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
Nov 11, 2014
STUDY OF TARGETED NANO DRUG DELIVERY SYSTEM FOR THE TREATMENT OF BREAST CANCER
M-Pharm Project Synopsis PresentationbyRAMANDEEP KAUR(1265329)Supervised byDr. S.L HARIKUMAR
Rayat and Bahra Institute of Pharmacy, Mohali, Sahauran 2013-14
CONTENTS IntroductionObjectivePlan of study
Materials and methods
Justification
3
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.
• There are 1.7 million women suffering from Breast cancer world wise and 522000 deaths occurs per year with breast cancer.
Targeted Drug Delivery SystemA 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.
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.
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.
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
APPROACHES TO DRUG TARGETING
3 different approaches:
1. Physical or Mechanical Approach
2. Biological Approach3. Chemical Approach
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.
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. Antibodies directed against specific cell surface
antigens,2. Endogenous carbohydrate-binding proteins (lectins),3. Glycoconjugates functioning as specific ligands for
receptors on specific cells that recognize particular sugar residues, and
4. Hormones functioning as specific ligands for receptors on specific targets.
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.
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.
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.
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.
CRITERIA FOR DRUG SELECTIONWHY 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.
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.
Basic features of Docetaxel Formula C43H53NO14
Mol. Weight 807.88 Colour off white Physical state solid Water solubility insoluble in water Melting point 232oC Log P 2.4
OBJECTIVE
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.
PLAN OF WORK
LITERATURE SURVEY
PROCUREMENT OF DRUG AND EXCIPIENTS
FORMULATION DEVELOPMENT
PLAN OF WORKLiterature surveyProcurement of drug and excipientsFormulation Development
A. Preformulation studies of drug and
excipients:
Melting pointPartition coefficient determinationSolubilityDetermination of absorption maximaDrug-excipient interaction studies
B. Formulation of nanosuspensionC. Characterization and evaluation of
nanosuspension Particle size and size distribution Zeta potential X-ray Diffraction Differential Scanning Calorimeter
D. In vitro release study of nanosuspension
E. Release kineticsF. In vivo studiesG. Cell line studiesH. Selection of optimised formulationI. Stability studyJ. Compilation of dataK. Statistical analysis
D. In vitro release study of nanosuspension
E. Release kineticsF. Cell line studiesG. Selection of optimised formulationH. Stability studyI. Compilation of dataJ. Statistical analysis
MATERIALS AND METHODS
DRUG : DOCETAXEL
POLYMERS : POLOXAMER 407
CHEMICALS REQUIRED:AcetoneMethanolAcetonitrileSLSEthyl acetate
EQUIPMENTS:
UV Spectrophotometer
SonicatorHomogenizerOptical microscopeFreeze dryerZeta sizerDscDigital weighing balance TEM.
FT-IR SEMCoulter CounterVortex mixerHPLCDissolution Apparatus
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
vehicles.
Drug-excipient interaction
studies: carried by Fourier-Transform
Infrared spectroscopy and DSC.
FORMULATION OF NANOSUSPENSION
Nanosuspension is prepared by
Homogenization Firstly, drug
powders are dispersed in a stabilizer
solution to form pre-suspension; 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.
CHARACTERIZATION OF NANOSUSPENSION:Size and shape :freeze fracture microscopy. Morphology : SEM
Entrappment efficiency :
Exhaustive
dialysis method .
Vesicle charge: zeta meter
:
Release kinetic studies:Zero order, first order, Higuchi model, Koresmeyer and Peppas model will be applied.In-vitro: cell line studies
In-vitro drug release studies: USP apparatus V will be used.
STABILITY STUDIES: will be conducted according to ICH guidelines.
STATISTICAL INTERPRATATION OF THE EXPERIMENTAL DATA:Using ANOVA
JUSTIFICATION
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 .
Therefore by nano targeted drug
delivery system we can enhance the
solubility and therapeutic effect of drug
and reduces the dose and dose related
adverse effects.