Supersaturated self-nanoemulsifying drug delivery systems (Super-SNEDDS) enhance the bioavailability of the poorly water-soluble drug simvastatin in dogs
Open accessAbstract
This study investigates the potential of supersaturated self-nanoemulsifying drug delivery systems (super-SNEDDS) to improve the bioavailability of poorly water-soluble drugs compared to conventional SNEDDS. Conventional SNEDDS contained simvastatin (SIM) at 75% of the equilibrium solubility (S (eq)). Super-SNEDDS containing SIM at 150 and 200% of S (eq) were produced by subjecting the SNEDDS preconcentrates to a heating and cooling cycle. The super-SNEDDS were physically stable over 10 months. During in vitro lipolysis of SNEDDS and super-SNEDDS the SIM concentration in the aqueous phase increased for the first 30 min almost proportional to the drug loads and amounts of preconcentrate employed. The 200% drug-loaded super-SNEDDS generated an amorphous SIM precipitate at the end of in vitro lipolysis. In vivo, the relative bioavailability of SIM from super-SEDDDS increased significantly to 180 ± 53.3% (p = 0.014) compared to the dosing of two capsules of (dose equivalent) 75% drug-loaded SNEDDS. A significant increase in the terminal half-life of elimination was observed for super-SNEDDS (2.3 ± 0.6 h) compared to conventional SNEDDS (1.4 ± 0.3 h) as well as a decreased area under the curve ratio of the SIM metabolite simvastatin acid to the parent compound (0.57 ± 0.20 and 0.90 ± 0.3), possibly due to a combination of saturation effects on presystemic metabolising enzymes and prolonged absorption along the small intestine. In summary, this study demonstrated that super-SNEDDS are a viable formulation option to enhance the bioavailability of poorly water-soluble drugs such as simvastatin while reducing the pill burden by an increased drug load of SNEDDS.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Lipids and Lipid-Based Formulations: Optimizing the Oral Delivery of Lipophilic Drugs
Porter, C. J. H., Trevaskis, N. L., & Charman, W. N. (2007) · Nature Reviews Drug Discovery · doi:10.1038/nrd2197 · Cited by 1,824 · see citing works
Solubilizing Excipients in Oral and Injectable Formulations
Strickley, R. G. (2004) · Pharmaceutical Research · doi:10.1023/b:pham.0000016235.32639.23 · Cited by 1,417 · see citing works
Pouton, C. W., & Porter, C. J. H. (2007) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2007.10.010 · Cited by 887 · see citing works
Nano-emulsions and Micro-emulsions: Clarifications of the Critical Differences
Anton, N., & Vandamme, T. (2010) · Pharmaceutical Research · doi:10.1007/s11095-010-0309-1 · Cited by 624 · see citing works
Hauss, D. J. (2007) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2007.05.006 · Cited by 597 · see citing works
Lipid-based vehicles for the oral delivery of poorly water soluble drugs
Humberstone, A., & Charman, W. N. (1997) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(96)00494-2 · Cited by 578 · see citing works
Shitara, Y., & Sugiyama, Y. (2006) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2006.03.003 · Cited by 574 · see citing works
Drug delivery strategies for poorly water-soluble drugs
Fahr, A., & Liu, X. (2007) · Expert Opinion on Drug Delivery · doi:10.1517/17425247.4.4.403 · Cited by 574 · see citing works
Kang, B. K., Lee, J. S., Chon, S. K., Jeong, S. Y., Yuk, S. H., Khang, G., Lee, H. B., & Cho, S. H. (2004) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2003.12.028 · Cited by 545 · see citing works
Hamelin, B. A. (1998) · Trends in Pharmacological Sciences · doi:10.1016/s0165-6147(97)01147-4 · Cited by 468 · see citing works
Lipid – An emerging platform for oral delivery of drugs with poor bioavailability
Chakraborty, S., Shukla, D., Mishra, B., & Singh, S. K. (2009) · European Journal of Pharmaceutics and Biopharmaceutics · doi:10.1016/j.ejpb.2009.06.001 · Cited by 412 · see citing works
Kovarik, J. M., Mueller, E. A., Kutz, K., van Bree, J. B., & Tetzloff, W. (1994) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.2600830336 · Cited by 295 · see citing works
A dynamic in vitro lipolysis model
Zangenberg, N. H., Müllertz, A., Kristensen, H. G., & Hovgaard, L. (2001) · European Journal of Pharmaceutical Sciences · doi:10.1016/s0928-0987(01)00169-5 · Cited by 287 · see citing works
Self-citationImproved Dose Linearity of Cyclosporine Pharmacokinetics from a Microemulsion Formulation
Mueller, E. A., Kovarik, J. M., van Bree, J. B., Tetzloff, W., Grevel, J., & Kutz, K. (1994) · Pharmaceutical Research · doi:10.1023/a:1018923912135 · Cited by 275 · see citing works
Thomas, N., Holm, R., Müllertz, A., & Rades, T. (2012) · Journal of Controlled Release · doi:10.1016/j.jconrel.2012.02.027 · Cited by 215 · see citing works
Self-citationKaukonen, A. M., Boyd, B. J., Porter, C. J. H., & Charman, W. N. (2004) · Pharmaceutical Research · doi:10.1023/b:pham.0000016282.77887.1f · Cited by 206 · see citing works
Serajuddin, A. T. M., Ranadive, S. A., & Mahoney, E. M. (1991) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.2600800905 · Cited by 203 · see citing works
A dynamic in vitro lipolysis model
Zangenberg, N. H., Müllertz, A., Kristensen, H. G., & Hovgaard, L. (2001) · European Journal of Pharmaceutical Sciences · doi:10.1016/s0928-0987(01)00182-8 · Cited by 194 · see citing works
Self-citationChristensen, J. Ø., Schultz, K., Møllgaard, B., et al. (2004) · European Journal of Pharmaceutical Sciences · doi:10.1016/j.ejps.2004.08.003 · Cited by 187 · see citing works
What determines drug solubility in lipid vehicles: Is it predictable?
Rane, S. S., & Anderson, B. D. (2007) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2007.10.015 · Cited by 176 · see citing works
Mueller, E. A., Kovarik, J. M., van Bree, J. B., Grevel, J., Lücker, P. W., & Kutz, K. (1994) · Pharmaceutical Research · doi:10.1023/a:1018922517162 · Cited by 170 · see citing works
Sassene, P. J., Knopp, M. M., Hesselkilde, J. Z., Koradia, V., Larsen, A. T., Rades, T., & Müllertz, A. (2010) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.22226 · Cited by 149 · see citing works
Self-citationPedersen, T. R., & Tobert, J. A. (2004) · Expert Opinion on Pharmacotherapy · doi:10.1517/14656566.5.12.2583 · Cited by 145 · see citing works
Zhang, Z., Bu, H., Gao, Z., et al. (2010) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2010.04.039 · Cited by 132 · see citing works
Clinical studies with oral lipid based formulations of poorly soluble compounds.
Fatouros, D. G., Karpf, D. M., Nielsen, F. S., & Müllertz, A. (2007) · PubMed Central · Cited by 98 · see citing works
Self-citationThomas, N., Müllertz, A., Graf, A., et al. (2012) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.23054 · Cited by 87 · see citing works
Self-citationTubić-Grozdanis, M., Hilfinger, J. M., Amidon, G. L., Kim, J. S., Kijek, P., Staubach, P., & Langguth, P. (2008) · Pharmaceutical Research · doi:10.1007/s11095-007-9519-6 · Cited by 84 · see citing works
Formulate-ability of ten compounds with different physicochemical profiles in SMEDDS
Thi, T. D., Speybroeck, M. V., Barillaro, V., et al. (2009) · European Journal of Pharmaceutical Sciences · doi:10.1016/j.ejps.2009.09.012 · Cited by 73 · see citing works
Localization of cytochromes p450 in human tissues: implications for chemical toxicity
McKinnon, R. A., & McManus, M. E. (1996) · Pathology · doi:10.1080/00313029600169783 · Cited by 40 · see citing works
Timed‐release formulation to avoid drug–drug interaction between diltiazem and midazolam
Sawada, T., Sako, K., Yoshihara, K., et al. (2003) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.10336 · Cited by 33 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Nanotechnology: A Promising Approach for Delivery of Neuroprotective Drugs
Naqvi, S., Panghal, A., & Flora, S. J. S. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.00494 · Cited by 305 · see citing works
“…system such as polymers, micelles, liposomes, dendrimers, nanocrystals, SLNPs have been used to improve efficacy, safety physiological properties pharmacokinetics, and pharmacodynamics of drugs (Figure 2) (Shegokar and Müller, 2010; Chan and Kwok, 2011; Gao et al., 2012; Thomas et al., 2013).”
MethodThomas, N., Richter, K., Pedersen, T. B., Holm, R., Müllertz, A., & Rades, T. (2014) · The AAPS Journal · doi:10.1208/s12248-014-9589-4 · Cited by 111 · see citing works
Self-citationMichaelsen, M. H., Wasan, K. M., Sivak, O., Müllertz, A., & Rades, T. (2016) · The AAPS Journal · doi:10.1208/s12248-015-9832-7 · Cited by 55 · see citing works
Self-citationSiqueira Jørgensen, S. D., Al Sawaf, M., Graeser, K., Mu, H., Müllertz, A., & Rades, T. (2018) · European Journal of Pharmaceutics and Biopharmaceutics · doi:10.1016/j.ejpb.2017.12.014 · Cited by 51 · see citing works
Self-citationMahmoud, H. (2013) · African Journal of Pharmacy and Pharmacology · doi:10.5897/ajpp2013.2987 · Cited by 43 · see citing works
Siqueira, S. D. V. S., Müllertz, A., Gräeser, K., Kasten, G., Mu, H., & Rades, T. (2017) · The AAPS Journal · doi:10.1208/s12248-016-0038-4 · Cited by 41 · see citing works
Self-citationIlie, A.-R., Griffin, B. T., Brandl, M., Bauer-Brandl, A., Jacobsen, A.-C., Vertzoni, M., Kuentz, M., Kolakovic, R., & Holm, R. (2020) · European Journal of Pharmaceutical Sciences · doi:10.1016/j.ejps.2020.105452 · Cited by 33 · see citing works
“, 2016), simvastatin (Thomas et al., 2013), fenofibrate (Thomas et al.”
Self-citation
- Authors
- Thomas, N., Holm, R., Garmer, M., Karlsson, J. J., Müllertz, A., & Rades, T.
- Affiliations
- University of Otago (NZ)
- Lundbeck (Denmark) (DK)
- University of Copenhagen (DK)
- Corresponding author
- Müllertz, Anette
- Venue
- The AAPS Journal
- Published
- 2012-11-21
- Volume
- 15
- Issue
- 1
- Pages
- 219-227
- ISSN
- 1550-7416 (ISSN-L)
- PMC
- PMC3535117
- OpenAlex
- W2087545318
- Semantic Scholar
- 92c1f8594c1c3d4bd083d4cd2fe8a92191ed420f
- Cited by
- 144
- References
- 30
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 5 · 2023: 8 · 2022: 6 · 2021: 7 · 2020: 23 · 2019: 13 · 2018: 13 · 2017: 6 · 2016: 15 · 2015: 10 · 2014: 13 · 2013: 10
- FWCI
- 6.54
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- The AAPS Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- H. Lundbeck A/S
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Drug Solubulity and Delivery Systems
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advancements in Transdermal Drug Delivery
- Keywords
- self-nanoemulsifying drug delivery system, simvastatin, poorly water-soluble drugs, bioavailability enhancement, in vitro lipolysis, drug solubility, elimination half-life, dogs
- MeSH terms
- Animals, Biological Availability, Dogs, Drug Stability, Emulsions, Solubility, X-Ray Diffraction, Drug Delivery Systems, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Simvastatin, Nanoparticles
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
