Targeted drug delivery system

M.pharm (Pharmaceutics) Molecular Pharmaceutics (NTDS) unit 1 part 1 Targeted Drug Delivery Systems: Concepts, Events and biological process involved in drug targeting.

1. Targeted drug delivery system Mehak Aggarwal m.Pharm (pharmaceutics)

2. Introduction content

3.  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- tumor cells but not to normal cells, To a specific organ (or) tissues by complexing with the carrier that recognizes the target. introduction

4. Reasons for Site specific delivery of drugs Pharmaceutical Drug instability in conventional dosage form Solubility Biopharmaceutical Low absorption High-membrane bounding Biological instability Pharmacokinetic / Pharmacodynamic Short half-life Large volume of distribution Low specificity Clinical Low therapeutic index.

5. 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.

6. IDEAL CHARACTERISTICS Biochemically inert (non-toxic). Non-immunogenic. Both physically and chemically stable in vivo and in vitro. Restrict drug distribution to target cells or tissues or organs Should have uniform capillary distribution. Controllable and predicate rate of drug release. Drug release does not effect the drug action. Therapeutic amount of drug release.

7. Minimal drug leakage during transit. Carriers used must be bio-degradable or readily eliminated from the body without any problem and no carrier induced modulation of diseased state. The preparation of the delivery system should be easy or reasonably simple, reproductive and cost effective.

8. 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.

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

10. 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. Cellular Uptake and Processing

11. Both require energy. ENDOCYTOSIS The process where a cell absorb extracellular material by engulfing it with their cell membrane to form a vesicle which is then pinched off intracellularly. These particles does not pass through the membrane, it is simply engulfed and enclosed.

12. EXOCYTOSIS The reverse process where materials are expelled or secreted from a cell. This is used to rid wastes and secreted substances (hormones) produced by the cell. It may be excretion or secretion. PHAGOCYTOSIS This is carried by specialized cells of mononuclear phagocyte system called phagocytes by absorption of specific blood component called ‘ opsonins ’. Phagocytic vacuole fuses with one or more lyosomes to form phagolysosomes. Digestion of particles occurs by lyosomal acid hydrolysis , making drug available to exert its effect.

13. PINOCYTOSIS Pinocytosis (a form of endocytosis) allows a cell to engulf large molecules and fluid that may be present in the extracellular region. The cell membrane folds inwards , encloses the fluid or particle to be transported and then fuses to form a vesicle. The vesicle detaches from the membrane and moves to the interior of the cell. It is of two types: Fluid phase pinocytosis and Receptor mediated pinocytosis Fluid phase pinocytosis, is non-specific & continuous process where macromolecules adheres to general cell surface site.

14. Receptor mediated pinocytosis, is a specific process where the macromolecules bind to specific cell receptor site. Receptor-mediated pinocytosis is a particularly efficient form of pinocytosis. A receptor on the surface of the cell binds to a molecule in the tissue fluid and the complex of binding molecule (ligand) and receptor is ingested . For example, this is how human cells take in the element iron, which is present in the tissue fluid bound to a protein called transferrin .

15. Oral, buccal, nasal, vaginal and rectal cavities are internally lined with one or more layers of epithelial cells. Depending on position and function in body, these cells vary. These cells are extremely cohesive. Absorption of low molecular weight drugs from oral route is well established. Various transport process used frequently by drugs to cross epithelial barrier lining are, Passive diffusion Carrier mediated. Endocytosis TRANSPORT ACROSS EPITHELIAL BARRIER

16. Additionally, polar molecules can diffuse through tight junction of epithelial cells i.e., paracellular route. Molecules less than 10 kDa are absorbed from nasal epithelium into systemic circulation in sufficient amount without need of added materials. Large molecule proteins (e.g., interferon, human growth hormone) requires both penetration enhancer & bio adhesives. This flux enhancers deleterious effect Nasal mucosa & mucociliary clearance. Cyclodestrins .

17. Overcome by Cyclodextrins Phospholipids PHOSPHOLIPIDS S ignificant increase in absorption of macromolecules. Biocompatible B ioresorbable N o or less threat of toxicity

18. Penetration enhancers improves intestinal absorption of peptides & other macromolecular drugs. These includes: Chelators: e.g., EDTA, citric acid, salicylates etc. Surfactants: Natural ,Semi synthetic ,Synthetic. Fatty acid & derivatives : e.g., oleic acid, sodium laurate, sodium caprate etc

19. Factors influencing the absorption of drugs from gastrointestinal tract : pH Enzymes Surface area M icroflora T ransit time

20. 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. Absorption of drugs from buccal via transcellular and paracellular later being dominant. 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 used to target to the uterus

21. For a drug to exert its therapeutic effects, it must move from the central circulation and interact with its extra vascular-extracellular or extra vascular- intracellular target. This process of trans vascular exchange is called “extravasation.” Extravasation is governed by: permeability through blood capillary walls Rate of blood & lymph Physicochemical factors like, molecular shape, size and charge of drug its Hlb characteristics EXTRAVASATION

22. 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 Extravasation which is governed by blood capillary walls. Factors that control permeability of capillaries: S tructure of the capillary wall Pathological condition Rate of blood and lymph supply Physicochemical factors of drug

23. The structure of the blood capillary varies in different organs tissues. It consists of a single layer of endothelial cells joined together by intercellular junctions. Depending on the morphology and continuity of the endothelial layer and the basement membrane blood capillaries are divided into: Continuous Fenestrated Sinusoidal

24. 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. 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.

25. 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. The endothelium of brain is the strongest of all endothelia formed by continuous non-fenestrated 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.

26. Lymphatic circulation is a path of minor importance in drug absorption into systemic circulation for two reasons: The lymph vessels are less accessible than the capillaries. The lymph flow is exceptionally slow. However, fats, fat-soluble vitamins & highly lipophilic drugs are absorbed through lymphatic circulation. LYMPHATIC UPTAKE

27. Advantage of lymphatic absorption of drugs: Avoidance of first pass effect. Compounds of high molecular weight (above 16,000) can be absorbed by lymphatic transport. Targeted delivery of drugs to lymphatic system as in certain case of cancer is possible

28. Reticuloendothelial (RES) System Comprised of a set of mononuclear phagocytic cells which originate from precursors in bone marrow, enter blood stream as monocytes and pass into various tissues where they differentiate into macrophages. Macrophages are essential part of defense function. An important function of macrophages is to engulf and remove circulating pathogens, tissue debris and damaged macromolecules . RETICULOEDNOTHELIAL SYSTEM (RES)

29. RES is also involved in formation of new R.B.C & W.B.C by destruction of older ones. Since macrophages are concentrated at site of inflammation such as tumors, drug targeting is thus achievable.