Skip to main content
SpringerLink
Log in

Long-acting injectable in situ gel of rasagiline: a patented product development

  • Original Article
  • Published:
Drug Delivery and Translational Research Aims and scope Submit manuscript

Abstract

Rasagiline has a certain potential in neuroprotection and delaying the progression of Parkinson’s disease (PD). However, the poor pharmacokinetics (PK) characteristics of conventional oral tablets and poor medication compliance limit the optimal efficacy of rasagiline. Based on this, we designed and optimized a sustained-release rasagiline in situ gel based on in vitro release and in vivo PK results. Among them, we found for the first time that aluminum hydroxide can effectively shorten the lag phase and promote early and late release, making the daily release more uniform. After subcutaneous administration of the optimized gel formulation at a monthly dose, the Cmax (64 ng/ml) was lower than that of free rasagiline (494 ng/ml) administered subcutaneously at a daily dose and comparable to that of oral administration of Azilect® (59.1 ng/ml) at a daily dose. In the meantime, the plasma concentration of rasagiline was mainly maintained at 5–10 ng/ml for about 1 month, and the active metabolite 1-aminoindane in plasma was also able to maintain a steady state. The rasagiline in situ gel has suitable viscosity and injectability, good repeatability of subcutaneous injection, and controllable impurities and can achieve sustained release in vivo with small burst release, which may have the clinical application advantages of maximizing the disease-modifying effect of rasagiline and improving medication compliance.

Graphical abstract

The rasagiline in situ gel was optimized through the feedback of in vitro release and in vivo pharmacokinetics (PK), in which the addition of aluminum hydroxide had a modulating effect on uniform release. The gel has low burst release and maintains steady-state blood drug concentration for about 1 month.

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
Fig. 5

Similar content being viewed by others

Data availability

All data will be available under request.

References

  1. Cheng HC, Ulane CM, Burke RE. Clinical progression in Parkinson disease and the neurobiology of axons. Ann Neurol. 2010;67(6):715–25. https://doi.org/10.1002/ana.21995.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Cotzias GC, Papavasiliou PS, Gellene R. Modification of Parkinsonism—chronic treatment with L-dopa. N Engl J Med. 1969;280(7):337–45. https://doi.org/10.1056/NEJM196902132800701.

    Article  CAS  PubMed  Google Scholar 

  3. Okun MS. Deep-brain stimulation for Parkinson’s disease. N Engl J Med. 2012;367(16):1529–38. https://doi.org/10.1056/NEJMct1208070.

    Article  CAS  PubMed  Google Scholar 

  4. Blandini F. Neuroprotection by rasagiline: a new therapeutic approach to Parkinson’s disease? CNS Drug Rev. 2005;11(2):183–94. https://doi.org/10.1111/j.1527-3458.2005.tb00269.x.

    Article  CAS  PubMed  Google Scholar 

  5. Weinreb O, Amit T, Riederer P, Youdim MB, Mandel SA. Neuroprotective profile of the multitarget drug rasagiline in Parkinson’s disease. Int Rev Neurobiol. 2011;100:127–49. https://doi.org/10.1016/B978-0-12-386467-3.00007-8.

    Article  CAS  PubMed  Google Scholar 

  6. Youdim MB. Rasagiline in Parkinson’s disease. N Engl J Med. 2010;362(7):657–9. https://doi.org/10.1056/NEJMc0910491.

    Article  CAS  PubMed  Google Scholar 

  7. Youdim MB, Gross A, Finberg JP. Rasagiline [N-propargyl-1R(+)-aminoindan], a selective and potent inhibitor of mitochondrial monoamine oxidase B. Br J Pharmacol. 2001;132(2):500–6. https://doi.org/10.1038/sj.bjp.0703826.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Goggi J, Theofilopoulos S, Riaz SS, Jauniaux E, Stern GM, Bradford HF. The neuronal survival effects of rasagiline and deprenyl on fetal human and rat ventral mesencephalic neurones in culture. Neuroreport. 2000;11(18):3937–41. https://doi.org/10.1097/00001756-200012180-00007.

    Article  CAS  PubMed  Google Scholar 

  9. Parkinson Study Group. A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease. Arch Neurol. 2004;61(4):561–6. https://doi.org/10.1001/archneur.61.4.561.

    Article  Google Scholar 

  10. Hauser RA, Lew MF, Hurtig HI, Ondo WG, Wojcieszek J, Fitzer-Attas CJ, et al. Long-term outcome of early versus delayed rasagiline treatment in early Parkinson’s disease. Mov Disord. 2009;24(4):564–73. https://doi.org/10.1002/mds.22402.

    Article  PubMed  Google Scholar 

  11. Olanow CW, Rascol O, Hauser R, Feigin PD, Jankovic J, Lang A, et al. A double-blind, delayed-start trial of rasagiline in Parkinson’s disease. N Engl J Med. 2009;361(13):1268–78. https://doi.org/10.1056/NEJMoa0809335.

    Article  CAS  PubMed  Google Scholar 

  12. Kang CE, Poon PC, Tator CH, Shoichet MS. A new paradigm for local and sustained release of therapeutic molecules to the injured spinal cord for neuroprotection and tissue repair. Tissue Eng Part A. 2009;15(3):595–604. https://doi.org/10.1089/ten.tea.2007.0349.

    Article  CAS  PubMed  Google Scholar 

  13. Jin Y, Kim IY, Kim ID, Lee HK, Park JY, Han PL, et al. Biodegradable gelatin microspheres enhance the neuroprotective potency of osteopontin via quick and sustained release in the post-ischemic brain. Acta Biomater. 2014;10(7):3126–35. https://doi.org/10.1016/j.actbio.2014.02.045.

    Article  CAS  PubMed  Google Scholar 

  14. Arranz-Romera A, Davis BM, Bravo-Osuna I, Esteban-Pérez S, Molina-Martínez IT, Shamsher E, et al. Simultaneous co-delivery of neuroprotective drugs from multi-loaded PLGA microspheres for the treatment of glaucoma. J Control Release. 2019;297:26–38. https://doi.org/10.1016/j.jconrel.2019.01.012.

    Article  CAS  PubMed  Google Scholar 

  15. Meissner WG, Frasier M, Gasser T, Goetz CG, Lozano A, Piccini P, et al. Priorities in Parkinson’s disease research. Nat Rev Drug Discov. 2011;10(5):377–93. https://doi.org/10.1038/nrd3430.

    Article  CAS  PubMed  Google Scholar 

  16. Collier TJ, Kanaan NM, Kordower JH. Ageing as a primary risk factor for Parkinson’s disease: evidence from studies of non-human primates. Nat Rev Neurosci. 2011;12(6):359–66. https://doi.org/10.1038/nrn3039.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kulkarni AS, Balkrishnan R, Anderson RT, Edin HM, Kirsch J, Stacy MA. Medication adherence and associated outcomes in Medicare health maintenance organization-enrolled older adults with Parkinson’s disease. Mov Disord. 2008;23(3):359–65. https://doi.org/10.1002/mds.21831.

    Article  PubMed  Google Scholar 

  18. Tarrants ML, Denarié MF, Castelli-Haley J, Millard J, Zhang D. Drug therapies for Parkinson’s disease: a database analysis of patient compliance and persistence. Am J Geriatr Pharmacother. 2010;8(4):374–83. https://doi.org/10.1016/j.amjopharm.2010.08.001.

    Article  CAS  PubMed  Google Scholar 

  19. Allison SD. Analysis of initial burst in PLGA microparticles. Expert Opin Drug Deliv. 2008;5(6):615–28. https://doi.org/10.1517/17425247.5.6.615.

    Article  CAS  PubMed  Google Scholar 

  20. Thote AJ, Chappell JT Jr, Gupta RB, Kumar R. Reduction in the initial-burst release by surface crosslinking of PLGA microparticles containing hydrophilic or hydrophobic drugs. Drug Dev Ind Pharm. 2005;31(1):43–57. https://doi.org/10.1081/ddc-43985.

    Article  CAS  PubMed  Google Scholar 

  21. Parent M, Nouvel C, Koerber M, Sapin A, Maincent P, Boudier A. PLGA in situ implants formed by phase inversion: critical physicochemical parameters to modulate drug release. J Control Release. 2013;172(1):292–304. https://doi.org/10.1016/j.jconrel.2013.08.024.

    Article  CAS  PubMed  Google Scholar 

  22. Gentile P, Chiono V, Carmagnola I, Hatton PV. An overview of poly(lactic-co-glycolic) acid (PLGA)-based biomaterials for bone tissue engineering. Int J Mol Sci. 2014;15(3):3640–59. https://doi.org/10.3390/ijms15033640.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Heidemann W, Jeschkeit S, Ruffieux K, Fischer JH, Wagner M, Krüger G, et al. Degradation of poly(D, L)lactide implants with or without addition of calciumphosphates in vivo. Biomaterials. 2001;22(17):2371–81. https://doi.org/10.1016/s0142-9612(00)00424-5.

    Article  CAS  PubMed  Google Scholar 

  24. Heidemann W, Ruffieux K, Fischer JH, Jeschkeit-Schubbert S, Jung H, Krueger G, et al. The effect of an admixture of sodium hydrogen phosphate or heparin-coating to poly(D, L)lactide–results of an animal study. Biomed Tech (Berl). 2003;48(10):262–8. https://doi.org/10.1515/bmte.2003.48.10.262.

    Article  CAS  PubMed  Google Scholar 

  25. Houchin ML, Neuenswander SA, Topp EM. Effect of excipients on PLGA film degradation and the stability of an incorporated peptide. J Control Release. 2007;117(3):413–20. https://doi.org/10.1016/j.jconrel.2006.11.023.

    Article  CAS  PubMed  Google Scholar 

  26. Jaganathan KS, Rao YU, Singh P, Prabakaran D, Gupta S, Jain A, et al. Development of a single dose tetanus toxoid formulation based on polymeric microspheres: a comparative study of poly(D, L-lactic-co-glycolic acid) versus chitosan microspheres. Int J Pharm. 2005;294(1–2):23–32. https://doi.org/10.1016/j.ijpharm.2004.12.026.

    Article  CAS  PubMed  Google Scholar 

  27. Armstrong MJ, Okun MS. Diagnosis and treatment of Parkinson disease: a review. JAMA. 2020;323(6):548–60. https://doi.org/10.1001/jama.2019.22360.

    Article  PubMed  Google Scholar 

  28. Bar-Am O, Weinreb O, Amit T, Youdim MB. The neuroprotective mechanism of 1-(R)-aminoindan, the major metabolite of the anti-parkinsonian drug rasagiline. J Neurochem. 2010;112(5):1131–7. https://doi.org/10.1111/j.1471-4159.2009.06542.x.

    Article  CAS  PubMed  Google Scholar 

  29. Berteau C, Filipe-Santos O, Wang T, Rojas HE, Granger C, Schwarzenbach F. Evaluation of the impact of viscosity, injection volume, and injection flow rate on subcutaneous injection tolerance. Med Devices (Auckl). 2015;8:473–84. https://doi.org/10.2147/MDER.S91019.

    Article  PubMed  Google Scholar 

  30. Kempe S, Mäder K. In situ forming implants - an attractive formulation principle for parenteral depot formulations. J Control Release. 2012;161(2):668–79. https://doi.org/10.1016/j.jconrel.2012.04.016.

    Article  CAS  PubMed  Google Scholar 

  31. Summerfield A, Meurens F, Ricklin ME. The immunology of the porcine skin and its value as a model for human skin. Mol Immunol. 2015;66(1):14–21. https://doi.org/10.1016/j.molimm.2014.10.023.

    Article  CAS  PubMed  Google Scholar 

  32. Tyler B, Gullotti D, Mangraviti A, Utsuki T, Brem H. Polylactic acid (PLA) controlled delivery carriers for biomedical applications. Adv Drug Deliv Rev. 2016;107:163–75. https://doi.org/10.1016/j.addr.2016.06.018.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the Jiangsu Simcere Pharmaceutical Co., Ltd. (Nanjing, China) for providing financial support for this study (No. SIM0399).

Author information

Authors and Affiliations

  1. State Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Pharmaceutical Co., Ltd., 210042, Nanjing, China

    Dongyang Zhao, Ping Chen, Yuanbin Hao, Jing Dong, Yu Dai, Qingqing Lu, Xin Zhang & Chia-Wen Liu

Authors
  1. Dongyang Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ping Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuanbin Hao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jing Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yu Dai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Qingqing Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chia-Wen Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Chia-Wen Liu designed and directed the project; Dongyang Zhao and Yu Dai optimized the formulation; Ping Chen, Yuanbin Hao, and Qingqing Lu conducted animal studies; Jing Dong and Xin Zhang investigated formulation stability; Dongyang Zhao and Chia-Wen Liu wrote the article.

Corresponding author

Correspondence to Chia-Wen Liu.

Ethics declarations

Ethics approval and consent to participate

The research did not involve human subjects. All institutional and national guidelines for the care and use of laboratory animals were followed.

Consent for publication

The manuscript has been read and approved by all the authors.

Conflicts of interest

Dongyang Zhao, Yu Dai, and Chia-Wen Liu are inventors on patent applications related to this work filed by the Jiangsu Simcere Pharmaceutical Co., Ltd. (No. CN202111511156.2, filed 2 December 2021; No. CN202210110574.9, filed 29 January 2022). The authors declare that they have no other competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhao, D., Chen, P., Hao, Y. et al. Long-acting injectable in situ gel of rasagiline: a patented product development. Drug Deliv. and Transl. Res. 13, 1012–1021 (2023). https://doi.org/10.1007/s13346-022-01261-z

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13346-022-01261-z

Keywords

Search

Navigation