2. Contents:
• NDDS Introduction
• About Nanoparticles
• Drug (Paclitaxel)& Polymer (HSA) Profile
• Developing Procedure for Paclitaxel Nanoparticles
• Evaluation Characteristics of Paclitaxel Nanoparticles
3. NDDS……………?
WHY I CALL “MAGIC BULLET”
Goals:
Provide a therapeutic amount of drug to targeted site of the body.
Maintain desire therapeutic efficacy of drug.
Minimize the levels of side effects.
4. Carriers Used for NDDS or TDD:
Carriers for transportation and retain of the loaded drug(s).
Colloidal carriers:
Vesicular systems: Liposomes; pharmacosomes; virosomes; immunoliposomes.
Micro particulate systems: Nanoparticles; Microparticles; Magnetic
Microspheres; Nanocapsules. Pramolecular delivery sys
Cellular carriers: Resealed erythrocytes; Serum albumin; Antibodies; Platelets;
Leukocytes.
Supramolecular delivery system:
Micelles; reverse micelles; mixed micelles; polymeric micelles; liquid crystal:
lipoproteins.
Polymer based systems:
Signal sensitive; muco-adhesive; biodegradable; bioerodable; solute synthetic
polymeric carriers.
6. INTRODUCTION ABOUT NANOTECHNOLOGY:
Nanotechnology is a broad interdisciplinary area of research, development and
industrial activity.
NANOPARTICLES:
Nanoparticles are the end products of a wide variety of physical, chemical and
biological processes some of which are novel and radically different, others of which
are quite commonplace.
Nanoparticles may be defined as submicron (<1µm) colloidal systems, generally, but
not necessarily, made of polymers (biodegradable or not).
7. Thus, this term is some what general, since it does not take into account the
morphology and structural organization of the system.
According to the process used for the preparation of Nanoparticles,
Nanospheres or Nanocapsules can be obtained.
Nanocapsules are vesicular systems in which the drug is confined to a cavity
surrounded by a unique polymeric membrane.
Nanospheres are matrix systems in which the drug is dispersed throughout the
particles.
8. GOALS:
Control the particle size, surface properties and release of pharmacologically
active agents in order to achieve the site-specific action of the drug at the
therapeutically optimal rate and dose regimen.
Difference between Liposomes and Nanoparticles:
Liposomes Nanoparticles
Protecting drugs from degradation.
Less targeting to site of action.
Reduction toxicity or side effects.
Low encapsulation efficacy.
Rapid leakage of water soluble drug
in the presence of blood components
and poor storage stability.
Increase the stability of drugs.
More targeting to site of action.
Increase the encapsulation efficacy.
Minimize the leakage of water
soluble drug in the presence of blood
components.
9. Advantages of Nanoparticles:
Particle size and surface characteristics of Nanoparticles can be easily
manipulated to achieve both passive and active drug targeting after parenteral
administration.
They control and sustain release of the drug during the transportation and at the
site of localization
Subsequent clearance of the drug so as to achieve increase in drug therapeutic
efficacy and reduction in side effects.
Drug Loading is relatively high and drugs can be incorporated into the systems
without chemical reaction.
Site-specific targeting can be achieved by attaching targeting ligands to surface of
particles.
The system can be used for various routes of administration including oral, nasal,
parenteral, intra-ocular etc.,
10. Preparation of Nanoparticles:
Nanoparticles can be prepared from a variety of materials such as
proteins, polysaccharides and synthetic polymers.
The selection of this materials is dependent on many factors including:
Size of Nanoparticles required.
Inherent properties of the drug, e.g.: aqueous solubility and stability.
Surface characteristics such as charge and permeability.
Degree of biodegradability, biocompatibility and toxicity.
Drug release profile desired.
Antigenicity of the final product.
11. Methods for Preparation of Nanoparticles:
Nanoparticles have been prepared most frequency by three methods:
1.Dispersion of preformed polymers.
2.Polymerization of monomers.
3.Ionic gelation or Coacervation of hydrophilic polymers.
Other methods such as,
1.Supercritical Fluid Technology
2.Particle Replication in Non-wetting Templates (PRINT)
12. Dispersion of Performed Polymers:
Used to prepare biodegradable nanoparticles from PLA, PLGA and PCA.
This technique can be used in various ways such as
1.Solvent Evaporation Method
2.Spontaneous Emulsification or Solvent Diffusion Method
Polymerization Method:
In this method monomers are polymerized to form nanoparticles in an aqueous
solution.
This technique has been reported for making Polybutylcyanoacrylate or
Polyalkylcyanoacrylate nanoparticles.
Nanocapsules formation and their particle size depends on the concentration of
the surfactants and stabilizers used.
13. Coacervation or Ionic Gelation Method:
Much research has been focused on the preparation of nanoparticles using
biodegradable hydrophilic polymers such as chitosan, gelatin and sodium alginate.
Supercritical Fluid Technology:
Supercritical Fluid Technology has been investigated as an alternative to prepare
biodegradable micro and nanoparticles because supercritical fluids are
environmentally safe.
A supercritical fluid can be generally defined as a solvent at a temperature above
its critical temperature, at which the fluid remains a single phase regardless of
pressure.
Supercritical CO2 is the most widely used supercritical fluid because of its mild
critical conditions, non-toxicity, non-flammability and low price.
14. Applications of Nanoparticulate Delivery
Systems:
1. Tumor targeting using nanoparticulate delivery systems.
2. Reversion of multidrug resistance in tumour cells.
3. Nanoparticles for oral delivery of peptides and proteins.
4. Targeting of nanoparticles to epithelial cells in the GI tract using ligands.
5. Nanoparticles for gene delivery.
6. Nanoparticles for drug delivery into the brain.
15. ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for
injectable suspension) (albumin-bound)
Currently Marketed Paclitaxel
Nanoparticles:
DESCRIPTION
ABRAXANE for Injectable Suspension (paclitaxel protein-bound particles for
injectable suspension) is an albumin-bound form of paclitaxel with a mean particle
size of approximately 130 nanometers. Paclitaxel exists in the particles in a non-
crystalline, amorphous state.
ABRAXANE is supplied as a white to yellow, sterile, lyophilized powder for
reconstitution with 20mL of 0.9% Sodium Chloride Injection, USP prior to intravenous
infusion.
Each single-use vial contains 100 mg of paclitaxel and approximately 900 mg of
human albumin. Each milliliter (mL) of reconstituted suspension contains 5 mg
paclitaxel. ABRAXANE is free of solvents.
ABRAXIS BIOSCIENCE
Distributed by Abraxis Bioscience, LLC
Bridgewater, NJ 08807
16. Preparation for Intravenous Administration: ABRAXANE is supplied as
a sterile lyophilized powder for reconstitution before use. AVOID ERRORS,
READ ENTIRE PREPARATION INSTRUCTIONS PRIOR TO
RECONSTITUTION.
1. Aseptically, reconstitute each vial by injecting 20 mL of 0.9% Sodium
Chloride Injection, USP.
2. Slowly inject the 20 mL of 0.9% Sodium Chloride Injection, USP, over a
minimum of 1 minute, using the sterile syringe to direct the solution flow onto
the INSIDE WALL OF THE VIAL.
3. DO NOT INJECT the 0.9% Sodium Chloride Injection, USP, directly onto
the lyophilized cake as this will result in foaming.
4. Once the injection is complete, allow the vial to sit for a minimum of 5
minutes to ensure proper wetting of the lyophilized cake/powder.
5. Gently swirl and/or invert the vial slowly for at least 2 minutes until
complete dissolution of any cake/powder occurs. Avoid generation of foam.
6. If foaming or clumping occurs, stand solution for at least 15 minutes until
foam subsides.
17. Stability:
Unopened vials of ABRAXANE are stable until the date indicated on the package
when stored between 20ºC to 25ºC (68ºF to 77ºF), in the original package. Neither
freezing nor refrigeration adversely affects the stability of the product.
Stability of Reconstituted Suspension in the Vial:
Reconstituted ABRAXANE should be used immediately, but may be refrigerated at 2ºC
to 8ºC (36ºF to 46ºF) for a maximum of 8 hours if necessary. If not used immediately,
each vial of reconstituted suspension should be replaced in the original carton to protect
it from bright light. Discard any unused portion.
Stability of Reconstituted Suspension in the Infusion Bag:
The suspension for infusion prepared as recommended in an infusion bag should be
used immediately, but may be stored at ambient temperature (approximately 25º C) and
lighting conditions for up to 8 hours.
18. Drug Profile:
Drug Name: Paclitaxel
Molecular Formula: C47H51NO14
Synonym:Taxol
Molecular weight:853.906g/mol
Melting point:214.5°C
BCS classification: Class IV (Low permeability and Low
solubility)
Storage: store at 2°C-8°C
Solubility: Insoluble in cold and hot water.
Bioavailability: 6.5%
Protein binding: 89 to 98%
Clinical use: Used for Ovarian, breast and lung cancers and
also used to treat AIDS related Kaposi’s Sarcoma
19. Polymer Profile:
Name: Human Serum Albumin 25% solution
Solubility: Soluble in water
Storage: Store BUMINATE 25% at room temperature, not
to exceed 30°C (86°F). Avoid freezing to prevent
damage to the bottle.
20. Method of Preparation of Paclitaxel
Nanoparticles:
HSA 25% Solution + Chloroform + Paclitaxel (solid form)
Formation of Mixture
By using Mechanical Stirrer or Magnetic Stirrer
In process checks: RPM, Time
Formation of Emulsion
containing Nanoparticles
By using High Shear Mixture
In process checks: RPM, Time
Formation of
Nanoemulsion
By using Homogenizer
In process checks: Pressure,
Cycles
(Continuous next
21. Formation of Solvent Free
Nanoemulsion
By using Rotary Vacuum Evaporator evaporate
chloroform
In process checks: RPM, Time &
Temperature.
Filtered Nanoemulsion
By using 0.2µm membrane filter, filter Nanoemulsion
Formation of Lyophilized
cake
Lyophilize the Nanoemulsion by using Lyophilizer
In process checks: Time (hrs),
Vacuum Pressure.
