Nanosuspension – An unique tool for improving the bioavailability of poorly soluble drugs Enhanc...
Outline  Therapeutical application and benefits of Nanoparticle dosage form  Nanosuspension – At preclinical phase...
Benefits of nanoparticle dosage form  Main application to BCS Class 2 ...
Techniques for producing nanoparticles  Nanosuspensions - Submicron colloidal dispersion systems.  Bottom-up ...
Wet media milling  Wet Media milling - comprises mechanical attrition of drug particles using milling media such as...
Theoretical considerations  According to Noyes and Whitney, the dissolution velocity is further enhanced because ...
Nanosuspension – Preclinical Phase  During preclinical pharmaceutical development, the API is in tight supply.  Al...
Nanosuspension – Clinical phase  Instrument: Stirred media mill  ...
Nanosuspension – Formulation design and characterization Formulation effect Drug substance prope...
Application of Vitamin E TPGS to produce nanosuspension – Case study 1  DS properties of compound A  Log P...
Particle size reduction of nanosuspension Particle size of drug substance after 3-4 hours of nanomilling for different...
Characterization of crystal properties XRD ...
Invitro / Invivo drug release from nanosuspension. 1400 ...
Invitro / Invivo drug release from nanosuspension. European Journal of Pharmaceutics and International Journal ...
Nanomilling - Stability Stability –  During the milling process due to the change of Gibbs free energy th...
Crystal growth in nanosuspension – Case study 2 Compound - A Initial ...
HPMC – Successfully inhibit crystal growth Because of the absorption of HPMC polymer on the surface of the nuclei the ...
Effect of SLS nanocrystal formulation Particle size distribution profile for nanomil...
Importance of surface hydrophobicity of drug on dissolution for dried Nanosuspension. For nano-suspension product...
Optimization of process parameters during nanomilling of Naproxen – Case study 3 ...
Combined effect of process parameters & stabilizerFragmentation of materials ...
Milling time depends upon Drug Morphology Particle size after 4 hrs milling: Naproxen vs. ...
Scale-up from planetary mill to stirred media mill using central composite statistical design ...
General Risk Considerations to Human Health NPs cause unique biological effects (including those potentially toxic t...
Conclusion  The wet milling media milling technique is considered to be an attractive technique in pharmaceutic...
Acknowledgements Sonali Bose, Yogita Krishnamachari, Subash Patel, Glen Biank, Al. Hollywood. Radha Vippagunta, Fr...
Questions Milling bead Impact Attrition API Milling bea...
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Nanosuspension – An unique tool for improving the bioavailability of poorly soluble drugs

Nanosuspension – An unique tool for improving the bioavailability of poorly soluble drugs - Indrajit Ghost, Novartis
Published on: Mar 3, 2016
Source: www.slideshare.net


Transcripts - Nanosuspension – An unique tool for improving the bioavailability of poorly soluble drugs

  • 1. Nanosuspension – An unique tool for improving the bioavailability of poorly soluble drugs Enhancing Drug Bioavailability & Solubility Boston, MA Indrajit Ghosh Principal Scientist Novartis Pharmaceuticals, NJ.1 January 2012
  • 2. Outline  Therapeutical application and benefits of Nanoparticle dosage form  Nanosuspension – At preclinical phase & Clinical phase  Nanosuspension – Formulation design and characterization - Case study 1  Stability approaches– Case study 2 Optimization of process parameters - Case study 3  Scale-up considerations  General risk considerations to human health2
  • 3. Benefits of nanoparticle dosage form  Main application to BCS Class 2 molecules.  Nanoparticulate dosage form has wide area of applications – oral, parenteral, transdermal, inhalation etc, by –  Improving the bioavailability  Decreasing the food effect  Decreasing intra subject variability  Reducing the dose  Increasing adhesiveness with intestinal membrane.  Reducing gastric irritation Rainer H. Müller et. al, EJPB3
  • 4. Techniques for producing nanoparticles  Nanosuspensions - Submicron colloidal dispersion systems.  Bottom-up approach (Dow Pharma ; BASF)  Top down approach (Elan’s NanoCrystal ; Sky-ePharma’s Dissocubes technology)  Wet Milling  High Pressure Homogenization Rainer H. Müller et. al, EJPB4
  • 5. Wet media milling  Wet Media milling - comprises mechanical attrition of drug particles using milling media such as yttrium stabilized zirconium oxide beads of definite size range (e.g. 0.1-0.5 mm ceramic beads)  Benefits –  Drug crystallinity remain intact during processing.  No organic solvent.  Unimodal size distribution.  Simple and cost effective5
  • 6. Theoretical considerations  According to Noyes and Whitney, the dissolution velocity is further enhanced because dc/dt is proportional to the dC / dt = DA(Cs-C) / h concentration gradient (cs-cx)/h.  According to Kelvin’s equation, there is an additional effect of increase in the saturation solubility (Cs) by shifting the dX / dt = DA(Cs-X/V) / h particle size from micron to submicron range. International Journal of Nanomedicine 2008:3(3) 295–309 66
  • 7. Nanosuspension – Preclinical Phase  During preclinical pharmaceutical development, the API is in tight supply.  Also pre-clinical development is typically characterized by short development time lines  Accelerated feasibility assessment of drugs from research.7
  • 8. Nanosuspension – Clinical phase  Instrument: Stirred media mill  Grinding media: Zirconium beads, 0.1 - 0.5 mm  Agitator speed: 1500 - 2500 rpm  Pump speed: 250 rpm  Recirculation: reduces milling time and decreases particle size Fshear Fpressure, impact8
  • 9. Nanosuspension – Formulation design and characterization Formulation effect Drug substance properties Bulk suspension properties  Effect of Solubilizer: Vitamin E  Size and size distribution:  Rheology  Particle charge(zeta  Sedementation rate TPGS, SLS, Pluronic F68, F127, potential): DOSS  Morphology by SEM, TEM, AFM  Effect of stabilizers / suspending  Crystalline status: By X- agents: PVP K-30, HPMC 3cps, HPC ray, DSC EXF  Surface coverage and morphology: SEM,TEM,AFM  Assay, Deg.9  Dissolution.
  • 10. Application of Vitamin E TPGS to produce nanosuspension – Case study 1  DS properties of compound A  Log P (in silico): 3.021, Log D (pH 6.8): 1.27  Solubility at 0.003 mg/ml (in water) (BCS class II)  Challenges  Morphology – Rod shaped, difficult to mill in compared to spherical shape, which has more SA available for milling.  Wettability – Very poor10
  • 11. Particle size reduction of nanosuspension Particle size of drug substance after 3-4 hours of nanomilling for different formulations. Particle size distribution profile for nanomilled Compound with different variants 450 400 Particle size (nm) 350 300 250 200 150 100 50 0 Start 30 min 5% Drug 5% Drug 5% Drug 5% Drug 5% Drug 5% Drug with 5% with 3% with 3% with 5% with 3% with 3% Vitamin Vitamin Vitamin Vitamin Vitamin Vitamin ETPGS ETPGS & ETPGS & ETPGS & ETPGS & ETPGS & 2% 2% 1% SLS 1% HPMC 1% PVP Pluronic Pluronic F68 F127 Composition of Nanosuspension The most effective nano range particle size was observed with 5% Vitamin ETPGS and 1 hr 3 hr also with 5% Vitamin ETPGS and 1% The “cleavage” and “fracture” mechanism HPMC 3 cps responsible for particle size reduction.11
  • 12. Characterization of crystal properties XRD 600 500 400 Lin (Counts) 300 Nanosuspension Drug Substance +Mannitol Freeze dried 200 Drug Substance 100 Pure drug 0 2 10 20 30 40 2-Theta - Scale12
  • 13. Invitro / Invivo drug release from nanosuspension. 1400 1200 Intralipid coarse suspension with 1000 salt 800 Nanosuspension with free base 600 400 200 0 0 10 20 30 40 50 60 The AUC of nanosuspension was increased by about 9 fold and the Cmax was increased by about 5 fold in compared to coarse suspension. Indrajit. Ghosh, et. al. International journal of pharmaceutics, 201113
  • 14. Invitro / Invivo drug release from nanosuspension. European Journal of Pharmaceutics and International Journal of Pharmaceutics 408 (2011) 157– Biopharmaceutics 78 (2011) 441–446 16214
  • 15. Nanomilling - Stability Stability –  During the milling process due to the change of Gibbs free energy thermodynamically unstable nanosuspensions formed which is responsible for Ostwald ripening and agglomeration phenomenon or crystal growth during process or during shelf life due to high particle mobility.  Proper selection of stabilizers are required for tailoring the particle surface. Steric stabilization Electrostatic stabilization No Yes Impact crystal structure15
  • 16. Crystal growth in nanosuspension – Case study 2 Compound - A Initial After 3 months Time Mean particle size (PCS) Initial 230.2 The use of polymer along with a surfactant have synergistic 1 month 312.0 stabilizing action. 3 months 477.816
  • 17. HPMC – Successfully inhibit crystal growth Because of the absorption of HPMC polymer on the surface of the nuclei the drug nucleation was inhibited. Change of particle size of nanomilled compound on storage 500 450 Initial Particle size (nm) 400 3 months 350 HPMC 300 250 200 5% Drug with 5% 5% Drug with 5% 5% Drug with 5% Vitamin ETPGS Vitamin ETPGS and Vitamin ETPGS and 1% HPMC 1% PVP PVP Composition of Nanosuspension17
  • 18. Effect of SLS nanocrystal formulation Particle size distribution profile for nanomilled Compound at different process time 900 Particle size (nm) 800 5% Drug with 5% Vitamin ETPGS 700 600 500 5% Drug with 5% Vitamin 400 ETPGS & 1% HPMC 300 200 5% Drug with 5% Vitamin 100 ETPGS and 1% SLS 0 0 1 2 3 4 5 6 Time Ostwald ripening was observed with SLS during Nanomilling.18
  • 19. Importance of surface hydrophobicity of drug on dissolution for dried Nanosuspension. For nano-suspension production, absorption of Vitamin E TPGS on the surface of drug is very critical. More hydrophobic compounds will result in more severe and harder-to- disintegrate agglomerates that will lower the dissolution rate of the product. J. Pharm. Sci. 35 (2008), 127-135.19
  • 20. Optimization of process parameters during nanomilling of Naproxen – Case study 3 Avg. particle size after 4 hours of milling 0.1mm, 400RPM, 5% Drug Content: Ratio comparison 1600 600 1400 Avg. Particle Size (nm) 1200 500 1000 particle size (nm) 800 400 600 1:1 (Drug:TPGS) 1 to 1 300 400 2:1 (Drug:TPGS) 2 to 1 200 200 4:1 (Drug:TPGS) 4 to 1 0 5%D, 5%D, 5%D, 5%D, 100 400RPM, 400RPM, 150RPM, 150RPM, 0.1mm 0.5mm 0.1mm 0.5mm 0 bead bead bead bead 0 1 2 3 4 5 Process parameters Time (hrs)  RPM - most significant process parameter with a faster RPM produced smaller particles.  Bead size - seem to be a complex parameter. An increase in the specific energy input (the RPM) combined with a decrease in the media diameter formed finer product in the shortest time.  Total drug content - did not seem to have significant effect. Indrajit. Ghosh, et. al. AAPS poster, 201120
  • 21. Combined effect of process parameters & stabilizerFragmentation of materials Particle growth through interparticulate collision Comparitive effect of process parameters from Pareto Chart on Particle size after 4 hrs 200 180 RPM Bead Size 160 Magnitude of effects Drug load 140 120 100 80 60 40 20 0 HPMC NS HPC EXF NS PVP NS Polymer type Although the process parameters determined the success of nanomilling process in terms of efficiency, however the drug-carrier system was also equally important for stabilizing the particles during the process by minimizing agglomeration or crystal growth of drug substance.21
  • 22. Milling time depends upon Drug Morphology Particle size after 4 hrs milling: Naproxen vs. Compound - A NAP – d50 = 23.632 µm Naproxen Compd. A Compound A – length = 103 – 135 µm22
  • 23. Scale-up from planetary mill to stirred media mill using central composite statistical design “When the particle size is decreased, the hardness of the material is increased” ......resulted to decrease of milling rate with time. Critical scale-up parameters  Agitator speed (Tip speed) Decrease of polydispersity index (PI) was observed with milling time of drug  Bead size crystals, which confirms that with prolonged milling time, remaining  Solid content. larger particles in the nanosuspension were broken down into smaller particles.23
  • 24. General Risk Considerations to Human Health NPs cause unique biological effects (including those potentially toxic to humans)  Biological effects can widely vary depending on slight alterations in their physicochemical and surface as well as pharmacological (target / off-target) properties  Each type of NPs must be assessed on its own. FDA: currently no testing requirements specific to NMs, but if research identifies toxicological risks unique to NMs, additional testing requirements may become necessary R.H. Müller et al.24
  • 25. Conclusion  The wet milling media milling technique is considered to be an attractive technique in pharmaceutical industries.  It is a very fast process, eliminates the use of organic solvent and thus make the process eco-friendly.  A significant increase of area under drug concentration / AUC observed when the drug substance was converted into nanocrystals, probably due to the increase in dissolution velocity and saturation solubility.  Although the process parameters determined the success of nanomilling process in terms of efficiency, however the drug-carrier ratio was also equally important for stabilizing the particles by minimizing agglomeration or crystal growth.  In this approach, common regulatory approved excipients are generally used, which give big advantage for the formulation to use in clinical studies and also to enter regulatory market.25
  • 26. Acknowledgements Sonali Bose, Yogita Krishnamachari, Subash Patel, Glen Biank, Al. Hollywood. Radha Vippagunta, Frances Liu. Easter Maulit Jay Lakshman, Ping Li, Michael Motto, Colleen Ruegger26
  • 27. Questions Milling bead Impact Attrition API Milling bead Thank you...... Indrajit Ghosh Principal Scientist & Project Leader Email: indrajit.ghosh@novartis.com27

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