Nano Suspensions

Nanosuspensions

Presented by : Mr. Satish S. Reddi

Guided by : Dr. M. R. Bhalekar

AISSMS COLLEGE OF PHARMACY, PUNE

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Content

Introduction

Methods of preparation

Sterilization and stability aspects

Characterization

Applications

Market status of nanosuspension

References

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Introduction

Nanosuspensions of drug are sub-micron colloidal dispersions of pure particles of drug, which are stabilized by surfactant.

They are distinguished from polymer nanoparticles, which are polymeric colloidal carriers of drugs and from solid lipid nanoparticles, which are lipidic carriers of drugs.

Nano is Greek word, which means ‘dwarf’. Nano is the factor of 10-9 or one billionth.

0.1 nm = Diameter of one hydrogen atom

2.5 nm = Width of a DNA molecule 1 micron = 1000 nm

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Why..?

Why nanosuspension, when other conventional methods of solubility

improvement are available..?

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Decision tree for selection of formulation approach

pH adjustment

salt formation

Co-solvents

Inclusion complex

Co-solvent Emulsion

Other lipidic carrier

Suitable molecular

shape

Dose?

Melting point?

Nanosuspension

log P?

Can salt be made?

Start

Water soluble?

Yes

Yes

No

No

High

Low

Low

High

Low

High

Yes

No

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Formulation consideration

Stabilizerse.g. cellulosics, poloxamers, polysorbates, lecithins and providones

Organic solventse.g. ethyl acetate, ethyl formate, butyl lactate, triacetin, etc

Co-surfactantse.g. bile salts, dipotassium glycerrhizinate, transcutol, glycofurol, ethanol, isopropanol, etc

Other additives e.g. Buffers, Osmogents, Antimicrobials, Cryoprotectants, etc

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Advantages of nanosuspensions

Increase in dissolution velocity:

It can be explained using by Noyes Whitney

dissolution model equation

Increase in saturation solubility:

It is explained by Ostwald-Freundlich’s equation

Long term physical stability

Ease of manufacture and scale up

Versatility

Improved biological performance…

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…Improved biological performance

Route of administration Potential benefits

Oral Rapid onset of actionIncreased bioavailability of drug Reduced fed/fasted ratio

Intravenous Sustained release via monocyte phagocytic system targetingReduced toxicityIncreased efficacy

Ocular High drug loadingHigher bioavailability

Pulmonary Increased delivery to deep lungMore consistent dosing

Subcutaneous/ Intramuscular

Reduced volume of administrationReduced irritationHigher bioavailability

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Methods of preparation

Bottom up technology

Top down technology

1. Pearl / Ball milling

2. High Pressure Homogenization

Melt emulsification method

Emulsion or microemulsion as template

Aerosol flow reactor method

Supercritical fluid based technologies

Highee technology

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Drug Solvent

Drug solution

Antisolvent

Precipitation

Nanosuspension

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It is also known as precipitation technique.

It involves two steps:

1. Initial creation of crystal nuclei

2. Subsequent growth

Particle size controlling parameters:

1. Temperature

2.Supersaturation

3. Surfactant concentration

Advantages

Disadvantages

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Pearl milling

Schematic representation of pearl milling

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Pearl milling

Also known as wet milling

Particle size controlling parameters:

1. No. of cycles

2. Speed of rotation

3. Hardness of drug

Dispersion with mean diameter >200nm is

obtained within 30-60 min

Advantages

Disadvantages

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High pressure homogenization

It has following types:

Microfluidisation

Piston-gap homogenizers

a. Dissocubes

b. Nanopure

c. Nanoedge

HPH (APV micron LAB 60)

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Microfluidisation

Also known as MRT (Microfluidics Reaction Technology).

In consist of reaction chamber where precipitation or

crystallization takes place.

Short dwell time inside high speed, high pressure and

high shear environment forces the reactant to interact

at nanoscale level.

It consists of two reactors:

1. Microfluidics mixer reactor (MMR)

2. Coaxial feed reactor (Co-Reactor)

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Microfluidisation

Patented interaction chamber

Inlet reservoir

OutletCooling jacket

Pump

Pressuregauge

Schematic representation of microfluidizer

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Microfluidisation

Particle size controlling factor:

1. Feed rate

2. Reactant ratios

3. Mixing intensity

4. Pressure

5. Residence time

Advantages

Disadvantages

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Dissocubes

This process is also known as Homogenization in

water

Developed by R. H. Muller et. al. (1999)

Instruments used:

1. APV micron LAB 40

2. APV micron LAB 60

3. Avestin

Instrument capacity: 40 ml t0 few thousand liters

Pressure: 100 t0 1500 bars (2800 t0 23500 psig)

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Dissocubes

Production of nanosuspension by HPH (APV micron LAB 40)

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Dissocubes

Working principle of Dissocubes

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Dissocubes

Parameters controlling particle size:

1. Power density of homogenizer

2. Number of homogenization cycle

3. Temperature

Advantages

Disadvantages

PCS data of azodicarbamide drug as function of no. of homogenization cycle

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Nanopure

In this method suspension is homogenized in water free

media

In Dissocubes technology:

- cavitation is rate determining step

- statics pressure is not be sufficient to initiate

cavitation

- disintegration requires higher temperature

- not suitable for thermolabile

In nanopure non-aqueous media homogenized at 00c or

even less

Also called as “deep-freeze” homogenization

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Nanoedge

Drug Solvent

Drug solution

Antisolvent

Precipitation

Nanosuspension

High Pressure Homogenizati

on

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Nanoedge

This technique is combination of precipitation and

homogenization technique.

Depending on precipitation condition, particles can be

completely amorphous, partially amorphous or

completely crystalline.

Second high energy addition step preserve size range

and converts all precipitated particles to crystalline

material.

In this way major drawback of precipitation technique

such as crystal growth and long term stability can be

resolved by this technique.

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Nanoedge

Raw materialAfter precipitation and before homogenization After homogenization

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Drug melt

High Pressure

Homogenization

Primary emulsion

Solvent

Cooling

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Particle size controlling factors:

1. Rate of cooling

2. Concentration of drug

3. Stabilizers used

Effect of surfactant and drug concentration on particle size (PCS data )

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Emulsion as template

Applicable for drugs which are soluble in organic

solvent or partially water miscible solvent

This method is used for poorly water soluble and

poorly bioavailable anticancer drugs shows five

fold increase in dissolution rate than commercial

product(Trotta et al 2001)

Two ways of fabricating drug nanosuspension:

1. Solvent diffusion method

2. Solvent evaporation method

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Solvent diffusion method

Partially water

miscible solvent

Highly water miscible solvent

Emulsion

Drug solution Water

Drug

Stabilizer

Precipitation

High Pressure

Homogenization

Nanosuspension

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Solvent evaporation method

Emulsion

Drug

Precipitation

Nanosuspension

Organic solvent

Drug solution Water

Evaporation

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Emulsion as template

Particle size controlling factor:

1. Intensity of mixing

2. Stabilizers

3. Water miscibility of solvent

4. Rate of evaporation

Advantages

Disadvantages

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Aerosol flow reactor method

DrugVolatile solvent

Nanodroplets suspended in

inert gas

Nanosuspension

Atomization using inert gas

Heated tubular laminar flow

Solvent evaporation and

Precipitation

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Aerosol flow reactor

Particle size controlling factors:

1. Temperature

2.Solution concentration

3. Type of atomization and atomization

efficiency

4. Drug solubility

Advantages

Disadvantages

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Other methods

Supercritical fluid based technologies:

1. Rapid expansion supercritical process (RESS)

2. Rapid expansion from supercritical to aqueous

solution(RESAS)

3. Supercritical anti-solvent process (SAS)

4. Supercritical anti-solvent enhanced mass transfer

(SASEM)

High gravity reactive precipitation (Highee technology)

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Overview of technologies

Nanocrystal Company Patent / Patent application

Hydrosol Novartis (prev. Sandoz)

GB 22 69 536

NanomorphTM Soligs / Abbott GB 22 00 048

NanoCrystalTM elan Nanosystem D 19637517

Dissocubes® SkyePharma US 5145684

Nanopure PharmaSol US 5858410

NANOEDGETM Baxter PCT/EP00/0635

Microfluidics® Microfluidics Inc US 6018080

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Sterilization aspects of nanosuspension

Thermal sterilization (Autoclaving):

1. The physical stability depends on composition of

stabilizing surfactant or surfactant mixture.

Drug Surfactant

PCS Diameter

Before autoclaving

After autoclaving

9% RMPK 22

0.6 % Phospholipon -90 380 nm 402 nm

9% RMPK 22 0.3% Tween-80 382 nm 1039 nm

PCS data after autoclaving (15 min, 2 bar, European Pharmacopeia)

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Aggregation is due to reduced efficiency of steric stabilizer.

Increase in temperature causes dehydration consequently

decrease in thickness of steric stabilizer layer.

Some steric stabilizer even reach their critical flocculation

temperature (CFT) at autoclaving conditions.

To Summarize:

For autoclaving, nanosuspensions need preferentially to be

stabilized by charged stabilizer such as phospholipon.

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Radiation sterilization (γ irradiation):

Drug Surfactant

LD data (diameter 99 %)

Before irradiation

After irradiation

9% RMPK 22

0.6 % Phospholipon -90 3.78 micron 3.70 micron

9% RMPK 22 0.3% Tween-80 4.35 micron 4.26 micron

LD data after γ irradiation (25 kGy for comparison only)

Stability under γ irradiation was observed for a range of other drug nanosuspension.

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In contrast, tarazepide nanosuspension shown

distinct increase in size after γ irradiation.

When measurement of zeta potential carried out

using Malvern Zetasizer at field strength 22 V/cm

found that:

zeta potential before γ irradiation: - 30.5 mV

zeta potential after γ irradiation: - 22.3 mV

Drop in zeta potential shows that some chemical

reaction must have taken place.

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Zeta potential of about ± 20 mV is not sufficiently

high to stabilize the particle long term.

For long term stability zeta potential of about ± 30

mV is required.

To summarize:

γ irradiation is possible with some

nanosuspension; it depend on nature of stabilizer

and drug.

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Aseptic production:

1.Baxter realized on aseptic line for production of

parentral nanosuspension.

2. In addition, it should be kept in mind that HPH

process itself has germ reducing effect.

3. Not only drug particles but also the bacteria

are disintegrated.

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Long term physical stability of nanosuspension

Physical insatiability in nanosuspension is expected

due to Ostwald ripening

According to Ostwald-Freundlich equation saturation

solubility increases with the decreasing particle size

This effect is more pronounce for particle below 1

micron.

Diffusion phenomenon due to particle size difference

Nanosuspensions are more homogeneous

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Long term physical stability of nanosuspension

Clofazemine nanosuspension showed distinct increase

in PCS diameter and LD 99% after two month storage.

RMPK-22 nanosuspension stabilized with phospholipon-

90 or tween-80 had PCS diameter of 564 nm after

production and 575 nm after two years of storage.

To summarize:

Storage of drug nanoparticles as an aqueous

suspension is possible if the stabilizing surfactant

mixture is optimal. Crystal growth dose not take place

if particles are relatively uniform in size.

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Dosage form based on nanosuspension

Topical formulations:

e.g. Creams , Water free ointments, etc.

Dosage form for administration in the mouth:

e.g. Sublingual system, Buccal system

Dosage forms for oral drug delivery to the GI

tract:

e.g. Tablets, Capsules, Pellets, etc.

Pulmonary delivery of nanosuspension

Parentral administration of nanosuspension

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Characterization test

Particle-size distribution:

1. Photon correlation spectroscopy (PCS)

2. Laser diffractometry (LD)

3. Coulter counter

Crystalline state and morphology:

1. Scanning electron microscopy (SEM)

2. Differential scanning colorimetry (DSC)

3. X-ray analysis

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Zeta potential:

1. Electrophoresis

2. Malvern zetasizer

Dissolution velocity/ Saturation solubility:

The method described in the pharmacopoeia

e.g. shaking experiment at different

temperature (40, 200

& 400)

Surface hydrophilicity/ hydrophobicity:

Hydrophobic interaction chromatography

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Chemical test:

1. Active ingredients

2. Degradation products

3. Moisture ( for lyophilized and solid dosage

forms)

4. Preservative

5. pH

Other specific test according to dosage from:

e.g. for parentral: Sterility, Pyrogenecity,

Syringeability, etc.

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Applications

Danazol nanosuspensions (Liversidge et al, 1995): Bioavailability 82.3% (reduced inter-subject

variability) whereas conventional suspension was only 5.2%

Atovaquone nanosuspension (Scholer et al., 2001):1.Poor bioavailability of 10-15% because of

dissolution rate limited absorption2.Oral nanosuspension increased bioavailability3. High adhesiveness of drug particles sticking on

biological surfaces & prolonged absorption time

Naproxen nanosuspension (Liversidge et al., 1995):1. Severe gastric irritation2. Reduced gastric irritation when particle size

reduced3. Reduced gastric residence time

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Applications

Ketoprofen nanosuspension (Remon et al., 2001):1. Incorporated into pellets to release the drug for 24 h2. This approach facilitate delivery of BCS Class IV

molecules

Bupravaquone nanosuspension (Kayser, 2001):1. Cryptosporidium parvum – main pathogen causing

diarrhea in immunosuppressant HIV patients 2. 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

3. Bupravaquone nanosuspensions – surface modified mucoadhesive nanosuspension – prolonged residence at the infection site – 10 fold reduction in infectivity scores

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Market status of nanosuspensions

Drug Indication Drug delivery company

Pharma company

Route status

Paclitaxel Anticancer American BioScience

American Pharmaceutical Partners

Intravenous Phase III

Sirolimus(RAPAMUNE®)

Immunosuppressant

Elan nanosystem

Wyeth Oral Marketed

Aprepitant (EMEND®)

Anti-emetic Elan nanosystem

Merck Oral Marketed

Cytokine inhibitor

Crohn’s disease

Elan nanosystem

Cytokine PharmaScience

Oral Phase II

Busulfan Anticancer SkyePharma Supergen Intrathecal Phase I

Fenofibrate(TriCor®)

Lipid lowering SkyePharma Abbott Oral Marketed

Insulin Diabetes BioSante Self-developed Oral Phase I

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Market status of nanosuspensions

Drug Indication Drug delivery company

Pharma company

Route status

Undisclosed multiple

Anti-infective

Baxter NANODOSAGE

Undisclosed Oral or Intravenous

Preclinical to Phase II

Undisclosed Anticancer Baxter NANODOSAGE

Undisclosed Oral or Intravenous

Preclinical to Phase II

Diagnostic Agent

Imaging agents

Elan nanosystem

Photogen Intravenous Phase I/II

Thymectacin

Anticancer Elan nanosystem

NewBiotics / IIex Oncology

Intravenous Phase I/II

Megsterol acetate(MEGACE®ES)

Appetite stimulant

Elan nanosystem

RAR Pharmaceutical

Oral Marketed

Fenofibrate(TriglideTM)

Lipid lowering Elan nanosystem

First Horizon Pharmaceutical

Oral Marketed

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Summary

Attractive drug delivery method for enhancing solubility

and bioavailability

Large scale production and sterilization 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

Success is evident by increase in the commercially

available products of nanosuspensions in the near

future

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References

1. Rainbow B. E., Nanosuspensions in drug delivery, Nature reviews Drug discovery, 3 (2004) 785-796

2. Patravale V. B., Date A. A. and Kulkarni R. M., Nanosuspensions: a promising drug delivery strategy, Journal of Pharmacy and Pharmacology, 56 (2004) 827-840

3. Arunkumar N, Deccaraman M and Rani C, Nanosuspension technology and its application in drug delivery, Asian journal of Pharmaceutics, July-Sept 2009, 168-173

4. Muller R. H., Jacobs C., Kayser O., Nanosuspensions as particulate drug formulations in therapy Rational for development and what we can expect for the future, Advance drug delivery reviews, 47 (2001) 3-19

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References

5. Arunkumar et al, Preparation and solid state characterization of Atrovastatin nanosuspension for enhanced solubility and dissolution, International journal of pharmtech research 1 (2009) 1725-1730

6. Leversidge M. E., Leversidge G. G. and Cooper E. R., Nanosizing: a formulation approach for poorly-water –soluble compounds, European journal of pharmaceutical science ,18 (2003) 113-120

7. Rainbow B. E., Nanosuspension for parentral delivery; Thassu D., Deleers M., and Pathak Y. (Eds), Nanoparticulate drug delivery, Informa healthcare publication, vol. 166, 33-48

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References

8. Keck C. M. and Muller R. H., Drug nanocrystals of poorly soluble drugs produced by high pressure homogenization, European journal of Pharmaceutics and Biopharmaceutics 62 (2006) 3-16

9. Jia L. Et al, Effect of Nanonization on Absorption of 301029: Ex Vivo and In Vivo Pharmacokinetic Correlations Determined by Liquid Chromatography/Mass Spectrometry Pharmaceutical Research, 19 (2002) 1091-1097

10. Kayser O. Nanosuspensions for the formulation of aphidicolin to improve drug targeting effects against Leishmania infected macrophages, International Journal of Pharmaceutics ,196 (2000) 253–256

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References

11. Date A. A. and Patravale V. B., Current strategies for engineering drug nanoparticles, Current opinion in colloid & interface science 9 (2004) 222 – 235.

12. Keck C. M. and Muller R. H., Drug nanocrystals of poorly soluble drugs produced by high pressure homogenization, European journal of Pharmaceutics and Biopharmaceutics 62 (2006) 3 -16.

13. Leversidge E. M. et al, Nanosizing: a formulation approach for poorly water soluble compounds, European journal of pharmaceutical sciences 18 (2003) 113 – 120.

Thank you…

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