Young Innovators 2011

Solubility and Dissolution Enhancement by Nanocaging

Limin Shi

University of Minnesota

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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.

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Current solubilization technique

• Nanocrystals

• Solid dispersion

• Amorphous solids

• Salt and cocrystal formation

• Cosolvent

• Complexation (e.g. cyclodextrins)

A solubilzation platform

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Aims

• Developing a universal technology for enhancing the solubility and dissolution rate of poorly soluble drugs without compromising their other performance

NanocagingA patent pending technology

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Model Compounds – Proof of Concept

• Felodipine • Celecoxib • Indomethacin

• Piroxicam • Ibuprofen • Flurbiprofen

http://drugbank.ca/

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Physical stability

5 10 15 20 25 30 35

Piroxicam 3 month

Celecoxib 3 month

Ibuprofen 3 month

Flurbiprofen 3 month

Felodipine 3 monthIn

ten

sity

2

Indomethacin 1 year

Excellent physical stability

• Experimental conditions 40oC 75% RH

7

3737ooCC

Solubility Enhancement - 1

FelodipineCelecoxib

IndomethacinPiroxicam

FlurbiprofenIbuprofen

0

1

2

3

4

So

lub

ilit

y (m

g/m

L)

Drug

Commercial drug crystal Nanocaged drug

169

S. Murdande, M. Pikal, R. Shanker, R. H. Bogner. Pharm. Res. 2010, 27, 2704

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Nanocaging

AmorphousAmorphous

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Dissolution Rate

• Tablets (200 MPa) 10% IMC Avicel PH101 Lactose Croscarmellose

Sodium Magnesum Stearate

• Experiments 37oC Sink condition USP type II dissolution

apparatus

0 20 40 60 80 100 1200

20

40

60

80

100

% R

elea

sed

Time (min)

Nanocaged IMC

IMC Crystalline

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Manufacturability

0

10

20

30

40

50

60

0 5 10 15 20

Major principal stress (kPa)

FF

c

Nanocaged IMC

Avicel PH102 0.00

2.00

4.00

6.00

8.00

10.00

0 100 200 300 400

Compaction pressure (MPa)

Ten

sile

str

eng

th (

MP

a)

Direct compression formulation

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Conclusions

• 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

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Acknowledgements

• Dr. Changquan Calvin Sun

• Sun group member

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References

• 1. Lipinski, C.A., et al., Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug 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. 167-177.

• 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. 1107-1111.

• 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

• 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.

Young Innovators 2011

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References

• 17. 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.

Young Innovators 2011

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BIOS/Contact info• 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 PharmaceuticsCollege of Pharmacy3-119 Weaver-Densford Hall308 Harvard Street S.E.Minneapolis, MN 55455Tel: 612-624-5443 (Office)E-Mail: shilimin02@gmail.com

Young Innovators 2011