Skip to main content

Advertisement

SpringerLink
Log in

CriticalSorb™ Promotes Permeation of Flux Markers Across Isolated Rat Intestinal Mucosae and Caco-2 Monolayers

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

Abstract

Purpose

CriticalSorb™ is a novel absorption enhancer based on Solutol® HS15, one that has been found to enhance the nasal transport. It is in clinical trials for nasal delivery of human growth hormone. The hypothesis was that permeating enhancement effects of the Solutol®HS15 component would translate to the intestine.

Methods

Rat colonic mucosae were mounted in Ussing chambers and Papp values of [14C]-mannitol, [14C]-antipyrine, FITC-dextran 4000 (FD-4), and TEER values were calculated in the presence of CriticalSorb™. Tissues were fixed for H & E staining. Caco-2 monolayers were grown on Transwells™ for similar experiments.

Results

CriticalSorb™(0.01% v/v) significantly increased the Papp of [14C]-mannitol, FD-4 [14C]-antipyrine across ileal and colonic mucosae, accompanied by a decrease in TEER. In Caco-2 monolayers, it also increased the Papp of [14C]-mannitol FD-4 and [14C]-antipyrine over 120 min. In both monolayers and tissues, it acted as a moderately effective P-glycoprotein inhibitor. There was no evidence of cytotoxicity in Caco-2 at concentrations of 0.01% for up to 24 h and histology of tissues showed intact epithelia at 120 min.

Conclusions

Solutol® HS15 is the key component in CriticalSorb™ that enables non-cytotoxic in vitro intestinal permeation and its mechanism of action is a combination of increased paracellular and transcellular flux.

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
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Costantino HR, Illum L, Brandt G, Johnson PH, Quay SC. Intranasal delivery: physicochemical and therapeutic aspects. Int J Pharm. 2007;337(1–2):1–24.

    Article  PubMed  CAS  Google Scholar 

  2. Illum L. Nasal drug delivery-possibilities, problems and solutions. J Control Release. 2003;87(1–3):187–98.

    Article  PubMed  CAS  Google Scholar 

  3. Ozsoy Y, Gungor S, Cevher E. Nasal delivery of high molecular weight drugs. Molecules. 2009;14(9):3754–79.

    Article  PubMed  CAS  Google Scholar 

  4. Davis SS, Illum L. Absorption enhancers for nasal drug delivery. Clin Pharmacokinet. 2003;42(13):1107–28.

    Article  PubMed  CAS  Google Scholar 

  5. Duan X, Mao S. New strategies to improve the intranasal absorption of insulin. Drug Discov Today. 2010;15(11–12):416–27.

    Article  PubMed  CAS  Google Scholar 

  6. Leary AC, Stote RM, Cussen K, O'Brien J, Leary WP, Buckley B. Pharmacokinetics and pharmacodynamics of intranasal insulin administered to patients with Type 1 diabetes: a preliminary study. Diabetes Technol Ther. 2006;8(1):81–8.

    Article  PubMed  CAS  Google Scholar 

  7. Maggio ET. Intravail™: highly effective intranasal delivery of peptide and protein drugs. Expert Opin Drug Deliv. 2006;3(4):529–39.

    Article  PubMed  CAS  Google Scholar 

  8. Illum L. Nasal drug delivery-recent developments and future prospects. J. Control. Release 2012 Jan 24. [Epub ahead of print]. PMID:22300620

  9. Arnold JJ, Fyrberg MD, Meezan E, Pillion DJ. Reestablishment of the nasal permeability barrier to several peptides following exposure to the absorption enhancer tetradecyl-beta-D-maltoside. J Pharm Sci. 2010;99(4):1912–20.

    PubMed  CAS  Google Scholar 

  10. Nepal PR, Han HK, Choi HK. Preparation and in vitro-in vivo evaluation of Witepsol H35 based self-nanoemulsifying drug delivery systems (SNEDDS) of coenzyme Q(10). Eur J Pharm. 2010;39(4):224–32.

    Article  CAS  Google Scholar 

  11. Alani AW, Rao DA, Seidel R, Wang J, Jiao J, Kwon GS. The effect of novel surfactants and Solutol HS 15 on paclitaxel aqueous solubility and permeability across a Caco-2 monolayer. J Pharm Sci. 2010;99(8):3473–85.

    Article  PubMed  CAS  Google Scholar 

  12. Coon JS, Knudson W, Clodfelter K, Lu B, Weinstein RS. Solutol HS 15, nontoxic polyoxyethylene esters of 12-hydroxystearic acid, reverses multidrug resistance. Cancer Res. 1991;51(3):897–902.

    PubMed  CAS  Google Scholar 

  13. Thayse G. Applications of Solutol(R) HS 15 (1999). http://worldaccount.basf.com/wa/NAFTA/Catalog/Pharma/info/BASF/exact/solutol_hs_15 . Accessed on December 21st, 2011.

  14. Christopher C, DeMerlis, Goldring JM, Velagaleti R, Brock W, Osterberg R. Regulatory update: the IPEC novel excipient safety evaluation procedure. Pharm Tech. 2009;33(11):72–82.

    Google Scholar 

  15. http://www.criticalpharmaceuticals.com/news.php. Accessed January 10th, 2012.

  16. Lewis AL, Jordan FM, Illum L. Evaluation of a novel absorption promoter for nasal delivery. Trans. 37th Int. Soc. Controlled Release Society Meeting. Abstract 93.

  17. Maher S, Brayden DJ. Overcoming poor permeability: translating permeation enhancers for oral peptide delivery. Drug Discovery Today Technologies. 2012: doi: 10.1016/j.ddtec.2011.11.006.

  18. Mudra DR, Borchardt RT. Absorption barriers in the rat intestinal mucosa. 3: effects of polyethoxylated solubilizing agents on drug permeation and metabolism. J Pharm Sci. 2010;99(2):1016–27.

    PubMed  CAS  Google Scholar 

  19. Buckingham LE, Balasubramanian M, Emanuele RM, Clodfelter KE, Coon JS. Comparison of Solutol HS 15,Cremophor EL and novel ethoxylated fatty acid surfactants as multidrug resistance modification agents. Int J Cancer. 1995;62(4):436–42.

    Article  PubMed  CAS  Google Scholar 

  20. Maher S, Kennelly R, Bzik V, Baird AW, Wang X, Winter D, et al. Evaluation of intestinal absorption enhancement and local mucosal toxicity of two promoters. I. Studies in isolated rat and human colonic mucosae. European J Pharm Sci. 2009;38(4):291–300.

    Article  CAS  Google Scholar 

  21. Hubatsch I, Ragnarsson EG, Artursson P. Determination of drug permeability and prediction of drug absorption in Caco-2 monolayers. Nat Protoc. 2007;2:2111–9.

    Article  PubMed  CAS  Google Scholar 

  22. Lennernas H, Palm K, Fagerholm U, Artursson P. Comparison between active and passive drug transport in human intestinal epithelial (Caco-2) cells in vitro and human jejunum in vivo. Int J Pharm. 1996;1(15):103–7.

    Article  Google Scholar 

  23. Troutman MD, Thakker DR. Rhodamine 123 requires carrier-mediated influx for its activity as a P-glycoprotein substrate in Caco-2 cells. Pharm Res. 2003;20:1200–9.

    Article  PubMed  CAS  Google Scholar 

  24. Cornwell MM, Pastan I, Gottesman MM. Certain calcium channel blockers bind specifically to multidrug-resistant human KB carcinoma membrane vesicles and inhibit drug binding to P-glycoprotein. J Biol Chem. 1987;262:2166–70.

    PubMed  CAS  Google Scholar 

  25. Decker T, Lohmann-Matthes ML. A quick and simple method for the quantitation of lactate dehydrogenase release in measurements of cellular cytotoxicity and tumor necrosis factor (TNF) activity. J Immunol Methods. 1988;115(1):61–9.

    Article  PubMed  CAS  Google Scholar 

  26. Berridge MV, Tan AS. Characterization of the cellular reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT): subcellular localization, substrate dependence, and involvement of mitochondrial electron transport in MTT reduction. Arch Biochem Biophys. 1993;303(2):474–82.

    Article  PubMed  CAS  Google Scholar 

  27. Uchiyama T, Sugiyama T, Quan YS, Kotani A, Okada N, Fujita T, et al. Enhanced permeability of insulin across the rat intestinal membrane by various absorption enhancers: their intestinal mucosal toxicity and absorption-enhancing mechanism of n-lauryl-beta-D-maltopyranoside. J Pharm Pharmacol. 1999;51:1241–50.

    Article  PubMed  CAS  Google Scholar 

  28. Lindmark T, Schipper N, Lazarova L, De Boer AG, Artursson P. Absorption enhancement in intestinal epithelial Caco-2 monolayers by sodium caprate: assessment of molecular weight dependence and demonstration of transport routes. J Drug Targeting. 1998;5(3):215–23.

    Article  CAS  Google Scholar 

  29. Maher S, Feighery L, Brayden DJ, McClean S. Melittin as an epithelial permeability enhancer I: investigation of its mechanism of action in Caco-2 monolayers. Pharm Res. 2007;24(7):1336–45.

    Article  PubMed  CAS  Google Scholar 

  30. Nakamura K, Takayama K, Nagai T, Maitani Y. Regional intestinal absorption of FITC-dextran 4,400 with nanoparticles based on beta-sitosterol beta-D-glucoside in rats. J Pharm Sci. 2003;92(2):311–8.

    Article  PubMed  CAS  Google Scholar 

  31. Tsutsumi K, Li SK, Ghanem AH, Ho NF, Higuchi WI. A systematic examination of the in vitro Ussing chamber and the in situ single-pass perfusion model systems in rat ileum permeation of model solutes. J Pharm Sci. 2003;92(2):344–59.

    Article  PubMed  CAS  Google Scholar 

  32. Yamashita S, Furubayashi T, Kataoka M, Sakani T, Sezaki H, Tokuda H. Optimized conditions for prediction of intestinal drug permeability using Caco-2 cells. European J Pharm Sci. 2000;10(3):195–204.

    Article  CAS  Google Scholar 

  33. Ungell AL, Nylander S, Bergdtrand S, Sjoberg A, Lennernas H. Membrane transport of drugs in different regions of the intestinal tract of the rat. J Pharm Sci. 1998;87(3):360–6.

    Article  PubMed  CAS  Google Scholar 

  34. Griffin J, Fletcher N, Blanchflower S, Clemence R, Brayden DJ. Selamectin is a potent substrate and inhibitor of human and canine P-glycoprotein. J Vet Pharm Ther. 2005;28:257–65.

    Article  CAS  Google Scholar 

  35. Ku S, Valagaleti R. Solutol®HS-15 as a novel excipient. Pharmaceutical Technology: 2010: 108–110. http://pharmtech.findpharma.com/pharmtech/Ingredients/Solutol-HS15-as-a-Novel-Excipient/ArticleStandard/Article/detail/694692. Accessed March, 12th, 2012.

  36. Li M, Si L, Pan H, Rabba AK, Yan F, Qiu J, et al. Excipients enhance intestinal absorption of ganciclovir by P-gp inhibition: assessed in vitro by everted gut sac and in situ by improved intestinal perfusion. Int J Pharm. 2011;403(1–2):37–45.

    Article  PubMed  CAS  Google Scholar 

  37. Nepal PR, Han HK, Choi HK. Preparation and in vitro-in vivo evaluation of Witepsol® H35 based self-nanoemulsifying drug delivery systems (SNEDDS) of coenzyme Q(10). Eur J Pharm Sci. 2010;39(4):224–32.

    Article  PubMed  CAS  Google Scholar 

  38. Guo F, Zhong H, He J, Xie B, Liu F, Xu H, et al. Self-microemulsifying drug delivery system for improved oral bioavailability of dipyridamole: preparation and evaluation. Arch Pharm Res. 2011;34(7):1113–23.

    Article  PubMed  CAS  Google Scholar 

  39. Bravo González RC, Huwyler J, Walter I, Mountfield R, Bittner B. Improved oral bioavailability of cyclosporin A in male Wistar rats. Comparison of a Solutol® HS 15 containing self-dispersing formulation and a microsuspension. Int J Pharm. 2002;245(1-2):143–51.

    Article  PubMed  Google Scholar 

  40. Guo L, Ma E, Zhao H, Long Y, Zheng C, Duan M. Preliminary evaluation of a novel oral delivery system for rhPTH1-34: in vitro and in vivo. Int J Pharm. 2011;420(1):172–9.

    Article  PubMed  CAS  Google Scholar 

  41. Petersen SB, Nolan G, Maher S, Rahbek UL, Guldbrandt M, Brayden DJ. Tetradecylmaltoside is a permeability enhancer: isolated rat colonic mucosae in Ussing chambers. Proc Intern Symp Control Rel Bioact Mater. 38: 2011: Abstract 759.

  42. Buckingham LE, Balasubramanian M, Safa AR, Shah H, Komarov P, Emanuele RM, et al. Reversal of multi-drug resistance in vitro by fatty acid-PEG-fatty acid diesters. Int J Cancer. 1996;65(1):74–9.

    Article  PubMed  CAS  Google Scholar 

  43. Troutman MD, Thakker DR. Rhodamine 123 requires carrier-mediated influx for its activity as a P-glycoprotein substrate in Caco-2 cells. Troutman MD, Thakker DR. Pharm Res. 2003;20(8):1192–9.

    Article  PubMed  CAS  Google Scholar 

  44. Pereira de Oliveira M, Garcion E, Venisse N, Benoit JP, Couet W, Olivier JC. Tissue distribution of indinavir administered as solid lipid nanocapsule formulation in mdr1a (+/+) and mdr1a (-/-) CF-1 mice. Pharm Res. 2005;(11):1898–1905.

Download references

Acknowledgments and Disclosures

This study was co-funded by Science Foundation Ireland grant 07/SRC B1144 and by a grant from Critical Pharmaceuticals (UK), from which ALL and LI are employees. VAB was recipient of a UCD Ad Astra Scholarship. An abstract of part of this study was presented at the AAPS Annual Meeting, New Orleans, USA (2010).

Author information

Authors and Affiliations

  1. School of Veterinary Medicine and Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland

    D. J. Brayden

  2. School of Veterinary Medicine and Conway Institute, University College Dublin, Belfield, Dublin 4, Dublin, Ireland

    V. A. Bzik

  3. Critical Pharmaceuticals Limited, BioCity Nottingham, Pennyfoot Street, Nottingham, NG1 IGF, UK

    A. L. Lewis & L. Illum

Authors
  1. D. J. Brayden
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. V. A. Bzik
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. L. Lewis
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L. Illum
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D. J. Brayden.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Brayden, D.J., Bzik, V.A., Lewis, A.L. et al. CriticalSorb™ Promotes Permeation of Flux Markers Across Isolated Rat Intestinal Mucosae and Caco-2 Monolayers. Pharm Res 29, 2543–2554 (2012). https://doi.org/10.1007/s11095-012-0785-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-012-0785-6

Key Words

Search

Navigation