Young Innovators 2011
Solubility and Dissolution Enhancement
by Nanocaging
Limin Shi
University of Minnesota
Background
•
Effectively delivery of active pharmaceutical ingredients
has become a major challenge to pharmaceutical industry
 About 40% of marketed drugs have low solubility
 80 – 90% drug candidates in the R&D pipeline could fail due to
solubility problems
Situation is becoming more serious
N. Babu, A. Nangia. Cryst. Growth. Des. 2011, 2662.
2
Current solubilization technique
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•
•
•
•
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Nanocrystals
Solid dispersion
Amorphous solids
Salt and cocrystal formation
Cosolvent
Complexation (e.g. cyclodextrins)
A solubilzation platform
3
Aims
•
Developing a universal technology for enhancing
the solubility and dissolution rate of poorly soluble
drugs without compromising their other
performance
Nanocaging
A patent pending technology
4
Model Compounds – Proof of Concept
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Felodipine
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Celecoxib
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Indomethacin
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Piroxicam
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Ibuprofen
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Flurbiprofen
http://drugbank.ca/
5
Physical stability
Experimental conditions
 40oC
 75% RH
Flurbiprofen 3 month
Intensity
•
Ibuprofen 3 month
Piroxicam 3 month
Celecoxib 3 month
Felodipine 3 month
Excellent physical stability
Indomethacin 1 year
5
10
15
20
25
30
35
2
6
Solubility Enhancement - 1
4
Commercial drug crystal
Nanocaged drug
37oC
Solubility (mg/mL)
3
2
169
1
0
n
in
m
en
ipine elecoxib
profe
ethac Piroxica lurbiprof
u
b
m
I
C
Felod
o
F
Ind
Drug
S. Murdande, M. Pikal, R. Shanker, R. H. Bogner. Pharm. Res. 2010, 27, 2704
7
Nanocaging
Amorphous
8
Dissolution Rate
•
Tablets (200 MPa)
 10% IMC
 Avicel PH101
 Lactose
 Croscarmellose
Sodium
 Magnesum Stearate
Experiments
 37oC
 Sink condition
 USP type II
dissolution apparatus
100
Nanocaged IMC
80
% Released
•
60
40
IMC Crystalline
20
0
0
20
40
80
60
Time (min)
100
120
9
Manufacturability
60
Tensile strength (MPa)
10.00
50
Nanocaged IMC
FFc
40
30
20
10
Avicel PH102
8.00
6.00
4.00
2.00
0.00
0
0
0
5
10
Major principal stress (kPa)
15
20
100
200
300
400
Compaction pressure (MPa)
Direct compression formulation
10
Conclusions
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•
•
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Nanocaging technique can be used to significantly
enhance solubility and dissolution rate of poorly
water soluble drugs
Bring life to old molecules and new promising drug
candidates
Nanocaged drugs have excellent physical stability,
good flexibility in drug loading, and superior
powder properties
It can serve as an enabling technology for direct
compression formulation of poorly soluble drugs
11
Acknowledgements
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Dr. Changquan Calvin Sun
•
Sun group member
12
References
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Lipinski, C.A., et al., Experimental and computational approaches to estimate
solubility and permeability in drug discovery and development settings. Adv. Drug
1.
Delivery Rev., 1997. 23(1-3): p. 3-25.
2.
Junghanns, J.-U.A.H. and R.H. Mueller, Nanocrystal technology, drug delivery
and clinical applications. Int. J. Nanomed., 2008. 3(3): p. 295-309.
3.
Hecq, J., et al., Preparation and characterization of nanocrystals for solubility
and dissolution rate enhancement of nifedipine. Int. J. Pharm., 2005. 299(1-2): p. 167177.
4.
Serajuddin, A.T.M., Solid Dispersion of Poorly Water-Soluble Drugs: Early
Promises, Subsequent Problems, and Recent Breakthroughs. J. Pharm. Sci., 1999.
88(10): p. 1058-1066.
5.
Murdande, S.B., et al., Solubility advantage of amorphous pharmaceuticals: I. A
thermodynamic analysis. J. Pharm. Sci., 2010. 99(3): p. 1254-1264.
6.
Hancock, B.C. and M. Parks, What is the true solubility advantage for amorphous
pharmaceuticals? Pharm. Res., 2000. 17(4): p. 397-404.
7.
Li, P., L. Zhao, and S.H. Yalkowsky, Combined Effect of Cosolvent and
Cyclodextrin on Solubilization of Nonpolar Drugs. J. Pharm. Sci., 1999. 88(11): p. 11071111.
8.
Tongiani, S., T. Ozeki, and V.J. Stella, Sulfobutyl ether-alkyl ether mixed
cyclodextrin derivatives with enhanced inclusion ability. J. Pharm. Sci., 2009. 98(12): p.
4769-4780.
Young Innovators 2011
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References
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9.
Serajuddin, A.T.M., Salt formation to improve drug solubility. Adv. Drug
Delivery Rev., 2007. 59(7): p. 603-616.
10.
Schultheiss, N. and A. Newman, Pharmaceutical Cocrystals and Their
Physicochemical Properties. Cryst. Growth Des., 2009. 9(6): p. 2950-2967.
11.
Murdande, S.B., et al., Solubility Advantage of Amorphous Pharmaceuticals: II.
Application of Quantitative Thermodynamic Relationships for Prediction of Solubility
Enhancement in Structurally Diverse Insoluble Pharmaceuticals. Pharm. Res., 2010.
27(12): p. 2704-2714.
12.
Zhang, H., et al., Formation and enhanced biocidal activity of water-dispersable
organic nanoparticles. Nat Nanotechnol, 2008. 3(8): p. 506-11.
13.
Davis, M.E., Ordered porous materials for emerging applications. Nature
(London, U. K.), 2002. 417(6891): p. 813-821.
14.
Heikkilae, T., et al., Cytotoxicity study of ordered mesoporous silica MCM-41
and SBA-15 microparticles on Caco-2 cells. Eur. J. Pharm. Biopharm., 2010. 74(3): p.
483-494.
15.
Shen, S.-C., et al., Stabilized amorphous state of ibuprofen by co-spray drying
with mesoporous SBA-15 to enhance dissolution properties. J. Pharm. Sci., 2010. 99(4):
p. 1997-2007.
16.
Kinoshita, M., et al., Improvement of solubility and oral bioavailability of a poorly
water-soluble drug, TAS-301, by its melt-adsorption on a porous calcium silicate. J.
Pharm. Sci., 2002. 91(2): p. 362-370.
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References
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Noyes, A.A. and W.R. Whitney, The rate of solution of solid substances in their
own solutions. J. Am. Chem. Soc., 1897. 19(12): p. 930-4.
18.
Hefter, G.T., R.P.T. Tomkins, and Editors, The Experimental Determination of
Solubilities. [In: Wiley Ser. Solution Chem.; 2003, 6]2003. 629 pp.
19.
Godec, A., et al., Vitrification from solution in restricted space: Formation and
stabilization of amorphous nifedipine in a nanoporous silica xerogel carrier. Int. J.
Pharm., 2007. 343(1-2): p. 131-140.
17.
Young Innovators 2011
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BIOS/Contact info
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BIOS: Limin Shi, Ph.D. is a postdoctoral fellow at the Pharmaceutical
Materials Science and Engineering Laboratory, College of Pharmacy,
University of Minnesota. His research has been dedicated to improving the
drug delivery using innovative particle engineering approaches. He has also
developed new particle engineering approaches for enhancing powder flow
and compaction properties, both of which are critical for successful
formulation and manufacture of tablet products. Moreover, he has identified
several mechanisms that are responsible for the over-granulation problem in
high shear wet granulation. All of his scientific achievements are expected to
benefit the society by helping the pharmaceutical industry to manufacture
high quality drug products in an efficient way.
Contact info:
Department of Pharmaceutics
College of Pharmacy
3-119 Weaver-Densford Hall
308 Harvard Street S.E.
Minneapolis, MN 55455
Tel: 612-624-5443 (Office)
E-Mail: shilimin02@gmail.com
Young Innovators 2011
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