DRUG DELIVERY AND DRUG DELIVERY AND TARGETINGTARGETING

Drug Delivery and Targeting Drug Delivery and Targeting SystemsSystems

It is dosage form or device that serve as drug It is dosage form or device that serve as drug

carrier to deliver the drug into targeted site carrier to deliver the drug into targeted site

upon application using suitable rout of upon application using suitable rout of

administration.administration.

Drug delivery and targeting systems are Drug delivery and targeting systems are

referred to as:referred to as:

"controlled release“ "monolithic" "controlled release“ "monolithic"

"sustained release" "smart“"sustained release" "smart“

"zero-order“ "stealth“ "zero-order“ "stealth“

"membrane-controlled“ "reservoir""membrane-controlled“ "reservoir"

Prolonged/sustained release:Prolonged/sustained release:The delivery system prolongs therapeutic The delivery system prolongs therapeutic levels of the drug in blood or tissue for an levels of the drug in blood or tissue for an extended period of time.extended period of time.

Zero-order release:Zero-order release:The drug release does not vary with time; The drug release does not vary with time; thus the delivery system maintains a thus the delivery system maintains a (relatively) constant effective drug level in (relatively) constant effective drug level in the body for prolonged periods.the body for prolonged periods.

Terminology of Drug Delivery and Terminology of Drug Delivery and Targeting SystemsTargeting Systems

Variable release:Variable release: The delivery system provides drug input at a variable The delivery system provides drug input at a variable

rate, to match, for example, endogenous circadian rate, to match, for example, endogenous circadian

rhythms, or to mimic natural biorhythms.rhythms, or to mimic natural biorhythms.

Bio-responsive release:Bio-responsive release: The system modulates drug release in response to a The system modulates drug release in response to a

biological stimulus (e.g. blood glucose levels biological stimulus (e.g. blood glucose levels

triggering the release of insulin from a drug delivery triggering the release of insulin from a drug delivery

device).device).

Modulated/self-regulated release:Modulated/self-regulated release: The system delivers the necessary amount of drug The system delivers the necessary amount of drug

under the control of the patient.under the control of the patient.

Rate-controlled release:Rate-controlled release:

The system delivers the drug at some preThe system delivers the drug at some pre­­

determined rate, either systemically or locally, determined rate, either systemically or locally,

for a specific period of time.for a specific period of time.

Targeted-drug delivery:Targeted-drug delivery:

The delivery system achieves site-specific The delivery system achieves site-specific

drug delivery independent on site and rout of drug delivery independent on site and rout of

administration administration

Temporal-drug delivery:Temporal-drug delivery:

The control of delivery to produce an effect in The control of delivery to produce an effect in

a desired time-related manner.a desired time-related manner.

Spatial-drug delivery:Spatial-drug delivery:

The delivery of a drug to a The delivery of a drug to a

specific region of the specific region of the

body (dependant on both body (dependant on both

route of administration route of administration

and drug distribution).and drug distribution).

Bioavailability:Bioavailability:

The rate and extent at The rate and extent at

which a drug is taken up which a drug is taken up

into the body.into the body.

1.1. Improve patient compliance.Improve patient compliance.

2.2. Use of less total drug.Use of less total drug.

3.3. FewerFewer local or systemic local or systemic side effects.side effects.

4.4. Minimal drug accumulation Minimal drug accumulation with long-term with long-term

dosage.dosage.

5.5. FewerFewer problems with potentiation or problems with potentiation or loss of loss of

drug drug activity with long-term use.activity with long-term use.

Advantages of controlled-release systemAdvantages of controlled-release system

6.6. Improved treatment efficiency.Improved treatment efficiency.

7.7. More rapid control of the patient's More rapid control of the patient's

condition.condition.

8.8. Less fluctuation in drug-blood level.Less fluctuation in drug-blood level.

9.9. Improved bioavailability for some drugs.Improved bioavailability for some drugs.

10.10. Improved ability to provide special effects Improved ability to provide special effects

(e.g., morning relief of arthritis by (e.g., morning relief of arthritis by

bedtime dosing).bedtime dosing).

11.11. Reduced cost.Reduced cost.

RATE-CONTROLLED RELEASE IN DRUG RATE-CONTROLLED RELEASE IN DRUG DELIVERY AND TARGETINGDELIVERY AND TARGETING

There are a number of mechanisms by which drug There are a number of mechanisms by which drug

release rate is controlled:release rate is controlled:

• Diffusion-controlled release mechanismsDiffusion-controlled release mechanisms

• Dissolution-controlled release mechanismsDissolution-controlled release mechanisms

• Osmosis-controlled release mechanismsOsmosis-controlled release mechanisms

• Mechanical-controlled release mechanismsMechanical-controlled release mechanisms

• Bio-responsive controlled release mechanismsBio-responsive controlled release mechanisms

DRUG TARGETING SYSTEMSDRUG TARGETING SYSTEMS

Advantages of Drug targeting delivery:

o improve Drug safety, minimized toxic side-effects

caused by drug action at non-target sites .

o improve Drug efficacy, as the drug is concentrated

at the site of action rather than being dispersed

throughout the body.

o improve Patient compliance, as increased safety

and efficacy make therapy more acceptable .

STRATIGES TO ACHIVE DRUG STRATIGES TO ACHIVE DRUG TARGETING SYSTEMSTARGETING SYSTEMS

local administration of drug with conventional

dosage forms.

Targeting the skin by apply the drug as

ointment, lotion, or cream. Direct injection of an anti-inflammatory agent

into a joint. oral delivery, targeting the drug to the small

intestine, colon, or gut lymphatics. By using

enteric coatings, prodrugs , osmotic pumps,

colloidal carriers and hydrogels .

By parenteral administration.

are most advanced , delivering drug to specific

targets sites , protect drugs from degradation &

premature elimination.

include the use of carriers as : Soluble carriers ; as monoclonal antibodies,

dextrans , soluble synthetic polymers.

Particulate carriers, such as liposomes, micro- and nano- particles, microspheres.

Target-specific recognition moieties, such as monoclonal antibodies, carbohydrates & lectins .

Pharmaceutical carriers

DOSAGE FORMS FOR ADVANCED DOSAGE FORMS FOR ADVANCED DRUG DELIVERY AND TARGETINGDRUG DELIVERY AND TARGETING

Are available, in a wide Are available, in a wide

range of sizes, from the range of sizes, from the

molecular level to large molecular level to large

devices.devices.

MolecularMolecular Drugs attached to Drugs attached to water-soluble carrierswater-soluble carriers, such as , such as

monoclonal antibodies, carbohydrates, lectins and monoclonal antibodies, carbohydrates, lectins and

immuno-toxins.immuno-toxins.

Such systems achieve site-specific drug delivery Such systems achieve site-specific drug delivery

following following parenteralparenteral administration. administration.

Release of the attached drug molecules at the Release of the attached drug molecules at the

target site achieved by target site achieved by enzymatic or hydrolytic enzymatic or hydrolytic

cleavage.cleavage.

Larger complexes include drug conjugates with Larger complexes include drug conjugates with

soluble natural or synthetic polymers.soluble natural or synthetic polymers.

Nano-­and­Micro-particlesNano-­and­Micro-particlesNano-­and­Micro-particlesNano-­and­Micro-particles

NanoparticlesNanoparticles are solid colloidal particles, are solid colloidal particles,

generally less than generally less than 200200 nm. nm.

Such systems include us of drug carrier polymer

poly (alkyl- cyanoacrylate)

Nanoparticles used for parenteral drug targeting

delivery.

Liposomes Liposomes , vesicular structures based on , vesicular structures based on

one or more lipid bilayer(s) encapsulating an one or more lipid bilayer(s) encapsulating an

aqueous core represent highly versatile aqueous core represent highly versatile

carriers.carriers.

MicroparticlesMicroparticles are colloidal particles in the, in are colloidal particles in the, in

the size range 0.2-100 the size range 0.2-100 µµm.m.

Include use of Include use of Synthetic polymersSynthetic polymers, such as , such as

polypoly (lactide-co-glycolide)(lactide-co-glycolide) as drug carrier. as drug carrier.

Include use of Include use of Natural polymersNatural polymers, such as , such as

albumin, gelatin , starch, albumin, gelatin , starch, used as micro-used as micro-

particulate drug carriers.particulate drug carriers.

MacrodevicesMacrodevicesMacrodevicesMacrodevices

are widely used in many applications, including:are widely used in many applications, including:

Parenteral drug deliveryParenteral drug delivery: : mechanical pumps, mechanical pumps,

implantable devices.implantable devices.

Oral drug deliveryOral drug delivery: solid : solid dosage forms such as dosage forms such as

tablets and capsules which incorporate tablets and capsules which incorporate

controlled release/ targeting technologies.controlled release/ targeting technologies.

Buccal drug deliveryBuccal drug delivery: : buccal adhesive patches buccal adhesive patches

and films.and films.

Transdermal drug deliveryTransdermal drug delivery: transdermal : transdermal patches, iontophoretic devices.patches, iontophoretic devices.

Nasal drug deliveryNasal drug delivery: nasal sprays and drops.: nasal sprays and drops.

Pulmonary drug deliveryPulmonary drug delivery: metered-dose : metered-dose inhalers, dry-powder inhalers, nebulizers.inhalers, dry-powder inhalers, nebulizers.

Vaginal drug deliveryVaginal drug delivery: vaginal rings, creams, : vaginal rings, creams, sponges.sponges.

Ophthalmic drug deliveryOphthalmic drug delivery: ophthalmic drops : ophthalmic drops and sprays.and sprays.

Properties of an "ideal" Properties of an "ideal" Drug Delivery dosage formDrug Delivery dosage form

1.1. Good Patient acceptability and complianceGood Patient acceptability and compliance

Parenteral delivery Parenteral delivery This is painful for the This is painful for the

patient, and requiring the intervention of patient, and requiring the intervention of

medical professionals.medical professionals.

The oral routeThe oral route, involves swallowing a tablet, , involves swallowing a tablet,

liquid or capsule, thus a much more convenient liquid or capsule, thus a much more convenient

and attractive route for drug delivery.and attractive route for drug delivery.

Transdermal patchesTransdermal patches are also well accepted by are also well accepted by

patients and convenient.patients and convenient.

Nebulizers, pessaries and suppositoriesNebulizers, pessaries and suppositories, have , have

more limited patient compliance.more limited patient compliance.

2) 2) ReproducibilityReproducibility

The dosage form should allow accurate and The dosage form should allow accurate and

reproducible drug delivery, particularly for drugs reproducible drug delivery, particularly for drugs

with a narrow therapeutic index.with a narrow therapeutic index.

3) 3) Ease of terminationEase of termination

The dosage form should be easily removed either The dosage form should be easily removed either

at the end of an application period, or in the case at the end of an application period, or in the case

of toxicity.of toxicity.

Transdermal adhesive patches and buccal tablet Transdermal adhesive patches and buccal tablet

are easily removed are easily removed

Non-biodegradable polymeric implants and Non-biodegradable polymeric implants and

osmotic pumps must be surgically take back at osmotic pumps must be surgically take back at

the end of treatment. the end of treatment.

4)4)Biocompatibility and absence of adverse Biocompatibility and absence of adverse

effectseffects

The drug delivery system should be non-toxic and The drug delivery system should be non-toxic and

non-immunogenic . non-immunogenic .

Dosage forms containing penetration enhancers Dosage forms containing penetration enhancers

has a harmful effects on epithelial tissue as well as has a harmful effects on epithelial tissue as well as

the increased epithelial permeability may allow the the increased epithelial permeability may allow the

entrance of potentially toxic agents. entrance of potentially toxic agents.

5) 5) Large effective area of contact Large effective area of contact

For drugs absorbed via passive mechanisms, For drugs absorbed via passive mechanisms,

increasing the area of contact of the drug with increasing the area of contact of the drug with

the absorbing surface will increase the amount the absorbing surface will increase the amount

absorbed.absorbed.

The dosage form can influence the size of the The dosage form can influence the size of the

area over which the drug is absorped . For area over which the drug is absorped . For

example, increasing the size of a transdermal example, increasing the size of a transdermal

patch increases transdermal bioavailability. patch increases transdermal bioavailability.

6) 6) Prolonged contact time Prolonged contact time

Ideally, the dosage form should facilitate a Ideally, the dosage form should facilitate a prolonged contact time between the drug and the prolonged contact time between the drug and the absorbing surface, thereby facilitating absorbing surface, thereby facilitating absorption.absorption.

Drug delivery to epithelial sites is often limited Drug delivery to epithelial sites is often limited by a variety of physiological clearance by a variety of physiological clearance mechanisms at the site of administration as mechanisms at the site of administration as mucociliary clearance and intestinal motility. mucociliary clearance and intestinal motility.

Bioadhesive materials (sometimes also termed Bioadhesive materials (sometimes also termed mucocadhesive) adhere to biological substrates mucocadhesive) adhere to biological substrates such as mucus or tissue and increase the such as mucus or tissue and increase the effective contact time. effective contact time.

maximize the amount of drug entering the maximize the amount of drug entering the

systemic circulation from the site of systemic circulation from the site of

administration, the delivery site should possess administration, the delivery site should possess

certain properties: certain properties: 1. A large surface area. A large surface area

2. Low metabolic activity

3 .Long Contact time

4. Adequate blood flow

5 .Accessibility

6 .Lack of variability

7 .Permeability

Properties of an "ideal" route of Properties of an "ideal" route of administrationadministration

A large surface area are facilitates absorption.A large surface area are facilitates absorption.

Due to the presence of the villi and the microvilli, Due to the presence of the villi and the microvilli,

the available surface area of the small intestine of the available surface area of the small intestine of

the gastrointestinal tract is very large, which is the gastrointestinal tract is very large, which is

important for oral drug delivery.important for oral drug delivery.

The surface area of the lungs is broad making this The surface area of the lungs is broad making this

region a promising alternative route to the region a promising alternative route to the

parenteral and oral routes for systemic drug parenteral and oral routes for systemic drug

delivery. delivery.

1) Large surface area1) Large surface area

2) Low metabolic activity2) Low metabolic activity

Degradative enzymes may deactivate the drug, prior Degradative enzymes may deactivate the drug, prior

to absorption.to absorption.

Poor drug bioavailability may thus be expected from Poor drug bioavailability may thus be expected from

an absorption site in which enzyme activity is high, an absorption site in which enzyme activity is high,

such as the gastrointestinal tract. Furthermore, such as the gastrointestinal tract. Furthermore,

drugs which are orally absorbed must first pass drugs which are orally absorbed must first pass

through the intestinal wall and the liver, prior to through the intestinal wall and the liver, prior to

reaching the systemic circulation. These" first-pass" reaching the systemic circulation. These" first-pass"

effects can result in a significant loss of drug activity.effects can result in a significant loss of drug activity.

Drug delivery via other routes (nasal, buccal etc.) Drug delivery via other routes (nasal, buccal etc.)

avoid intestinal first-pass effects, as metabolic avoid intestinal first-pass effects, as metabolic

activity at these sites is often lower than in the activity at these sites is often lower than in the

gastrointestinal tract, these routes are highly gastrointestinal tract, these routes are highly

attractive alternatives for the systemic delivery of attractive alternatives for the systemic delivery of

enzymatically labile drugs. enzymatically labile drugs.

3) Contact time3) Contact time

The length of time the drug is in contact with The length of time the drug is in contact with

the absorbing tissue will influence the amount the absorbing tissue will influence the amount

of drug which crosses the mucosa.of drug which crosses the mucosa.

Materials administered to different sites of the Materials administered to different sites of the

body are removed from the site of body are removed from the site of

administration by a variety of natural administration by a variety of natural

clearance mechanisms. clearance mechanisms.

For example, intestinal motility moves material in the For example, intestinal motility moves material in the

stomach or small intestine towards the large intestine.stomach or small intestine towards the large intestine.

In the buccal cavity, the administered dosage form is In the buccal cavity, the administered dosage form is

washed daily with 0.5-2 liters of saliva. washed daily with 0.5-2 liters of saliva.

In the nasal cavity and the upper and central lungs, an In the nasal cavity and the upper and central lungs, an

efficient selfefficient self cleansing mechanism referred to as the cleansing mechanism referred to as the

"mucociliary escalator" is in place to remove any "mucociliary escalator" is in place to remove any

foreign material.foreign material.

In the eye, materials are diluted by tears and removed In the eye, materials are diluted by tears and removed

via the lachrymal drainage system.via the lachrymal drainage system.

4) Blood supply4) Blood supply

Adequate blood flow from the absorption Adequate blood flow from the absorption

site is required to carry the drug to the site is required to carry the drug to the

site of action post-absorption. site of action post-absorption.

5) Accessibility5) Accessibility

Certain absorption sites, for example the alveolar Certain absorption sites, for example the alveolar

region of the lungs, are not readily accessible region of the lungs, are not readily accessible

and thus may require quite complex delivery and thus may require quite complex delivery

devices to ensure the drug reaches the devices to ensure the drug reaches the

absorption site. absorption site.

Delivery efficiency to such sites may also Delivery efficiency to such sites may also

therefore be low. therefore be low.

In contrast, other sites, such as the skin, are In contrast, other sites, such as the skin, are

highly accessible. highly accessible.

6) Lack of variability6) Lack of variability Lack of variability is essential to ensure Lack of variability is essential to ensure

reproducible drug delivery.reproducible drug delivery.

This is important principle for the delivery of This is important principle for the delivery of

highly potent drugs with a narrow therapeutic highly potent drugs with a narrow therapeutic

window.window.

Due to such factors as extremes of pH, enzyme Due to such factors as extremes of pH, enzyme

activity, intestinal motility, presence of food/ fluid activity, intestinal motility, presence of food/ fluid

etc., the gastrointestinal tract can be a highly etc., the gastrointestinal tract can be a highly

variable absorption site.variable absorption site.

Diseases such as the common cold and hay fever Diseases such as the common cold and hay fever

are alter the physiological conditions of the nose, are alter the physiological conditions of the nose,

contributing to the variability of this site. contributing to the variability of this site.

The presence of disease can also compromise the The presence of disease can also compromise the

reproducibility of drug delivery in the lungs.reproducibility of drug delivery in the lungs.

Cyclic changes in the female menstrual cycle mean Cyclic changes in the female menstrual cycle mean

that large fluctuations in vaginal bioavailability.that large fluctuations in vaginal bioavailability.

7) Permeability7) Permeability A more permeable epithelium obviously facilitates A more permeable epithelium obviously facilitates

greater absorption.greater absorption.

Some epithelia are relatively more permeable than Some epithelia are relatively more permeable than

others.others.

For example, the skin is an extremely impermeable For example, the skin is an extremely impermeable

barrier, whereas the permeability of the lung barrier, whereas the permeability of the lung

membranes towards many compounds is much membranes towards many compounds is much

higher than the skin and is also higher than that of higher than the skin and is also higher than that of

the small intestine and other mucosal routes.the small intestine and other mucosal routes.

The vaginal epithelium is relatively permeable, The vaginal epithelium is relatively permeable,

particularly at certain stages of the menstrual cycle. particularly at certain stages of the menstrual cycle.

STRATEGIES TO INCREASE DRUG STRATEGIES TO INCREASE DRUG ABSORPTIONABSORPTION

a) Manipulation of the Druga) Manipulation of the Drug

The physicochemical properties of a drug The physicochemical properties of a drug

which influence drug absorption include:which influence drug absorption include:

• lipid solubility and partition coefficient.lipid solubility and partition coefficient.

• pKa.pKa.

• molecular weight and volume.molecular weight and volume.

• aqueous solubility.aqueous solubility.

• chemical stability.chemical stability.

These properties can be manipulated to achieve These properties can be manipulated to achieve

more favorable absorption characteristics for a drugmore favorable absorption characteristics for a drug

For example, various lipidization strategies can be For example, various lipidization strategies can be

employed to increase the lipophilicity of the drug and employed to increase the lipophilicity of the drug and

thereby increase its membrane-penetrating ability and thereby increase its membrane-penetrating ability and

absorption via transcellular passive diffusion.absorption via transcellular passive diffusion.

The hydrogen-bonding tendency of a drug molecule The hydrogen-bonding tendency of a drug molecule

can be minimized by substitution, esterification or can be minimized by substitution, esterification or

alkylation of existing groups on the molecules, which alkylation of existing groups on the molecules, which

will decrease the drug's aqueous solubility and will decrease the drug's aqueous solubility and

favoring partitioning of the drug into lipidic favoring partitioning of the drug into lipidic

membranes.membranes.

Drug solubility may be enhanced by the use of Drug solubility may be enhanced by the use of

amorphous or anhydrous forms, or the use of the amorphous or anhydrous forms, or the use of the

corresponding salt form of a lipophilic drug.corresponding salt form of a lipophilic drug.

Low molecular weight analogues of an active moiety Low molecular weight analogues of an active moiety

can be developed, to facilitate trans-membrane can be developed, to facilitate trans-membrane

transport. By prepare derivatives which are transport. By prepare derivatives which are

substrates of natural transport carriers like peptides.substrates of natural transport carriers like peptides.

b) Manipulation of the formulationb) Manipulation of the formulation

Various formulation additives may be Various formulation additives may be

included in the dosage form in order to included in the dosage form in order to

maximize drug absorption.maximize drug absorption.

1. Penetration enhancers1. Penetration enhancers

Penetration enhancers are substances that Penetration enhancers are substances that

facilitate absorption of solutes across facilitate absorption of solutes across

biological membranes.biological membranes.

2. Mucoadhesives2. Mucoadhesives

Mucoadhesives, which are generally hydrophilic Mucoadhesives, which are generally hydrophilic

polymers, may be included in a dosage form to polymers, may be included in a dosage form to

increase drug bioavailability.increase drug bioavailability.

These agents are believed to act by:These agents are believed to act by:

• Increasing the contact time of the drug at the Increasing the contact time of the drug at the

absorbing surface.absorbing surface.

• Increasing the local drug concentration at the Increasing the local drug concentration at the

site of adhesion/absorption.site of adhesion/absorption.

• Protecting the drug from dilution and Protecting the drug from dilution and

possible degradation.possible degradation.

3. Enzyme inhibitors3. Enzyme inhibitors

Enzyme inhibitors in a formulation may help Enzyme inhibitors in a formulation may help

to overcome the enzymatic activity of the to overcome the enzymatic activity of the

epithelial barrier.epithelial barrier.

The use of protease inhibitors facilitates the The use of protease inhibitors facilitates the

absorption of therapeutic peptides and absorption of therapeutic peptides and

proteins.proteins.