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I

Inntroduction
Chapter 1 INTRODUCTION
Plants being rich sources of natural entities have been used for their medicinal value
since antiquity. Out of 250,000 species of flowering plants found on earth, about 2,000 species
of plants have been exploited for medicinal purposes throughout the world. A total of 45,000
plant species have been identified in India, out of which 1500 plants have been mentioned
with their medicinal uses in Ayurveda, including 800 species which have been used as ethno-
medicine for the prevention and treatment of various human ailments. Recently, development
of resistance by many pathogens against a number of synthetic drugs, antibiotics in particular,
has been seen as the major concern for clinicians and physicians globally. Such a scenario
warrants an urgent need to develop newer and safer drugs, with an alternate mode of action. It
has been widely recognised and accepted for ages that medicines of plant origin not only help
resist and recover from various ailments but are also without noticeable side effects. The
compounds isolated from medicinal plants have potential to serve as lead molecules for the
development of safer and better alternatives to synthetic drugs against various diseases. They
may also augment the efficacy of already existing synthetic drugs if used in combination
(Botanical Survey of India, 1983).

Several plant species are good sources of drugs which have therapeutic properties or
exert beneficial pharmacological effects on the body, thus termed as ‘Medicinal Plants’. A
substantial proportion of Indian population still relies on natural and herbal products.
Additionally, it has been seen that around 80% of global population prefer to use herbal drugs
against cancer, hepatic dysfunction, AIDS, diarrhoea, hyper- or hypo-glycaemia, graft
rejection, autoimmune disorders, as antioxidants and for immune dysfunctions. The healing
characteristics of these plants are attributed to the presence of complex biologically active
ingredients which are synthesised naturally and produced by plants in response to the normal
metabolic processes and accumulate in them to combat unfavourable environmental factors.
These phytochemicals belong to a wide range of chemical classes i.e. indoles, phytosterols,
sesquiterpenes, etc. and are collectively called ‘Secondary Metabolites’. Secondary
metabolites and other phytochemicals like alkaloids, flavonoids, glycosides, volatile

Introduction........
oils/essential oils, polysaccharides, phenols, gums, terpenes, tannins, saponins, terpenoids, etc.
possess a wide array of curative properties and act as anti-oxidants, anti-cancer agents,
immune-modulators, co-enzymes, etc. (Jouad et al, 2001).

Bone, though a rigid tissue is an equally dynamic one that is continuously moulded,
shaped and repaired. Its microstructure is patterned so as to be maximally strong while having
the least possible mass, as per the physiological needs of any organism. Once formed, bone
undergoes a continuous renewing process called bone remodelling. This process of bone
remodelling involves break down (resorption, by osteoclasts) and build-up (synthesis, by
osteoblasts), occurring at a microscopic scale throughout the skeleton. Due to the process of
continuous architectural modifications, bones at times become susceptible to imbalances of
remodelling which results in noticeable defects in skeletal structure and function leading to
morbidity and reduction of lifespan. Usually such disorders occur as a result of excess
osteoclastic activity that favors resorption over synthesis, such as osteoporosis, rheumatoid
arthritis, multiple myeloma, periodontal disease and metastatic cancers. Osteoporosis is a
systemic skeletal disease characterized by low bone density and micro architectural
deterioration of bone tissue with a consequent increase in bone fragility. In its early stages,
osteoporosis usually goes undiagnosed as it remains asymptomatic. It becomes clinically
evident only after fractures occur as bone density continues to decrease with advancing age.
Age and sex are two most important predisposing factors of osteoporosis. Females are three
times more vulnerable to develop osteoporosis, partly because peak bone mass is lower in
females as compared to males and partly because of the hormonal changes after menopause.
Additionally, women usually have a longer life span than men and consequently greater
reductions in bone mass over time.

For centuries, extract of rhizome of turmeric (Curcuma longa Linn.) has been used as
anti-inflammatory agents in Ayurvedic and Traditional Chinese Medicine (TCM). During the
course of in vivo studies assessing turmeric’s antiarthritic effects, it was observed that turmeric
extracts containing substances called curcuminoids prevent formation of osteoclasts
(osteoclastogenesis) and destruction of periarticular bone in a model of rheumatoid arthritis.
Curcumin is a yellow phenolic compound present naturally in various types of herbs,

Introduction........
especially in turmeric. It was first extracted by Vogel, while its structure was elucidated by
Milobedeska and subsequently synthesized by Lampe. It acts as a natural antioxidant and
exhibits a number of pharmacological activities such as anti-microbial, anti-inflammatory,
anti-Alzheimer and anti-cancer in preclinical as well as clinical studies. Moreover, it possesses
antirheumatic, hepatoprotective, antidiabetic, neuroprotective, nephroprotective,
hypoglycaemic and cardioprotective activities. It also suppresses thrombosis, and provides
protection against myocardial infarction (Sou, 2012).

Curcumin, molecular weight of 368.37 g/mol, being insoluble is water, is administered


conventionally by oral route only. A promising advantage of its oral administration is minimal
side effects after clinical application as a drug. Even though turmeric has been traditionally
used in indigenous medicine and as a spice since ancient times, its systemic beneficial effects
have been minimal. This fact can be attributed to the characteristic water insoluble nature of
the active components, first pass metabolism, poor gastrointestinal absorption and subsequent
rapid elimination. These factors together limit the practical availability of the drug in an
animal model system. In order to overcome these limiting factors and for the successful
application of curcumin in medicine, there is a need to develop a proficient drug delivery
system that could enhance its systemic bioavailability. Two main approaches have recently
been in vogue to increase the bioavailability of curcumin. First strategy is based on the
chemical modification of the curcumin molecule into water soluble derivatives, whereas the
second strategy is based on the formulation of efficient nanoparticulate drug delivery system.

Nanotechnology is an evolving field that utilizes the physicochemical attributes of


nanomaterials as a means to control their dimensions, surface area and shape in order to
generate different nanoscale-sized materials. A nanoparticle may be defined as an ultrafine
microscopic particle with at least one dimension less than hundred nanometres.
Nanotechnology has application in research and day to day life. One of the fastest growing
areas of nanotechnology is its use in medical research particularly in drug delivery systems.
Nanoparticles such as phospholipid vesicles (liposomes), micelles, solid lipid nanoparticles,
nanoemulsion, polymeric nanoparticles, proteins, cyclodextrin, etc. have been tested as drug
delivery carriers. These nanoparticulate drug delivery systems appear to be a promising

Introduction........
strategy for curcumin delivery for its enhanced system availability and could be exploited for
its therapeutic nature in prevention and alleviation of the symptoms of osteoporosis.

Thus, keeping in view of the above facts regarding medicinal properties of curcumin
and preparation of novel nanoparticle formulations, this study was designed to develop an
efficient drug delivery system for aqueous extract of Curcuma longa with the following
objectives:

 To prepare and quantify curcumin nanoparticles, in a formulation of curcumin from


Curcuma longa.

 To prepare and characterize primary culture of bone marrow derived mesenchymal


stem cells and rat osteoblasts.

 To evaluate the toxicity of curcumin nanoparticles in osteoblast culture.

 To evaluate the induction and differentiation of rat osteoblasts by curcumin


nanoparticles using gene specific markers.

Introduction........