Kirtipal Kaur et al.

/ Journal of Pharmacy Research 2010, 3(9),2083-2087

Review Article
ISSN: 0974-6943 Available online through
www.jpronline.info
Regulations in Nanotechnology: A Brief Review
Kirtipal Kaur* 1, A. Gupta2, R.K. Narang2, R.S.R. Murthy 2
1
* Nanomedicine Research Centre, Department of Pharmaceutics, Post-graduate and Research,
2
ISF College of Pharmacy, Moga- 142001, Punjab, India.
Received on: 15-04-2010; Revised on: 18-05-2010; Accepted on:13-07-2010

ABSTRACT
The present review article presents a brief overview of the need for better compliance with the regulatory concerns in the field of nanotechnology. As the emerging
field of nanotechnology is revolutionary, widespread and interdisciplinary in nature but the emphasis here is made on area of product formulation and development.
The term “superior stuff in tiny parcels” possesses invariable advantages but at the same may not be fruitful because of imparting disadvantages in disguise. Thus
regulations from the laboratory via industrial to the consumption level is the need of the hour to track a better definition of novel drug delivery systems ensuring
therapeutic claims and proving promising candidates.

Key words: Nanotechnology; Regulatory; Novel drug delivery systems.

INTRODUCTION

Nanotechnology, the term derived from the Greek word nano, meaning dwarf,
applies the principles of engineering, electronics, physical and material science,
and manufacturing at a molecular or submicron level. The materials at nano-
scale could be a device or a system or these could be supra-molecular structures,
complexes or composites. Nanotechnology is the study of the controlling of
matter on an atomic and molecular scale. Generally nanotechnology deals with
structures of the size 100 nanometers or smaller in at least one dimension, and
involves developing materials or devices within that size.
Importance of Nanotechnology:
Nanotechnology is very diverse, ranging from extensions of conventional de-
vice physics to completely new approaches based upon molecular self-assembly.
Nanotechnology has application in diverse fields, but the present review deals
mainly with the pharmaceutical field. The various services offered by
nanotechnology are represented in fig 1.
One nanometer(nm) is one billionth, or 10-9, of a meter. Nanotechnology gives
us an opportunity to reconsider old concepts and explore new forms of relating
innovators, authors,and their creations in ways that both, encourage innova-
tion, and promise mutual benefit.Ultimately it is observed that nanotechnology
involves the convergence not just of every other technology, but also of world
views [11] .
The benefits of nanotechnology are
1)The life span of the drugs can be resurrected by reformulating the drugs
through novel delivery system,
2) The effective patent protection can be enhanced,
3) Drug delivery formulation involves low-cost research compared to that for
the discovery of a new molecules, and
4) Minimizing use of expensive drugs would reduce the cost of the product.
Nanotechnology Research in drug delivery
Novel drug delivery technologies represent a strategic tool for expanding drug
markets as it addresses issues of extending product life (line extension), or can
add to their performance and acceptability, either by increasing efficacy or
improving safety and patient compliance. This technology permits the delivery
of drugs that are highly water-insoluble or unstable in the biological environ-
ment. Advantages of nanosizing of drugs has the potential to: increase surface
area, enhance solubility, increase rate of dissolution, increase oral bioavailability,
more rapid onset of therapeutic action, decrease the dose needed, decrease fed/
fasted variability and decrease patient to patient variability. Various materials
including techniques used in nanotechnology having different properties seize
distinct applications, some of which are discussed in table 1.
Table1. Different techniques, properties and applications of nanotechnology

S.No. Material/ technique Property Applications Ref

.
1 Sorting biomolecules.
2 Nanosizing in the range
of 100–200 nm.
3 Quantum dots
4 Ligands on a
nanoparticle surface.
5 Nanoparticles.
Fig 1. Nanotechnology related goods and services
6 Nanoporous materials.
*Corresponding author.
7 Increased particle adhesion.
Kirtipal Kaur
Nanomedicine Research Centre, Department of Pharmaceutics, Post-graduate 8 Nanoparticles in the range of
and Research, ISF College of Pharmacy, Moga- 142001, Punjab, India. 20–50 nm.
Tel.: + 91-9815756664 9 Nanoshells ~130nm
E-mail:anuts86@yahoo.co.in
Nanotechnology has capacity for de Gene analysis [2]
novo DNA sequencing. and sequencing.
Improving low solubility. More effective treatment [3]
with existing drugs.
Emits photon when stimulated Diagnosis of cancer [4]
by UV light
These molecules can be engineered The ligand target receptors [5]
to a high degree of accuracy. can recognise damaged
tissue, attach to it and
release a therapeutic drug.
Evading body’s immune system The tumour endothelium can [6]
whilst directing a therapeutic agent be targeted and extravasation
to the desired site. of targeting tumour can be
harnessed
Evading body’s immune system When coupled to sensors, [7]
whilst directing a therapeutic agent drug-delivering implants
to the desired site. could be developed.
Degree of localised drug retention Slow drug release. [8]
increased.
Larger particles cannot enter tumour Cancer treatment [9]
pores while nanoparticles can easily
move into a tumour.
Silica core surrounded by gold that Colon carcinomas, tumors [10]
can be coated by targeting ligans or
polymers

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Table1. Different techniques, properties and applications of nanotechnology
Example of some of Nanotechnology Products (Nanomedicine) in the market
S/N Product Composition Application Manufacturer

1 Abelcet Amphotericin B/ lipid complex Fungal infections Enzon (Bridgewater, NJ, USA)
2 Abraxane Paclitaxel (anticancer drug) bound Enhanced dose tolerance and hence, effect. Bicon and Abraxis Bioscience
albumin particles Elimination of solvent associated toxicity
3 Adagen PEG- adenosine deaminase Immunodeficiency disease Enzon
4 Ambisome Liposomal amphotericin B Fungal infections Gilead (Foster City, CA, USA), Fujisawa (Osaka, Japan)
5 Amphotec Amphotericin B/ lipid colloidal dispersion Fungal infections Intermune (Brisbane, CA, USA)
6 Copaxone Coplymer of alanine, lysine, Multiple sclerosis TEVA Pharmaceuticals (Petach Tikva, Israel)
glutamic acid and tyrosine
7 Daunoxome Liposomal daunorubicin Kaposi sarcoma Gilead
8 Depcyt Liposomal cytarabine Cancer Skye Pharm, London, Enzon
9 Doxil/ Caelyx Liposomal doxorubicin Cancer, Kaposi sarcoma Ortho Biotech (Bridgewater, NJ, USA); Schering- Plough (Kelinworth, NJ, USA)
10 Emend Nanocrystalline aprepitant Antiemetic Elan Drug Delivery (King of Prussia, PA, USA), Merck & Co
. (Whitehouse Station, NJ, USA)
11 Epaxal Berna Virosomal hepatitis vaccine Hepatitis A Berna Biotech (Berna, Switzerland)
12 Estrasorb Estradiol in micellar nanoparticles Menopausal therapy Novavax (Malvern, PA, USA)
13 Inflexal V Berna Virosomal influenza vaccine Influenza Berna Biotech
14 Myocet Liposomal doxorubicin Breast cancer Zeneus Pharma (Oxford, UK)
15 Macugen Pegylated anti- VEGF aptamer Age- related macular degeneration OSI Pharmaceuticals (Melville, NY, USA), Pfizer (New York)
16 Megace ES Nanocrystalline megasterol acetate Eating disorder Elan Drug Delivery, Par Pharmaceutical Companies (Woodcliff Lake, NU, USA)
17 Neulasta PEG- G- CSF Febrile neutropenia Amgen (Thousand Oaks, CA, USA)
18 Oncaspar PEG- asparaginase Leukemia Enzon
19 Pegasys PEG- a- interferon 2a Hepatitis C Nektar (San Carlos, CA, USA), Hoffmann- La Roche (Basel)
20 PEG- Inton PEG- a- Interferon 2b Hepatitis C Enzon, Schering- Plough
21 Rapamune Nanocrystallized rapamycin Enhanced dissolution rate and Elan Drug technologies
(immunosuppressant) in a tablet bioavailability
22 Renagel Crosslinked poly(allylamine) resin Chronic kidney disease Genzyme (Cambridge, MA, USA)
23 Rexin- G A retroviral vector carrying cytotoxic genes Effective in pancreatic cancer treatment Epieus Biotechnologies
24 Somavert PEG- HGH Acromegally Nektar, Pfizer
25 Tricor Nanocrystalline fenofibrate Lipid regulation Elan Drug Delivery, Abbott (Abbott Park, IL, USA)
26 Triglide Nanocrystalline fenofibrate Lipid regulation SkyePharma, First Horizin, Pharmaceuticals (Alpharette, USA)
27 Visdyne
Liposomal verteporfin Age- related macular degeneration OLT (Vancouver, Canada), Novartis (Basel)

Safety Issues FDA Regulation of Nanotechnology Products

Nanotechnology is an exciting new field with hopes for improvements in a wide
variety of uses. The nanoparticulate material may have greater toxicity than material
in the larger size range [11]. Nanoparticles are on the same scale as cellular components
and larger proteins have led to the suggestion that they might evade the natural
defences of humans and other species and damage cells. It is important to set these
concerns as humans have always been exposed to some types of nanoparticles arising
from natural sources such as atmospheric photochemistry and forest fires, and expo-
sures to millions of pollutant nanoparticles per breath. The properties that are ex-
ploited by researchers and industry such as high surface reactivity, accessibility might
have pessimistic health and environmental impacts and might result in greater toxic-
ity. There is an ongoing struggle within science to redefine how values will be
incorporated into scientific research and this is also something that drives the research
itself. The different modes of veridiction represented by toxicology and materials
chemistry are synthesized into a new one by the invention of safety by design [12].
Most disagree on whether nanotechnology poses known or unknown risks, and have
different opinions about and definitions of uncertainty; many would support a redefi-
nition of their practices in terms of uncertainty rather than risk, but would do so in
different ways [ 3 ]. ‘Safety by Design’ opened up a range of difficult questions. Far from
being a scientific ‘breakthrough’ or a simple scientific fact (things many studies in the
history and philosophy of science have demonstrated are hard won), safety by design
is more like a solvent: it decomposes and reveals. Safety by design has also raised a
new challenge to the definition of materials and their environmental regulation (FDA,
EPA or toxicology communities) [12]. Nano-scientists are now paying more attention
to such issues is by no means simply about the success of ‘responsibility’ or ‘ethics’
but also has to do with the active work of creating a novel field in which new things
can be produced—new ‘structure-function’ relationships that are both useful in terms
of safety (mode of concern) and useful in more conventional terms of understanding
how to control matter (mode of control).
Researchers
lack of safety
Experiments performed
with safety Unsafe experiments
Not performed on with sometiomes
Adult stem cells embryonicstem cells horrible results
Thus pro-life group Masspanic about
raises ethical concerns human enhancement
technologies
Funding is cut on /or
proposed on human Public has ethical
embryonic research and safety
concerns
Fig 2. Representation of few concerns
Journal of Pharmacy Research Vol.3.Issue 9.September 2010
The mission of the Food and Drug Administration is, in part, to ensure that the
drugs, drug delivery systems, cosmetics, medical devices, vaccines, and food
products reaching the marketplace are safe and effective. The FDA paradigm
for regulation of these products is based on the concepts of “risk management”,
i.e. risk identification, risk analysis, and risk control. Every degradable medical
device or injectable pharmaceutical generates particulates that pass through a
size range during the processes of their absorption by the body. Although the
several pieces of enabling legislation have established several formalisms for
regulation with different names for each product type, they all basically fall into
three categories: Premarket Approval, Premarket “Acceptance” and Post Mar-
ket Surveillance.
Premarket Approval:
Prior to introduction into the marketplace, new pharmaceuticals, high-risk
medical devices, food additives, colors, and biological require approval by FDA.
Typically the producer/sponsor of the product identifies and assesses the risks
presented by the product and addresses each risk and how it will be minimized in
a product application. FDA staff then reviews these documents, often with the
assistance of an Advisory Committee. A per-approval inspection of the manu-
facturing plant is often required.
Premarket “Acceptance”:
For these products, FDA receives and reviews some form of notice that the
products will be marketed. These products are often copies of similar products
that were approved previously or are products prepared to approve specifica-
tions. The review process of these products is significantly more rapid than Pre-
Market Approval.
Post Market Surveillance :
FDA manages the risks of products like foods, cosmetics, radiation emitting
electronic products, and materials such as food additives and food packaging
that are “generally recognized as safe” (GRAS). For these products, market
entry and distribution are at the discretion of the manufacturer/producer. All
these products are generally regulated by the application of Good Manufacturing
Practices. FDA monitors the behavior of these products and takes regulatory
action if adverse events occur that threaten public or individual health.
Coordination of Policy with Other Government Agencies
Within FDA, the Office of Science and Health Coordination (OC/OSHC), coor-
dinates regular discussions on nanotechnology among the major experts from
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every organizational entity within the Agency. In addition the Centers within
FDA, e.g. Drugs and Medical Devices, have organized similar regular discussion
groups. The purpose of these meetings is to share experiences with the review of
the products, insure that each Center is aware of product guidance that may be
developing elsewhere within the Agency, and generally educate staff and policy
makers about nanotechnology. Safety issues are identified and studied. In a
similar manner, FDA coordinates knowledge and policy with the other US
Government agencies as a member of the Nanoscale Science and Engineering
Technology (NSET), subcommittee of the National Science and Technology
Council (NSTC) Committee on Technology. Also, FDA and NIOSH co-chair the
NSET Working Group on Nanomaterials Environmental and Health Implica-
tions (NEHI) to define new test methods/protocols to define safety of these
products. Finally, FDA is a direct contributor to the evaluations of the toxicity
of materials supported by the NIEHS and the National Toxicology Program
(NTP).
Current Issues in Nanotechnology
There are several issues under discussion in various forums related to the FDA’s
regulation of nanotechnology products. FDA expects many nanotechnology
products that are regulated to span the regulatory boundaries between pharma-
ceuticals, medical devices and biological. These will be regulated as “Combina-
tion Products” for which the regulatory pathway has been established by statute.
In such cases, FDA will determine the “primary” mode of action of the product.
This decision will determine the regulatory framework for the product, i.e. a
drug, medical device or biological product. The product application will be
managed by the appropriate FDA Center with consultations from the other
Centers. FDA has traditionally regulated many products with particulate mate-
rials in this size range. FDA believes that the existing battery of pharmaco-
toxicity tests is probably adequate for most nanotechnology products that will
be regulated. Particle size is not the issue. As new toxicological risks that derive
from the new materials and/or new conformations of existing materials are
identified, new tests will be required. FDA regulates products, not technology.
FDA, for example, regulates very few materials but many types of products.
This will affect the stage at which the FDA becomes engaged in the regulation of
nanotechnology and when, in the process, regulation takes effect. In addition,
FDA regulates only to the “claims” made by the product sponsor. If the manu-
facturer makes no nanotechnology claims regarding the manufacture or perfor-
mance of the product, FDA may be unaware at the time that the product is in the
review and approval process that nanotechnology is being employed. Within
this issue is embedded the definition of nanotechnology. It is quite likely that
new therapeutic benefits are being derived from products that are smaller than
their traditional form but fall above the 100 nm size-range limit of
nanotechnology. FDA has only limited authority over some potentially high-
risk products, e.g. cosmetics. As many products are regulated only if they cause
adverse health-related events in use. To date there have been comparatively few
resources available to assess the risks of these products. Other government
agencies have different missions with regards to nanotechnology, e.g. to solve
environmental problems; improve technology to address disease, etc. Few re-
sources currently exist to assess the risks that would derive to the general
population from the wide-scale deployment of nanotechnology products.
Status of research and the concerns
Current research into applications of nanotechnology includes efforts to ap-
proach a better drug delivery system, which can be ensured by addressing the
problems faced at the time of production of formulations, some of the issues are
to minimize the amount of solvents required for preparation (residual amount if
any on accumulation may be injurious) and other detrimental chemicals used in
manufacturing, to improve energy competence and energy storage capabilities
(cost effectiveness issue is achieved), and to remove importunate pollutants
from soil and water supplies, all of which offer hope of benefiting the environ-
ment and increasing sustainability. Access to the human body can occur through
various routes but the common vulnerable areas are the lungs, the skin or the
intestinal tract [13]. As a consequence of inherent properties nanoparticles allo-
cate invasion, evasion or cause damage to defensive mechanisms. Nanotechnology
may involve changes in the pharmacokinetics of nanoparticles, which is due to
several reasons. After delivering the drug to the site of action change in the
pharmacology, toxicology (systemic, cellular, genomic) and interactions of
drug with other ubiquitous components are essential. As the particle size de-
creases, the propensity towards violent dust cloud explosions increases leaving
Journal of Pharmacy Research Vol.3.Issue 9.September 2010
those who work in such industries susceptible to endangerment [14,15,16].
The principal determinants of the toxicity of nanoparticles are:
·Total surface area presented to the target organ;
·Chemical reactivity of the surface (including any surface components such as transition metals
and modifications by using agents that boost there uptake such as pegylating agents), and par-
ticularly its ability to take part in reactions that release free radicals;
·Physical dimensions of the particle that allow it to penetrate to the organ or into cells or that
prevent its removal;
· Solubility, in soluble particles such as salts that may disperse before initiating a toxic reaction.
Assessment of likely risks to health of novel systems:
Exposure studies
· Size (as it is an important factor in escaping or activating the host immune system)?
· Can system reach the site of action responsible for therapeutic effect?
In vitro studies
· Is system stable and durable (an indication responsible for residence time and its outcome)?
· Does system kill cells, provoke inflammation and release free radicals?
· What is the effect of removal of surface engineered moieties and their toxicity?
Small mammal (in vivo) studies
· Does system persist in preferred organ during following the suitable route of administration?
· Does system cause an inflammatory response following administration?
· Does system cause any acute/ chronic disease after prolong use?
· Does system cause local and systemic toxicity?
Toxicologists, environmental scientists and engineers, biologists, as well as
ethicists and social scientists altogether are involved in studying the properties
of new nanomaterials. Thus appeared ‘nanotoxicology’ [17, 18] and one called
‘nanoethics’, both arguably attempting to define and own some version of
‘safety’ in nanotechnology. For nanotoxicologists, for instance, ‘safety’ is not
a property of materials, but a spectrum of (poorly understood) risks; environ-
mental scientists and engineers, in addition, see this spectrum of risks as more
than just a question of engineered materials, but one of complex ecosystems and
subtle differences in the processes of manufacturing, disposing, and remediation
of man-made materials.
Regulatory requirement in nanotechnology
Regulatory requirement is essential to minimize the risk posed by the
nanotechnology. Regulation requires assessment of hazard (the intrinsic harm-
fulness of the material) and assessment of the likelihood or duration of expo-
sure, these factors combining to produce the risk to any exposed biological or
human population The consumers may be directly (the person approaching
actively) or indirectly (the layman receiving passively) effected by the
nanomaterials when they reach public domain. Humans or other organisms are
harmed when they are in physical contact with the material or be involved in
the processes in such a way that the material contacts or enters the body and
takes part in reactions with cells, leading to tissue-damaging reactions. Any such
damage is anticipated if the material has toxic properties and reaches the target
organ in sufficient dose. If the material is released into the air, it may be inhaled
directly and organisms may ingest materials that have entered the water system
or been deposited on vegetation. This is the dominant pathway for humans
exposed to manufactured nanoparticles released in the workplace, and for all
organisms exposed to nanoparticles from sources such as combustion. In addi-
tion to inhalation by air-breathing organisms, exposure to nanoparticles could
occur from surface contact (for example in cosmetic skin preparations such as
the sunscreens) or from ingestion (if nanoparticles are to be added to food or
drink in the future). Risk can be controlled by restraining release of the material
to air or water, and/or by interrupting the pathways by which the substance
reaches the receptor where it could cause harm (for example an organ in the
body), making an understanding of exposure pathways and likely quantities are
essential to risk management. Applications of nanoparticles through the novel
systems even employ parenteral routes (such as IV, IP, IM, SC) thus staking the
body at risk, as vital organs are within the vicinity of nanoparticles for there
localized or distant areas of therapeutic effect. Other organisms such as bacteria
and protozoa may take in nanoparticles through their cell membranes, and thus
allow the particles to enter a biological food chain. There are many human
impacts of pollutant nanoparticles; research on the impacts of particulate air
pollution on the natural environment and on non-human species within it has
primarily been concerned with the impact of pollutant gases such as sulphur
dioxide and ozone rather than particles. It is plausible that soil or water organ-
isms could take up manufactured nanoparticles escaping into the natural envi-
ronment and that these particles could, depending on their surface activity,
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 Kirtipal Kaur et al. / Journal of Pharmacy Research 2010, 3(9),2083-2087
interfere with vital functions. The evidence that nanoparticles may inhibit
motility and phagocytosis of macrophages, for example, suggests that similar
effects might be expected on simple soil organisms. As with human toxicology,
the dose to which the organisms are exposed would be expected to be critical in
determining toxicity. Based on persistence, bioaccumulation and toxicity par-
ticles have potential to damage the environment or human health through the
environment. Thus the research areas to be addressed are:
· Development of suitable and practical methods for measurement of manufactured nanoparticles in
the air and other media, including properties reflects their toxicity such as surface area and poten-
tial to release free radicals.
· Investigation of methods of measuring the exposures of workers to manufactured nanoparticles
in laboratories and manufacturing processes.
· Development of international agreement on measurement standards.
· Establishment of protocols for investigating the long-term fate of nanoparticles as products
containing them approach the market, to determine whether, how and to what extent they might
come into contact with the natural environment.
· In conjunction with research on environmental remediation, an understanding of the transport
and behaviour of nanoparticles and tubes in air, water and soil, including their interactions with
other chemicals.
· Epidemiological investigation of the inter-relations of exposure and health outcomes in those
industrial processes, such as welding, carbon black and titanium dioxide manufacture, where
nanoparticle exposure has been known to have occurred for some time.
· Development of internationally agreed protocols and models for investigating the routes of
exposure and toxicology to humans and non-human organisms of nanoparticles in the indoor and
outdoor environment, including investigation of bioaccumulation. This includes an understand-
ing of the impact of different sizes of nanoparticles and different types of coating.
· In collaboration with pharmaceutical nanoscientists and air pollution toxicologists, fundamen-
tal studies of the mechanisms of interaction of nanoparticles with cells and their components,
particularly the effects on blood vessels, the skin, heart and the nervous system.
·Development of protocols for in vitro and in vivo toxicological studies of any new nanoparticles
likely to go into large-scale production and which could impact people or the natural environ-
ment.
· Further investigation of the absorption through skin of different commercial nanoparticles used
in dermal preparations, in particular any changes that may occur if the skin is damaged before
application.
· Determination of the risk of explosion associated with a representative range of nanopowders
Fig 3. The different levels of control for risk management decisionmaking
Route of administration
The route of administration is an important parameter as distinct variables are
generated when targeted drug delivery is used. The desired formulation should not
only aim at ideal performance but safety, environmental impacts etc. are a must
for its complete evaluation. In addition to adverse environmental and health
risks, ethical issues related to nanotechnology have to be well thought-out. Al-
though no fundamentally new ethical dilemmas are anticipated, the relevant
ethical issues must not be ignored and a conscientious approach to the develop-
ment of nanotechnology products is recommended [19,20]. The general consider-
ations for nanotechnology products are described below:
1.) Characterization:
What are the forms in which particles are presented to hosts, cells and cell organelle. Soluble vs.
insoluble particles, organic vz inorganic particles, Nanoemulsions, nanocrystal colloid disper-
sions, liposomes, nanoparticles that are combination products (drug- device, drug- biologic, drug-
device- biologic)
What are the standard tools used for characterization of nanoparticle properties?
What are the validated assays to detect and quantify nanoparticles in drug product and tissues?
How do we determine long and short term stability of nanomaterials (in various environments)?
What are the critical physical and chemical properties including residual solvents, processing
variables, impurities and excipients.
How does physical characterization impact product quality and performance?
What are the critical steps in scale- up and manufacturing process for nanotechnology products?
How are characterization and manufacturing procedures assessed for personalized therapies?
- What is the level of characterization needed? Preclinical: ADME, toxicology? CMC: extent of
physical characterization?
Journal of Pharmacy Research Vol.3.Issue 9.September 2010
2.) Safety:
As the particle size gets smaller, there may be size specific- effects on activity, such as:
Will nanoparticles gain access to tissues and cells that normally would be bypassed by larger
particles?
Once nanoparticles enter tissues, how long do they remain there?
How are they cleared from tissues and blood?
If nanoparticles enter cells, what effects do they have on cellular and tissue functions?
Might there be different effects in different cell types?
ADME (Absorption, Distribution, Metabolism, Excretion):
What are the differences in ADME profile of nanoparticles vs larger particles for the same drug?
Are current methods using for measuring drug levels in blood and tissues adequate for assessing
levels of nanoparticles (appropriatenees of methods, limits of detection)?
How accurate are mass balance studies, especially if levels of drug administered are very low i.e. can
100% of the amount of drug be accounted for?
How the clearance of nanoparticles is accurately assessed? If nanoparticles concenterate in particu-
lar tissues how clearance is assessed accurately?
Can nanoparticles be successfully labeled for ADME studies?
Fig 4. General considerations
3.) Environmental impact
Can nanoparticles be released into the environment following human and animal use?
What methodologies would identify the nature and quantify the extent of nanoparticle release in
environment?
What might be the environmental impact on other species (animals, fish, plants, micro-organisms).
Current Preclinical tests for safety evaluations- Pharmacology , safety
pharmacology , toxicology (including clinical pathology, and histopathologic
analysis), ADME, genotoxicity, development toxicity, immunotoxicity, carci-
nogenicity, others.
Patents and Publications
Over the past decade, the first nanomedicine products have been introduced into
the market. Compared with the total pharmaceutical and medical device mar-
ket, nanomedicines currently constitute a tiny niche. For the most part,
nanotechnology in medicine has an enabling function. In most cases, it consti-
tutes only a functional component of a medical product; however, its great
strength lies in its versatility: nanotechnology has the potential to add innova-
tive functionality to many pharmaceutical products and medical devices. Since
the beginning of this decade, the interest of the pharmaceutical and medical
device industry is slowly picking up; patent activities in particular have in-
creased in recent years. Nevertheless, the investment of corporations in the
development of nanomedicines is still very cautious and is currently the biggest
stumbling block for commercialization. Furthermore, the uncertainty of whether
novel nanotechnology-specific medical regulations will be implemented that
might add further requirements to the approval process for nanomedicines
hampers their commercialization. An early clarification of this issue is impor-
tant for companies planning investments in nanomedicines. Notwithstanding
the commercial activities, nanomedicine is still technology driven and scientific
challenges lie ahead. The chemistry of nanosized molecules is not well under-
stood, and the manufacturing of such nanomaterials as dendrimers or pharma-
ceutical- grade liposomes is still costly. Furthermore, much remains to be learned
about the modification of nano-scale carriers so that circulation lifetime, bio-
distribution and penetration of biological tissues are optimized
Conclusion
At the conclusion, Regulation is an interdisciplinary and important integral
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 Kirtipal Kaur et al. / Journal of Pharmacy Research 2010, 3(9),2083-2087
part of research and development. A drug delivery system if formulated as per Period Before nanotechnology (past) Transition period (present) Mature nanotechnology
(future)
the concerned regulations posses several distinct advantages such the desired Technology Emulsion based preparation Nano/ micro fabrication Nano/ micro fabrication
therapeutic effect achievement with toxicology properly investigated and re- of nano/ microparticles
Examples -Liposome -Microchip system -Nano/ micro machines for
vealed, the characterization imposed by the regulatory agencies if performed scale- up production
allows its easy processing, clearance by the ethical committees and ensures -Polymer micelles -Micro needle transdermal
safety to the human mankind. The FDA regulations are for products not tech- delivery systems
-Dendrimers -Layer by layer assembled
nologies, it regulates claims made by the product sponsor, it has limited author- systems
ity over high risk products, such as cosmetics. Therefore, factories and research -Nanoparticles -Micro dispensed particles
-Nanocrystals
laboratories should treat manufactured nanoparticles as if they were hazardous, -Microparticles
and seek to reduce or remove them from waste streams. One of the difficulties
in determining potential future exposure of the environment and humans to Table2. Example of drug delivery technologies in relation to the cur-
manufactured nanoparticles is the lack of information about both the extent to rent nanotechnology revolution [21].
which they will be used in products and also the likelihood of such particles being
released from nanomaterials such as composites in a form or quantity that REFERENCES:
might cause harm to humans or the environment. As an integral part of the 1. David K, Let’s Get Small: An Introduction to Transitional Issues in Nanotech and Intellectual Property.
innovation and design process of products and materials containing nanoparticles, Nanoethics. 3, 2009, 157–166.
2. Marziali A, Akeson M, New DNA sequencing methods, Ann. Rev. Biomed. Eng. 3, 2001, 195-223.
industry should assess the risk of release of these components throughout the 3. Liversidge EM, Liversidge GG, Cooper ER, Nanosizing: a formulation approach for poorly-water-
life cycle of the product and make this information available to the relevant soluble compounds, Eur. J. Pharm. Sci. 18 (2), 2003, 113-120.
4. Gao X, Cui Y, Levenson RM, Chung LWK, Nie S, 2004. In vivo cancer targeting and imaging with
regulatory authorities. The greatest potential source of concentrated environ- semiconductor quantum dots, Nat. Biotech. 22(8), 2004, 969- 976.
mental exposure in the near term comes from the application of nanoparticles 5. Chan WCW, Chithrani BD, Ghazani AA, Determining the Size and Shape Dependence of Gold Nanoparticle
to soil or waters for remediation (and possibly for soil stabilization and to Uptake into Mammalian Cells, Nano Lett. 6 (4), 2006, 662–668.
6. Emerich DF, Thanos CG, The pinpoint promise of nanoparticle-based drug delivery and molecular
deliver fertilisers), The use of free (that is, not fixed in a matrix) manufactured diagnosis, Biomol. Eng. 23 (4), 2006, 171- 184.
nanoparticles in environmental applications such as remediation should be pro- 7. Emerich DF, Thanos CG, Targeted nanoparticle-based drug delivery and diagnosis. J. Drug. Targ. 15 (3),
2007, 163- 181.
hibited until appropriate research has been undertaken and it can be demon- 8. Pugno NM, A New Concept for Smart Drug Delivery: Adhesion Induced Nanovector Implosion.Open
strated that the potential benefits outweigh the potential risks. The safety of Med. Chem. J. 2, 2008, 62–65.
ingredients that exploit new and emerging technologies like nanotech, for which 9. Ruizhi X, Ma J, Sun X, Chen Z, Jiang X, Guo Z, Huang L, Li Y, Wang M, Wang C, Liu J, Fan X, Gu J, Chen
X, Zhang Y, Gu N, Ag nanoparticles sensitize IR-induced killing of cancer cellsAg nanoparticles sensitize
there is incomplete toxicological information, should include the requirement IR. Cell Res. 19, 2009, 1031-1034.
for all relevant data related to safety assessments, and the methodologies used to 10. Yadav BS, Gupta S, Kesharwani R, Mishra KP, Singh NK, The Role of Nanodrugs for Targeted Drug
obtain them, to be placed in the public domain. Delivery in Cancer Treatment, Arch. Apll. Sci. Res. 2(1), 2010, 37-51.
11. Report of The Royal Academy of Engineering, The Royal Society. Nanoscience and nanotechnologies:
opportunities and uncertainties. 2004.
Future aspects 12. Christopher MK, Beyond Implications and Applications: the Story of ‘Safety by Design’. Nanoethics, 3,
2009, 79–96.
Nanoparticulate systems can potentially be used as promising candidates, an- 13. Hoet PH, Bruske- Hohlfeld I, Salata OV, Nanoparticles- known and unknown health risks. J. Nanobiotechnol.
swering many unrevealed mysteries (molecular mechanisms of diseases using 2, 2004, 12.
diagnostic agents) of dreadful disease which have cursed mankind since time 14. Abrahamson J, Dinniss J, Ball lightning caused by oxidation of nanoparticle networks from normal
lightning strikes on soil, Nature. 403, 2009, 519- 521.
immemorial for eg. Cancer, Tuberculosis etc. While some of the nanotechnology 15. Sikkeland T, Skuterud L, Goltsova NI, Lindmo T, Reconstruction of doses and deposition in the western
based products approved by the U.S. FDA, several others are under development traces from the V Chernobyl accident. Health Phys. 72, 1997, 750- 758.
16. Chesser RK, Bondarkov M, Baker RJ, Wickliffe JK, Rodgers BE, Reconstruction of radioactive plume
and clinical assessment, with anticipated FDA approval in then not so distant characteristics along Chernobyl’s Western Trace. J. Environ. Radioact. 71, 2004, 147- 157.
future. Till date few resources are available to assess the products which are 17. Oberdoerster G, Oberdoerster E, Oberdoerster J, Nanotoxicology: an emerging discipline evolving from
regulated only when they cause adverse health- related events when in use. studies of ultrafine particles. Environ Health Perspect. 113(7), 2005, 823–839.
18. Kurath M, Maasen S, Toxicology as a nanoscience?—Disciplinary identities reconsidered. Part Fibre
Toxicol. 3, 2006, 6.
19. Grunwald A, Nanotechnology- a new field of ethical inquiry? Sci. Eng. Ethics, 11, 2005, 187- 201.
20. Berne RW, Towards the conscientious development of ethical nanotechnology, Sci. Eng. Ethics, 10, 2004,
627- 638.
21. Kinam P, Nanotechnology: What it can do for drug delivery, J. Ctrl. Rel., 120, 2007, 1–3.

Source of support: Nil, Conflict of interest: None Declared

Journal of Pharmacy Research Vol.3.Issue 9.September 2010 2083-2087