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Amnon Hoffman

Institute of Drug Research
Faculty of Medicine
The Hebrew University, Jerusalem 91120, Israel
Tel: +972-2-6757014 / 7615; Fax: +972-2-6757246
E-mail: amnonh@ekmd.huji.ac.il

Self Nano-Emulsifying Drug Delivery Systems (SNEDDS) for Improved Bioavailability of BCS Class 2 Compounds: Effects on Solubilization, Intra-Enterocyte Metabolism, and P-gp Efflux

Purpose: Numerous BCS Class 2 compounds exhibit low and erratic bioavailability. SNEDDS was previously reported to improve bioavailability of Class 2 compounds. SNEDDS previously developed by our group significantly improved oral bioavailability of Cyclosporine A in humans. Our study aims to elucidate the mechanisms involved in the improved bioavailability achieved by incorporation of these compounds into SNEDDS

Methods: SNEDDS of amiodarone (AM) and tacrolimus (TCR), Class 2 compounds, were developed and optimized. PK was assessed in-vivo. Permeability was evaluated in-vitro (Caco-2) and ex-vivo (Ussing chamber). Solubilization was assessed by in-vitro dynamic lipolysis model. LDH assay was used for cytotoxicity evaluation. The effect on intraenterocyte metabolism was evaluated in CYP3A4 microsomes. P-gp efflux inhibition was determined in-vitro, using talinolol - a P-gp substrate that is not subjected to intraenterocyte metabolism. Transepithelial electrical resistance and mannitol permeability were measured to assess tissue damage.

Results: In-vivo, AM-SNEDDS showed significantly higher AUC vs. AM (9.230.83 vs. 6.283.0 hr*g/ml) with significantly higher Cmax following PO administration. No effect on bioavailability was found when AM was administered 2h subsequent to blank SNEDDS. AM-SNEDDS exhibited more consistent absorption. Similar findings were observed in TCR studies, coupled with prominent reduction in plasma concentrations variation coefficient. Talinolol Caco-2 studies resulted in significantly higher permeability coefficient (Papp) of talinolol-SNEDDS vs. talinolol. AM-SNEDDS ex-vivo Papp was significantly higher than AM. Higher solubilized AM concentrations were found following AM-SNEDDS lipolysis vs. AM (90.51.33% and 59.19.45 % of initial conc. respectively). Significantly higher intact AM concentrations remained following incubation of AM-SNEDDS vs. AM with CYP3A4 (102.45.61% and 68.571.17%respectively). Adding blank SNEDDS to testosterone before incubation also resulted in significantly reduced testosterone metabolism. SNEDDS membrane toxicity was negligible and no damage to tissue integrity or tight junctions structure was observed.

Conclusions: Our SNEDDS not only improves solubilization, but also reduces intra-enterocyte metabolism and P-gp activity. Thus, our SNEDDS increases bioavailability of Class 2 compounds and reduces their typical high variability in bioavailability by multi-processes mechanism. Nonetheless, the effect of our SNEDDS on bioavailability is reversible, and can't be attributed to interruption of the GI wall structure or cell membrane damage. These notable findings contribute to our understanding of the investigated phenomenon of the in-vivo impact of SNEDDS on oral bioavailability. Better mechanistic understanding of these fundamental processes will further lead to finding intelligent pharmaceutical solutions for the enhanced bioavailability and reduced variability of Class 2 drugs and drug candidates

Five most significant publications and number of citations:

  • Klausner, E.A., Lavy, E., Friedman, M. and Hoffman, A. (2003). Expandable gastroretentive dosage forms. J. Control. Release 90(2):143-162. (98 citations)
  • Stepensky D., Friedman M., Srour W., Raz I. and Hoffman A. (2001). Preclinical evaluation of pharmacokinetic-pharmacodynamic rationale for oral CR metformin formulation. J. Contr. Rel. 71:107-115. (58 citations)
  • Gershkovich, P. and Hoffman, A. (2005). Uptake of lipophilic drugs by plasma derived isolated chylomicrons: linear correlation with intestinal lymphatic bioavailability. Eur. J. Pharm. Sci. 26(5):394-404 (38 citations)
  • Dahan, A. and Hoffman, A. (2007). The effect of different lipid based formulations on the oral absorption of lipophilic drugs: The ability of in-vitro lipolysis and consecutive ex-vivo intestinal permeability data to predict in-vivo bioavailability in rats. Eur. J. Pharm. Biopharm.67(1):96-105. (23 citations)
  • Ovadia O, Greenberg S, Chatterjee J, Laufer B, Opperer F, Kessler H, Gilon C, Hoffman A. (2011) The effect of multiple N-methylation on intestinal permeability of cyclic hexapeptides. Mol Pharm. 2011 Apr 4;8(2):479-87

New patents and patents utilization (2009-2011)

  • Hoffman, A., Elgert A.. Domb, A: Pro-nanodispersion liquid formulations for improved bioavailability and advanced biodistribution. Israeli Patent application (2010)
  • Almog O., Eskira Y., Bersudskyb, Y.,Tal-Gane Y., Ovadiad, O., Agam, G., Hoffman, A., Gilon, C., Synthetic peptides Interefering with binding of calbindin-D28k to inositol monophosphatase-1 for the treatment of mood disorders. PCT (2011).
  • Breuer, E, Reich, R, Frant, J. and Hoffman, A.: Novel carbamoylphosphonates inhibitors and uses thereof. (2010) PCT/IL2010000115.
  • Friedman M. Hoffman A. Burshtein G. Oral sustained release formulation of huperzine a. Israeli Patent application (2009), PCT 2011

Cooperation with industries and defense projects (2010-2011):

Development of a protein based oral sustained release delivery system of huperzine A - Nofar 2010 Unipharm

Success stories:

  • Active P (a start-up incubator company) for developing of novel peptide based drugs based on our respective patents
  • Intec Pharma - a drug delivery development company, based on our patent, have completed phase II studies with the novel gastroretetive Accordion Pill

Cooperation with other researchers/universities in Israel:

Within Hebrew University:
Prof. Abraham Domb (nano particles as drug delivery systems)
Prof. Chaim Gilon (development of orally available drug leads based on active peptides)
Prof. Michael Friedman (novel controlled release (CR) drug delivery systems)
Dr. Eran Lavy (development of CR drug delivery systems for veterinary applications)
Dr. Eliad Davidson (improving pharmacotherapy of pain)
Prof. Eli Breuer and Prof. Reuven Reich (Novel antimetastatic phosphonates medications)

With other universities:
Prof. Galila Agam and Dr. Orna Almog BGU (Novel antipsychotic drugs based on active peptide
Prof. Josepf Holoshitz University of Michigan Ann Arbor Development of novel anti artheriosclerosis drug
Prof. Horst Kessler Technische Universitat Munchen (TUM) Munich Germany

Research grants:

ISF 2009-2012 peptide template for enhanced oral bioavailability of drugs

Students, postdocs and researchers:

Ph.D. students(Present): Sarit Greenberg, Anna Elgart, Ira Solodkin, Joseph Fanous, Gregory Burstien, Michael Valitzki.
Graduated: Arik Zur, Oded Ovadia, Avi Swed, Ehud Horwitz, Simon Haroutiunian
M.Sc students: Chava Kleiman

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