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.