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Recent Innovations In Liquid Dosage Form-IIA Seminar On Presented By:SWAPNIL SANGHAVIRoll No. : 15Sem-II, M.Pharm.Department Of Pharmaceutics,Nootan Pharmacy College, Visnagar.1

NANOSUSPENSIONINTRODUCTIONPREPARATIONEVALUATIONAPPLICATIONS2

MORE THAN 40% OF DRUGS ARE POORELY SOLUBLE IN WATER, SO THEY SHOW PROBLEMS IN FORMULATING THEM IN CONVENTIONAL DOSAGE FORMS.

FOR CLASS II DRUGS (e.g.-Itraconazole & Carbamazepine), WHICH ARE POORELY SOLUBLE IN AQUEOUS AND ORGANIC MEDIA, THE PROBLEM IS MORE COMPLEX.

VARIOUS APPROACHES TO RESOLVE PROBLEMS OF LOW SOLUBILITY AND LOW BIOAVAILABILITY - MICRONIZATION, CO-SOLVANCY, OILY SOLUTION, SALT FORMATION - SOME OTHER TECHNIQUES ARE LIPOSOMES, EMULSIONS, MICROEMULSION, SOLID DISPERSION, - CYCLODEXTRIN INCLUSION COMPLEX ETC.

MANY OF THESE TECHNIQUES ARE NOT UNIVERSALLY APPLICABLE TO ALL DRUGS OR ARE NOT APPLICABLE TO DRUGS WHICH ARE NOT SOLUBLE IN BOTH AQUEOUS & ORGANIC MEDIA. A DIFFERENT BUT SIMPLE APPROACH IS NEEDED TO TACKLE THE FORMULATION PROBLEM TO IMPROVE THEIR EFFICACY AND TO OPTIMIZE THE THERAPY WITH RESPECT TO PHARMACOKINETICS3NANOSUSPENSION

A pharmaceutical nanosuspension is defined as very finely dispersed solid drug particles in an aqueous or organic vehicle for either oral and topical use or parenteral and pulmonary administration.

The particle size distribution of the solid particles in nanosuspensions is usually less than one micron with an average particle size ranging between 200 and 600 nm.

Nanosuspensions differ from nanoparticles.Nanoparticles are commonly polymeric colloidal carriers of drugs whereas solid lipid nanoparticles are lipidic carriers of drugs. In nanosuspension technology, the drug is maintained in the required crystalline state with reduced particle size, leading to an increased dissolution rate and therefore improved bioavailability.

4Nanosuspension:

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Bottom Up technology6

Main advantage is the use of simple and low cost equipments.

Basic challenge is that during the precipitation procedure growing of the crystals need to be controlled by addition of surfactant to avoid formation of microparticles.

Limitation of this precipitation technique is that the drug needs to be soluble in at least one solvent and the solvent needs to be miscible with non-solvent.Moreover,It is not applicable to the drugs, which are poorly soluble in both aqueous and non-aqueous media.7

Top Down Approaches8

Media MillingThe nanosuspensions are prepared by using high shear media mills. The milling chamber charged with milling media, water, drug & stabilizer is rotated at very high shear rate under controlled temp. for 2-7 days.The milling medium is composed of glass, zirconium oxide or highly cross-linked polystyrene resin. The high energy shear forces are generated as a result of impaction of milling media with the drug resulting into breaking of microparticulate drug to nanosized particles.

The major concern with this method is the residues of milling media remaining in the finished product could be problematic for administration9

ADVANTAGES OF MEDIA MILLINGapplicable to the drugs that are poorly soluble in both aqueous and organic media.Very dilute as well as highly concentrated nanosuspensions can be prepared by handling 1mg/ml to 400mg/ml drug quantity.DISADVANTAGES OF MEDIA MILLING1. Nanosuspensions contaminated with materials eroded from balls may be problematic when it is used for long therapy. 2. The media milling technique is time consuming. 3. Some fractions of particles are in the micrometer range. 4. Scale up is not easy due to mill size and weight. 10

High pressure Homogenisation in Water(Dissocubes) The instrument can be operated at pressure varying from 100 1500 bars (2800 21300psi) and up to 2000 bars with volume capacity of 40ml (for laboratory scale).

Have to be started with micronized drug particle size less than 25 to prevent blocking of homogenization gap.

So it is essential to prepare a presuspension of the micronized drug in a surfactant solution using high speed stirrer.11

High pressure homogenizerCavitation, High shear forces and collision of particles against each other

The drug suspension, contained in a cylinder of diameter about 3 mm, passes suddenly through a very narrow homogenization gap of 25 m, which leads to a high streaming velocity.

In the homogenization gap, according to Bernoullis equation, the dynamic pressure of the fluid increases with the simultaneous decrease in static pressure below the boiling point of water at room temperature.12

- water starts boiling at room temperature, leading to the formation of gas bubbles, which implode when the suspension leaves the gap (called Cavitation) and normal air pressure is reached again.

- The implosion forces are sufficiently high to break down the drug microparticles into nanoparticles.

- Additionally, the collision of the particles at high speed helps to achieve the nano-sizing of the drug.

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Advantages Drugs that are poorly soluble in both aqueous and organic media can be easily formulated into nanosuspensions.

Ease of scale-up and little batch-to-batch variation

Narrow size distribution of the nanoparticulate drug present in the final product.

Allows aseptic production of nanosuspensions for parenteral administration.

Flexibility in handling the drug quantity, ranging from 1 to 400mg/mL, thus enabling formulation of very dilute as well as highly concentrated nanosuspensions.Disadvantages Prerequisite of micronized drug particles.

Prerequisite of suspension formation using high-speed mixers before subjecting it to homogenization14

Homogenisation In Nonaqueous Media (Nanopure) The drugs that are chemically labile can be processed in such non-aqueous media or water-miscible liquids like polyethyleneglycol-400 (PEG), PEG1000 etc. The homogenization can be done at room temperature, 0o C and below freezing point (-20o C). 15

Combined Precipitation And Homogenization (Nanoedege)Precipitated drug particles(nanosize desired)

Continues to grow till microcrystal sizeSo the precipitated particle suspension is subsequently homogenized which preserve the particle size obtained after the precipitation step.16

Emulsification - Solvent Evaporation Technique17

Evaluation of NanosuspensionsIn-Vitro Evaluation -Particle size & Size Distribution -Particle Charge (Zeta potential) -Crystalline state & Morphology -Saturation Solubility & Dissolution Velocity

In- Vivo Evaluation -Surface Hydrophobicity -Interaction with Body Protein18

193 nm to 3 m0.052000 m

Particle Charge ( zeta potential)Gives idea about physical stability of the NanosuspensionElectrostatically stabilized nanosuspension

>+30 eVElectrostatic & Steric stabilization>+20eV

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Crystalline State and Particle MorphologyDifferential Scanning Calorimetry Crystalline StructureX- Ray DiffractionChange in physical state and extent of amorphous drug.

21SCANNING ELECTRON MICROSCOPY

Saturation solubility & Dissolution VelocityHelp to anticipate In-vivo performance

blood profiles, plasma peaks, bioavailability22

APPLICATIONSOral applications:23

e.g.:IMPROVED BIOAVAILABILITY1) Atovaquone 10-15% bioavailable high dose (750mg, twice a day)NANOSUSPENSION 2.5 FOLD INCREASE IN BIOAVAILABILITY

2) Danazole poorly soluble gonadotropin inhibitorMarketed Suspension(Danocrine) 5.2% BioavailabilityNANOSUSPENSION 82.5% BIOAVAILABILITY

QUICK ONSET OF ACTION:

3) NAPROXEN, an NSAID

24Swapnil Sanghavi

2) Parenteral Applications:Since the drug particles are directly nanosized, it becomes easy to process almost all drugs for parenteral administration.

Moreover, the absence of any harsh solvents/co-solvents and/or any potentially toxic ingredient in nanosuspensions enables them to bypass the limitations of parenteral administration attributed to conventional formulations strategies.

Hence, nanosuspensions enable significant improvement in the parenterally tolerable dose of the drug, leading to a reduction in the cost of the therapy and also improved therapeutic performance25

e.g. :

1)The maximum tolerable dose of paclitaxel nanosuspension was found to be three times higher than the currently marketed Taxol, which uses Cremophore EL and ethanol to solubilize the drug.

Paclitaxel nanosuspensions at doses of 90 and 100mg/kg showed no cases of death , whereas Taxol at a concentration of 30mg/ kg showed a 22% death rate.26

OCULAR APPLICATIONS:

Nanosuspensions, by their inherent ability to improve the saturation solubility of the drug, represent an ideal approach for ocular delivery of hydrophobic drugs.

Moreover, the nanoparticulate nature of the drug allows itsprolonged residence in the cul-de-sac, giving sustainedrelease of the drug.

To achieve sustained release of the drug for a stipulated time period, nanosuspensions can be incorporated in a suitable hydrogel base or mucoadhesive base or even in ocular inserts.27

PULMONRARY APPLICATIONS:

The nanoparticulate nature of the drug allows the rapid diffusion and dissolution of the drug at the site of action.At the same time, the increased adhesiveness of the drug to mucosal surfaces offers a prolonged residence time for the drug at the absorption site.This ability of nanosuspensions to offer quick onset of action initially and then controlled release of the active moiety is highly beneficial and is required by most pulmonary diseases

e.g.: Budesonide, a poorly water-soluble corticosteroid, hasbeen successfully formulated as a nanosuspension for pulmonary delivery28

Patented technologies for Preparation:29

MARKETED NANOSUSPENSIONS:

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31Microsuspension is a registered trademark used for Aqueous Solutions Sold As a Component of Veterinary Pharmaceutical Preparations For Use In the Treatment of Respiratory Disease In Livestock and owned by G. C. Hanford Manufacturing Company.

Drug is in micro size range.

No significant advantages over the macrosuspension or Nanosuspension.

Same methods of preparation as the Nanosuspension.

MICROSUSPENSION (?)

Questions asked

Write a Note On Nanosuspension5m(GTU remedial- Dec 2010)32

REFERENCES Jiraporn CHINGUNPITUK, Nanosuspension Technology for Drug Delivery, Walailak J Sci & Tech 2007; 4(2): 139-153.

V. B. Patravale, Abhijit A. Date and R. M. Kulkarni, Nanosuspensions: a promising drug delivery strategy JPP 2004, 56: 827840

Rong Liu Water-Insoluble Drug Formulation Second Edition, page no. 122-123

Nanoparticle Technology for Drug Delivery, edited by Ram B. Gupta and Uday B. Kompella

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34What the caterpillar calls THE END, Butterfly calls it.THE BEGINNING !!!SWAPNIL M. SANGHAVI NPC, VISNAGAR