Nanoparticles and Nanocrystals

Supervised by: Prof. Ashok Kumar Done by: Hussein Talal Ashur ID: 201117011

Definitions

Nanoparticle is a microscopic particle with at least one dimension less than 100 nm. Polymeric Nanoparticles are also defined as polymeric particles made of natural or synthetic polymers ranging from 10-100 nm in which drug may be bound in solid solution or dispersion, adsorbed or chemically attached

Definitions

Nanoclusters have at least one dimension between 1 and 10 nm and a narrow size distribution. Nanopowders are agglomerates of ultrafine particles, nanoparticles, or nanoclusters. Nanometer-sized single crystals, or single-domain ultrafine particles, are often referred to as Nanocrystals.

Advantages of Nanoparticles
a) Longer shelf-stability b) High carrier capacity c) Ability to incorporate hydrophilic and hydrophobic drug molecules d) Can be administered via different routes e) Longer clearance time

Advantages of Nanoparticles f) Ability to sustain the release of drug

g) Can be utilized for imaging studies

h) Increase the bioavailability of drugs i) Targeted delivery of drugs at cellular and nuclear level

Advantages of Nanoparticles j) Development of new medicines which are more safe

k) Prevent the multi-drug resistance mediated efflux of chemotherapeutic agents

l) Product life extension

Disadvantages of nanoparticles a) Involves higher manufacturing costs which may in turn lead to increase in the cost of formulation b) Involves use of harsh toxic solvents in the preparation process c) May trigger immune response and allergic reactions

Nanoparticles production processes

Nanoparticles can be produced by either 1. Dispersion-based processes (which involves breaking larger

micrometer-sized particles into nanoparticles) or 2. precipitation-based processes

1-Dispersion-based processes a) Wet milling b) High-pressure Homogenization (Air jet milling) c) Emulsification Technology

2-precipitation-based processes
a) Spray freezing into liquid (SFL) b) Evaporative precipitation into aqueous solution (EPAS).

Nanoparticles
Wet milling is an attrition-based process in which the drug is dispersed first in an aqueous-based surfactant solution. The resulting suspension is subjected to wet milling using a pearl mill in the presence of milling media.

Wet milling

Wet milling provides a method to reduce the particle size of poorly soluble API.

Intensive process Particle recovery required

Air jet milling ( High pressure homogenization) High-pressure homogenization is based on the principle of cavitation (i.e., the formation, growth, and implosive collapse of vapor bubbles in a liquid (9-11). In this process, a drug presuspension (containing drug in the micrometer range) is prepared by subjecting the drug to air jet milling in the presence of an aqueous surfactant solution.

Particle-particle collisions No heat or moving parts

Spray freezing into liquid (SFL) An aqueous, organic, or aqueousorganic cosolvent solution; aqueousorganic emulsion; or drug suspension is atomized into a cryogenic liquid such as liquid nitrogen to produce frozen nanoparticles which are subsequently lyophilized to obtain free flowing powder

Table 1 Overview of nanoparticles and their applications in Life Sciences

Particle class Natural materials or derivatives Materials Chitosan Dextrane Gelatine Alginates Liposomes Starch Branched polymers Carbon based carriers Polylactic acid Poly(cyano)acrylates Polyethyleinemine Block Polycaprolactone SPIONS USPIONS Cd/Zn-selenides Silica-nanoparticles Mixtures of above Application Drug/Gene delivery

Dendrimers Fullerenes Polymer carriers

Drug delivery Photodynamics Drug delivery Drug/gene delivery

copolymers Imaging (MRI) Imaging In vitro diagnostics Gene delivery

Ferrofluids Quantum dots Various

Classification of Nanoparticles
Liposomes Micelles Polymeric nanoparticles Dendrimers

Fullerenes
Nanoshells Carbon Nanotubes

Liposomes (Lipid based drug carriers)

A self-closing spherical particle that is composed of natural or

synthetic amphiphilic lipid molecules (lipid bilayer)

Microscopic spherical vesicles that form when phospholipids are

hydrated.
Doxorubicin liposomal ( Doxil)

is used to treat metastatic ovarian cancer and AIDS-related Kaposi's sarcoma.

Liposomes Doxil is the drug doxorubicin HCl encapsulated in an antibody linked PEGylated liposome PEG (polyethylene glycol) makes the liposome less vulnerable to immune system PEGylation, by increasing the molecular weight of a molecule, can impart several significant pharmacological advantages over the unmodified form, such as:
1. 2. 3. 4. 5.

Improved drug solubility Reduced dosage frequency, Extended circulating life Increased drug stability Enhanced protection from proteolytic degradation

Micelles Micelle is an aggregate of amphipathic molecules in water, with the nonpolar portions in the interior and the polar portions at the exterior surface, exposed to water.
Hydrophobic drugs can be encapsulated, into inner core.

Block copolymers self assemble in solution to form micelles.

Polymeric Nanoparticles
As name only suggest polymeric nanoparticles are nanoparticles

which are prepared from polymers

The drug is dissolved, entrapped, encapsulated or attached to a

nanoparticles and depending upon the method of preparation, nanoparticles, nanospheres or nanocapsules can be obtained.

Nanocapsules are vesicular systems in which the drug is confined to a cavity surrounded by a polymer membrane, while nanospheres are matrix systems in which the drug is physically and uniformly dispersed.

Polymeric Nanoparticles Biodegradable polymeric nanoparticles have attracted considerable attention as potential drug delivery devices in view of their applications in drug targeting to particular organs/tissues, as carriers of DNA in gene therapy, and in their ability to deliver proteins, peptides and genes through oral route of administration.
In cancer, targeted polymeric NPs can be used to deliver

chemotherapies to tumor cells with greater efficacy and reduced cytotoxicity on peripheral healthy tissues.

Polymeric Nanoparticles Recently, a nanoparticle formulation of paclitaxel, in which serum albumin is included as a carrier [nanometer-sized albumin-bound paclitaxel (Abraxane) has been applied in the clinic for the treatment of metastatic breast cancer.

Besides metastatic breast cancer, Abraxane has also been evaluated

in clinical trials involving many other cancers including nonsmall-cell lung cancer (phase II trial) and advanced nonhematologic malignancies.

Polymeric Nanoparticles

Some examples of biodegradable polymers involved in polymeric NPs production 1. Polylactides (PLA).
2.
3.

Polyglycolides (PGA).
Poly(lactide-co-glycolides) (PLGA).

4.
5.

Polyanhydrides.
Polyorthoesters.

6.

Polycyanoacrylates

Polymeric Nanoparticles During the 1970, scientists first began to encapsulate and entrap drugs within polymers
Encapsulation involves surrounding drug molecules with a solid

polymer shell

Entrapment involves the suspension of drug molecules within a

polymer matrix.

Polymeric Nanoparticles
Drug release from nanoparticles is achieved either by Diffusion

and/or Erosion In case of diffusion:

1. polymer absorbs water it and swells in size
2. Swelling created voids throughout the interior polymer 3. Smaller molecule drugs can escape via the voids at a known rate

controlled by molecular diffusion (a function of temperature and drug size)

Dendrimers
Dendrimers are a highly branched type of nanoparticle that can

target specific cells based on the molecular "hooks" on the ends of the polymers that make up their outer surface. There are two basic structural types: 1. One is the globular structure with a central core from which polymer branches radiate; 2. The second type has no central core and consists simply of a series of highly branched polymers.

Dendrimers
The manufacturing process is a series of repetitive steps starting

with a central initiator core.

Each subsequent growth step represents a new "generation" of

polymer with a larger molecular diameter, twice the number of reactive surface sites, and approximately double the molecular weight of the preceding generation.

Dendrimers
Product Application Company

Vivagel

Vaginal Gel for preventing HIV

Starpharm a Dade Behring

Stratus CS Cardiac Marker

SuperFect Gene Transfection

Alert Ticket

Qiagen

Anthrax Detection US Army Research Laboratory

Fullerenes (Carbon 60) are spherical cages containing from 28 to more than 100 carbon

atoms.

They can be subjected to extreme pressures and regain their original shape when the pressure is released.
Hence they find application as NanoPharmaceuticals with large drug payload in their cage like structure.

They are being explored as potential new antimicrobial

agents in view of their potency for induction of reactive oxygen species after photoexcitation

Fullerenes (Carbon 60)

Nanoshells
Nanoshells have a core of silica and a metallic outer layer. These nanoshells can be injected safely, as demonstrated in

animal models.

Because of their size, nanoshells will preferentially concentrate in

cancer lesion sites.

Nanoshells

This physical selectivity occurs through a phenomenon called

enhanced permeation retention (EPR).

Can further decorate the nanoshells to carry molecular conjugates

to the antigens that are expressed on the cancer cells themselves or in the tumor microenvironment.

For example, tumor accumulation via enhanced permeability and retention.

Nanoshells

Carbon Nanotube Carbon nanotubes are carbon cylinders composed of benzene rings that have been applied in biology as sensors for detecting DNA and protein, diagnostic devices for the discrimination of different proteins from serum samples, and carriers to deliver vaccine or protein .
Carbon nanotubes are completely insoluble in all solvents,

generating some health concerns and toxicity problems.

However, the introduction of chemical modification to carbon

nanotubes can render them water-soluble and functionalized so that they can be linked to a wide variety of active molecules such as peptides, proteins, nucleic acids, and therapeutic agents.

Carbon Nanotube Antifungal agents (amphotericin B) or anticancer drugs (methotrexate) have been covalently linked to carbon nanotubes with a fluorescent agent.

In an in vitro study, drugs bound to carbon nanotubes were shown

to be more effectively internalized into cells compared with free drug alone and to have potent antifungal activity.

Carbon Nanotube

Targeted delivery of nanoparticles For anticancer drugs to be effective in cancer treatment,

1. they should after administration, be able to reach the desired

tumor tissues through the penetration of barriers in the body with minimal loss of their volume or activity in the blood circulation. (Penetrability)
2. after reaching the tumor tissue, drugs should have the ability to

selectively kill tumor cells without affecting normal cells with a controlled release mechanism of the active form. (Selectivity)

Targeted delivery of nanoparticles

These two basic strategies are also associated with improvements

in patient survival and quality of life by increasing the intracellular concentration of drugs and reducing dose-limiting toxicities simultaneously.

Increasingly, nanoparticles seem to have the potential to satisfy

both of these requirements for effective drug carrier systems.

Size and Surface Characteristics of Nanoparticles

To effectively deliver drug to the targeted tumor tissue, nanoparticles must have the ability to remain in the bloodstream for a considerable time without being eliminated. Conventional surface nonmodified nanoparticles are usually caught in the circulation by the reticuloendothelial system, such as the liver and the spleen, depending on their size and surface characteristics. The fate of injected nanoparticles can be controlled by adjusting their size and surface characteristics.

Size of Nanoparticles
One of the advantages of nanoparticles is that their size is tunable.

The size of nanoparticles used in a drug delivery system should be large enough to prevent their rapid leakage into blood capillaries but small enough to escape capture by fixed macrophages that are lodged in the reticuloendothelial system

The size of nanoparticles should be up to 100 nm to reach tumor

tissues by passing through these particular vascular structures.

Surface Characteristics of Nanoparticles

Nanoparticles should ideally have a hydrophilic surface to escape

macrophage capture. This can be achieved in two ways:

1. coating the surface of nanoparticles with a hydrophilic polymer,

such as PEG 2. alternatively, nanoparticles can be formed from block copolymers with hydrophilic and hydrophobic domains

 Drug nanocrystals are crystals with a size in the nanometer range,

which means they are nanoparticles with a crystalline character.

A further characteristic is that drug nanocrystals are composed of

100% drug; there is no carrier material as in polymeric nanoparticles.

Dispersion of drug nanocrystals in liquid media leads to so called

nanosuspensions .

 In general the dispersed particles need to be stabilized, such as by

surfactants or polymeric stabilizers.

Dispersion media can be water, aqueous solutions or nonaqueous

media (eg, liquid polyethylene glycol [PEG], oils).

Depending on the production technology, processing of drug

microcrystals to drug nanoparticles can lead to an either crystalline or to an amorphous product, especially when applying precipitation.

 Properties of nanocrystals 1. Increase of dissolution velocity by surface area enlargement:

The size reduction leads to an increased surface area and thus according to the Noyes-Whitney equation (Noyes and Whitney 1897) to an increased dissolution velocity. Therefore micronization is a suitable way to successfully enhance the bioavailability of drugs where the dissolution velocity is the rate limiting step. By moving from micronization further down to nanonization, the particle surface is further increased and thus the dissolution velocity increases too

 Properties of nanocrystals 1. Increase of dissolution velocity by surface area enlargement:

 Properties of nanocrystals 2. Increase in saturation solubility

(cs- saturation solubility, cx - bulk concentration, h - diffusional distance).

Production of nanocrystals
1. Precipitation methods

2. Milling methods
3. Homogenization methods

Table: Advantages and disadvantages of different methods for the production of nanocrystals
Advantages Disadvantages
- needs to be stabilized - organic solvent residue - not universally applicable, only drugs with certain properties are possible (eg, soluble in at least one solvent)

Technology

Precipitation

- finely dispersed drug - good control of desired size

Milling

- residue from milling media - can be a slow process (several - low energy technique days) - proven by 4 FDA approved drugs - needs to be stabilized - large batches difficult to produce due to size of milling chamber

Homogenization

- universally applicable - no problem with large batches - fast method (several minutes possibly) - water free production possible

- high energy technique - great experience needed

Products in the market

1. Rapamune Sirolimus (immunosuppressive agent) was the first

marketed product introduced in 2000 by Wyeth Pharmaceuticals, Comparing the oral bioavailability of solution and nanocrystal tablet, the bioavailability of the nanocrystals is 21% higher compared to the solution.

Products in the market

2. Emendintroduced in 2001 by Merck. The drug is aprepitant,

used for treatment of emesis. Aprepitant will only be absorbed in the upper gastrointestinal tract. Bearing this in mind nanoparticles proved to be ideal to ideally exploit this narrow absorption window. The drug nanocrystals are contained within a hard gelatin capsule as pellets

Products in the market

3. Tricoris being marketed by Abbott Laboratories and the active

ingredient is fenofibrate. The absorption of fenofibrate in fed patients is up to 35% higher than in nonfed patients. The nanocrystal technology makes the fenofibrate independent of meals. Plasma levels in fed and fasting condition are bioequivalent (data on file, Abbott Labs).

Table: Examples of pharmaceuticals products based on nanotechnologies

Brand name Emend (Merck & Co. Inc.) Description Advantages Nanocrystal aprepiant (antiemetic) in a Enhanced dissolution rate & capsule bioavailability Enhanced dissolution rate& bioavailability Enhance dose tolerance and hence effect elimination of solvent associated toxicity Effective in pancreatic cancer treatment

Rapamune Nanocrystallied Rapamycin (Wyeth-Ayerst Laboratories) (immunosuppressant) in a tablet Abraxane Paclitaxel (anticancer drug) bound (American Biosciences, Inc.) albumin particles

Rexin-G (Epeius Biotechnology corporation) Olay Moisturizers (Proctor and Gamble)

A retroviral vector carrying cytotoxic gene

Contains added transparent, better protecting nano zinc oxide particles

Offer better UV protection

Trimetaspheres (Luna Nanoworks)

MRI images

enhanced MRI images at least 25 times better than current contrast agents
Better protection from infection

SILCRYST (Nucryst Pharmaceuticals)

Enhance the solubility and sustained release of silver nanocrystals

Future Direction and Opportunities

Together with the progression of nanoscale drug delivery systems,

advances in nanoscale imaging suggest the potential for the development of multifunctional smart nanoparticles that may facilitate the realization of individualized cancer therapy.
Almost all types of nanoparticles including polymeric

nanoparticles, nanocrystals, polymeric micelles, dendrimers and carbon nanotubes have been evaluated for their suitability as multifunctional nanoparticles that can be applied for simultaneous in vivo imaging and treatment of cancers.

Future Direction and Opportunities

Eventually, multiplex nanoparticles may be capable of: 1. detecting malignant cells 2. visualizing their location in the body (real-time in vivo imaging),

killing the cancer cells with minimal side effects by sparing normal cells (active targeting and controlled drug release or photothermal ablation), and 4. monitoring treatment effects in real time.
3.

Multifunctional nanoparticle.

References:
1. 2. 3. 4.

http://clincancerres.aacrjournals.org/content/14/5/1310.full#F1 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2626933/ http://www.nanopharmaceuticals.org/Polymeric_nanoparticles.html http://www.pharmainfo.net/reviews/nanoparticles-and-its-applicationsfield-pharmacy http://www.authorstream.com/Presentation/issra-366349nanoparticles-science-technology-ppt-powerpoint/ http://www.authorstream.com/Presentation/aSGuest115913-1207997nanoparticles-in-drug-delivery/ Drug delivery and nanoparticles: Applications and hazards Wim H De Jong, Paul JA Borm http://www.nanoparticles.org/pdf/Berkland.pdf

5.

6.

7.

8.