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Review article: Biomedical intelligence

Vol. 148 No. 2526 (2018)

Excipients: not so inert? When the excipient plays the role of an active substance, as exemplified by systemic lupus

  • Sylviane Muller
Cite this as:
Swiss Med Wkly. 2018;148:w14631


It is well recognised that the historical timeline required for developing a drug, beginning with target identification and validation, is long and often tedious. It requires a large set of competences in various areas of molecular and cellular biology, chemistry, pharmacology, imaging, and model animal experimentation. Once the active molecule appears to be ready for human testing in controlled clinical trials, then the question arises of how to formulate it to render it stable, adequately packaged, according to the chosen route of administration, and bioavailable to reach its target in the affected organs. Historically, excipients have been considered inert and devoid of medicinal effect or influence. In fact, excipients are seldom neutral and some of them have been found to play a significant role, for example by initiating or participating in chemical and physical interactions with the active substance, leading in certain cases to compromise its therapeutic activity. It is difficult today to appreciate the number of potential drugs that have been discarded as a result of limited efficacy due to inappropriate excipients. This matter is presented here, with the peptide P140 (Lupuzor) as example. Two formulations of P140, differing in the excipients used (mannitol or trehalose), have been evaluated in patients affected by systemic lupus erythematosus in two successive phase IIb clinical trials. P140 was shown to reduce excessive autophagy activity discovered in some lupus immune cell subsets. One of the two excipients, namely trehalose, has been claimed to exert an intrinsic stimulating activity on autophagy process, which was found therefore to counteract the beneficial peptide effects.


  1. Galvao J, Davis B, Tilley M, Normando E, Duchen MR, Cordeiro MF. Unexpected low-dose toxicity of the universal solvent DMSO. FASEB J. 2014;28(3):1317–30. doi:.
  2. Bochner F, Hooper WD, Tyrer JH, Eadie MJ. Factors involved in an outbreak of phenytoin intoxication. J Neurol Sci. 1972;16(4):481–7. doi:.
  3. USP General Information Chapter <1078> Good manufacturing practices for bulk pharmaceutical excipients. USP 35-NF 30 (United States Pharmacopeial Convention) USP, Rockville, MD, USA, 2011.
  5. Chaudhari SP, Patil PS. Pharmaceutical excipients: a review. Int J Adv Pharm Biol Chem. 2012;1:21–34.
  6. Chakraborty A, Dhar P. A review on potential of proteins as an excipient for developing a nano-carrier delivery system. Crit Rev Ther Drug Carrier Syst. 2017;34(5):453–88. doi:.
  7. Irwin JJ, Pottel J, Zou L, Wen H, Zuk S, Zhang X, et al. A molecular basis for innovation in drug excipients. Clin Pharmacol Ther. 2017;101(3):320–3. doi:.
  8. Darji MA, Lalge RM, Marathe SP, Mulay TD, Fatima T, Alshammari A, et al. Excipient Stability in Oral Solid Dosage Forms: A Review. AAPS PharmSciTech. 2018;19(1):12–26. doi:.
  9. Ohtake S, Wang YJ. Trehalose: current use and future applications. J Pharm Sci. 2011;100(6):2020–53. doi:.
  10. Luyckx J, Baudouin C. Trehalose: an intriguing disaccharide with potential for medical application in ophthalmology. Clin Ophthalmol. 2011;5:577–81.
  11. Pinto-Bonilla JC, Del Olmo-Jimeno A, Llovet-Osuna F, Hernández-Galilea E. A randomized crossover study comparing trehalose/hyaluronate eyedrops and standard treatment: patient satisfaction in the treatment of dry eye syndrome. Ther Clin Risk Manag. 2015;11:595–603.
  12. Zhao J, Wang S, Bao J, Sun X, Zhang X, Zhang X, et al. Trehalose maintains bioactivity and promotes sustained release of BMP-2 from lyophilized CDHA scaffolds for enhanced osteogenesis in vitro and in vivo. PLoS One. 2013;8(1):e54645. doi:.
  13. Izmitli A, Schebor C, McGovern MP, Reddy AS, Abbott NL, de Pablo JJ. Effect of trehalose on the interaction of Alzheimer’s Aβ-peptide and anionic lipid monolayers. Biochim Biophys Acta. 2011;1808(1):26–33. doi:.
  14. Sarkar S, Davies JE, Huang Z, Tunnacliffe A, Rubinsztein DC. Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and alpha-synuclein. J Biol Chem. 2007;282(8):5641–52. doi:.
  15. Jain NK, Roy I. Effect of trehalose on protein structure. Protein Sci. 2009;18(1):24–36.
  16. Vidal RL, Matus S, Bargsted L, Hetz C. Targeting autophagy in neurodegenerative diseases. Trends Pharmacol Sci. 2014;35(11):583–91. doi:.
  17. Zimmer R, Wallace DJ, Muller S. Randomized, double-blind, placebo-controlled studies of P140 peptide in mannitol (Lupuzor) and trehalose (Forigerimod) in patients with SLE. Arthritis Rheum. 2012;64(Suppl 10):2620.
  18. Schall N, Page N, Macri C, Chaloin O, Briand JP, Muller S. Peptide-based approaches to treat lupus and other autoimmune diseases. J Autoimmun. 2012;39(3):143–53. doi:.
  19. Muller S, Wallace DJ. The importance of implementing proper selection of excipients in lupus clinical trials. Lupus. 2014;23(7):609–14. doi:.
  20. Monneaux F, Briand JP, Muller S. B and T cell immune response to small nuclear ribonucleoprotein particles in lupus mice: autoreactive CD4(+) T cells recognize a T cell epitope located within the RNP80 motif of the 70K protein. Eur J Immunol. 2000;30(8):2191–200. doi:.<2191::AID-IMMU2191>3.0.CO;2-R
  21. Monneaux F, Hoebeke J, Sordet C, Nonn C, Briand JP, Maillère B, et al. Selective modulation of CD4+ T cells from lupus patients by a promiscuous, protective peptide analog. J Immunol. 2005;175(9):5839–47. doi:.
  22. Monneaux F, Lozano JM, Patarroyo ME, Briand JP, Muller S. T cell recognition and therapeutic effect of a phosphorylated synthetic peptide of the 70K snRNP protein administered in MR/lpr mice. Eur J Immunol. 2003;33(2):287–96. doi:.
  23. Page N, Gros F, Schall N, Décossas M, Bagnard D, Briand JP, et al. HSC70 blockade by the therapeutic peptide P140 affects autophagic processes and endogenous MHCII presentation in murine lupus. Ann Rheum Dis. 2011;70(5):837–43. doi:.
  24. Page N, Schall N, Strub JM, Quinternet M, Chaloin O, Décossas M, et al. The spliceosomal phosphopeptide P140 controls the lupus disease by interacting with the HSC70 protein and via a mechanism mediated by gammadelta T cells. PLoS One. 2009;4(4):e5273. doi:.
  25. Page N, Gros F, Schall N, Briand JP, Muller S. A therapeutic peptide in lupus alters autophagic processes and stability of MHCII molecules in MRL/lpr B cells. Autophagy. 2011;7(5):539–40. doi:.
  26. Gros F, Arnold J, Page N, Décossas M, Korganow A-S, Martin T, et al. Macroautophagy is deregulated in murine and human lupus T lymphocytes. Autophagy. 2012;8(7):1113–23. doi:.
  27. Macri C, Wang F, Tasset I, Schall N, Page N, Briand JP, et al. Modulation of deregulated chaperone-mediated autophagy by a phosphopeptide. Autophagy. 2015;11(3):472–86. doi:.
  28. Monneaux F, Parietti V, Briand JP, Muller S. Importance of spliceosomal RNP1 motif for intermolecular T-B cell spreading and tolerance restoration in lupus. Arthritis Res Ther. 2007;9(5):R111. doi:.
  29. Wilhelm M, Wang F, Schall N, Kleinmann J-F, Faludi M, Nashi EP, et al. Lupus regulator peptide P140 represses B-cell antigen differentiation by reducing HLA class II overexpression. Arthritis Rheum. 2018. [Epub ahead of print.] doi:.
  30. Muller S, Monneaux F, Schall N, Rashkov RK, Oparanov BA, Wiesel P, et al. Spliceosomal peptide P140 for immunotherapy of systemic lupus erythematosus: results of an early phase II clinical trial. Arthritis Rheum. 2008;58(12):3873–83. doi:.
  31. Zimmer R, Scherbarth HR, Rillo OL, Gomez-Reino JJ, Muller S. Lupuzor/P140 peptide in patients with systemic lupus erythematosus: a randomised, double-blind, placebo-controlled phase IIb clinical trial. Ann Rheum Dis. 2013;72(11):1830–5. doi:.
  32. Wang F, Muller S. Manipulating autophagic processes in autoimmune diseases: a special focus on modulating chaperone-mediated autophagy, an emerging therapeutic target. Front Immunol. 2015;6:252. doi:.
  33. Aguib Y, Heiseke A, Gilch S, Riemer C, Baier M, Ertmer A, et al. Autophagy induction by trehalose counteracts cellular prion infection. Autophagy. 2009;5(3):361–9. doi:.
  34. Renna M, Jimenez-Sanchez M, Sarkar S, Rubinsztein DC. Chemical inducers of autophagy that enhance the clearance of mutant proteins in neurodegenerative diseases. J Biol Chem. 2010;285(15):11061–7. doi:.
  35. Castillo K, Nassif M, Valenzuela V, Rojas F, Matus S, Mercado G, et al. Trehalose delays the progression of amyotrophic lateral sclerosis by enhancing autophagy in motoneurons. Autophagy. 2013;9(9):1308–20. doi:.
  36. Fernandez-Estevez MA, Casarejos MJ, López Sendon J, Garcia Caldentey J, Ruiz C, Gomez A, et al. Trehalose reverses cell malfunction in fibroblasts from normal and Huntington’s disease patients caused by proteosome inhibition. PLoS One. 2014;9(2):e90202. doi:.
  37. Sumpter MD, Tatro LS, Stoecker WV, Rader RK. Evidence for risk of cardiomyopathy with hydroxychloroquine. Lupus. 2012;21(14):1594–6. doi:.
  38. Tselios K, Gladman DD, Su J, Urowitz MB. Antimalarials as a risk factor for elevated muscle enzymes in systemic lupus erythematosus. Lupus. 2016;25(5):532–5. doi:.
  39. Sarkar S, Rubinsztein DC. Small molecule enhancers of autophagy for neurodegenerative diseases. Mol Biosyst. 2008;4(9):895–901. doi:.
  40. Mizushima N, Yoshimori T, Levine B. Methods in mammalian autophagy research. Cell. 2010;140(3):313–26. doi:.
  41. Fleming A, Noda T, Yoshimori T, Rubinsztein DC. Chemical modulators of autophagy as biological probes and potential therapeutics. Nat Chem Biol. 2011;7(1):9–17. doi:.
  42. Gros F, Muller S. Pharmacological regulators of autophagy and their link with modulators of lupus disease. Br J Pharmacol. 2014;171(19):4337–59. doi:.
  43. Levine B, Packer M, Codogno P. Development of autophagy inducers in clinical medicine. J Clin Invest. 2015;125(1):14–24. doi:.
  44. DeBosch BJ, Heitmeier MR, Mayer AL, Higgins CB, Crowley JR, Kraft TE, et al. Trehalose inhibits solute carrier 2A (SLC2A) proteins to induce autophagy and prevent hepatic steatosis. Sci Signal. 2016;9(416):ra21. doi:.
  45. Mayer AL, Higgins CB, Heitmeier MR, Kraft TE, Qian X, Crowley JR, et al. SLC2A8 (GLUT8) is a mammalian trehalose transporter required for trehalose-induced autophagy. Sci Rep. 2016;6(1):38586. doi:.
  46. Mardones P, Rubinsztein DC, Hetz C. Mystery solved: Trehalose kickstarts autophagy by blocking glucose transport. Sci Signal. 2016;9(416):fs2. doi:.
  47. Yoon YS, Cho ED, Jung Ahn W, Won Lee K, Lee SJ, Lee HJ. Is trehalose an autophagic inducer? Unraveling the roles of non-reducing disaccharides on autophagic flux and alpha-synuclein aggregation. Cell Death Dis. 2017;8(10):e3091. doi:.
  48. Muller S, Brun S, René F, de Sèze J, Loeffler JP, Jeltsch-David H. Autophagy in neuroinflammatory diseases. Autoimmun Rev. 2017;16(8):856–74. doi:.
  49. Li B, Wang F, Schall N, Muller S. Rescue of autophagy and lysosome defects in salivary glands of MRL/lpr mice by a therapeutic phosphopeptide. J Autoimmun. 2018;90:132–45. doi:.
  50. Baek KH, Park J, Shin I. Autophagy-regulating small molecules and their therapeutic applications. Chem Soc Rev. 2012;41(8):3245–63. doi:.