Targeted Drug Delivery Systems

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TARGETED DRUG DELIVERY SYSTEMS

Vishnu Datta MDept. of pharmaceuticsJSSCP, MYSOREJSS University

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Biological processes and events involved in drug targeting2

Agenda

Concept. Introduction

Advantages and Disadvantages

Targeted Drug delivery

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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

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SMART DRUG THERAPY???

INDEED1..

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Reasons for Site specific delivery of drugs2

Pharmaceutical • Drug instability in conventional dosage

form• SolubilityBiopharmaceutical • Low absorption • High-membrane bounding• Biological instabilityPharmacokinetic / Pharmacodynamic • Short half-life• Large volume of distribution• Low specificity Clinical • Low therapeutic index.

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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.

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IDEAL CHARACTERISTICS

Targeted drug delivery system should be-

HOW??• 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.

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IDEAL CHARACTERISTICS

• 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.

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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 DisadvantagesTargeted drug delivery systems

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Biological processes and events involved in drug targeting2

• Cellular Uptake and Processing

• Transport across the epithelial barrier

• Extravasation• Lymphatic Uptake

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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

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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

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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

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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

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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

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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

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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 Extravasation which is governed by blood capillary walls

• Factors that control permeability of capillaries • Structure of the capillary wall

• Pathological condition • Rate of blood and lymph supply• Physicochemical factors of drug

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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 • Sinusoidal

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Extravasation

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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 endothelialgaps 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

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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

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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

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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

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Lymphatic Uptake

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Lymphatic Uptake

• Factors know to influence the clearance of drugs from interstitial sites

Route of administration Size and surface characteristics of

particles Formulation medium The composition and pH of the interstitial fluid and Disease 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

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References:

1. 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

2. 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.

3. Encyclopaedia of controlled delivery by Edith Mathiowitz

4. S.P Yyas and R.K Khar Controlled drug Delivery concepts and advances Vallabh prakashan first edition

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~~~Thank you~~~