Prepared by

Guided by:

MAYURI B .YADAV

PROF. Dr. S. N. DHOLE

FIRST SEMESTER, M.PHARM,

ASSO. PROFFESOR

DEPT OF PHARMA...
CONTENTS…..











12/13/2013

Introduction
Formulation
Properties Of Nanosuspensions
Method Of Preparation
...
INTRODUCTION

Definition :
A pharmaceutical nanosuspension is defined as “very finely
dispersed solid drug particles in an...
Need of Nanosuspension
More than 40% of drugs are poorly soluble in water, so they show problems in
formulating them in co...
Major Advantages of Nanosuspensions

 Can be applied for the poorly water soluble drugs.
 Reduced tissue irritation in c...
Disadvantages :
Physical stability, sedimentation and compaction can causes problems.
It is bulky sufficient care must b...
FORMULATION CONSIDERATIONS

 Stabilizer:lecithine,PVPK30,PVA,SLS,Cellulosics,Poloxamers,Polysorbates,

Lecithin

and

Pov...
Cont……
 Co-surfactants:Transcutol, glycofurol, ethanol ,iso-propanol , bile salts Dipotassium

glycerrhizinate etc.
 Oth...
Properties of Nanosuspensions
Physical Long-term stability
Internal structure of Nanosuspensions
Adhesiveness
Crystall...
METHOD OF PREPRATION

12/13/2013

10
Method of preparation

12/13/2013

11
Microemulsions
as Templates

Bottom up
Technology

Techniques to
prepare
Nanosuspensions

Emulsions as
Templates

Hydrosol...
Bottom up Technology: (Hydrosols)
the drug + organic solvent
Mixed with

miscible antisolvent
water-solvent mixture the dr...
Media milling (NanoCrystals)
Principle
The high energy and shear forces
generated the impaction of the
milling media with ...
High pressure homogenization
R.H.Muller developed Dissocubes technology in 1999
Operated at pressure varying from 1000-150...
Homogenization in non-aqueous media
Nanopure
the drug suspensions in the non- aqueous media were homogenized at 0º C
or ev...
Combined precipitation and homogenization
(Nanoedge)
The drug is dissolved in an organic solvent and this solution is mixe...
Nanojet technology
Principle :
Emulsions as templates Apart from the
use of emulsions as a drug delivery
vehicle,they can ...
Microemulsions as templates

(Eccleston 1992)..

Principle :
The drug can be either loaded in the internal phase or pre-fo...
EVALUATION PARAMETER

Evaluations of
Nanosuspensions

In Vitro Evaluation

In Vivo Evaluation

 Particle size & distribut...
In vitro Evaluations
 Mean particle size and size distribution:
The mean particle size and the width of particle size dis...
Saturation solubility and dissolution velocity:
Saturation solubility is compound specific constant depending upon
temper...
 In Vivo Evaluation
Generally the formulations are administered by required route and the plasma
drug concentrations are ...
CURRENT MARKETED FORMULATION
Sr. no.

Product

Drug Compound

Company

1

RAPAMUNE

Sirolimus

Wyeth

2

EMEND®

Aprepitan...
12/13/2013

25
PHARMACEUTICAL APPLICATIONS

 Oral Drug Delivery
 Parental Administration
 Ophthalmic Drug Delivery
 Pulmonary drug De...
CONCLUSION
Nanosuspensions appear to be a unique and yet commercially viable
approach to poor bioavailability that are ass...
Geeta V. Yadav* And Sushma R. Singh A Review Article On Nanosuspension: A
Promising Drug Delivery System Pharmacophore (A...
Patravale V. B., Date A. And Kulkarni R. M. A Review Article On Nanosuspensions: A
Promising Drug Delivery Strategy Journ...
12/13/2013

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  1. 1. Prepared by Guided by: MAYURI B .YADAV PROF. Dr. S. N. DHOLE FIRST SEMESTER, M.PHARM, ASSO. PROFFESOR DEPT OF PHARMACEUTICS DEPT OF PHARMACEUTICS Modern College Of Pharmacy (For Ladies), Moshi, Pune 12/13/2013 2
  2. 2. CONTENTS…..           12/13/2013 Introduction Formulation Properties Of Nanosuspensions Method Of Preparation Evaluation Parameter Current Marketed Formulation Literature Survey Pharmaceutical Applications Conclusion References 2
  3. 3. INTRODUCTION Definition : A pharmaceutical nanosuspension is defined as “very finely dispersed solid drug particles in an aqueous vehicle, 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 200-600nm.  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.. 12/13/2013 3
  4. 4. Need of Nanosuspension More than 40% of drugs are poorly soluble in water, so they show problems in formulating them in conventional dosage forms. Also, for class II which poses a significant challenge for the formulators. Major issues associated with poorly water-soluble compounds Poor bioavailability. Fed/fasted variation in bioavailability . Lack of dose-response proportionality . Suboptimal dosing . Use of harsh excipients, i.e., excessive use of co-solvents and other excipients . Use of extreme basic or acidic conditions to enhance solubilization 12/13/2013 4
  5. 5. Major Advantages of Nanosuspensions  Can be applied for the poorly water soluble drugs.  Reduced tissue irritation in case of subcutaneous/intramuscular administration.  Rapid dissolution and tissue targeting can be achieved by IV route of administration.  Oral administration of nanosuspensions provide rapid and improved bioavailability.  Higher bioavailability and more consistent dosing in case of ocular administration and inhalation delivery .  Long-term physical stability due to the presence of stabilizers.  Nanosuspensions can be incorporated in tablets, pellets, hydrogels and suppositories 12/13/2013 5
  6. 6. 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 . 12/13/2013 6
  7. 7. FORMULATION CONSIDERATIONS  Stabilizer:lecithine,PVPK30,PVA,SLS,Cellulosics,Poloxamers,Polysorbates, Lecithin and Povidones.  Organic solvents:water miscible solvents:- ethanol & isopropanol Partially water miscible :- ethyl acetate, ethyl formate,butyl lactate, triacetin, propylene carbonate & benzyl alcohol  Surfactants:Example: Tweens and Spans - widely used surfactants 12/13/2013 7
  8. 8. Cont……  Co-surfactants:Transcutol, glycofurol, ethanol ,iso-propanol , bile salts Dipotassium glycerrhizinate etc.  Other additives:Buffers (acetate, phosphate) cryprotectants (sucrose as sugar) osmogent (mannitol, sorbitol). 12/13/2013 8
  9. 9. Properties of Nanosuspensions Physical Long-term stability Internal structure of Nanosuspensions Adhesiveness Crystalline state and morphology  Increase in Saturation Solubility and Dissolution Velocity of drug Nanosuspension Provide passive targeting Nanosuspension provide Versatility Nanosuspension enhance Bioavailability Nanosuspension provide Long-term physical stability 12/13/2013 9
  10. 10. METHOD OF PREPRATION 12/13/2013 10
  11. 11. Method of preparation 12/13/2013 11
  12. 12. Microemulsions as Templates Bottom up Technology Techniques to prepare Nanosuspensions Emulsions as Templates Hydrosols Top down Technology Media Milling Nanocrystals 12/13/2013 High pressure homogenization in water DissoCubes High pressure homogenization in non aqueous solvents Nanopure Combined precipitation and HPH Nanoedge 12
  13. 13. Bottom up Technology: (Hydrosols) the drug + organic solvent Mixed with miscible antisolvent water-solvent mixture the drug precipitates Limitation the drug needs to be soluble in at least one solvent and this solvent needs to be miscible with nonsolvent. Top Down Technology Media Milling (Nanocrystals),  High Pressure Homogenization in water (Disso cubes),  High Pressure Homogenization in non aqueous media (Nanopure) combination of Precipitation and High-Pressure Homogenization (Nanoedege) . 12/13/2013 13
  14. 14. Media milling (NanoCrystals) Principle The high energy and shear forces generated the impaction of the milling media with the drug provide the energy input to break the microparticulate drug into nano-sized particles. The milling medium is composed of glass, zirconium oxide or highly cross-linked polystyrene resin. mean diameters<200nm is 30–60 min. Advantages: Drugs that are poorly soluble in both aqueous and organic media little batch-to-batch variation. Narrow size distribution of the final nano-sized product. 12/13/2013 Liversidge et al. (1992). Fig, Schematic representation of the media milling process Limitations : The major concern is the generation of residues of milling media, which may be introduced in the final product as a result of erosion. 14
  15. 15. High pressure homogenization R.H.Muller developed Dissocubes technology in 1999 Operated at pressure varying from 1000-1500 bars (2800–21300psi) and up to 2000 bars with volume capacity of 40ml (for laboratory scale). Principle : Based on cavitation in the aqueous phase. The particles cavitations forces are sufficiently high to convert the drug micro particles into nano particles. The concern with this method is the need for small sample particles before loading and the fact that many cycles of homogenization are required Advantages Figure:- the high-pressure homogenization process Disadvantages :  Prerequisite of micronized drug Narrow Size Distribution Of The particles. Nanoparticulate Drug Present In The Final Product  Prerequisite of suspension formation Allows Aseptic Production Of Nanosuspensions using high-speed mixers before subjecting 12/13/2013 15 For Parenteral Administration Low Risk Of Product Contamination
  16. 16. Homogenization in non-aqueous media Nanopure 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 : The dispersion medium need not be removed. Evaporation is faster and under milder conditions. This is useful for temperature sensitive drugs. For i.v. injections, isotonic nanosuspensions are obtained by homogenizing in water-glycerol mixtures. 12/13/2013 16
  17. 17. Combined precipitation and homogenization (Nanoedge) The drug is dissolved in an organic solvent and this solution is mixed with a miscible anti-solvent for precipitation. In the water-solvent mixture, the solubility is low and the drug precipitates. Precipitation has also been coupled with high shear processing. Advantages The major drawback of the precipitation technique, such as crystal growth and long-term stability, can be resolved using the Nanoedge technology 12/13/2013 17
  18. 18. Nanojet technology Principle : Emulsions as templates Apart from the use of emulsions as a drug delivery vehicle,they can also be used as templates to produce nanosuspensions .The emulsions templates is applicable for those drugs that are soluble in either volatile organic solvent or partially water-miscible solvent. An organic solvent or mixture of solvents loaded with the drug is dispersed in the aqueous phase containing suitable surfactants to form an emulsion The organic phase is then evaporated under reduced pressure so that The drug particles precipitate instantaneously to form a nanosuspension stabilized by surfactants.. Advantages : Use of specialized equipment is not necessary.  Particle size can easily be controlled by controlling the size of the emulsion droplet.  Ease of scale-up if formulation is 12/13/2013 optimized properly.  •Disadvantages Safety concerns because of the use of hazardous solvents in the process. High amount of surfactant/stabilizer is required as compared to the production techniques described earlier. 18
  19. 19. Microemulsions as templates (Eccleston 1992).. Principle : The drug can be either loaded in the internal phase or pre-formed microemulsions can be saturated with the drug by intimate mixing.The suitable dilution of the microemulsion yields the drug nanosuspension by the mechanism described earlier. Advantages :High Drug Solubilization, Long Shelf-life And Ease Of Manufacture, Make Them An Ideal Drug Delivery Vehicle. Need For Less Energy Input For The Production Of Nanosuspensions By Virtue Of Microemulsions. 12/13/2013 19
  20. 20. EVALUATION PARAMETER Evaluations of Nanosuspensions In Vitro Evaluation In Vivo Evaluation  Particle size & distribution  Particle charge (zeta Potential)  Crystalline state & Morphology Saturation solubility & dissolution rate  Solubility 12/13/2013 Evaluation of surface modified Surface hydrophilicity  Adhesion properties  Interaction with body proteins 20
  21. 21. In vitro Evaluations  Mean particle size and size distribution: The mean particle size and the width of particle size distribution called Polydidpersity Index are determined by Photon Correlation Spectroscopy (PCS). Laser Diffractometry (LD) particles ranging from 0.05- 80μm upto 2000µm. Atomic Force microscop is used for visualization of particle shape. Particle charge (Zeta Potential): Particle charge determines the stability of nanosuspension. For electrostatically stabilized nanosuspension a minimum zeta potential of ±30mV  Crystalline state and particle morphology: Differential Scanning colorimeter (DSC) determines the crystalline structure.. The X-Ray Diffraction[30] (XRD) is also used for determining change in physical state and extent of amorphous drug. Scanning electron microscopy is also used to get exact information about particle morphology. 12/13/2013 21
  22. 22. Saturation solubility and dissolution velocity: Saturation solubility is compound specific constant depending upon temperature and the properties of dissolution medium. Kelvin equation and the Ostwald-Freundlich equations can explain increase in saturation solubility  Stability : stabilizers are used to decrease the chances of Ostwald ripening and to improve the stability of the suspension by providing a steric or ionic barrier. Stabilizers like cellulosic, Poloxamers, Polysorbates, lecithin, polyoleate and Povidones are generally used in the nanosuspensions. PH: Drug content: Total volum of nanosuspension = total volum of nanosuspension x amount of drug in aliquot/volum of aliquot 12/13/2013 22
  23. 23.  In Vivo Evaluation Generally the formulations are administered by required route and the plasma drug concentrations are determined by HPLC-UV visible spectrophotometry. Surface hydrophilicity/hydrophobicity (which determines interaction with cells prior to phagocytosis), adhesion properties and the interaction with body proteins are generally evaluated by in vivo parameters Interaction with body proteins : In vitro interaction between nanoparticles and mucin can be studied by incubation of mucin and nanoparticles (1:4 weight ratio) either in acidic or in neutral medium. The incubation is carried out under stirring at temperature of 37ºC. The dispersions is then be centrifuged, is incubated for 2 h at 37º C. According to this procedure, the absorbance of mucin can be measured by colorimetry at λmax of the drug. 12/13/2013 23
  24. 24. CURRENT MARKETED FORMULATION Sr. no. Product Drug Compound Company 1 RAPAMUNE Sirolimus Wyeth 2 EMEND® Aprepitant Merck 3 TriCor® Fenofibrate Abbott 4 MEGACE®ES Megestrol Acetate PAR Pharmaceutical 5 Avinza® Morphine Sulphate King Pharmaceutical 6 Focalin®XR Dexmethylphenidate Novartis Hydrochloride 7 Ritalin® Methylphenidate Novartis Hydrochloride 8 LA.Zanaflex 12/13/2013 Tizanidine CapsulesTM Hydrochloride Acorda 24
  25. 25. 12/13/2013 25
  26. 26. PHARMACEUTICAL APPLICATIONS  Oral Drug Delivery  Parental Administration  Ophthalmic Drug Delivery  Pulmonary drug Delivery  Target Drug Delivery  Topical Formulations  Mucoadhesion Of The Nanoparticles 12/13/2013 26
  27. 27. CONCLUSION Nanosuspensions appear to be a unique and yet commercially viable approach to poor bioavailability that are associated with the delivery of hydrophobic drugs, including those that are poorly soluble in aqueous as well as organic media. Production techniques such as media milling and high pressure homogenization have been successfully for large-scale production of nanosuspensions. Attractive features, such as increased dissolution velocity, increased saturation solubility, improved bioadhesivity, versatility in surface modification and ease of post-production processing, have widened the applications of nanosuspensions for various routes. 12/13/2013 27
  28. 28. Geeta V. Yadav* And Sushma R. Singh A Review Article On Nanosuspension: A Promising Drug Delivery System Pharmacophore (An International Research Journal)Pharmacophore 2012, Vol. 3 (5), 217-243 Nakarani M., Misra K., Patel K.,Vaghani S., Itraconazole Nanosuspension For Oral Delivery: Formulation, Characterization And In Vitro Comparison With Marketed Formulation Daru Vol. 18, No. 2 2010 84-91. Singh K.*, Chandra D., & Et.Al. Nanosuspension: Way To Enhance The Bioavailibility Of Poorly Soluble, International Journal Of Current Trends In Pharmaceutical Research Ijctpr, 2013: Vol. 1(4): 277-287 Shah M. , Dr. Patel N., Dr. M.R. Patel, Dr. K.R. Patel Nano Suspension: A Novel Approch For Drug Delivery System Journal Of Pharmaceutical Science And Bioscintific Research Volume 1,Issue 1: July-August 2011 (1-10) . Patravale V. B., Date A. And Kulkarni R. M. A Review Article On Nanosuspensions: A Promising Drug Delivery Strategy Journal Of Pharmaceutics And Pharmacology Jpp 2004, 56: 827–840 12/13/2013 28
  29. 29. Patravale V. B., Date A. And Kulkarni R. M. A Review Article On Nanosuspensions: A Promising Drug Delivery Strategy Journal Of Pharmaceutics And Pharmacology Jpp 2004, 56: 827–840 Jawahar* N., Subramanya Nainar Meyyanathan2, Venkatachalam Senthil1, Kuppusamy Gowthamarajan1,Kannan Elango3 Study On Studies On Physico-Chemical And Pharmacokinetic Properties Of Olanzapine Through Nanosuspension Vol 5(10)2013; 196-202. Chingunpituk J., A Review On Nanosuspension Technology For Drug Delivery Walailak J Sci & Tech 2007; 4(2): 139-153. Barrett E. Rabinow A Review On Characterization Of Drug Nanosuspensions Workshop On Characterization Of Nanomaterials For Medical And Health Applications May 19, 2005. Ana Maria Mendes Cerdeira State That Production And Stabilization Of NanosuspensionsOf Poorly Soluble Drug Substances 2007 ; 1-182 Debjit Bhowmik , G.Harish1, S.Duraivel , B. Pragathi Kumar , Vinod Raghuvanshi Nanosuspension -A Novel Approaches In Drug Delivery System Vol. 1 No. 12 2012 50-64. Ch.Prabhakar K.Bala Krishna A Review On Nanosuspensions In Drug Delivery International Journal Of Pharma And Bio Sciences Voi. 2 Jan-March 2011 ;549-560. 12/13/2013 29
  30. 30. 12/13/2013 30
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