23rd Annual Symposium of the Finnish Society of Physical Pharmacy 9 th February 2012 Mesoporous silicon for increasing drug bioavailability: from material to tablets Luis Maria Bimbo Division of Pharmaceutical Technology University of Helsinki, FINLAND www.helsinki.fi/yliopisto 10.2.2012 1
Biopharmaceutics Classification System (BCS) 2 www.helsinki.fi/yliopisto 10.2.2012
Silicon material Farmasian tiedekunta / Henkilön nimi / Esityksen nimi www.helsinki.fi/yliopisto 10.2.2012 3
Particle manufacture Teflon O-ring I Pore size control Homogenous PSi layer Si wafer Metal Anode Teflon Anodization cell for one side etching 10.2.20124
Particle manufacture HF-Ethanol Adapted from: Bimbo et al. ACS Nano (2010) 4(6):3023-32 Farmasian tiedekunta / Henkilön nimi / Esityksen nimi www.helsinki.fi/yliopisto 10.2.2012 5
PSi Top-down production (electrochemically) TCPSi (hydrophilic) TOPSi (hydrophilic) THCPSi (hydrophobic) Si x C y SiO 2 Si i C x H Microparticles 1.2 75 m Nanoparticles 50 nm 900 nm Pore size 8 80 nm 53 75 µm 10.2.2012 6
Particle manufacture Sieving 10 m Ball Milling 500 nm www.helsinki.fi/yliopisto
Particle manufacture 164 nm nanopores 53 75 µm Courtesy: J. Salonen 10.2.20128 www.helsinki.fi/yliopisto 53 75 µm
Faster Drug Release www.helsinki.fi/yliopisto
N O S N H N H O 2 N Ranitidine Drug release 100 ph 7.4 120 100 ph 6.8 80 80 Release (%) 60 40 20 Loaded Ranitidine Release (%) 60 40 20 Loaded Ranitidine 0 0 20 40 60 80 100 Time (min) 0 0 20 40 60 80 100 Time (min) 120 100 ph 5.5 BCS: Class III Release (%) 80 60 40 20 Loaded Ranitidine Sustained release 0 0 20 40 60 80 100 Time (min) Adapted from: Kaukonen et al. Eur. J. Pharm. Biopharm. (2007 ) 66, 348-356. Farmasian tiedekunta / Henkilön nimi / Esityksen nimi www.helsinki.fi/yliopisto 10.2.2012 10
COOH O NH 2 S O Cl N H O Furosemide Drug release Release rate (%) 100 80 60 40 20 0 0 50 100 150 200 250 300 350 400 100 80 60 40 20 ph 5.5 0 0 50 100 150 200 250 300 350 400 Time (min) ph 7.4 Reduced ph dependence Enhanced dissolution BCS: Class IV Adapted from: Kaukonen et al. Eur. J. Pharm. Biopharm. (2007 ) 66, 348-356. 11 www.helsinki.fi/yliopisto 10.2.2012
Indomethacin Drug release BCS: Class II Adapted from: Bimbo et al. Biomaterials (2011) 32(34):9089-99 Farmasian tiedekunta / Henkilön nimi / Esityksen nimi www.helsinki.fi/yliopisto 10.2.2012 12
Drug molecules
Griseofulvin Drug permeation Enhanced permeation Reduced ph dependency Adapted from: Bimbo et al. Biomaterials (2011) 32(34):9089-99 www.helsinki.fi/yliopisto 10.2.201214
Indomethacin Drug permeation Adapted from: Bimbo et al. Biomaterials (2011) 32(34):9089-99 Farmasian tiedekunta / Henkilön nimi / Esityksen nimi www.helsinki.fi/yliopisto 10.2.2012 15
Cell VIability Bioerosion Viability Caco-2 cells 125 Control 100 75 50 25 [ M ] Orthosilicic Acid (H 4 SiO 4 ) Cell viability (%) 100 75 50 25 0 www.helsinki.fi/yliopisto
www.helsinki.fi/yliopisto
FITC-labelled particles FITC molecule Farmasian tiedekunta / Henkilön nimi / Esityksen nimi www.helsinki.fi/yliopisto 10.2.2012 18
Particle permeation studies Permeability results FITC-labelled THCPSi nanoparticles % Permeated FITC-THCPSi nanoparticles 5 4 3 2 1 0 15 g/ml 50 g/ml 500 g/ml 0 1 2 3 4 5 6 Time (h) Adapted from: Bimbo et al. ACS Nano (2010) 4(6):3023-32 Farmasian tiedekunta / Henkilön nimi / Esityksen nimi www.helsinki.fi/yliopisto 10.2.2012 19
In vivo studies 18 F-labelled particles Oral route Plain 18 F-labelled THCPSi particles www.helsinki.fi/yliopisto 10.2.2012 20
In vivo studies (Oral studies) Plain 18 F-labelled particles Adapted from: Bimbo et al. ACS Nano (2010) 4(6):3023-32 Farmasian tiedekunta / Henkilön nimi / Esityksen nimi www.helsinki.fi/yliopisto 10.2.2012 21
In vivo studies (Oral studies) Plain 18 F-labelled particles Adapted from: Bimbo et al. ACS Nano (2010) 4(6):3023-32 Farmasian tiedekunta / Henkilön nimi / Esityksen nimi www.helsinki.fi/yliopisto 10.2.2012 22
Tablet Preformulation Adapted from: Tahvanainen et al. Int. J. Pharm (2012) 422: 125-131 Farmasian tiedekunta / Henkilön nimi / Esityksen nimi www.helsinki.fi/yliopisto 10.2.2012 23
Tablet Preformulation X-ray tomography image of a tablet containing IMC-loaded TOPSi microparticles. Scale bar 1 mm, voxel size 2.5 m. Adapted from: Tahvanainen et al. Int. J. Pharm (2012) 422: 125-131 Farmasian tiedekunta / Henkilön nimi / Esityksen nimi www.helsinki.fi/yliopisto 10.2.2012 24
Tablet preformulation Indomethacin Drug release Uncompressed IMCloaded TOPSi microparticles and tablets containing TOPSi-IMC microparticles or bulk IMC at ph 5.5. Adapted from: Tahvanainen et al. Int. J. Pharm (2012) 422: 125-131 Farmasian tiedekunta / Henkilön nimi / Esityksen nimi www.helsinki.fi/yliopisto 10.2.2012 25
Tablet preformulation Indomethacin Drug release Uncompressed IMCloaded TOPSi microparticles, tablets containing TOPSi-IMC microparticles or IMC across differentiated Caco-2 cell monolayers at 37 C and ph of 5.5 Adapted from: Tahvanainen et al. Int. J. Pharm (2012) 422: 125-131 Farmasian tiedekunta / Henkilön nimi / Esityksen nimi www.helsinki.fi/yliopisto 10.2.2012 26
HFBII-Particles Particle characterization Hydrophobin class II (HFBII) fungal protein Self-assemble at water-air interfaces Can change surface properties hydrophobic > hydrophilic Can be used as anti-fouling agent www.helsinki.fi/yliopisto
HFBII-Particles Particle characterization Plain THCPSi particles THCPSi-HFBII Adapted from: Bimbo et al. Biomaterials (2011) 32(34):9089-99 Farmasian tiedekunta / Henkilön nimi / Esityksen nimi www.helsinki.fi/yliopisto 10.2.2012 28
HFBII-Nanoparticles Cellular association A HT-29 cellular association B C D Bimbo et al. Unpublished results www.helsinki.fi/yliopisto
HFBII-Nanoparticles Cellular association A Hydrophilic domain Hydrophobic domain Drug molecule www.helsinki.fi/yliopisto
HFBII-Nanoparticles Indomethacin Drug release Adapted from: Bimbo et al. Unpublished results Farmasian tiedekunta / Henkilön nimi / Esityksen nimi www.helsinki.fi/yliopisto 10.2.2012 31
HFBII-Nanoparticles Gastric retentions Sarparanta et al Biomaterials 33 (2012) 3353 3362 The results are expressed as units of photostimulable luminescence (PSL) per mm 2 normalized to the administered dose of 18 F-radiolabeled particles in MBq. www.helsinki.fi/yliopisto 10.2.201232
Advantages of mesoporous silicon as a drug carrier Abundant material Top-down manufacture Tunable and homogeneous pore structure, which affects drug release High loading capacity Confined pore structure that enables fast dissolution profiles from drugs Possibility to protect drugs against the acidic environment of the stomach Easy surface modification Possibility to formulate tablets with high dissolution and permeation rates Farmasian tiedekunta / Henkilön nimi / Esityksen nimi www.helsinki.fi/yliopisto 10.2.2012 33
Acknowledgements GROUP MEMBERS UH COLLABORATORS Personal funding sources: T. Heikkilä, M.Sc. COLLABORATORS Cont. H.A. Santos, Doc. L. M. Bimbo, Ph.D. T. Limnell, Ph.D. P. Kinnari, M.Sc. D. Liu, M.Sc. M. Tahvanainen, M.Sc. K. Strommer, M.Sc. T. Rotko, M.Sc. D. Neves, M.Sc. J. Hirvonen, Prof. L. Peltonen, Doc. T. Laaksonen, Doc. Radiochemistry Lab. UH A. Airaksinen, Doc. M. Sarparanta, M.Sc. M. Nyman E. Kukk, Ph.D. Dep. Physical Sciences UH A. Kallonen K. Hämäläinen M. Peura R. Serimaa, Prof. Industrial Physics UTU E. Mäkilä, MSc. J. Salonen, Doc. T. Heikkilä, M.Sc. University of Helsinki Research Funds [projects # 490039, 127099], 2009 2011 Academy of Finland [projects # 252215, 256394], 2009 2016 Dept. of Physics UEF V.-P. Lehto, Prof. J. Riikonen, M.Sc. Nanobiomaterials VTT M. Linder, Prof. P. Laaksonen, D.Sc. Dep. Applied Physics AU E. I. Kauppinen, Prof. J. Raula, D.Sc. Dep. Biosciences UEF J. Rytkönen, M.Sc. Farmasian tiedekunta / Henkilön nimi / Esityksen nimi www.helsinki.fi/yliopisto 10.2.2012 34
Acknowledgments Institute of Biotechnology, University of Helsinki Department of Biological and Environmental Sciences, Faculty of Biosciences, University of Helsinki Division of Pharmaceutical Technology, Faculty of Pharmacy, University of Helsinki Funding from the University of Helsinki Research Funds and Academy of Finland projects is acknowledged Farmasian tiedekunta / Henkilön nimi / Esityksen nimi www.helsinki.fi/yliopisto 10.2.2012 35
Farmasian tiedekunta / Henkilön nimi / Esityksen nimi www.helsinki.fi/yliopisto 10.2.2012 36