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Nanosuspensions
Presented by : Mr. Satish S. Reddi
Guided by : Dr. M. R. Bhalekar
AISSMS COLLEGE OF PHARMACY, PUNE
04/08/2023 01:47:12 PM 2
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
04/08/2023 01:47:12 PM 4
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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Bottom up technology
Drug Solvent
Drug solution
Antisolvent
Precipitation
Nanosuspension
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Bottom up technology
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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Melt emulsification method
Drug melt
High Pressure
Homogenization
Primary emulsion
Solvent
Cooling
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Melt emulsification method
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
04/08/2023 01:47:15 PM 34
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
04/08/2023 01:47:15 PM 36
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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Sterilization aspects of nanosuspension
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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Sterilization aspects of nanosuspension
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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Sterilization aspects of nanosuspension
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.
04/08/2023 01:47:15 PM 40
Sterilization aspects of nanosuspension
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.
04/08/2023 01:47:15 PM 41
Sterilization aspects of nanosuspension
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.
04/08/2023 01:47:15 PM 42
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
04/08/2023 01:47:16 PM 43
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.
04/08/2023 01:47:16 PM 44
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
04/08/2023 01:47:16 PM 45
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
04/08/2023 01:47:16 PM 46
Characterization test
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
04/08/2023 01:47:16 PM 47
Characterization test
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.
04/08/2023 01:47:16 PM 48
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
04/08/2023 01:47:16 PM 49
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
04/08/2023 01:47:16 PM 50
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
04/08/2023 01:47:16 PM 51
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
04/08/2023 01:47:17 PM 52
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
04/08/2023 01:47:17 PM 53
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
04/08/2023 01:47:17 PM 54
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
04/08/2023 01:47:17 PM 55
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
04/08/2023 01:47:17 PM 56
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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