Nanosuspension – An unique tool for improving the bioavailability of poorly soluble drugs - Indrajit Ghost, Novartis

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 health
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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, EJPB
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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, EJPB
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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 effective
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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 6
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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.
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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, impact
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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.
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 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 poor
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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.
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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 - Scale
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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, 2011
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14. Invitro / Invivo drug release from
nanosuspension.
European Journal of Pharmaceutics and International Journal of Pharmaceutics 408 (2011) 157–
Biopharmaceutics 78 (2011) 441–446 162
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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 structure
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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 477.8
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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 Nanosuspension
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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.
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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.
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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, 2011
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21. Combined effect of process parameters &
stabilizer
Fragmentation 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.
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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 µm
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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.
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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.
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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.
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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 Ruegger
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27. Questions
Milling bead
Impact
Attrition API
Milling bead
Thank you......
Indrajit Ghosh
Principal Scientist & Project Leader
Email: indrajit.ghosh@novartis.com
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