1.

Introduction

1.1. Nanotechnology
Nanotechnology is the science and technology at nano scale, which ranges about 1-100
nanometer. The term nanotechnology is derived from the Greek word nano, meaning dwarf
and applies the principles of engineering and manufacturing at a molecular level.
Nanotechnology can be defined as the science and engineering involved in the design,
synthesis, characterization, and application of materials and devices whose smallest
functional organization in at least one dimension is on the nanometer scale or one billionth
of a meter. At these scales, consideration of individual molecules and interacting groups of
molecules in relation to the bulk macroscopic properties of the material or device becomes
important, since it is control over the fundamental molecular structure that allows control
over the macroscopic chemical and physical properties.

Nanotechnology as a concept which was first discussed in 1959 by renowned physicist

Richard Feynman in his talk “There’s Plenty of Room at the Bottom” in which he described
possibility of synthesis with direct manipulation of atom [1]. Norio Taniguchi was the one
who first used the term Nano Technology in 1974. With the help of Feynman concept, K
Eric Drexler used the term nanotechnology in 1986 in his book “Engines of Creation: The
Coming Era of Nanotechnology” proposing the idea of a nanoscale “assembler” and also
in 1986, Drexler co-founded The Foresight Institute for increasing awareness of
nanotechnology and its implications. With the invention of scanning tunneling microscope
in 1981 by Gerd Binning and Heinrich Rohrer (Nobel Prize Winners in Physics in 1986)
at IBM Zurich Research Laboratory [2][3] and discovery of Fullerenes in 1985 by Harry
Kroto, Richard Smalley and Robert Kurl (Nobel Prize in Chemistry in 1996) [4][5], kick
started the growth of nanomaterials in modern era.

1|Page
Nanotechnology has find its applications in different field. The impact of nanotechnology
extends from its medical, ethical, mental, legal and environmental applications, to fields
such as engineering, biology, chemistry, computing, materials science, and
communications. Major benefits of nanotechnology include improved manufacturing
methods, water purification systems, energy systems, physical enhancement,
nanomedicine, better food production methods, nutrition and large-scale infrastructure
auto-fabrication.

1.2. Nanobiotechnology
In the last few decades nanotechnology has found its way into the field of biology. The
insertion of nanotechnology into biology is nanobiotechnology, bionanotechnology or
nanobiology [6]
. It is the merge of two disciples’ nanotechnology and biology. Concepts
that are enhanced through nanobiology include: nanodevices (such as biological
machines), nanoparticles, and nanoscale phenomena that occurs within the discipline of
nanotechnology. This technical approach to biology allows scientists to imagine and create
systems that can be used for biological research.

The objective of nanobiotechnology is the application of nanotools in relevant

biological/medical problems, like [7];

 Developing new tools, such as peptoid nanosheets, for medical and biological
purposes
 New nanotools are often made by refining the applications of the nanotools that are
already being used.
 The imaging of native biomolecules, biological membranes, and tissues is also a
major topic for the nanobiology researchers
 The use of cantilever array sensors
 The application of nanophotonics for manipulating molecular processes in living
cells

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Nanomedicines is the medical application of nanotechnology. Nanomedicines has become
one of the important areas in the research of nanotechnology and is used widely in
diagnosis, treatment and prevention of diseases. Nanomedicine depends on several
overlapping molecular technologies, which are themselves subsumed within young, but
progressively developing field, including [8]:

 The construction of nanoscale-sized structures for diagnostic, biosensors and local

drug delivery
 The ongoing revolution in genomics, proteomics and Nano engineered microbes
 The creation of molecular nanobots capable of identifying and eliminating host
pathogens, replacing/repairing cells or cellular components in-vivo

Objectives of using nanomedicines is to

 Reduce toxicity
 Targeted drug delivery to a specific site (thus reducing side effect)
 Lesser dosage through improved bioavailability,
 Improving shelf life by enhancing their stability
 Controlled release of drug into the body.

All of this will ultimately contribute to increased safety, efficacy, patient compliance and
decreased cost of medical expense [9].

1.3. Drug delivery

Drug delivery refers to approaches, formulations, technologies, and systems
for transporting a pharmaceutical compound in the body as needed to safely
achieve its desired therapeutic effect [10].It may involve scientific site-targeting within the
body, or it might involve facilitating systemic pharmacokinetics; in any case, it is typically
concerned with both quantity and duration of drug presence. Drug delivery is often
approached via a drug's chemical formulation, but it may also involve medical devices or

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drug-device combination products. Drug delivery is a concept heavily integrated with
[11]
dosage form and route of administration .Drug delivery technologies modify drug
release profile, absorption, distribution and elimination for the benefit of improving
product efficacy and safety, as well as patient convenience and compliance. Drug release
is from: diffusion, degradation, swelling, and affinity-based mechanisms [12].Most common
routes of administration include the preferred non-invasive peroral (through the mouth),
topical (skin), transmucosal (nasal, buccal/sublingual, vaginal, ocular and rectal) and
inhalation routes [13].

There are many way of developing drug delivery system with the help of nanotechnology
such as, depot preparation, transdermal drug delivery system, enhanced bioavailability
through improved dissolution and absorption and more[14].

Drug Delivery Systems enable the introduction of a therapeutic agent into the body by
means of a formulation or device and improves the efficacy and safety of the agent by
controlling rate, time and place of release of the drug. Drug delivery systems are classified
as the following [15]:

 Delayed release
 Sustained release
 Site-specific targeting
 Receptor targeting

A controlled drug delivery system is usually designed to deliver the drug at particular rate.
Safe and effective blood levels are maintained for a period as long as the system continues
to deliver the drug. Controlled drug delivery usually results in constant blood levels of the
active ingredient as compared to the uncontrolled fluctuations observed when multiple
doses of quick releasing dosage forms are administered to a patient [16].

The drug could be loaded either on a reservoir device from where it is released through
various processes such as osmosis, physical stimuli, etc.; or on a solid matrix device where

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the drug is uniformly loaded and released. Controlled release systems can be classified
according to their release mechanism and preparation methods. Physical systems include
diffusion controlled systems such as porous systems and biodegradable/bioerodable
systems. Chemical systems employ immobilization of drugs in order to achieve the
sustained release effect [17].

1.4. Sustained release system

Sustained release dosage forms are designed to release a drug at a predetermined rate by
maintaining a constant drug level for a specific period of time with minimum side effects.
The sustained release drug delivery system optimizes the biopharmaceutical,
pharmacokinetic and pharmacodynamics properties of a drug in such a way that its utility
is maximized, side-effects are reduced and cure of the disease is achieved. There are several
advantages of sustained release drug delivery over conventional dosage forms [18]:

 Improved patient compliance due to less frequent drug administration

 Reduction of fluctuation in steady-state drug levels
 Maximum utilization of the drug
 Increased safety margin of drug
 Reduction in healthcare costs through improved therapy
 Shorter treatment period.

1.5. Transdermal drug delivery

Transdermal patch is an adhesive patch containing medicine that is placed in the skin to
deliver a specific dose of medication through the skin, into the bloodstream. It often
promotes healing of a particular area of body. An advantage of a transdermal drug delivery
route over other types of medication delivery such as oral, topical, intravenous,
intramuscular, etc. is that the patch provides a controlled release of the medication into the
patient, usually through either a porous membrane covering a reservoir of medication or
5|Page
through body heat melting thin layers of medication embedded in the adhesive.
Transdermal drug delivery offers controlled release of the drug into the patient, it enables
a steady blood level profile, resulting in reduced systemic side effects and, sometimes,
improved efficacy over other dosage forms.

1.6. Mesoporous silica gel

Mesoporous silica gel can be easily synthesized with the help of sol-gel technique. The
structural feature of silica gel are nanoscale size, mesoporous structure, surface to volume
ratio and easily tunable surface. The silica gels are biocompatible; that is it does not have
any adverse effect on the body tissue and cell. Its nontoxic nature and stability under
various biological atmosphere has made it an interesting material to be used for various
medical application [19]. Silica gel synthesized through sol-gel is also used for encapsulation
of many biological material such as protein, antigen, DNA, RNA and even plant and animal
cells without harming their biological functioning [20].

Drug delivery through silica gel can be controlled [21] i.e. it can deliver a constant supply
of active ingredients, at a definite rate, continuously for a certain amount of time, an amount
of drug equivalent to the eliminated by the body. Sustained Release (S.R) / Controlled
Release (C.R) has an advantage over convention form of drug dosage such as reduced
dosage frequency to such an extent that one daily dose is sufficient for therapeutic
management by maintaining uniform plasma concentration thus maximizing drug
utilization and to treat or cure condition in shortest possible time by smallest quantity of
drug, thus assuring patient compliance [22].

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1.7. Curcumin
Turmeric is a spice that comes from the root Curcumalonga L., a member of ginger family
(Zingaberaceae). It has been used for centuries as spices and food preservatives in southern
Asia and it is also used as coloring agent due to its bright yellow pigment. The extract of
curcumin have various medical properties such as antioxidant, antibacterial, antiviral, anti-
inflammatory, antifungal and cancer chemo
[23]
preventive actions . Curcumin, a yellow
compound isolated from its rhizome, is responsible
for its bioactive effects. Curcumin’s basic coloring
substance is curcuma longa and two related
compounds, demethoxycurcumin (DMC) and
bisdemethoxycurcumin (BDMC), together known
as curcuminoid. The chemical structure of three
curcuminoids are shown in figure 1.

Figure 1. Chemical structure of three

curcuminoids

The total curcuminoid which is about 4-6% of turmeric, also contains 2-4% essential oil
and 2-3% fixed oil and various volatile oils, including turmerone, atlantone and
zingiberone [24].

1.7. Calcium hydroxide

Calcium hydroxide also known as slaked lime (Hindi: Chuna) have antimicrobial and
[25]
healing properties . It is used in various dental surgeries and implants due to its
antimicrobial and healing properties. Our ancestor also used it into the inflamed area as it
absorbs water and thus reduces inflammation.

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Our ancestors has gifted us with the knowledge of using turmeric and slaked lime as a
mixture to cure inflammation and pain in our joints without having any adverse effect. We
can use the beneficiary property of turmeric and slaked lime as a potential replacement of
pain-killers and NSAIDs (Non-Steroidal Anti-Inflammatory Drugs), which may contain
serious side effects.

In this study we will encapsulate curcumin and slaked lime into the nano pores of
silica gel and study their release kinetics in stimulated body fluid (SBF). We will then
plot the release data against time and try to figure out the kinetic model, best suited
for the release of the herbal drug in in-vitro release study like zero-order (cumulative
amount of drug release versus time), first-order (log cumulative percentage of drug
remaining versus time), Higuchi (cumulative percentage of release versus square root
of time), and Korsmeyer–Peppas (log cumulative percentage of drug released versus
log time) equation models. Also we will be making a transdermal patch out of the
nanocomposite containing the herbal drug.

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2. Literature Review

2.1. Nanotechnology in drug delivery

Nano materials as a drug carrier have very promising application. A great progress have
been made in controlled release and site specific drug delivery using nanotechnology. Drug
delivery is the method or process of administering a pharmaceutical compound to achieve
a therapeutic effect in humans or animals. In a review conducted by O.M. Koo et al. on
biophysical attributes of the drug delivery and imaging platforms as well as the biological
aspects that enable targeting of these platforms to injured and diseased tissues and cells.
The principles of passive and active targeting of nanosized carriers to inflamed and
cancerous tissues with increased vascular leakiness, overexpression of specific
epitopes, and cellular uptake of these nanoscale systems are discussed. Different
preparation method and properties of different nano scale system such as liposomes,
micelles, emulsions, nanoparticulates, and dendrimer nanocomposites, and clinical
indications are also indicated in this study [26].

In a review conducted by Bonifácio et al, delivery of herbal medicine with the help of
nanomaterial was described. Nanomaterial can deliver herbal medicine at a sufficient
concentration during the entire treatment period, directing it to the desired site of
action [27].

In a study conducted by Ochekpe et al, various nanostructures employed in drug delivery,

their methods of fabrication and challenges of nano drug delivery are reviewed. Some
challenges such as drug effectiveness, toxicity, stability, pharmacokinetics and drug
regulatory control, which are associated with drug delivery using nanotechnology, are
discussed in this review [28].

Therapeutics such as nucleic acid, proteins/peptides, vaccines, anti-cancer and many other
drugs have disadvantages like low bio-availability, rapid clearance and high toxicity. In a
9|Page
paper written by Webster and Sundaram, using nanocarrier for controlled drug release
and/or increase selective cell targeting, cellular uptake, drug solubility and circulation time
of such drugs is discussed. Using nanocarrier for drug delivery has led to more
efficacious drug delivery and action of therapeutics, has been highlighted in the paper.
Structure and material such as liposomes, polymersomes, dendrimers, cyclodextrins-
containing polymers, carbon nanotubes and gold nanoparticles are also discussed [29].

2.2. Silica gel as biomaterial

In a review conducted by Tarn et al, biofunctionality and biocompatibility of mesoporous
silica gel has been shown. Using colloidal chemistry and evaporation-induced self-
assembly uniformly sized, porous, and dispersible nanoparticles can be synthesized. This
mesoporous silica nanoparticles being used as “nanocarriers”, are used to deliver drug and
other cargo to cells. The exceptionally high surface area of MSNPs, often exceeding
1000 m2/g, and the ability to independently modify pore size and surface chemistry,
enables the loading of diverse cargos and cargo combinations at levels exceeding those
of other common drug delivery carriers such as liposomes or polymer conjugates.
This is because noncovalent electrostatic, hydrogen-bonding, and van der Waals
interactions of the cargo with the MSNP internal surface cause preferential adsorption of
cargo to the MSNP, allowing loading capacities to surpass the solubility limit of a solution
or that achievable by osmotic gradient loading. The ability to independently modify the
MSNP surface and interior makes possible engineered biofunctionality and
biocompatibility.

The intrinsic porosity of the MSNP surface reduces the extent of hydrogen bonding or
electrostatic interactions with cell membranes as does surface coating with polymers or
lipid bilayers. Furthermore, the high surface area and low extent of condensation of the
MSNP Siloxane framework promote a high rate of dissolution into soluble silicic acid
species, which are found to be nontoxic. Potential toxicity is further mitigated by the high

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drug capacity of MSNPs, which greatly reduces needed dosages compared with other
nanocarriers [30].

2.3. Silica gel as a sustained release system

Inorganic porous material are promising carrier of various types of drug. The porous
structure is beneficial to attain controlled, sustained or pulsatile release in drug delivery
application. The diffusion rate of entrapped drug, gene or protein can be controlled by the
materials porous and hydrophilic characteristics. Moreover, porous inorganic materials
demonstrate high mechanical and chemical stability under a range of physiological
conditions.

Teoli et al, investigated the potential for wet silica gel for entrapment and sustained release
of proteins. They entrapped model proteins, BSA, ribonuclease-A and avidin, with
differing molecular weights and/or isoelectric points into two silica polymer formulation
having different silica content (4% and 12% wt/v). The conformational stability of the
proteins after entrapment and their release after immersion into physiological conditions
were measured. Circular dichroism analysis showed that protein conformation is
maintained after entrapment and stability is enhanced. Protein-free formulations were
injected intramuscularly into BALB/c mice to monitor the in vivo fate of the matrix, and
the results showed that the gel is totally reabsorbed, without any apparent surrounding
inflammation process. The time required for matrix bioerosion varied between one to three
weeks, depending on its SiO2 content. Erosion was also measured in vitro and the
contribution of erosion and diffusion to the release of the embedded proteins was
quantified. The study indicates that wet silica polymers obtained by the sol-gel route
are promising matrices for the sustained release of protein drugs [31].

M. Ahola et al, incorporated Torimifene citrate into silica xerogel matrix and release
kinetics was studied in invitro system and the effect of drug amount, drying
temperature and polyethylene glycol (PEG) on the release rate of toremifene citrate

11 | P a g e
and degradation of the silica xerogel matrixes were investigated. With the addition of
PEG (Mw 4600/10000) specific surface area of the matrix decrease and release rate of the
drug was also lowered. Reducing the amount of drug also lowered the release rate but the
drying temperature did not affected the release rate. The release profile was suggested to
be zero ordered and thus the release rate was controlled by erosion of silica xerogel
matrix[32].

Bhattacharyya, et al. conducted an in-vitro study which demonstrated that thin sol-gel
silica films can be applied to titanium implants for the controlled release of antibiotic
and adjuvant. A multilayer thin film can be deposited containing both hydrophilic
vancomycin and hydrophobic farnesol. Efforts are being made to combat methicillin-
resistant Staphylococcus aureus with regular doses of vancomycin. One technique is to use
combinational therapeutics. In vitro experiments showed that farnesol can be used as an
adjuvant with conventional antibiotics. The biggest challenge is that farnesol is highly
water insoluble. This limits its bioavailability if it were to be used along with vancomycin
at the site of infection when the treatment needs to be administered. An effective strategy
for the simultaneous delivery of antibiotic and adjuvant in order to treat methicillin-
resistant Staphylococcus aureus infections were designed [33].

2.4. Release kinetics

There are a number of model which determine the kinetics of drug release. These
mathematical modeling help us to optimize the design of therapeutic device to yield
information on the efficacy of various release model. M.A Kalam et al has reviewed
various kinetic modeling on drug release from controlled drug delivery system such as

 Statistical methods (exploratory data analysis method, repeated measures design,

multivariate approach [MANOVA: multivariate analysis of variance]
 Model dependent methods (zero order, first order, Higuchi, Korsmeyer-Peppas
model, Hixson Crowell, Baker-Lonsdale model, Weibull model, etc.)

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  Model independent methods

In our text we will be concentrating on various model dependent method. Model dependent
methods are based on different mathematical functions, which describe the dissolution
profile. Once a suitable function has been selected, the dissolution profiles are evaluated
depending on the derived model parameters. The model dependent approaches included
zero order, first order, Higuchi, Hixson-Crowell, Korsmeyer-Peppas etc [34].

Zero order model: Dissolution of drug from a dosage form that do not disaggregate and
release the drug slowly that is where drug release rate is independent of its concentration
can be represented as:
A0-At = kt---------------- (I)
Where A0 is initial amount of drug in the dosage form; At is the amount of drug in the
dosage form at time ‘t’ and ‘k’ is the proportionality constant.

Dividing this equation by A0;

1-(At /A0) = kt/A0 or 1-At /A0=k0t--------------- (II)

Where 1- (At /A0) represents the fraction of drug dissolved in time ‘t’ and k0 the zero order
release constant.

Graphical representation of fraction of drug dissolved verses time will be linear. This
relation can be used to determine the drug dissolution of various types of modified release
dosage forms e.g. some transdermal systems, matrix tablets with low soluble drugs (Varles,
1995) coated forms, and osmotic systems etc. The dosage forms following this profile,
release the same amount of drug by unit time and it is the ideal method of drug release in
order to achieve a prolonged pharmacological action.

First order kinetics: The first order kinetics was first applied for drug dissolution studies
by Gibaldi and Feldman in 1967 (Gibaldi and Feldman, 1970) and later by Wagner in 1969
(Wagner, 1967). In this case the drug release rate is concentration dependent; that can be
depicted in decimal logarithm as

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Log At = LogA0 + K1t/2.303------------ (III)

Where At is the amount of drug released in time‘t’, A0 is the initial amount of the drug in
the solution and K1 is the first order release constant.

Here the graphical representation of the decimal logarithm of drug released verses time
will be linear. Example: The dosage form follows this profile such as those containing
water soluble drug in a porous matrices ( Mulye and Turko, 1995) release the drug that is
proportional to the amount of drug released by unit time diminish.

Hixson-Crowell model: To evaluate the drug release with changes in the surface area and
the diameter of the particles /tablets, HixsonCrowell in 1931 (Hixson and Crowell, 1931)
recognized that the particle regular area is proportional to the cubic root of its volume,
desired an equation as

A01/3 – At1/3 = kst --------------- (IV)

Where A0 is the initial amount of drug in the dosage form, At is the remaining amount of
drug in the dosage form at time’t’ and ks is a constant incorporating the surface volume
relation. Example: Tablets where the dissolution occurs in planes that are parallel to the
drug surface if the tablet dimensions diminish proportionality in such a manner that the
initial geometrical form keeps constant all the time. Here a graphical representation of the
cubic root of the unreleased fraction of the drug verses time will be linear if the equilibrium
conditions are not reached and if the geometrical shape of the dosage form diminishes
proportionally overtime. This model is used by assuming that release rate is limited by the
drug particles dissolution rate and not by the diffusion.

Higuchi model: This model is based on the hypotheses that (a) initial drug concentration
in the matrix is much higher than drug solubility; (b) drug diffusion takes place only in one
dimension (edge effect must be negligible); (c) drug particles are much smaller than system
thickness; (d) matrix swelling and dissolution are negligible; (e) drug diffusivity is
constant; and (f) perfect sink conditions are always attained in the release environment.
Accordingly, model expression is given by the equation:

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ft = Q = A[D(2C-Cs)Cst]1/2------------(V)

Where Q is the amount of drug released in time t per unit area A, C is the drug initial
concentration, Cs is the drug solubility in the matrix media and D is the Diffusivity of the
drug molecules (diffusion coefficient) in the matrix substance. To study the dissolution
from a planar heterogeneous matrix system, where the drug concentration in the matrix is
lower than its solubility and the release occurs through pores in the matrix, the expression
is given by equation:

ft = Q =[D𝛿/𝜁(2C-𝛿Cs)Cst]1/2 ------------(VI)

Here δ is the porosity of the matrix, 𝜁 is the tortuosity of the matrix and D, Q, A, Cs and t
having the meaning assigned above. Tortuosity is defined as the dimensions of radius and
branching of the pores and canals in the matrix. In a general way it is possible to simplify
the Higuchi model as (generally known as the simplified Higuchi model):

𝑓𝑡 = 𝑄 = 𝐾𝐻 √𝑡 ------------- (VII)

Where, KH is the Higuchi dissolution constant. The data obtained were plotted as
cumulative percentage drug release versus square root of time.

Korsmeyer-Peppas model: In 1983 Korsmeyer et al. (Korsmeyer et al, 1983) developed

a simple, semi-empiric model, when diffusion is the main drug release mechanism, relating
exponentially the drug release to the elapsed time (t).

At /A∞ = atn --------------------------- (VIII)

Where ’a’ is the constant incorporating structural and geometrical characteristic of the
dosage form, n is the release exponent , indicative of the drug release mechanism and the
function of ‘t’ is At /A∞ ( fractional release of drug).

In 1985 Peppas (Peppas, 1985) used this n value in order to characterize different release
mechanism concluding for values for a slab, of n = 0.5 for Fickian Diffusion, between 0.5
and 1.0 or n = 1.0, for mass transfer following a non-fickian model. 0.5 < n < 1.0, for
15 | P a g e
anomalous transport. To determine the exponent ‘n’ the position of the release curve where
At /A∞ < 0.6 should only be used. This model is generally used to analyze the release of
polymeric dosage form, where the release mechanism is not well known or when more than
one type of release phenomenon could be involved. When there is the possibility of a burst
effect, the equation (VIII) becomes (Kim and Fassihi, 1997)

At /A∞ = atn + b---------------- (IX)

Where ‘b’ is the burst effect. The Korsmeyer equation i.e. equation (IX) were considered
inappropriate since the introduction of the lag period was essential to describe the
accurately the quantity of drug released.

An equation

At /A∞ = [k (t-l)n + k’ (t-l)2n]------(X)

Incorporating a lag period (l), kinetic constant (k and k’) for diffusion and erosion
controlled release and a diffusional exponent (n) produced the best fit of the data. The
kinetic constants were not normally additive, k’ becoming increasingly negative with
increase in temperature

2.5. Curcumin as an herbal drug

Curcumin, 1, 7-bis (4-hydroxy-3-methoxyphenyl)-1,6- heptadien-3,5-dione, is a lipophilic
molecule that rapidly permeates cell membrane. Typical extract of Curcuma longa L.
contains the structures I to III, (I) Diferuloylmethane/Curcumin (II)
Bisdemethoxycurcumin (III) demethoxycurcumin. All three structures has been shown in
Figure.1. There is a controversy whether I or II is the most potent antioxidant, anti-
inflammatory and anti-tumor agent. Curcumin is nearly insoluble in water and is quite
stable in acidic pH of the stomach. In a review done by Julie S. Jurenka, it is stated that
bioavailability of curcumin is very low, as it is rapidly metabolized, conjugated in liver and
excreted into feces. Jurenka has shown the anti-inflammatory mechanism of curcumin and

16 | P a g e
various research are done on inflammatory diseases such as rheumatoid arthritis,
osteoarthritis, inflammatory bowel diseases etc. But the problem lies in the bioavailability
of curcumin which may be solved with the help of advanced nanomaterials [35].

A review on therapeutic efficacy of curcumin was done by Noorafshan et al, which

concluded that curcumin has the potential for prevention/or treatment for various
diseases including cancer, due to its ability to affect a wide range of molecular target
and an excellent safety profile [36].
33

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3.Methodology

3.1. Extraction of Curcumin from Turmeric roots

Curcumin is insoluble in water but is soluble in organic solvent such as methanol, ethanol
and acetone. The choice of solvent for extraction is limited to few solvent due to national
and international food processing law. Solvents like hexane, acetone, alcohol (ethanol,
methanol), isopropanol and ethyl acetate are used in extraction of oleoresins of spices. The
curcuminoids are poorly soluble in hydrocarbon solvents, whereas alcohol and acetone are
good extractants.

The process for extraction [24]:

 The turmeric root will be ground into powder.

 The moisture in the powder should be completely eliminated by drying.
 The dried powder then will be washed and treated with suitable solvent such as
acetone, alcohol etc.
 Distillation should be done to separate the mixture of solute and solvent.
 The oleoresin which we get should be further washed using selective solvent such
as hexane (it has higher absorption coefficient)
 After washing we will get curcumin powder which will be ready for our use.

3.2. Synthesis of silica nanoparticle with sol-gel process

Sol-gel process is to get SiO2 nanocomposite. It is a two-step process 1.Hydrolysis
2.Polycondensation.

1. Hydrolysis: As TEOS is insoluble in water, to facilitate this miscibility we use C2H5OH

or alcohol as solvent. After that the TEOS reacts with water and forms- Silicon
Tertrahydroxide (Si(OH)4). The equations is as follows:

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 Si(OC2H5)4 + 4H2O Si(OH)4 + 4C2H5OH

2. Polycondensation: The mixture of DI-Water and ethanol is added drop wise in the mixture
of TEOS and ethanol with the help of micropipette while the mixture of TEOS and ethanol is
stirred at constant speed at room temperature with the help of magnetic stirrer. At this stage
the Si(OH)4 forms a 3D network of silica with Nano pores. The equation is as follow:

OH OH
Si(OH)4 + Si(OH)4 OH-Si-O-Si-OH + H2O
OH OH
After this the solution is kept for aging to get a long chain of silicoxane bond.

OH OH OH OH

OH-Si-O-Si-OH + HO-Si-O-Si-OH nSiO2 + nH2O

OH OH OH OH

3.3. Preparation of Curcumin-Lime mixture

incorporated silica gel
Extracted curcumin and calcium hydroxide will be mixed together and will be dissolved in
organic solvent as they are insoluble in water. The mixture is then added to the solution of
TEOS and ethanol during polycondensation stage. As the water and alcohol will be
evaporated during aging, the mixture of curcumin and calcium hydroxide will fill the
nanopores of SiO2 nanocomposite.

3.4. Preparation of Stimulated Body Fluid (SBF)

The pH of a human blood is around 7.35-7.4. and other body fluid such as saliva, spinal
fluid is also near neutral. So we will be preparing SBF which will be around pH of 7. The
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process of preparation of SBF is mixing 750ml of DI-water with the ingredients one by one
given in the table 1.

Table 1. Composition of SBF

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References
1. The Wall Street Journal, Feynman and the Futurists. http:
//online.wsj.com/news/articles/SB2000142405274870 3580904574638160601840456
2. Binnig, G.; Rohrer, H. (1986). "Scanning tunneling microscopy". IBM Journal of Research
and Development. 30 (4): 355–69.
3. "Press Release: the 1986 Nobel Prize in Physics". Nobelprize.org. 15 October
1986. Archived from the original on 5 June 2011. Retrieved 12 May 2011.
4. Kroto, H. W.; Heath, J. R.; O'Brien, S. C.; Curl, R. F.; Smalley, R. E. (1985). "C 60:
Buckminsterfullerene". Nature. 318 (6042): 162–163. Bibcode:
1985Natur.318..162K. doi:10.1038/318162a0.
5. Adams, W. W.; Baughman, R. H. (2005). "RETROSPECTIVE: Richard E. Smalley (1943-
2005)". Science. 310 (5756): 1916. doi:10.1126/science.1122120. PMID 16373566
6. Ehud Gazit, Plenty of room for biology at the bottom: An introduction to bionanotechnology.
Imperial College Press, 2007, ISBN 978-1-86094-677-6
7. "Nanobiology". Swiss Nanoscience Institute.
8. "ISO/TS 80004-1:2015 - Nanotechnologies — Vocabulary — Part 1: Core
terms". International Organization for Standardization. 2015. Retrieved 2018-01-08.
9. Sahoo SK, Labhasetwar V. Nanotech approaches to drug delivery and imaging. Drug Discov
Today 2003; 8(24): 1112-20.
10. "Drug Delivery Systems (definition)".
11. "Drug delivery - definition of drug delivery by Medical dictionary". TheFreeDictionary.com.
12. Wang, NX.; von Recum, HA (2011). "Affinity-Based Drug Delivery". Macromol Biosci. 11:
321–332. doi:10.1002/mabi.201000206.
13. "Definition". Retrieved 2008-05-27.
14. Application of Nanotechnology in Pharmaceutical Formulation Design and Development;
Ram S. Thakur and Ruchi Agrawal
15. K.P.S Kumar, D. Bhowmik, S. Srivastava, S. Paswan, A.S. Dutta. “Sustained Release Drug
Delivery System Potential.” The Pharma Innovation, Vols. 1, (2012): 46-56.
16. B. Amruta, K. Ramesh. " Oral Controlled Drug Delivery System." In Drug Delivery Systems:
A Review, by A.V Gothaskar. 2004.
17. R.F. Popovici, E.M. Seftel, G.D. Mihai, E. Popovici, V.A. Voicu. "Controlled Drug Delivery
System Based on Ordered Mesoporous." Journal of Pharmaceutical Sciences, Vols 100,
(2011): 704-714.
18. L. Khalane, A. Alkunte, A. Birajdar. "Sustained Release Drug Delivery System: A Concise
Review." Pharma Tutor (Pharmacy Infopedia), 2008. http://www.pharmatutor.org.
19. Asefa,T., & Tao, Z (2012). Biocompatibility of Mesoporous Silica Nanoparticles. Chemical
Research in Toxicology, 25(11), 2269-2278.
20. Gill, I. (2001). Bio-doped nanocomposite polymers: sol–gel bioencapsulates. Chemistry of
Materials, 13, 3404-3421

21 | P a g e
 21. Nanoporous inorganic membranes or coatings for sustained drug delivery in implantable
devices: Evin Gultepe, Dattatri Nagesha, Srinivas Sridhar, Mansoor Amij; Volume 62, Issue
3, 8 March 2010, Pages 305-315
22. Overview on Controlled Release Dosage Form Sathish Ummadi, B. Shravani, N. G.
Raghavendra Rao, M. Srikanth Reddy, B. Sanjeev Nayak. Vol. 3, No. 4 (2013): 258-269
23. Therapeutic uses of curcuma longa (turmeric); Pratibha Mehta Luthra, Rambir Singh and
Ramesh Chandra; Indian Journal of Clinical Biochemistry, 2001, 16(2), 153-160
24. Extraction of curcumin from turmeric root: Ashok Kumar Popuri, Bangaraiah Pagala; ISSN
2319-9725
25. Mechanisms of antimicrobial activity of calcium hydroxide: a critical review (Review).
International Endodontic Journal, 32, 361±369, 1999
26. Role of nanotechnology in targeted drug delivery and imaging:a concise review ;Otilia M.
Koo, MS, Israel Rubinstein, MD, Hayat Onyuksel, PhD; Nanomedicine: Nanotechnology,
Biology, and Medicine 1 (2005) 193– 212
27. Nanotechnology-based drug delivery systems and herbal medicines: a review; Bruna Vidal
Bonifácio, Patricia Bento da Silva, Matheus Aparecido dos Santos Ramos, Kamila Maria
Silveira Negri, Taís Maria Bauab, Marlus Chorilli; International Journal of Nanomedicine
2014:9 1–15
28. Nanotechnology and Drug Delivery Part 2: Nanostructures for Drug Delivery; Nelson A
Ochekpe1*, Patrick O Olorunfemi2 and Ndidi C Ngwuluka2; Tropical Journal of
Pharmaceutical Research, June 2009; 8 (3): 275-287
29. Webster DM, Sundaram P, Byrne ME.; Injectable nanomaterials for drug delivery: carriers,
targeting moieties, and therapeutics.
30. Mesoporous Silica Nanoparticle Nanocarriers: Biofunctionality and Biocompatibility;
Derrick Tarn, Carlee E. Ashley, Min Xue, Eric C. Carnes, Jeffrey I. Zink, and C. Jeffrey
Brinker; Acc. Chem. Res., 2013, 46 (3), pp 792–801
31. Wet sol-gel derived silica for controlled release of proteins.;Teoli D, Parisi L, Realdon N,
Guglielmi M, Rosato A, Morpurgo M.; J Control Release. 2006 Dec 1;116(3):295-303
32. Silica xerogel carrier material for controlled release of toremifene citrate.; Manja Ahola, Pirjo
Kortesuo, Ilkka Kangasniemi, Juha Kiesvaara, Antti Yli-Urpo.; International Journal of
Pharmaceutics 195 (2000) 219–227
33. S. Radin, S. Bhattacharyya, P. Ducheyne. “Nanostructural control of the release of
macromolecules from silica sol–gels.” Acta Biomaterialia, Vol. 9, (2013): 7987–7995
34. RELEASE KINETICS OF MODIFIED PHARMACEUTICAL DOSAGE FORMS: A
REVIEW. M.A. Kalam1 , M. Humayun1 , N. Parvez2*, S.Yadav2 , A.Garg2 , S.Amin,1 ,Y.
Sultana1 and A. Ali.1; Continental J. Pharmaceutical Sciences 1: 30 - 35, 2007
35. Julie S. Jurenka; Anti-inflammatory properties of curcuma longa: A review of preclinical and
clinical research
36. Ali Noorafshan and Soheil Ashkani-Esfahani; A Review of Therapeutic Effects of Curcumin

22 | P a g e