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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
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
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.
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.
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
Classification of Nanoparticles
Liposomes Micelles Polymeric nanoparticles Dendrimers
Fullerenes
Nanoshells Carbon Nanotubes
hydrated.
Doxorubicin liposomal ( Doxil)
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.
Polymeric Nanoparticles
As name only suggest polymeric nanoparticles are nanoparticles
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.
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
polymer matrix.
Polymeric Nanoparticles
Drug release from nanoparticles is achieved either by Diffusion
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
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
Qiagen
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.
agents in view of their potency for induction of reactive oxygen species after photoexcitation
Nanoshells
Nanoshells have a core of silica and a metallic outer layer. These nanoshells can be injected safely, as demonstrated in
animal models.
Nanoshells
to the antigens that are expressed on the cancer cells themselves or in the tumor microenvironment.
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,
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.
to be more effectively internalized into cells compared with free drug alone and to have potent antifungal activity.
Carbon Nanotube
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)
in patient survival and quality of life by increasing the intracellular concentration of drugs and reducing dose-limiting toxicities simultaneously.
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
such as PEG 2. alternatively, nanoparticles can be formed from block copolymers with hydrophilic and hydrophobic domains
nanosuspensions .
microcrystals to drug nanoparticles can lead to an either crystalline or to an amorphous product, especially when applying precipitation.
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
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
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
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.
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
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).
Rapamune Nanocrystallied Rapamycin (Wyeth-Ayerst Laboratories) (immunosuppressant) in a tablet Abraxane Paclitaxel (anticancer drug) bound (American Biosciences, Inc.) albumin particles
MRI images
enhanced MRI images at least 25 times better than current contrast agents
Better protection from infection
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.
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
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