Mesoporous silicon for increasing drug bioavailability: from material to tablets

Transkriptio

1 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

2 Biopharmaceutics Classification System (BCS)

3 Silicon material Farmasian tiedekunta / Henkilön nimi / Esityksen nimi

4 Particle manufacture Teflon O-ring I Pore size control Homogenous PSi layer Si wafer Metal Anode Teflon Anodization cell for one side etching

5 Particle manufacture HF-Ethanol Adapted from: Bimbo et al. ACS Nano (2010) 4(6): Farmasian tiedekunta / Henkilön nimi / Esityksen nimi

6 PSi Top-down production (electrochemically) TCPSi (hydrophilic) TOPSi (hydrophilic) THCPSi (hydrophobic) Si x C y SiO 2 Si i C x H Microparticles m Nanoparticles 50 nm 900 nm Pore size 8 80 nm µm

7 Particle manufacture Sieving 10 m Ball Milling 500 nm

8 Particle manufacture 164 nm nanopores µm Courtesy: J. Salonen µm

9 Faster Drug Release

10 N O S N H N H O 2 N Ranitidine Drug release 100 ph ph Release (%) Loaded Ranitidine Release (%) Loaded Ranitidine Time (min) Time (min) ph 5.5 BCS: Class III Release (%) Loaded Ranitidine Sustained release Time (min) Adapted from: Kaukonen et al. Eur. J. Pharm. Biopharm. (2007 ) 66, Farmasian tiedekunta / Henkilön nimi / Esityksen nimi

11 COOH O NH 2 S O Cl N H O Furosemide Drug release Release rate (%) ph Time (min) ph 7.4 Reduced ph dependence Enhanced dissolution BCS: Class IV Adapted from: Kaukonen et al. Eur. J. Pharm. Biopharm. (2007 ) 66,

12 Indomethacin Drug release BCS: Class II Adapted from: Bimbo et al. Biomaterials (2011) 32(34): Farmasian tiedekunta / Henkilön nimi / Esityksen nimi

13 Drug molecules

14 Griseofulvin Drug permeation Enhanced permeation Reduced ph dependency Adapted from: Bimbo et al. Biomaterials (2011) 32(34):

15 Indomethacin Drug permeation Adapted from: Bimbo et al. Biomaterials (2011) 32(34): Farmasian tiedekunta / Henkilön nimi / Esityksen nimi

16 Cell VIability Bioerosion Viability Caco-2 cells 125 Control [ M ] Orthosilicic Acid (H 4 SiO 4 ) Cell viability (%)

17

18 FITC-labelled particles FITC molecule Farmasian tiedekunta / Henkilön nimi / Esityksen nimi

19 Particle permeation studies Permeability results FITC-labelled THCPSi nanoparticles % Permeated FITC-THCPSi nanoparticles g/ml 50 g/ml 500 g/ml Time (h) Adapted from: Bimbo et al. ACS Nano (2010) 4(6): Farmasian tiedekunta / Henkilön nimi / Esityksen nimi

20 In vivo studies 18 F-labelled particles Oral route Plain 18 F-labelled THCPSi particles

21 In vivo studies (Oral studies) Plain 18 F-labelled particles Adapted from: Bimbo et al. ACS Nano (2010) 4(6): Farmasian tiedekunta / Henkilön nimi / Esityksen nimi

22 In vivo studies (Oral studies) Plain 18 F-labelled particles Adapted from: Bimbo et al. ACS Nano (2010) 4(6): Farmasian tiedekunta / Henkilön nimi / Esityksen nimi

23 Tablet Preformulation Adapted from: Tahvanainen et al. Int. J. Pharm (2012) 422: Farmasian tiedekunta / Henkilön nimi / Esityksen nimi

24 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: Farmasian tiedekunta / Henkilön nimi / Esityksen nimi

25 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: Farmasian tiedekunta / Henkilön nimi / Esityksen nimi

26 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: Farmasian tiedekunta / Henkilön nimi / Esityksen nimi

27 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

28 HFBII-Particles Particle characterization Plain THCPSi particles THCPSi-HFBII Adapted from: Bimbo et al. Biomaterials (2011) 32(34): Farmasian tiedekunta / Henkilön nimi / Esityksen nimi

29 HFBII-Nanoparticles Cellular association A HT-29 cellular association B C D Bimbo et al. Unpublished results

30 HFBII-Nanoparticles Cellular association A Hydrophilic domain Hydrophobic domain Drug molecule

31 HFBII-Nanoparticles Indomethacin Drug release Adapted from: Bimbo et al. Unpublished results Farmasian tiedekunta / Henkilön nimi / Esityksen nimi

32 HFBII-Nanoparticles Gastric retentions Sarparanta et al Biomaterials 33 (2012) 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

33 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

34 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 # , ], Academy of Finland [projects # , ], 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

35 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

36 Farmasian tiedekunta / Henkilön nimi / Esityksen nimi