INTRODUCTION:
Radiopharmaceuticals play an
important role in the field of medicine. The global radiopharmaceutical
applications market is expected to grow from $4.9 billion in 2010 and to $ 7.9
billion in 201, at a CAGR of 9.25% from 2010 to 2015. There is a significant
increase in the global demand of radiopharmaceuticals, with the increasing
incidences of cardic, neurological and cancer
disease.
Radiopharmaceuticals, as the name
suggests, are pharmaceutical formulations consisting of radioactive substances
(radioisotopes and molecules labeled with radioisotopes), which are intended
for use either in diagnosis or therapy or diagnosis.
Radiopharmaceuticals are
essential components of nuclear medicine practice. A modality
where radiopharmaceuticals are administered to patients for diagnosing,
managing and treating number of diseases.
A variety of radiopharmaceuticals are
being developed which have different targeting mechanisms, routes and forms of
administration. Some are given in the simple salt form, or attached to more
complex molecules.
It has been used extensively in the
field of nuclear medicine as non-invasive diagnostic imaging agents to provide
both functional and structural information about organs and diseased tissues.
They may be given to the patient in several ways, e.g. orally, parenterally, or placed into the eye or the bladder
Radiopharmaceuticals are used for diagnosis or therapeutic treatment of
human diseases; hence nearly 95% of radiopharmaceuticals are used for
diagnostic purposes, while the rest is used for therapy. Radiopharmaceuticals
usually have no pharmacologic effects, as they are used in tracer quantities.
There is no dose-response relationship in this case, which thus differs
significantly from conventional drugs[1-3].
History and growth:
Radiopharmaceuticals are medicinal formulations containing
radioisotopes which are safe for administration in humans for diagnosis or for
therapy. Although radiotracers were tried as a therapeutic medicine immediately
after the discovery of radioactivity, the first significant applications came
much later with the availability of cyclotrons for acceleration of particles to
produce radioisotopes. Subsequently, nuclear reactors realised
the ability to prepare larger quantities of radioisotopes. Radioiodine
(iodine-131), for example, was first introduced in 1946 for the treatment of
thyroid cancer, and remains the most efficacious method for the treatment of
hyperthyroidism and thyroid cancer.
One of the major goals for setting up nuclear research reactors was for
the preparation of radioisotopes. Among the several applications of
radioisotopes, medical applications were considered to be of the highest
priority. Most of the medium flux and high flux research reactors now are
routinely used to produce radioisotopes for medical, and also industrial,
applications. The most commonly used reactor produced isotopes in medical
applications are molybdenum-99 (for production of technetium-99m), iodine-131,
phosphorus-32, chromium-51, strontium-89, samarium-153, rhenium-186 and
lutetium-177[1,4].
DEFINITIONS AND TERMINOLOGY:
Radiopharmaceutical refers to any medicinal or pharmaceutical product, which when
ready for use contains one or more radionuclides
(radioactive isotopes) intended for human use either for diagnosis or therapy.
Nuclide is
an elemental species characterized by its mass number ‘A’, (the sum of the
number of protons and neutrons in its nucleus), its atomic number ‘Z’ (number
of protons which is also same as number of electrons in a neutral atom) and
also by its nuclear energy state.
Fig 1: Chemical
element and its mass and atomic number
Isotopes of
an element are nuclides with the same atomic number ‘Z’ but different mass
numbers ‘A’. They occupy the same place in the periodic table and have similar
chemical properties.
Example: 
C and 
C
Radionuclide Nuclides
containing an unstable arrangement of protons and neutrons that transform
spontaneously to either a stable or another unstable combination of protons and
neutrons with a constant statistical probability by emission of radiation.
These are said to be radioactive and are called radionuclides.
Radioactivity The
phenomenon of emission of radiation owing to the spontaneous transformation or
disintegration of the radionuclide is known as ‘Radioactivity’. However, the
term radioactivity is also used to express the physical quantity (activity or
strength) of this phenomenon. The radioactivity of a preparation is the number
of nuclear disintegrations or transformations per unit time.
They put out radiation, mostly in the form of alpha and beta particles
that target the affected areas. They’re most often used in small amounts for
imaging tests, but larger doses can be used to deliver radiation[2,3,5].
Fig 2: Emission
of radiation form radionuclide
Half-Life Period:
The time in which a given quantity of a radionuclide decays to half its
initial value is termed as half-life (t 1/2).
Units of radioactivity:
In the International System (SI), the unit of radioactivity is one
nuclear transmutation per second and is expressed in Becquerel (Bq), named after the scientist Henri Bequerel.
The old unit of radioactivity was Curie (Ci), named
after the scientists Madame Marie Curie and Pierre Curie, the pioneers who
studied the phenomenon of radioactivity. One Ci is
the number of disintegrations emanating from 1 g of Radium-226, and is equal to
3.7 x 10 10 Bq.
Categories:
Radiopharmaceuticals can be divided into four categories:
Radiopharmaceutical preparation:
Any medicinal product which, when ready for use, contains one or more radionuclides (radioactive isotopes) included for a
medicinal purpose.
Radionuclide generator:
A system in which a daughter radionuclide (short
half-life) is separated by elution or by other means from a parent radionuclide
(long half-life) and later used for production of a radiopharmaceutical
preparation.
Radiopharmaceutical precursor:
It is a chemical compound or ligand used in
the synthesis of the radiopharmaceutical preparation. It could either be an
inactive chemical compound or a radiolabeled
intermediate produced for the preparation of radiopharmaceutical formulation,
prior to administration.
Kit for radiopharmaceutical preparation:
In general a vial containing the nonradionuclide
components of a radiopharmaceutical preparation, usually in the form of a
sterilized, validated product to which the appropriate radionuclide is added or
in which the appropriate radionuclide is diluted before medical use. In
most cases the kit is a multidose vial and production
of the radiopharmaceutical preparation may require additional steps such as
boiling, heating, filtration and buffering. Radiopharmaceutical preparations derived
from kits are normally intended for use within 12 hours of preparation[1,6].
Production of radioisotopes:
Radionuclides used in radiopharmaceuticals are produced artificially by the
radioactive decay of other radioactive atoms. This can be carried out by by any of the following methods
Radionuclide Generator:
The radioisotope generator is an ion
exchange column containing resin or alumina upon which a long – lived parent
nuclide has been adsorbed. It is made up of glass or plastic column and the bottom
of this is filled with adsorbent material on which parent nuclide is adsorbed.
After 4-5 half lives, the daughter nuclide growth is eluted in carrier free state with appropriate solvent. This method is used for
the production of Ga68, Kr81, Rb82, Tc99 and
In113. Due to its ideal imaging energy and physical half life as
well as the ability to bind to so many compounds, approximately 85% of all
imaging procedures in US are preferred following administration of Tc99.
An Ideal Generator Systems includes:
1 If intended for clinical use, the output of the generator must
be sterile and progeny-free
2 The chemical properties of the daughter must be different than
those of the parent to permit separation of daughter from parent. Most often,
separations are performed chromatographically.
3 Generator should ideally be eluted with 0.9% saline solution
and should involve no violent chemical reactions. Human intervention should be
minimal to minimize radiation dose.
4.
Daughter isotope should be short-lived gamma-emitting nuclide (physical
half-life = hrs days)
5 Physical half-life of parent should be short enough so daughter
re-growth after elution is rapid, but long enough for practicality.
6 Daughter chemistry should be suitable for preparation of a wide
variety of compounds, especially those in kit form.
7 Very long-lived or stable granddaughter so no radiation dose is
conferred to patient by decay of subsequent generations.
8 Inexpensive, effective shielding of generator, minimizing
radiation dose to users.
9 Easily recharged (we do NOT recharge Mo/Tc generators, but store them in decay areas after their
useful life is over).
Thermal
neutron reactor:
Radioisotopes used in nuclear
medicine are almost all synthetic. For thermal neutron reactor-produced radioisotopes,
reactor is source of thermal neutrons. An reaction
occurs and it causes an increase in atomic weight by one and no change in
atomic number. Same element is therefore present, e.g., Mo98 after
reaction produces Mo99.
Reactor yield dependent up on following.
1 Neutron flux in reactor (n/sec/cm2)
2 Nuclear capture cross section.
3 Number of target atoms.
4 Decay of product after it is formed.
5 Length of irradiation.
6 Isotope enrichment of target
Cyclotron produced radionuclides:
The cyclotron and similar particle accelerators can be used only with
charged particles such as electrons, protons and deuterons. This is because the
operation of such machine depends upon the interaction of magnetic and/or
electrostatic fields with the charge of particles undergoing acceleration. A
beam of charged particles is produced by accelerating ions around a widening
circle using magnetic field for control and electric current for acceleration.
Various separation techniques are available to separate product from target. It
includes production of C11, N13, O15 and F18
isotopes.
Cyclotron yield is
dependent upon:
1 Number of target atoms.
2 Energy of particles.
3 Decay of product after it is formed.
4 Length of irradiation.
5 Isotope enrichment of target
Nuclear Reactor/ Pile produced:
Nuclear reactor is the most common method to produce radioactive
materials for the use in industry, academic research and medicines. Uranium
fission reaction produces a large supply of neutrons. One neutron for each uranium atom undergoing fission is used to sustain
the reaction. The remaining neutrons are used either to produce plutonium or
used to produce radioactive products by causing the neutrons to interact with
specific substances, which have been inserted into the pile, the latter process
being known as neutron activation. Production of Xe133, Mo99
and I131 is carried out bu this methodthe fission reaction may be represented by the
following equation.
U235 + n → *U236 → 2.3n + I131,
Mo99 and Others
The radionuclides produced by these ways are
used in radiopharmaceuticals in the form of proper dosage forms. The physical
form of radiopharmaceuticals depends upon the type study or characteristics of
organ. They can be in the form of gases, gases in solution, liquids, true
solutions, colloidal solutions or suspensions, macroaggregates,
microsphere, emulsion, freeze dried solids and capsules.
Currently there are over 100 radiopharmaceuticals developed using
either reactor or cyclotron produced radioisotopes and which are used for the
diagnosis of several common diseases and the therapy of a few selected
diseases, including cancer. Radiopharmaceuticals production involves handling
of large quantities of radioactive substances and chemical processing. Aspects
which need to be addressed in radiopharmaceuticals production, including the
management of radioisotope production, include import, operation and
maintenance of processing facilities, complying with the codes of current good
manufacturing practices (cGMP), ensuring effective
quality assurance and quality control (QA and QC) systems, registration of the
products with national/regional health authorities and radioactive material
transport etc. Radiopharmaceuticals production, unlike conventional
pharmaceuticals production, is still on a relatively small scale and
implementing the cGMP guidelines which are applicable
for the drugs industry is both difficult and expensive. Ensuring cGMP compliance is a demanding task for a small scale
manufacturer, as it involves taking care of several aspects prior to, during
and after production. These include the development of well qualified
personnel, use of controlled materials and procedures, availability of
qualified equipment, production of the products in designated clean areas, applying
validated processes and analytical methods, full documentation of the process
and release of the final product by a qualified person[1,3,5-7].
Therapeutic uses of radiopharmaceuticals:
Radionuclide therapy employing radiopharmaceuticals labelled
with beta emitting radionuclides is emerging as an
important part of nuclear medicine. In addition to the management of thyroid
cancer, radionuclide therapy is utilized for bone pain palliation, providing
significant improvement in the quality of life of cancer patients suffering
from pain associated with bone metastasis as well as for the treatment of joint
pain, as in rheumatoid arthritis. Though the sale of therapeutic
radiopharmaceuticals is currently much lower compared to that of diagnostic
products, a steep increase over the next 5-6 years is predicted since several
new products for treating lymphoma, colon cancer, lung cancer, prostate cancer,
bone cancer and other persistent cancers are expected to enter the market.
Development of sophisticated molecular carriers and the availability of radionuclides in high purity and adequate specific activity
are contributing towards the successful application of radionuclide therapy.
Radiopharmaceuticals for bone pain
palliation:
Persons suffering from breast, lung and prostate cancer develop
metastasis in bones in the advanced stage of their diseases and therapeutic
radiopharmaceuticals containing radionuclides such as
strontium-89, samarium-153 and rhenium-186/188 are used for effective
palliation of pain from skeletal metastases. The IAEA has initiated a programme for the development and clinical application of
lutetium-177 based radiopharmaceuticals for bone pain palliation. It can be
prepared in large quantities for bone pain palliation application in low/medium
flux research reactors, which are available in several countries. The long
half-life of lutetium-177 provides logistic advantages for production and
testing of the products as well as the feasibility to supply the products to
places far away from the production site.
Radiopharmaceuticals for primary cancer
treatment:
Targeted radionuclide therapy involves the use of radiopharmaceuticals
to selectively deliver cytotoxic (toxic to cells)
levels of radiation to a disease site, as this would potentially deliver the
absorbed radiation dose more selectively to cancerous tissues. Advances in tumour biology, recombinant antibody technology, solid phase peptide synthesis and radiopharmaceuticals
chemistry have led to investigations on several new radiotherapeutic
agents. Radiolabelled peptides as molecular vectors
are being developed for targeted therapy. When labelled
with therapeutic radionuclides, peptide molecules
have the potential to destroy receptor-expressing tumours,
an approach referred to as peptide receptor radionuclide therapy (PRRT).
Yttrium-90 and lutetium-177 are frequently used as radionuclides
in such PRRT studies. During the development, the assessment of the relative
effectiveness of different radiopharmaceuticals for cancer therapy is complex because
of the large number of variables to be considered, some related to the
biological carrier and others to the radioisotope. Comparing the therapeutic
efficacy in patients is not feasible in most cases, and so development of
laboratory methods that can be used for reliable and efficient comparative
evaluation of promising therapeutic radiopharmaceuticals is an important need.
Radiopharmaceuticals for radiosynoviorthesis:
Radiosynoviorthesis or radiosynovectomy is a
technique wherein a radiopharmaceutical is delivered into the affected synovial
compartment (the interior of joints that is lubricated by fluid) of patients
suffering from joint pain, as in the case of rheumatoid arthritis.
Beta-emitting radiolabelled colloids are widely used
for this purpose. Several radiopharmaceuticals have been developed using
phosphorus-32, yttrium-90, samarium-153, holmium-166, erbium-169, lutetium-177,
rhenium-186, etc. and some of them are registered for human use. The radiation
properties of each therapeutic isotope determine their respective use and
applicability for the joint size[2,6-9].
Table 1:
Applications of radiopharmaceuticals in healthcare system
|
S. No |
Element |
Applications |
|
1 |
Molybdenum-99/ technetium-99m |
Diagnostic
imaging in oncology, cardiology and bone scanning, and the functional imaging
of organs such as kidneys, liver, brain and lungs. |
|
2 |
Iodine-131 |
Treatment
of thyroid gland disorders and cancer. |
|
3 |
Xenon-133 |
Diagnostic
lung function imaging. |
|
4 |
Strontium-89
|
Treatment
of painful bone metastases. |
|
5 |
Iridium-192
|
Cancer
treatment, including cancer of the lungs, head, neck, mouth, tongue and
throat, and treatment of vascular constriction. |
|
6 |
Samarium-153
|
Treatment
of metastatic bone pain and bone cancer. |
|
7 |
Rhenium-186
|
Treatment
of metastatic bone pain and arthritis. |
|
8 |
Iodine-125
|
Treatment
of prostate cancer and ocular cancer. |
|
9 |
Yttrium-90
|
Treatment
of arthritis and malignant lymphomas. |
|
10 |
Erbium-169
|
Treatment
of arthritis in smaller joints |
|
11 |
Lutetium-177
|
Treatment
of tumours. |
|
12 |
Holmium-166
|
Development
of treatments for liver cancer and blood cancer. |
Labelling and packaging:
Labelling:
The label on the container should state:
·
the name of the
product and the name of the radionuclide;
·
any product
identification code;
·
the name of the
manufacturer;
·
an identification
number (batch number);
·
for liquid
preparations, the total radioactivity in the container, or the radioactive
concentration per millilitre, at a stated date and,
if necessary, hour, and the volume of liquid in container;
·
for solid preparations,
such as freeze-dried preparations, the total radioactivity at a stated date
and, if necessary, hour;
·
for capsules, the
radioactivity of each capsule at a stated date and, if necessary, hour and the
number of capsules in the container;
·
In addition, the
label on the package should state: qualitative and quantitative composition;
·
the route of
administration;
·
the expiry date;
·
any special storage conditions.
Information on batch coding should be provided to the authorities.
Packaging:
The suitability of packaging material for the product and for the labeling
procedure to be carried out should be described. It may be necessary to
describe special radiation shielding.
Package leaflets:
Package leaflets play a particularly important role for semi-manufactured
products such as preparation kits and should include:
·
the name of the
product and a description of its use;
·
a list of the
contents of the kit;
·
the name and the
address of the manufacturer of the kit;
·
identification
and quality requirements concerning the radio labeling materials that can be
used to prepare the radiopharmaceutical;
·
directions for
preparing the radiopharmaceutical including range of activity and volume and a
statement of the storage requirements for the prepared radiopharmaceutical;
·
a statement of
the useful life of the prepared radiopharmaceutical;
·
indications and
contra-indications in respect of the prepared radiopharmaceutical;
·
warnings and
precautions in respect of the components and the prepared radiopharmaceutical
including radiation safety aspects;
·
where applicable,
the pharmacology and toxicology of the prepared radiopharmaceutical including
route of elimination and effective half-life;
·
the radiation
dose to the patient from the prepared radiopharmaceutical;
·
precautions to be
taken by the user and the patient during the preparation and administration of
the product and special precautions for the disposal of the container and its
unused contents;
·
a statement of
recommended use for the prepared radiopharmaceutical and the recommended
dosage;
·
a statement of
the route of administration of the prepared radiopharmaceutical;
·
and, if it is appropriate for particular kits (i.e. those
subject to variability beyond the recommended limits) the leaflet should
contain the methods and specifications needed to check radiochemical purity.
Storage:
Store in an airtight container in a place that is sufficiently shielded
to protect personnel from expoure to primary or
secondary emissions and that complies with national and international
regulations concerning the storage of radioactive substances. During storage,
containers may darken due to irradiation. Such darkening does not necessarily
involve deterioration of the preparations.
Radiopharmaceutical preparations are intended for use within a short
time and the end of the period of validity must be clearly stated.
Radiopharmaceuticals intended for parentral
use should be stored in such a manner so that pharmaceutical purity of the
product is maintained[2,8,9].
CONCLUSION:
Nowadays there are different types of radiopharmaceuticals are
available and having an important role in diagnosis of disease. Recently,
however, there has been a significant growth of this branch of nuclear medicine
with the introduction of a number of new radionuclides
and radiopharmaceuticals for the treatment of metastatic bone pain, neuroendocrine and other tumors. Today the field of
radionuclide therapy is going through an extremely interesting and exciting
phase and is poised for greater growth and development in the coming years.
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Received on 29.09.2015 Accepted
on 19.10.2015
© Asian Pharma Press All
Right Reserved
Asian J. Res. Pharm. Sci.
5(4): Oct.-Dec. 2015; Page 221-226
DOI: 10.5958/2231-5659.2015.00032.6