TARGETED DRUG DELIVERY SYSTEM for pharmacy students.pptx

a brief introduction for pharmacy students regarding targeted drug delivery

1. TARGETED DRUG DELIVERY SYSTEM(Active and Passive Systems)

2. DRUG TRANSPORT PATHWAYS Paracellular Pathway: The paracellular route is a passive, diffusional transport pathway, taken by small , hydrophilic molecules , for example mannitol, which can pass through the various types of junctions between adjacent epithelial cells . The rate of passive diffusion follows Fick’s Law. Passive diffusion is driven by a concentration gradient and is inversely related to molecular weight. This route is therefore not suitable for large molecular weight drugs, which are too large to cross between cell junctions.

3. Transcellular Pathway: The transcellular pathway involves the movement of the drug across the epithelial cell, by active and/or passive processes . These are: Transcellular passive transport Active or Carrier-mediated transport

4. 1.Transcellular passive transport (diffusion) Low molecular weight and lipophilic drug molecules are usually absorbed transcellularly, by passive diffusion across the epithelial cells . With respect to passive diffusion, the outer membrane of the epithelial cell may be regarded as a layer of lipid, surrounded on both sides by water. Thus for transport through the membrane, there are three barriers: the external water-lipid interface; the lipid membrane; the internal lipid-water interface

5. In the process of passive diffusion: lipid-soluble substances move into the lipid membrane according to their lipid/water partition coefficient; molecules then diffuse across the lipid phase according to the concentration gradient established across the membrane; the molecules distribute out at the other side of the membrane, according to their lipid/water partition coefficient. The rate of diffusion through the membrane follows Fick’s Law, which states that the rate of diffusion across a membrane is proportional to the difference in concentration on each side of the membrane.

6. 2. Carrier-mediated transport: In this situation , specialized membrane protein molecules transport substrates across the cell membranes, either against the concentration gradient (active transport), or with the concentration gradient (facilitated diffusion). In active transport , carriers may transport substrates against a concentration gradient, in an energy consuming process. This form of transport may occur through “dynamic pores”, consisting of proteins or protein systems which span the plasma membrane.

7. Active absorption is associated with a series of steps : 1. The substrate forms a complex with the carrier(e.g. ATPase transport proteins ) in the membrane surface. 2 .The substrate-carrier complex moves through the membrane. 3 .The substrate is released from the complex at the other side of the membrane. 4.The carrier molecule (now free) then returns to the surface of the membrane, and is ready to bind with further substrates. Substrates may include drugs, small ions, and other endogenous substances.

8. Facilitated diffusion involves carrier-mediated transport down a concentration gradient . A much larger number of substances are believed to be transported by facilitated diffusion than active transport, including vitamins such as thiamine, nicotinic acid, riboflavin and vitamin B6, various sugars and amino acids. Both processes exhibit classical saturation kinetics, since there are only a finite number of carrier molecules. In passive transport (paracellular or transcellular), the rate of transport is directly proportional to the drug concentration. In carrier-mediated , transport is only proportional to the drug concentration at low concentrations of drug. At higher concentrations, the carrier mechanism becomes saturated and the rate of absorption remains constant.

9. Endocytic processes All the above transport mechanisms are only applicable to the absorption of small molecules, less than approximately 500 Da. There is evidence that larger molecules can be absorbed with low efficiency due to endocytosis. Endocytosis is defined as the internalization of plasma membrane with concomitant engulfment of extracellular material and extracellular fluid. The process can be divided into two types, pinocytosis phagocytosis.

10. Pinocytosis: Pinocytosis is a non-specific process that goes on continually in all cell types, in which the plasma membrane invaginates and forms an inward channel, into which extracellular fluid flows. Solutes dissolved in the extracellular fluid, including large (soluble) macromolecules, may flow with the extracellular fluid into the invaginations and become internalized. This process, i.e. the uptake of macromolecules in solution, is known as fluid-phase pinocytosis .

11. Alternatively, uptake may involve: adsorptive pinocytosis , in which macromolecules bind to non-specific membrane receptors, prior to pinocytosis; receptor-mediated pinocytosis , in which macromolecules bind to specific membrane receptors, prior to pinocytosis. The invaginated membrane then “pinches off” to form detached vesicles. The pinocytic vesicles ( endosomes ) migrate inwardly and fuse with lysosomes, which contain many lysosomal enzymes, to form secondary lysosomes. The ligand is degraded by the lysosomal enzymes, the degraded products are released and the membrane is recycled back to the plasma membrane. Example: some peptides and proteins are known to enter intestinal mucosal cells through pinocytosis.

12. Phagocytosis: The process of phagocytosis involves the internalization of particulate matter. The phagocytic process occurs in a number of stages. Adsorption: the drug/particulate adsorbs to the phagocytic cell surface. This process may be facilitated by serum proteins knows as opsonins , which cover the particulate and promote adsorption and ingestion. Ingestion: the cell membrane moves outwards, surrounding the particle surface, and forms a vesicle, known as a phagosome , which detaches from the plasma membrane to float freely within the cytoplasm. Digestion: the internalized phagosome eventually fuses with intracellular lysosomes and degradation by lysosomal enzymes again takes place. When digestion is complete, the lysosomal membrane may rupture, discharging its contents into the cytoplasm.

13. Phagocytosis is only carried out by the specialized cells (“professional phagocytes”) of the mononuclear phagocyte systems ( MPS ; also known as the reticuloendothelial system, RES ), which include the circulating blood monocytes and both fixed and free macrophages . Fixed macrophages are found lining certain blood and lymph-filled spaces, such as the sinusoids of the liver (these cells are commonly referred to as Kuppfer cells ), bone marrow and spleen. The process of phagocytosis is of particular relevance when particulate delivery systems, such as microspheres, liposomes and other advanced delivery systems are used. Such particulate carriers are susceptible to MPS clearance.

14. Pore transport A further mechanism of transcellular transport is via the aqueous pores which exist in many lipid membranes. The pores are of the order of 0.4 nm in diameter, thus very small hydrophilic molecules such as water, urea and low molecular weight sugars can diffuse through these channels and thus be absorbed by epithelial cells. However, most drugs are generally much larger ( ≥1 nm in diameter) than the pore size, and this route is therefore of minor importance for drug delivery.

15. Targeted drug delivery system ‘ Targeted drug delivery system is a special form of drug delivery system where the medicament is selectively targeted or delivered only to its site of action and not to the non-target organs or tissues or cells.’ It is a method of delivering medication to a patient in a manner that increases the concentration of the medication in some parts of the body relative to others. Targeted drug delivery seeks to concentrate the medication in the tissues of interest while reducing the relative concentration of the medication in the remaining tissues. This improves efficacy and reduce side effects.

16. Targeted drug delivery , sometimes called  smart drug delivery , is a method of delivering  medication  to a patient in a manner that increases the  concentration  of the medication in some parts of the body relative to others. This means of delivery is largely founded on nanomedicine , which plans to employ  nanoparticle -mediated drug delivery in order to combat the downfalls of conventional drug delivery. These nanoparticles would be loaded with drugs and targeted to specific parts of the body where there is solely diseased tissue, thereby avoiding interaction with healthy tissue. The goal of a targeted  drug delivery  system is to prolong, localize, target and have a protected drug interaction with the diseased tissue.

17. The conventional  drug delivery system  is the absorption of the drug across a  biological membrane , whereas the targeted release system releases the drug in a dosage form. Targeted drug delivery systems have been developed to optimize regenerative techniques. The system is based on a method that delivers a certain amount of a therapeutic agent for a prolonged period of time to a targeted diseased area within the body. This helps maintain the required plasma and tissue drug levels in the body, thereby preventing any damage to the healthy tissue via the drug. The drug delivery system is highly integrated and requires various disciplines, such as chemists, biologists, and engineers, to join forces to optimize this system

18. 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 complexion with the carrier that recognizes the target.

19. OBJECTIVE : 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 enzyme replacement therapy. To achieve site specific delivery of a drug, an effective targeting system may comprise drug , carrier and targeting group .

20. REASON FOR DRUG TARGETING In the treatment or prevention or diseases. Pharmaceutical drug instability in conventional dosage form Low solubility , biopharmaceutical low absorption, high-protein bounding, biological instability, pharmacokinetic / pharmacodynamic short half life, large volume of distribution, low specificity, low therapeutic index.

21. IDEAL CHARACTERISTICS It should be nontoxic, biocompatible, biodegradable, and physicochemical stable in vivo and in vitro . Restrict drug distribution to target cells or tissues or organs and 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. 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.

22. ADVANTAGES OF TARGETTED DELIVERY Drug administration protocols may be simplified. Toxicity is reduced by delivering a drug to its target site, there by reducing harmful systemic effects. Drug can be administered in a smaller dose to produce the desire effect. Avoidance of hepatic first pass metabolism. Enhancement of the absorption of target molecules such as peptides and particulates. Dose is less compared to conventional drug delivery system. No fluctuation in plasma concentration. Selective targeting to infective cells as compare to normal cells.

23. DISADVANTAGES OF TARGETTED DELIVERY Rapid clearance of targeted systems. Immune reactions against intravenous administered carrier systems. Insufficient localization of targeted systems into tumor cells. Diffusion and redistribution of released drugs. Requires highly sophisticated technology for the formulation.

24. Requires skill for manufacturing, storage and administration. Drug deposition at the target site may produce toxicity symptoms. Difficult to maintain stability of dosage form. E.g.: Resealed erythrocytes have to be stored at 4 C. Drug loading is usually low. E.g. As in micelles. Therefore it is difficult to predict /fix the dosage regimen.

25. STRATEGIES OF DRUG TARGETING

26. 1) Passive Targeting (Passive drug delivery system): In passive targeting, the drug's success is directly related to circulation time. This is achieved by cloaking the nanoparticle with some sort of coating. Several substances can achieve this, with one of them being polyethylene glycol (PEG). By adding PEG to the surface of the nanoparticle, it is rendered hydrophilic, thus allowing water molecules to bind to the oxygen molecules on PEG via hydrogen bonding.

27. The result of this bond is a film of hydration around the nanoparticle which makes the substance antiphagocytic . The particles obtain this property due to the hydrophobic interactions that are natural to the  reticuloendothelial system (RES) , thus the drug-loaded nanoparticle is able to stay in circulation for a longer period of time. To work in conjunction with this mechanism of passive targeting, nanoparticles that are between 10 and 100 nanometers in size have been found to circulate systemically for longer periods of time.

28. 2) Inverse Targeting : In this type of targeting attempts are made to avoid passive uptake of colloidal carrier by RES (Reticulo Endothelial Systems) and hence the process is referred to as inverse targeting. To achieve inverse targeting, RES normal function is suppressed by pre injecting large amount of blank colloidal carriers or macromolecules like dextran sulphate. This approach leads to saturation of RES and suppression of defence mechanism. This type of targeting is a effective approach to target drug(s) to non-RES organs.

29. 3) Active Targeting (active drug delivery systems) : Active targeting of drug-loaded nanoparticles enhances the effects of passive targeting to make the nanoparticle more specific to a target site. There are several ways that active targeting can be accomplished. One way to actively target diseased tissue in the body is to know the nature of a receptor on the cell for which the drug will be targeted to.  Researchers can then utilize cell-specific ligands that will allow the nanoparticle to bind specifically to the cell that has the complementary receptor. This form of active targeting was found to be successful when utilizing transferrin as the cell-specific ligand. The transferrin was conjugated to the nanoparticle to target tumor cells that possess transferrin-receptor mediated endocytosis mechanisms on their membrane. This means of targeting was found to increase uptake, as opposed to non-conjugated nanoparticles .

30. Active targeting can also be achieved by utilizing magnetoliposomes , which usually serves as a contrast agent in magnetic resonance imaging. Thus, by grafting these liposomes with a desired drug to deliver to a region of the body, magnetic positioning could aid with this process. Furthermore, a nanoparticle could possess the capability to be activated by a trigger that is specific to the target site, such as utilizing materials that are pH responsive. Most of the body has a consistent, neutral pH. However, some areas of the body are naturally more acidic than others, and, thus, nanoparticles can take advantage of this ability by releasing the drug when it encounters a specific pH. Another specific triggering mechanism is based on the redox potential. One of the side effects of tumors is  hypoxia , which alters the redox potential in the vicinity of the tumor. By modifying the redox potential that triggers the payload release the vesicles can be selective to different types of tumors.

31. By utilizing both passive and active targeting, a drug-loaded nanoparticle has a heightened advantage over a conventional drug. It is able to circulate throughout the body for an extended period of time until it is successfully attracted to its target through the use of cell-specific ligands, magnetic positioning, or pH responsive materials. Because of these advantages, side effects from conventional drugs will be largely reduced as a result of the drug-loaded nanoparticles affecting only diseased tissue

32. Incorporation of antigen specific antibodies (i.e. monoclonal antibodies) . Attachment of cell receptor-specific ligands (glucose, ,transferrin,. Folic acid or by albumin protein). 3 . Types First order targeting (organ compartmentalization). Second order targeting (cellular targeting). Third order targeting (intracellular targeting).

33. First order targeting (organ compartmentalization): Describes delivery to discrete organ or tissue. Second order targeting (cellular targeting). Represents targeting a specific cell type within a tissue(tumor cells verses normal cells). Third order targeting (intracellular targeting). Implies delivery to a specific intracellular organ in the target cell ( e.g lysosomes)

34. 5) Dual Targeting : In this targeting approach carrier molecule itself have their own therapeutic activity and thus increase the therapeutic effect of drug. For example , a carrier molecule having its own antiviral activity can be loaded with antiviral drug and the net synergistic effect of drug conjugate was observed.

35. 6) Double Targeting : Temporal and spatial methodologies are combined to target a carrier system, then targeting may be called double targeting. Spatial placement relates to targeting drugs to specific organs, tissues, cells or even subcellular compartment. whereas temporal delivery refers to controlling the rate of drug delivery to target site.

36. CARRIER OR MARKERS Targeted drug delivery can be achieved by using carrier system. Carrier is one of the special molecule or system essentially required for effective transportation of loaded drug up to the pre selected sites. They are engineered vectors, which retain drug inside or onto them either via encapsulation and transport or deliver it into vicinity of target cell.

37. Carrier can do so either through an inherent characteristics or acquired (through structural modification). They interact directly or selectively with biological target or they are engineered to release drug in the proximity of the target cell lines demanding optimal pharmacological action. TYPES OF CARRIERS ON BASIS OF NATURE OF ORIGIN: Endogenous (Low density lipoprotein, high density lipoproteins, serum albumin, chylomicrons, erythrocytes). Exogenous (microparticulates, soluble polymeric and biodegradable drug carriers).

38. CARRIER SYSTEMS USED FOR TARGETED DRUG DELIVERY 1. Colloidal carriers: a) Vesicular system: Liposomes, Niosomes , Pharmacosomes , virosomes , Immunoliposomes b) Microparticulate system: Microparticles, Nanoparticles, Magnetic microspheres, Albumin microspheres, nanocapsules. 2. Cellular Carriers: Resealed erythrocytes, serum albumin, antibodies, platelets, leukocytes.

39. 3. Supramolecular delivery systems: Micelles, reverse micelles, mixed micelles, polymeric micelles. Liquid crystals, lipoproteins( chylomicron, VLDL, LDL). Synthetic LDL mimicking particles (supramolecule biovector system). 4. Polymer based systems: Muco -adhesives, biodegradable, bioerodible. Soluble synthetic polymeric carriers. 5. Macromolecular carriers: a) Proteins, glycoproteins and artificial viral enevlopes (AVE).

40. b) Glycosylated water soluble polymers( poly L- lysine) c) Immunological Fab fragments, antibody – enzyme complex. d) Toxins , immunotoxins . e) Lectins and polysacchrides .

41. EXAMPLES OF SOME DRUG CARRIER SYSTEMS LIPOSOMES “ Are simple microscopic, concentric bilayered vesicles in which an aqueous material is entirely enclosed by a membranous lipid bilayer mainly composed of natural or synthetic phospholipids. ”

42. NIOSOMES “ Niosomes are essentially non-ionic surfactant based multilamellar or unilamellar vesicles in which an aqueous solution of solute (s) is entirely enclosed by a membrane resulted from the organization of surfactant macromolecules as bilayers ” They enhance penetration of drugs . Thy are used for: Targeting of bioactive agents. Delivery of peptide drugs. Transdermal delivery of drug.

43. MICELLE Micelle is an aggregate of amphipathic molecules in water , with the nonpolar portions in the interior and the polar portions at the exterior surface, exposed to water. Hydrophobic drugs can be encapsulated/ solubalized , into inner core.

44. VIROSOMES A  virosome  is a drug or vaccine delivery mechanism consisting of unilamellar phospholipid membrane (either a mono- or bi-layer) vesicle incorporating virus derived proteins to allow the  virosomes  to fuse with target cells.  Virosomes  are not able to replicate but are pure fusion-active vesicles.

45. Virosomes are immuno modulating liposomes consisting of surface glycoprotein of influenza virus (immune stimulating reconstituted influenza virosome ) etc. Virosomes must be target oriented and their fusogenic characteristics could be exploited in genome grafting and cellular micro injection.

46. PHARMACOSOMES The term pharmacosome comprises of two main parts Pharmacon (active principle) and some carriers. Drug covalently bound to lipid may exist in a colloidal dispersion as ultrafine, micelles or hexagonal aggregates which are known as pharmacosomes Some times the amphipathic drug can self assemble to form vesicle and these vesicles are termed as pharmacosomes.

47. DENDRIMERS Dendrimers precisely defined, synthetic nanoparticles that are approximately between 1-100 nm in diameter. They are made up of layers of polymer surrounding a control core. The dendrimers surface contains many different sites to which drugs may be attach. Application : In gene transfection, medical imaging.

48. MICROSPHERES Microsphere are characteristically free flowing powders consisting of proteins or synthetic polymers which are biodegradable in nature and ideally having a particle size less than 200um.

49. POLYMERIC NANOPARTICLES In recent years, biodegradable polymeric nanoparticles have attracted considerable attention as potential drug delivery devices in view of their applications in drug targeting to particular organ/tissues, as carriers of DNA in gene therapy and in their ability to deliver proteins, peptides and genes through a per oral route of administration.

50. RESEALED ERYTHROCYTES Erythrocytes have been extensively studied for their potential carrier capabilities for the delivery of drugs and drug loaded microspheres. Such cells could be used as circulating carriers to disseminate a drug within a prolonged period of time in circulation or in target-specific organs, including the liver, spleen, and lymph nodes.

51. REFRENCES Modern Pharmaceutics volume 2 Application and advances page no. 329-380