. Faraj
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  4. Patrick P. DeLuca
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Correspondence to Susan D’Souza.

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D’Souza, S., Faraj, J.A., Dorati, R. et al. A Short Term Quality Control Tool for Biodegradable Microspheres. AAPS PharmSciTech 15, 530–541 (2014). https://doi.org/10.1208/s12249-013-0052-0

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