Targeted drug delivery systems By Vishnu Datta M

Introduction
Advantages and disadvantages
Basic biological process and events in Targeted delivery

1. Targeted Drug Delivery Systems

2. Targeted Drug Delivery Systems Vishnu Datta M Dept . of pharmaceutics JSSCP , MYSORE JSS University

3. Biological processes and events involved in drug targeting 2 Agenda Concept. Introduction Advantages and Disadvantages Targeted Drug delivery

4. Introduction It is a special form of drug delivery system where the pharmacologically active agent or medicament is selectively targeted or delivered only to its site of action or absorption and not to the non-target organs or tissues or cells. The drug may be delivered: To the capillary bed of the active sites, To the specific type of cell (or) even an intracellular region. Ex- tumour cells but not to normal cells, To a specific organ (or) tissues by complexing with the carrier that recognizes the target

5. SMART DRUG THERAPY??? INDEED 1 ..

6. Reasons for Site specific delivery of drugs 2 Pharmaceutical D rug instability in conventional dosage form Solubility Biopharmaceutical L ow absorption H igh-membrane bounding B iological instability Pharmacokinetic / Pharmacodynamic S hort half-life L arge volume of distribution L ow specificity Clinical L ow therapeutic index.

7. OBJECTIVES To achieve a desired pharmacological response at a selected sites without undesirable interaction at other sites, there by the drug have a specific action with minimum side effects & better therapeutic index. Ex- in cancer chemotherapy and in enzyme replacement therapy.

8. IDEAL CHARACTERISTICS Targeted drug delivery system should be- HOW?? Biochemically inert (non-toxic ) N on-immunogenic . B oth physically and chemically stable in vivo and in vitro . R estrict drug distribution to target cells or tissues or organs S hould have uniform capillary distribution . C ontrollable and predicate rate of drug release.

9. IDEAL CHARACTERISTICS Drug release does not effect the drug action. Therapeutic amount of drug release. Minimal drug leakage during transit. C arriers used must be bio-degradable or readily eliminated from the body without any problem and no carrier induced modulation of diseased state. T he preparation of the delivery system should be easy or reasonably simple, reproductive and cost effective.

10. ADVANTAGES Control of drug delivery on to a particular site or vicinity with predetermined or expected release kinetics DISADVANTAGES Expensive Technical skill required Stability issues both Chemical and physical biological as well Yield comparatively very less Advantages and Disadvantages Targeted drug delivery systems

11. Biological processes and events involved in drug targeting 2 Cellular Uptake and Processing Transport across the epithelial barrier Extravasation Lymphatic Uptake

12. Cellular Uptake and Processing Following administration low molar mass drugs can enter into or pass through various cells by simple diffusion process. Targeted drug delivery usually have macro molecular assemblies hence cannot enter by such simple process. Hence take up by a process called ENDOCYTOSIS Steps involved : Internalization of the plasma membrane Concomitant with engulfment of extracellular material

13. Cellular Uptake and Processing Phagocytes^^^^ rest of the cells opsosins immunoglobulin G complement C3b fibronectin dysopsonins IgA & sIgA impart degree of hydrophilicity >>>decrease the uptake

14. Cellular Uptake and Processing Compared with phagocytosis pinocytosis is a universal phenomenon in all the cells pinocytosis does not require any external stimulus Pinocytosis is divided into two types: Fluid phases pinocytosis Adsorptive pinocytosis Compared with phagocytosis fluid phase pinocytic capture of molecules is relatively slower being directly proportional to the concentration and size dependant

15. Transport across the epithelial barrier The oral buccal nasal vaginal and rectal cavities are internally lined with one or more layers of epithelial cells Depending on the position and function in the body epithelial cells can be varied forms Three layer physiology: Epithelial Lamia propria Basal lamina Low molar mass drugs cross the above by passive difussion carrier mediated systems ans selective and non-selective endocytosis

16. Transport across the epithelial barrier The polar materials diffuse through tight junctions of epithelial cells Passive transport is usually higher in damaged mucosa where as active transport depends on structural integrity of epithelial cells Positively charged particles showed increased uptake than negatively charged counterparts. Absoption of drugs from buccal via transcellular and paracellular later being dominant

17. Transport across the epithelial barrier Some proposals Ex-vaginal cavity could be an effective delivery site for certain pharmaceuticals Such as calcitonin for the treatment of postmenopausal osteoporosis It was demonstrated that when delivered vaginally first undergo uterine pass effect suggesting that the vaginal route can be useed to target to the uterus

18. Extravasation Many diseases result from the dysfunction of cells located outside the cardiovascular system thus for a drug to exert its therapeutic effects it must exit from the central circulation this process of trans vascular exchange is called E xtravasation which is governed by blood capillary walls Factors that control permeability of capillaries Structure of the capillary wall Pathological condition R ate of blood and lymph supply Physicochemical factors of drug

19. Extravasation The structure of the blood capillary varies in different organs tissues. It consists of a single layer of endothelial cells joined together by intercellular juctions Depending on the morphology and continuity of the endothelial layer and the basement membrane blood capillaries are divided into Continuous Fenestraded S inusoidal

20. Extravasation

21. Extravasation Continuous capillaries are common and widely distributed in the body exhibit tight inter endothelial junctions and an uninterrupted basement membrane Fenestrated capillaries shows inter-endothelial gaps of 20-80nm Sinusoidal capillaries show inter endothelial gaps of 150nm Depending on the tissue or organ the basal membrane is either absent ex-liver or present in discontinuous ex-spleen and bone marrow

22. Extravasation Macromolecules can transverse the normal endothelium by passive process such as nonspecific fluid phase trans capillary pinocytosis and passage through inter endothelial junctions gaps or fenestrate or by receptor-mediated transport systems Organs such as the lung with very large surface areas have a proportionately large total permeability and consequently a high extravasation Depends on charge shape, size, HLB, characteristics of macromolecules

23. Extravasation The endothelium of brain is the strongest of all endothelia formed by continous nonfenestrated endothelial cells which show no pinocytic activity Soluble macromolecules permeate the endothelial barrier more readily than particulate macromolecules the rate of movement of fluid across the endothelium appears to be directly related to the diff between the hydrostatic and osmotic forces

24. Lymphatic Uptake Following extravasation drug molecules can either reabsorb into the blood stream directly or enter into the lymphatic system and return with the lymph to the blood circulation Also drugs administered by subcutaneous intracellular transdermal peritoneal routes can reach the systemic circulation by lymphatic system

25. Lymphatic Uptake

26. Lymphatic Uptake Factors know to influence the clearance of drugs from interstitial sites R oute of administration S ize and surface characteristics of particles F ormulation medium T he composition and pH of the interstitial fluid and D isease within the interstitium The direct delivery of drugs into lymphatics has been proposed as a potential approach to kill malignant lymphoid cells located in lymph nodes

27. References: Muller, R; Keck, C (2004). "Challenges and solutions for the delivery of biotech drugs – a review of drug nanocrystal technology and lipid nanoparticles".  Journal of Biotechnology   113  (1–3): 151–170.  doi : 10.1016/j.jbiotec.2004.06.007 Target-Oriented Drug Delivery Systems(9) by Vijay kumar Modern Pharmaceutics Volume 2 Applications and Advances; Fifth edition edited by Alexander T. Florence Pg.no 329-342. Encyclopaedia of controlled delivery by E dith M athiowitz S.P Y yas and R.K Khar Controlled drug Delivery concepts and advances Vallabh prakashan first edition

28. ~~~Thank you~~~