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A SEMINAR ON

NANOSUSPENSIONPresented by,

OMKAR S. BHANDWALKAR M. Pharm. Sem.-I,

Under the guidance of,

Asso. Prof. Dr. P. K. PAWAR

Head of Department,

Dept. of Pharmaceutics

Gourishankar Institute of Pharmaceutical Education and

Research, Limb, Satara.

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CONTENTS

Introduction Need of Nanosuspension Advantages of Nanosuspension Disadvantages of Nanosuspension Method Of Preparation Formulation Considerations Characterization of Nanosuspension Current Marketed Formulations Pharmaceutical Applications Conclusion References

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INTRODUCTION

Definition:“A very finely dispersed solid drug particles in an aqueous

vehicle in which diameter of suspended particle is less than 1 µm in size, stabilized by surfactants, for either oral and topical use or parentral and pulmonary administration, with reduced particle size, leading to an increased dissolution rate and therefore improved bioavailability”.

Average particle size ranges from 200-600 nm.

In nanosuspension technology, the drug is maintained in the required crystalline state with reduced particle size, Improved bioavailability leading to an increased dissolution rate.

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NEED OF NANOSUSPENSION

Poor bioavailability. Lack of dose-response proportionality . Use of harsh excipients, i.e., excessive use of

co-solvents and other excipients . Use of extreme basic or acidic conditions to

enhance solubilization Use for poorly water soluble as well as poorly organic

soluble drugs

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ADVANTAGES

Can be applied for the poorly water soluble drugs. Rapid dissolution and tissue targeting can be achieved by IV route of administration. Oral administration of nanosuspensions provide rapid and improved bioavailability. Long-term physical stability due to the presence of stabilizers. Nanosuspensions can be incorporated in tablets, pellets, hydrogels.

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DISADVANTAGES

Physical stability, sedimentation and compaction can

causes problems.

It is bulky sufficient care must be taken during

handling and transport.

Uniform and accurate dose cannot be achieved unless

suspension .

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METHODS OF PREPARATION 1) PRECIPITATION METHOD

2) MICROEMULSION TEMPLATE

3) MEDIA MILLING

4) HIGH PRESSURE HOMOGENIZATION

5) HOMOGENIZATION IN AQ. MEDIA

6) HOMOGENIZATION IN NON AQ. MEDIA

7) NANOJET TECHNOLOGY

8) NANOEDGE

9) SUPERCRITICAL FLUID METHOD

10) SOLVENT EVAPORATION METHOD

11) CO-GRINDING METHOD

1. PRECIPITATION METHOD

drug + organic solvent mixed with

miscible antisolvent

precipitation

Advantages: •Simple Process•Low cost of Equipments

Disadvantages: •Drug needs to be soluble in at least one solvent and this solvent needs to be miscible with nonsolvent•Crystal Growth

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2) MICROEMULSIONS TEMPLATE:

Dispersion of two immiscible liquids

Stabilized by Surfactant or Cosurfactant

Advantages :-High Drug Solubilization, Long Shelf-life And Ease Of Manufacture

Uniform particle distribution

Disadvantages:Requires high amount of Surfactants and Stabilizers

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3) MELT EMULSIFICATION METHOD

Drug + Aq. Solution having stabilizer

Heated this solution above Melting Point of Drug

Homogenized by High Pressure Homogenizer for formation of Emulsion

Emulsion is cooled to Precipitate

Advantages :-Avoidance of organic solvent

Disadvantages:

Formation of large particles

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4) MEDIA MILLING:

Advantages:Drugs that are poorly soluble in both aqueous and organic

media

Disadvantages:Nanosuspension contaminated with materials eroded from balls

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The Nanosuspension is prepared by high share media mills. The milling Chamber charged with Milling media, Water, Drug, Stabilizer is rotated at very high shear rate at controlled temperature.The milling medium is composed of Glass, Zirconium oxide and highly cross linked polystyrene resin.

5) HIGH PRESSURE HOMOGENIZATION

AdvantagesLow Risk Of Product Contamination

Allows Aseptic Production of Nanosuspensions For Parenteral

Administration

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Drug + Stabilizer to form Presuspension

Presuspension is homogenized by High Pressure homogenizer at low

pressure

Homogenized at high pressure

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HIGH PRESSURE HOMOGENIZATION

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6) HOMOGENIZATION IN AQUEOUS MEDIA

Forcing the of the suspension under pressure through a narrow aperature valve.

Dissocubes was developed by Muller et al in 1999.

This instrument can be operated at pressure varying from 100-1500 bars (2800-21300 psi)

7) HOMOGENIZATION IN NON-AQUEOUS MEDIA

The drug suspensions in the non- aqueous media were homogenized at 0º C or even below the freezing point and hence are called Deep-freeze homogenization

Advantages :

Evaporation is faster and under milder conditions. This is useful for temperature sensitive drugs.

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8) NANOJET TECHNOLOGY

This technique uses a chamber where stream of suspension divided into more parts which colloid with each other at high pressure.

The high shear force produced during process results in particle size reduction.

Disadvantage: obtained product contains larger particles of microemulsion.

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9) NANOEDGE It is a combined method of Precipitation and

Homogenization. The drug is dissolved in an organic

solvent and this solution is mixed with a miscible anti-solvent for precipitation.

The precipitated particle suspension is homogenized.

Advantage: Drawback of the precipitation technique, such as crystal growth and long-term stability, can be resolved

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10) SUPERCRITICAL FLUID METHOD

In this process micronization of drug particles within narrow range of particle size is carrird out.

It forms particles size range 5-2000 nm in diameter.

Disadvantage:Surfactants in Supercritical CO2 and high pressure requires

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11) SOLVENT EVAPORATION METHOD

Drug + Polymer in organic solvent

Dropped by syringe in dist. water containing surfactant

Homogenized using magnetic stirrer

Solvent removal by air drying

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SOLVENT EVAPORATION METHOD

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CO-GRINDING METHOD

Nanosuspension is also prepared by dry milling techniques.

In this method, dry grinding of poorly water soluble drugs with soluble polymers and copolymers are dispersing in liquid medium.

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FORMULATION CONSIDERATIONS

Stabilizer:-

Lecithine, PVPK 30, PVA, SLS, Poloxamers, Polysorbates,

Organic solvents:-

water miscible solvents:- ethanol & isopropanol

Partially water miscible :- ethyl acetate, ethyl formate,butyl lactate, triacetin,

propylene carbonate & benzyl alcohol Surfactants:-Tweens and Spans - widely used surfactants

Co-surfactants:-

Transcutol, glycofurol, ethanol ,iso-propanol , bile salts Dipotassium

glycerrhizinate etc.

Other additives:-

Buffers (acetate, phosphate)

cryprotectants (sucrose as sugar)

In vitro Evaluations: Mean particle size and size distribution:•The mean particle size distribution and its ranges named Polydispersity index (PI) is measured by Laser Diffractometry (LD), Photon Correlation Spectroscopy and Coulter Counter method. PI gives the physical stability. A PI value 0.1 – 0.25 shows narrow size distribution.•LD can detect and quantify drug microparticles and also gives volume size distribution.•The Coulter counter gives the absolute no. of particles per volume for the different size classes.

Drug Entrapment Efficiency:

Initial Drug – Free DrugEntrapment Efficiency (%) = × 100

Initial Drug

Transmission Electron Microscopy (TEM):For the morphological evaluation of nanoparticles.Fourier Transform Infrared Spectroscopy (FTIR):

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CHARACTERIZATION OF NANOSUSPENSION

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X-ray Powder Diffraction (XPRD):Differential Scanning Calorimetry (DSC):Particle charge (Zeta Potential):

Particle charge determines the stability of nanosuspension.

For electrostatically stabilized nanosuspension a minimum zeta potential of ±30 mV

In Vitro Drug Release: Saturation Solubility: Stability Study: In Vivo Evaluation:

CHARACTERIZATION OF NANOSUSPENSION

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CURRENT MARKETED FORMULATION

Sr. no. Product Drug Compound Company1 RAPAMUNE Sirolimus Wyeth2 EMEND® Aprepitant Merck3 TriCor® Fenofibrate Abbott4 MEGACE®ES Megestrol Acetate PAR

Pharmaceutical5 Avinza® Morphine

SulphateKing Pharmaceutical

6 Focalin®XR Dexmethylphenidate Hydrochloride

Novartis

PHARMACEUTICAL APPLICATIONS

Oral Drug Delivery

Parental Administration

Ophthalmic Drug Delivery

Pulmonary drug Delivery

Target Drug Delivery

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CONCLUSION

Nanosuspension solved the poor bioavailability problems of poorly water as well

as organic soluble drugs. Media milling and High Pressure Homogenizer are used for

large scale production of Nanosuspension. Nanosuspension can be administered

through Oral, Parenteral, Pulmonary and Ocular routes. Nanosuspension is simple,

less requirements of excipients, increased dissolution rate and saturation solubility.

Patel, V., Agrawal, Y., 2011. Nanosuspension: An Approach to Enhance Solubility of Drugs. Journal of Advance Pharmaceutical Technology, 81-87.

Shid, R., Dhole, S., Kulkarni, N., Shid, S.,2013. Nanosuspension: A Review. International Journal of Pharmaceutical Sciences Review and Research, 98-106Mudgil, M., Pawar, P., 2013. Preparation and In Vitro/Ex Vivo Evaluation of Moxifloxacin-Loaded PLGA Nanosuspension for Opthalmic Application. Scientia Pharmaceutica, 591-606.Kamble, V., Jagdale, D., Kadam, V., 2010. Nanosuspension A Novel Drug Delivery system. International Journal of Pharma and Bio Sciences, 352-360.Wagh, K., Patil, S., Akarte, A., Baviskar, D., Nanosuspension- A New Approach of Bioavailability Enhancement. International Journal of Pharmaceutical Sciences Review and Research, 61-65.

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REFERENCES

THANK YOU

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