Docstoc

Nanosuspensions

Document Sample
Nanosuspensions Powered By Docstoc
					T. Geetha, M.S. (Pharm.), Ph.D.

16 May 2009

1 of 33

T. Geetha

Contents
Introduction • Nanotechnology • Nanopharmaceuticals Nanosuspensions • Production methods • Characterization • Advantages • Applications Summary
16 May 2009 2 of 33 T. Geetha

Nanotechnology

Introduction

Any application of science that deals with elements between 1-100 nm in size, in which size is critical to the application’s ultimate purpose “Nano” means dwarf in Greek, a nanometer is one billionth of a meter i.e. 10-9 meter

16 May 2009

3 of 33

T. Geetha

Nanotechnology

Introduction

Nanotechnology deals with phenomena whose physics or chemistry differs from that of bulk materials Nanoparticles are particles in which the small size influences the intrinsic properties or behaviour of the particle
CdSe nanoparticles

16 May 2009

4 of 33

T. Geetha

Size dependent changes in nanoparticles
Surface effects Quantum confinement effects

Introduction

16 May 2009

5 of 33

T. Geetha

Surface effects

Introduction

Structure of the system depends on arrangement of atoms or molecules For bulk materials, the surface atoms form a negligible part of the total number of atoms In nanometer scale, number of atoms exposed at the surface increases significantly Atoms at the surface have fewer direct neighbours than atoms in the bulk

16 May 2009

6 of 33

T. Geetha

Surface effects (Contd…)

Introduction

Property is a consequence of mean coordination number (number of nearest neighbours) Particles with a large fraction of atoms at the surface have low mean coordination number, thus different properties Atoms in the interior of the bulk are more highly coordinated, form more bonds, thus more stable than those at the surface

16 May 2009

7 of 33

T. Geetha

Quantum confinement effects

Introduction

Energy of the system is imparted by the collective energies of electronic states of the matter Energies of electronic states depend on 1/L2, where L is the dimension of the system in that particular direction Variation in the number of atoms in a system will result in significant variation in the energies and energy separations of the individual electronic states

16 May 2009

8 of 33

T. Geetha

Quantum confinement effects

Introduction

The organization of energy levels into which electrons can climb or fall is different in nanoparticles than bulk materials Based on this, the electronic transitions and the properties associated with it will change significantly
Bulk Metal Unoccupied states Occupied states Decreasing the size… Nanoscale metal

Unbound electrons have motion that is not confined
16 May 2009 9 of 33

Electron motion becomes confined, and quantization sets in
T. Geetha

Nanopharmaceuticals

Introduction

Materials at nanoscale can be stronger, lighter and highly soluble with totally different physicochemical properties The practical application can be demonstrated with a simple example of carbon, which is the main building block of coal & diamond Classification
• Nano-engineered drugs • Nanocarriers

16 May 2009

10 of 33

T. Geetha

Nano-engineered drugs

Introduction

Nano-design of the existing drug molecules and drugs in discovery pipeline to nanocrystals, nanoprecipitates, nanosupensions & nanoparticles might help in:

• Increasing the solubility & bioavailability of drug molecules • Development of different dosage forms (e.g., nanosuspensions for parenterals) • Exploring different routes of administrations (e.g., nasal and ophthalmic delivery provides a patient-friendly alternative)

16 May 2009

11 of 33

T. Geetha

Nanosuspension

Introduction

Colloidal dispersions of nano-size drug particles stabilized by surfactants Used to formulate drugs insoluble in both oil and water (The crystal energy of the compound is high, which reduces the tendency of the crystal to dissolve regardless of the solvent) Nanocrystal Technology (Elan) - one of the earliest scalable technology for nanosizing drugs

16 May 2009

12 of 33

T. Geetha

Mechanism of increase in solubility
Reduction of particle size

Nanosuspension

Reduction of particle size

Increase in surface area
16 May 2009

Increase in wetting
13 of 33

Increased solubility
T. Geetha

Formulation Considerations
Stabilizer
• Wetting of drug particles and prevent agglomeration

Nanosuspension

• Cellulosics, poloxamers, polysorbates, lecithins & povidones

Co-surfactants
• Bile salts, dipotassium glycerrhizinate, transcutol, glycofurol etc.

Organic solvents
• Required if nanosuspension is prepared using emulsion or microemulsion as a template • Ethanol, Isopropanol, ethyl acetate, ethyl formate, butyl lactate etc.

Other additives – Buffers, polyols etc.
16 May 2009 14 of 33 T. Geetha

Production methods
Precipitation Media milling Homogenization
• Microfluidization • Piston-gap homogenizers

Nanosuspension

Emulsion / microemulsion as templates

16 May 2009

15 of 33

T. Geetha

Precipitation
Micronization by colloidal or jet mills
• Enhancing solubilization of poorly soluble drugs

Production methods

• Increase in dissolution velocity by increasing surface area • Does not change saturation solubility, so no increase in bioavailability

Precipitation
• By dissolving drug in a solvent and adding the mixture to a nonsolvent • NanoMorph by SOLIQS/Abbott – relatively simple and low cost equipment, easy scale-up by use of static blenders or micromixers • Limitations - Crystal growth during storage, drug to be soluble in at least one solvent
16 May 2009 16 of 33

T. Geetha

Media milling

Production methods

Drug powder is dispersed in a surfactant solution - Milling using high-shear media or pearl mills Milling medium composed of glass, zircon oxide, or highly cross-linked polystyrene resin Milling chamber is charged with milling media, water and stabilizer Milling media or pearls are rotated at a very high shear rate Impaction of drug with milling media, high shear forces and energy generated – nanoparticles formation Advantage - Useful for very poorly soluble drugs, easy scaleup, little batch-to-batch variation, high flexibility in handling large quantities Drawback - Generation of residues of milling media as a result of erosion
16 May 2009 17 of 33 T. Geetha

Production methods

Media milling

16 May 2009

18 of 33

T. Geetha

Homogenization
Micro fluidization

Production methods

• Based on the principle of jet stream - the suspension passes with high velocity inside the homogenization chamber • Z-type chamber – The suspension changes the direction according to letter Z, leading particle collision and shear forces • Y-type chamber – suspension stream is divided into two stream, which then collide frontally • Drawbacks - High number of passes through the micro fluidizer, which is not production friendly - Contains large fraction of micro particles
16 May 2009 19 of 33 T. Geetha

Homogenization
Piston-gap homogenization
High Pressure homogenization in water (Dissocubes)

Production methods

Homogenization in water - free media and water mixtures (Nanopure) • Homogenization in propylene glycol • Process can be performed at 0oC and well below freezing point • Useful for chemically and thermally labile drugs (e.g., Omeprazole) Combination (Nanoedge) Technology Precipitation and homogenization

• Combination of precipitation and homogenization

16 May 2009

20 of 33

T. Geetha

Production methods

Piston-gap homogenization

16 May 2009

21 of 33

T. Geetha

Production methods

High-pressure homogenization in water
High-pressure homogenization in water by forcing of suspension under pressure through a valve that has a narrow aperture Cavitations, high shear forces and collision against each other In the homogenization gap, the dynamic pressure of the fluid increases with decrease in static pressure below the boiling point of water at room temperature Water starts boiling, leading to formation of gas bubbles, implode when the suspension leaves the gap (cavitations) Implosion forces break down the drug micro particles into nanoparticles

16 May 2009

22 of 33

T. Geetha

Production methods

Emulsion / microemulsion as templates
Applicable for drugs soluble in volatile organic, partially water-miscible solvents Solvents can be used as the dispersed phase Solvents loaded with drug is dispersed in aqueous phase containing surfactants Organic phase is evaporated under reduced pressure so that the drug particles precipitate instantaneously to form a nanosuspension stabilized by surfactants Using microemulsion as template, the drug can be loaded in the internal phase or pre-formed emulsions can be saturated with intimate mixing Suitable dilution of microemulsion yields the drug nanosuspension

16 May 2009

23 of 33

T. Geetha

Characterization
Particle size & size distribution Zeta potential Crystalline status Dissolution velocity & saturation solubility In-vivo studies Protein adsorption pattern

16 May 2009

24 of 33

T. Geetha

Characterization
Particle size and size distribution
• Photon correlation spectroscopy (3 nm to 3 μm) • Laser diffraction microscopy – for large number of particles and aggregates (0.05 to 80 μm) • Coulter counter – for I.V nanosuspension to get absolute number of particles per unit volume

Particle charge (zeta potential)
• Indicates product stability • Depends on stabilizer and property of drug • Minimum value of zeta potential for a product stabilized by electrostatic repulsion, is 30mV • For combined electrostatic and steric stabilization, 20mV
16 May 2009 25 of 33 T. Geetha

Characterization
Crystalline status
• By XRD, DSC and electron microscopy • Required when drug exists in different polymorphic forms

Dissolution velocity and saturation solubility
• To assess in-vivo performance • Various physiological buffers (USP) can be used

In vivo studies
• Surface hydrophilicity/hydrophobicity determines interaction with cells prior to phagocytosis • Hydrophobic interaction chromatography

Protein adsorption pattern
• Key factor for organ distribution • By 2-D Poly-acrylate gel electrophoresis

16 May 2009

26 of 33

T. Geetha

Advantages
Increase in drug loading without extreme pH conditions or use of toxic solvents - Reduced toxicity and increased efficacy Increase in dissolution velocity and saturation solubility leading to improved in-vivo performance, irrespective of the route of administration Increase in drug loading with less volume for parenteral and ophthalmic use Increased resistance to hydrolysis and oxidation, so improved physical stability Potential for I.V sustained release via monocyte phagocytic system targeting Potential for reduced first pass metabolism for oral administration Easy to manufacture and scale-up

16 May 2009

27 of 33

T. Geetha

Applications
Oral nanosuspensions like Rapamune and Emend are available in market Indibulin - Oral and I.V - Phase I & preclinical Parenterally tolerable dose of drugs improved with nanosuspensions (e.g., Paclitaxel, Etoposide and Camptothecin) Danazol nanosuspensions (Liversidge et al, 1995a)
• Bioavailability 82.3% (reduced inter-subject variability) whereas conventional suspension was only 5.2%

16 May 2009

28 of 33

T. Geetha

Applications
Atovaquone nanosuspension (Scholer et al., 2001)
• Poor bioavailability of 10-15% because of dissolution rate limited absorption • Oral nanosuspension increased bioavailability • High adhesiveness of drug particles sticking on biological surfaces & prolonged absorption time

Naproxen nanosuspension (Liversidge et al., 1995)
• Severe gastric irritation • Reduced gastric irritation when particle size reduced • Reduced gastric residence time

Amphotericin B nanosuspension (Kayser et al., 2003)
• Improved oral absorption-Reduction in number of L. donovani parasites in the liver of infected female mice
16 May 2009 29 of 33 T. Geetha

Applications
Ketoprofen nanosuspension (Remon et al., 2001)
• Incorporated into pellets to release the drug for 24 h • This approach facilitate delivery of BCS Class IV molecules

Bupravaquone nanosuspension (Kayser, 2001)
• Cryptosporidium parvum – main pathogen causing diarrhea in immunosuppressant HIV patients • Targeting the drug to the pathogen located in the epithelial membrane gut wall is essential - Increasing the time for the drug in the GI tract to prolong the pharmacological window with regard to the fast washing out during diarrhea • Bupravaquone nanosuspensions – surface modified mucoadhesive nanosuspension – prolonged residence at the infection site – 10 fold reduction in infectivity scores
16 May 2009 30 of 33

T. Geetha

Summary
Attractive drug delivery method for enhancing solubility and bioavailability Large scale production is possible Can be administered using various routes like oral, parenteral, ocular and pulmonary Oral nanosuspensions can be converted to dosage forms like tablets or capsules Site-specific delivery needs more investigation Success is evident by increase in the commercially available products of nanosuspensions in the near future

16 May 2009

31 of 33

T. Geetha

Thanks …
16 May 2009 32 of 33 T. Geetha

References
Kayser, O. (2001) A new approach for targeting to Cryptosporidium parvum using mucoadhesive nanosuspensions: research and applications. Int. J. Pharm. 214: 83–85 Kayser, O., Olbrich, C., Yardley, V., Kiderlen, A. F., Croft, S. L. (2003) Formulation of amphotericin B as nanosuspension for oral administration. Int. J. Pharm. 254: 73–75 Liversidge, G. G., Conzentino, P. (1995) Drug particle size reduction for decreasing gastric irritancy and enhancing absorption of naproxen in rats. Int. J. Pharm. 125: 309– 313 Liversidge, G. G., Cundy, K. C. (1995) Particle size reduction for improvement of oral bioavailability of hydrophobic drugs. I Absolute oral bioavailability of nanocrystalline danazole in beagle dogs. Int. J. Pharm. 127: 91–97 Mu¨ ller, R. H., Jacobs, C. (2002a) Buparvaquone mucoadhesive nanosuspension: preparation, optimisation and long-term stability. Int. J. Pharm. 237: 151–161 Remon, J. P., Vergote, G. J., Vervaet, C., Driessche I., Hoste, S., Smedt, S., Demeester, J., Jain, R. A., Ruddy, S. (2001) An oral controlled release matrix pellet formulation containing nanocrystalline ketoprofen. Int. J. Pharm. 219: 81–87 Scho¨ ler, N., Krause, K., Kayser, O., Mu¨ ller, R. H., Borner, K.,Hahn, H., Liesenfeld, O. (2001) Atovaquone nanosuspensions show excellent therapeutic effect in a new murine model of reactivated toxoplasmosis. Antimicrob. Agents Chemother. 45: 1771–1779

16 May 2009

33 of 33

T. Geetha


				
DOCUMENT INFO
Shared By:
Categories:
Tags:
Stats:
views:1169
posted:10/3/2009
language:English
pages:33