Treatment of breast cancer by TDDS


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Treatment of breast cancer by TDDS

  1. 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
  2. 2. CONTENTS  Introduction  Objective  Plan of study  Materials and methods  Justification
  3. 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. 4. 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.
  5. 5. 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.
  6. 6. 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.
  7. 7. 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
  8. 8. APPROACHES TO DRUG TARGETING  3 different approaches: 1. 2. 3. Physical or Mechanical Approach Biological Approach Chemical Approach
  9. 9. 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. 
  10. 10. 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.
  11. 11. 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. 
  12. 12. 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. 
  13. 13. 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.
  14. 14. 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.
  15. 15. 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.
  16. 16. 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.
  17. 17. 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
  18. 18. OBJECTIVE
  19. 19. 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.
  21. 21. 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
  22. 22. B. C.     Formulation of nanosuspension Characterization and evaluation of nanosuspension Particle size and size distribution Zeta potential X-ray Diffraction Differential Scanning Calorimeter
  23. 23. 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
  24. 24. 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
  25. 25. DRUG : DOCETAXEL POLYMERS : POLOXAMER 407 CHEMICALS REQUIRED: Acetone Methanol Acetonitrile SLS Ethyl acetate
  26. 26. EQUIPMENTS: UV Spectrophotometer Sonicator Homogenizer Optical microscope Freeze dryer Zeta sizer Dsc Digital weighing balance TEM FT-IR SEM Coulter Counter Vortex mixer HPLC Dissolution Apparatus
  27. 27. 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
  28. 28. vehicles. Drug-excipient interaction studies: carried by Fourier-Transform Infrared spectroscopy and DSC.
  29. 29. 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.
  30. 30. CHARACTERIZATION OF NANOSUSPENSION: Size and shape :freeze fracture microscopy. Morphology : SEM Entrappment efficiency : Exhaustive dialysis method . Vesicle charge: zeta meter
  31. 31. 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. 34. 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 .
  35. 35. 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