Skip to main content
SpringerLink
Log in

In Vitro–In Vivo Correlations of Scalable PLGA-Risperidone Implants for the Treatment of Schizophrenia

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

ABSTRACT

Purpose

Nonadherence to antipsychotic medications is a major obstacle preventing optimal outcomes for patients with schizophrenia. Extended release systems exist in the form of depot injections, but these formulations exhibit several disadvantages. To address these concerns, we previously demonstrated proof of concept for an antipsychotic implant containing risperidone and the biodegradable polymer poly(lactic-co-glycolic) acid (PLGA).

Methods

We build upon recently published data by utilizing a scalable single-screw extrusion system for the production of PLGA-risperidone implants. Implants were composed of 40% risperidone and 60% PLGA, with varying ratios of lactide to glycolide (50:50, 65:35, 75:25 or 85:15). Risperidone release was assessed in vitro and in vivo in rats, and Level A, B and C correlations (IVIVCs) attempted for all. Bioavailability was verified with locomotor testing

Results

Level B analysis yielded the greatest correlation between in vitro and in vivo data (R 2 = 0.9425), while Level C yielded the lowest (R 2 = 0.8336). Although, based on qualitative results, a Level A correlation was not achieved, it did produce an R 2 of 0.9261. Locomotor testing demonstrated that peak serum concentrations coincide with significant reductions in activity.

Conclusion

Data demonstrate the applicability of our modeling system and advance long-term, implantable antipsychotics toward clinical application.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

REFERENCES

  1. Siegel SJ, Dankert M, Phillips JM. Psychosis and schizophrenia (chapter 55). In: Waldman S, Terzic A, editors. Pharmacology and therapeutics: principles to practice. Philadelphia: Elsevier; 2008.

    Google Scholar 

  2. Wu EQ et al. The economic burden of schizophrenia in the United States in 2002. J Clin Psychiatry. 2005;66(9):1122–9.

    Article  PubMed  Google Scholar 

  3. Rice DP. The economic impact of schizophrenia. J Clin Psychiatry. 1999;60 Suppl 1:4–6. discussion 28–30.

    PubMed  Google Scholar 

  4. Crown WH et al. Hospitalization and total medical costs for privately insured persons with schizophrenia. Adm Policy Ment Health. 2001;28(5):335–51.

    Article  PubMed  CAS  Google Scholar 

  5. Kane JM. Utilization of long-acting antipsychotic medication in patient care. CNS Spectr. 2006;11(12 Suppl 14):1–7. quiz 7–8.

    PubMed  Google Scholar 

  6. Lieberman JA et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353(12):1209–23.

    Article  PubMed  CAS  Google Scholar 

  7. Gilmer TP et al. Adherence to treatment with antipsychotic medication and health care costs among Medicaid beneficiaries with schizophrenia. Am J Psychiatry. 2004;161(4):692–9.

    Article  PubMed  Google Scholar 

  8. Robinson D et al. Predictors of relapse following response from a first episode of schizophrenia or schizoaffective disorder. Arch Gen Psychiatry. 1999;56(3):241–7.

    Article  PubMed  CAS  Google Scholar 

  9. Weiden PJ, Olfson M. Cost of relapse in schizophrenia. Schizophr Bull. 1995;21(3):419–29.

    PubMed  CAS  Google Scholar 

  10. Schooler NR. Relapse and rehospitalization: comparing oral and depot antipsychotics. J Clin Psychiatry. 2003;64 Suppl 16:14–7.

    PubMed  Google Scholar 

  11. Melkersson K. Differences in prolactin elevation and related symptoms of atypical antipsychotics in schizophrenic patients. J Clin Psychiatry. 2005;66(6):761–7.

    Article  PubMed  CAS  Google Scholar 

  12. Melkersson KI, Hulting AL, Brismar KE. Elevated levels of insulin, leptin, and blood lipids in olanzapine-treated patients with schizophrenia or related psychoses. J Clin Psychiatry. 2000;61(10):742–9.

    PubMed  CAS  Google Scholar 

  13. Ozcanli T et al. Severe liver enzyme elevations after three years of olanzapine treatment: a case report and review of olanzapine associated hepatotoxicity. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30(6):1163–6.

    Article  PubMed  CAS  Google Scholar 

  14. Benazzi F. Risperidone-induced hepatotoxicity. Pharmacopsychiatry. 1998;31(6):241.

    Article  PubMed  CAS  Google Scholar 

  15. Yadalam KG, Simpson GM. Changing from oral to depot fluphenazine. J Clin Psychiatry. 1988;49(9):346–8.

    PubMed  CAS  Google Scholar 

  16. Rabin C et al. In vitro and in vivo demonstration of risperidone implants in mice. Schizophr Res. 2008;98(1–3):66–78.

    Article  PubMed  CAS  Google Scholar 

  17. Siegel SJ et al. Surgically implantable long-term antipsychotic delivery systems for the treatment of schizophrenia. Neuropsychopharmacology. 2002;26(6):817–23.

    Article  PubMed  CAS  Google Scholar 

  18. Kitchell JP, Wise DL. Poly(lactic/glycolic acid) biodegradable drug-polymer matrix systems. Methods Enzymol. 1985;112:436–48.

    Article  PubMed  CAS  Google Scholar 

  19. Schakenraad JM et al. In vivo and in vitro degradation of glycine/DL-lactic acid copolymers. J Biomed Mater Res. 1989;23(11):1271–88.

    Article  PubMed  CAS  Google Scholar 

  20. Sharon AC, Wise DL. Development of drug delivery systems for use in treatment of narcotic addiction. NIDA Res Monogr. 1981;28:194–213.

    PubMed  CAS  Google Scholar 

  21. Sabel BA et al. Levodopa delivery from controlled-release polymer matrix: delivery of more than 600 days in vitro and 225 days of elevated plasma levels after subcutaneous implantation in rats. J Pharmacol Exp Ther. 1990;255(2):914–22.

    PubMed  CAS  Google Scholar 

  22. Okada H, Toguchi H. Biodegradable microspheres in drug delivery. Crit Rev Ther Drug Carrier Syst. 1995;12(1):1–99.

    PubMed  CAS  Google Scholar 

  23. Janssen PA et al. Pharmacology of risperidone (R 64 766), a new antipsychotic with serotonin-S2 and dopamine-D2 antagonistic properties. J Pharmacol Exp Ther. 1988;244(2):685–93.

    PubMed  CAS  Google Scholar 

  24. Davis JM, Chen N, Glick ID. A meta-analysis of the efficacy of second-generation antipsychotics. Arch Gen Psychiatry. 2003;60(6):553–64.

    Article  PubMed  CAS  Google Scholar 

  25. Nasrallah HA. The roles of efficacy, safety, and tolerability in antipsychotic effectiveness: practical implications of the CATIE schizophrenia trial. J Clin Psychiatry. 2007;68 Suppl 1:5–11.

    PubMed  CAS  Google Scholar 

  26. Brown CS et al. Atypical antipsychotics: Part II: adverse effects, drug interactions, and costs. Ann Pharmacother. 1999;33(2):210–7.

    Article  PubMed  CAS  Google Scholar 

  27. Iyer SS, Barr WH, Karnes HT. Profiling in vitro drug release from subcutaneous implants: a review of current status and potential implications on drug product development. Biopharm Drug Dispos. 2006;27(4):157–70.

    Article  PubMed  CAS  Google Scholar 

  28. Amidon GL et al. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res. 1995;12(3):413–20.

    Article  PubMed  CAS  Google Scholar 

  29. United States Pharmacopeial Convention. The United States pharmacopeia. The national formulary, United States Pharmacopeial Convention: Rockville, Md., p. v.

  30. Marder SR, Meibach RC. Risperidone in the treatment of schizophrenia. Am J Psychiatry. 1994;151(6):825–35.

    PubMed  CAS  Google Scholar 

  31. Naiker DV et al. Dose determination of haloperidol, risperidone and olanzapine using an in vivo dopamine D2-receptor occupancy method in the rat. Eur J Pharmacol. 2006;540(1–3):87–90.

    Article  PubMed  CAS  Google Scholar 

  32. Tarazi FI, Zhang K, Baldessarini RJ. Long-term effects of olanzapine, risperidone, and quetiapine on dopamine receptor types in regions of rat brain: implications for antipsychotic drug treatment. J Pharmacol Exp Ther. 2001;297(2):711–7.

    PubMed  CAS  Google Scholar 

  33. Moran-Gates T et al. Effects of risperidone on dopamine receptor subtypes in developing rat brain. Eur Neuropsychopharmacol. 2007;17(6–7):448–55.

    Article  PubMed  CAS  Google Scholar 

  34. Metzger KL et al. Pharmacokinetic and behavioral characterization of a long-term antipsychotic delivery system in rodents and rabbits. Psychopharmacology (Berl). 2007;190(2):201–11.

    Article  CAS  Google Scholar 

  35. Siegel SJ et al. Effect of drug type on the degradation rate of PLGA matrices. Eur J Pharm Biopharm. 2006;64(3):287–93.

    Article  PubMed  CAS  Google Scholar 

  36. Rinaki E, Dokoumetzidis A, Macheras P. The mean dissolution time depends on the dose/solubility ratio. Pharm Res. 2003;20(3):406–8.

    Article  PubMed  CAS  Google Scholar 

  37. Halene TB et al. Assessment of NMDA receptor NR1 subunit hypofunction in mice as a model for schizophrenia. Genes Brain Behav. 2009;8:661–75.

    Article  PubMed  CAS  Google Scholar 

  38. Huang X, Chestang BL, Brazel CS. Minimization of initial burst in poly(vinyl alcohol) hydrogels by surface extraction and surface-preferential crosslinking. Int J Pharm. 2002;248(1–2):183–92.

    Article  PubMed  CAS  Google Scholar 

  39. Huang X, Brazel CS. On the importance and mechanisms of burst release in matrix-controlled drug delivery systems. J Control Release. 2001;73(2–3):121–36.

    Article  PubMed  CAS  Google Scholar 

Download references

ACKNOWLEDGEMENTS

Funding provided by NIMH Grant 5R01MH074672-04.

Author information

Authors and Affiliations

  1. Translational Neuroscience Program, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, 19104, USA

    Laura C. Amann, Michael J. Gandal, Robert Lin, Yuling Liang & Steven J. Siegel

  2. Department of Pharmacology, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, 19104, USA

    Robert Lin

  3. Medical Scientist Training Program, University of Pennsylvania, Philadelphia, Pennsylvania, 19104, USA

    Michael J. Gandal

  4. Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, 19104, USA

    Michael J. Gandal

  5. Department of Psychiatry, Translational Research Laboratories, University of Pennsylvania, Rm. 2202, 125 S. 31st Street, Philadelphia, Pennsylvania, 19104, USA

    Steven J. Siegel

Authors
  1. Laura C. Amann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael J. Gandal
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Robert Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yuling Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Steven J. Siegel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Steven J. Siegel.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Amann, L.C., Gandal, M.J., Lin, R. et al. In Vitro–In Vivo Correlations of Scalable PLGA-Risperidone Implants for the Treatment of Schizophrenia. Pharm Res 27, 1730–1737 (2010). https://doi.org/10.1007/s11095-010-0152-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-010-0152-4

KEY WORDS

Search

Navigation