1. STUDY OF TARGETED NANO DRUG DELIVERY
SYSTEM FOR THE TREATMENT OF BREAST
CANCER
M-Pharm Project Synopsis Presentation
by
RAMANDEEP KAUR
(1265329)
Supervised by
Dr. S.L HARIKUMAR
Rayat and Bahra Institute of Pharmacy, Mohali,
Sahauran
2013-14
3. BREAST CANCER
• There are 1.7 million women suffering from Breast
cancer world wise and 522000 deaths occurs per year
with breast cancer.
One out of every seven women will be diagnosed
with breast cancer in 2007
Therefore novel techniques like nano targeted
drug delivery systems are needed today with better
treatment options over other treatments like
Chemotherapy, Radiation therapy, Surgery to
remove cancerous tissue etc.
3
4.
5. A special form of drug delivery system where the
pharmacological active agents or medicament is
selectively targeted or delivered only to its site of action
or absorption and not to the non target tissues or
organs.
6. ADVANTAGES OF DRUG TARGETING
Drug administration protocols may be simplified.
Drug quantity may be greatly reduced as well as the
cost of therapy.
Drug concentration in the required sites can be
sharply increased without negative effects on non
target compartments.
7. DISADVANTAGES OF DRUG TARGETING
Rapid clearance of targeted system
Immune reactions against intravenous administered
carrier system.
Insufficient localization of targeted systems into
tumour cells.
Diffusion and redistribution of released drugs.
8. IDEAL CHARACTERISTICS OF TDDS
Non toxic and non immunogenic
Chemically Stable invivo and invitro
Minimal drug leakage during transit
Carriers must be bio degradable
Controllable and predictable drug release
9. APPROACHES TO DRUG TARGETING
3 different approaches:
1.
2.
3.
Physical or Mechanical Approach
Biological Approach
Chemical Approach
10. PHYSICAL OR MECHANICAL
APPROACH
Involves formulation of drug using particulate
delivery device physical localization
differential release of drug.
Site specificity is due to higher drug concns at
the site.
Also called ‘passive targeting’ exploit natural
fate of particles.
Carrier systems may be microspheres,
nanoparticles or liposomes.
Crucial factors—size & surface of particles.
11. BIOLOGICAL APPROACH
Involves delivery of the drug using carrier system with
targeting moiety either in-built (by virtue of the
structure of the carrier) or is chemically coupled.
4 approaches:
1.
2.
3.
4.
Antibodies directed against specific cell surface
antigens,
Endogenous carbohydrate-binding proteins (lectins),
Glycoconjugates functioning as specific ligands for
receptors on specific cells that recognize particular
sugar residues, and
Hormones functioning as specific ligands for receptors
on specific targets.
12. ANTIBODIES FOR ANTIGEN TARGETING
higher immune response—when antigens are
directed to antigen presenting cells (APCs) &
lymphocytes.
Done by coupling antigen with a ligand of strong
binding affinity for molecules of MHC.
E.g. coupling of viral antigens to monoclonal
antibodies against a mouse Class II MHC.
Advantage:
Preparation of safer vaccines.
Targeting without use of carriers.
Targeted antigen required only in 1st injection.
Upto 1,000 fold increase in efficiency achieved.
13. CHEMICAL APPROACH
Incorporates targeting consideration into the drug
design process—for design of safe, localized delivery.
Targeting to active biological molecules based on
predictable enzymatic activation. CDS is produced by
chemical reactions with target drug, covalently
coupled with carrier & protective moieties convert
to CDS1 CDS2 … CDSn.
Allow sustained release of drugs also.
14. HYPOTHESIS
The proposed research work is concerned about enhancing
the bioavailability of poorly water soluble drugs (BCS class II
and IV).The bioavailability of Docetaxel is limited due to poor
solubility. So, we can increase the solubility by formulating it
as nanosuspension. Due to their small sizes
nanosuspension can pass through interstitial spaces
between cells.Tumor cells typically have larger interstitial
spaces than healthy cells. The drug particles collect in centre
bringing therapeutic to kill the tumour from inside out.
15. Also we can target the drug to the site by
antibody drug conjugates in which drug is
attached with specific antibody will target a
certain marks. Ab will track those protein
down the body and attach themselves to
suface of cancer cells.Biochemical reactions
will take place. Ag triggers a signal in tumor
cell and absorb Ab with drug and drug will be
released at the site.This can further
enhance the therapeutic effect and
decreasing the dose and dose related side
effects.
16. WHY Docetaxel?
Docetaxel is clinically well established anti-mitotic
chemotherapy medication used mainly for the
treatment of breast cancer. It is BCS class iv drug
which have low solubility and low permeability.
Docetaxel interferes with the normal function of
microtubule growth. docetaxel induces programmed
cell death (apoptosis) in cancer cells by binding to
an apoptosis stopping protein called Bcl-2 (B-cell
leukemia 2) and thus arresting its function.
17. Therefore TDDS will be followed to enhance the
bioavailability of drug and reduce its side effects
by formulating nanosuspension solubility of
Docetaxel will also improve because of their small
sizes, nanosuspension can pass through interstitial
spaces between cells.Tumor cells typically have
larger interstitial spaces than healthy cells. The
drug particles collect in centre bringing therapeutic
to kill the tumour from inside out.
18. Basic features of Docetaxel
Formula
Mol. Weight
Colour
Physical state
Water solubility
Melting point
Log P
C43H53NO14
807.88
off white
solid
insoluble in water
232oC
2.4
20. The main objective is to study the targeted nano
drug delivery system for the treatment of breast
cancer using the model drug (Docetaxel) by
formulating a nanosuspension to achieve the
desired pharmacological response.
22. PLAN OF WORK
Literature survey
Procurement of drug and excipients
Formulation Development
A. Preformulation studies of drug and excipients:
Melting point
Partition coefficient determination
Solubility
Determination of absorption maxima
Drug-excipient interaction studies
24. D.
E.
F.
G.
H.
I.
J.
K.
In vitro release study of nanosuspension
Release kinetics
In vivo studies
Cell line studies
Selection of optimised formulation
Stability study
Compilation of data
Statistical analysis
25. D.
E.
F.
G.
H.
I.
J.
In vitro release study of nanosuspension
Release kinetics
Cell line studies
Selection of optimised formulation
Stability study
Compilation of data
Statistical analysis
29. PRE-FORMULATION STUDIES:
Melting point: It is done by capillary fusion
method.
Partition coefficient: It is determined by shake
flask method.
Solubility studies: The solubility studies of drug
are carried out in different solvent systems (i.e.
Organic, aqueous & pH dependent) and in different
31. FORMULATION OF NANOSUSPENSION
Nanosuspension is prepared by Homogenization Firstly, drug
powders are dispersed in a stabilizer solution to form presuspension; then pre-suspension will homogenized by the high-
pressure homogenizer at a low pressure for several times as a kind
of premilling, and finally will homogenized at a high pressure for
10-25 cycles until the nanosuspensions with the desired size will
prepare.
32. CHARACTERIZATION OF NANOSUSPENSION:
Size and shape :freeze fracture
microscopy.
Morphology : SEM
Entrappment efficiency : Exhaustive
dialysis method .
Vesicle charge: zeta meter
33. In-vitro
drug release studies: USP
apparatus V will be used.
Release kinetic studies:
Zero order, first order, Higuchi model, Koresmeyer and
Peppas model will be applied.
:
In-vitro: cell line studies
34. STABILITY STUDIES:
will be conducted according to ICH guidelines.
STATISTICAL INTERPRATATION
THE EXPERIMENTAL DATA:
Using ANOVA
OF
36. Docetaxel is class iv drug with low solubility and low
permeability.
The therapeutic efficiency of drug is limited due to
above problems.
Docetaxel has also complex structure and their cell
killing properties are sensitive to any chemical
modification
Therefore use of targeting drug delivery by Ab drug
conjugation system can overcome such problems .
37. Therefore by nano targeted drug delivery system
we can enhance the solubility and therapeutic effect
of drug and
adverse effects.
reduces the dose and dose related