ON TARGET

Targeted Drug Delivery Systems

Dr. Gajanan S. Sanap M.Pharm.,Ph.D Department of Pharmaceutics

Ideal College of Pharmacy and ResearchKalyan 421- 306

COLON TARGETED DRUG DELIVERY

Introduction Anatomy of colon Criteria of drug selection Approaches of colon targeting EVALUATION Reference

CONTENTs

INTRODUCTIONTargeted drug delivery systems: The major goal of any drug delivery system is to supply a therapeutic

amount of drug to a target site in a body. Targeted drug delivery implies selective and effective localization of

drug into the target at therapeutic concentrations with limited access to non target sites.

A targeted drug delivery system is preferred in drugs having instability, low solubility and short half life,

Definition:-Colon drug delivery system refers to targeted delivery of drug in to the lower parts of GI tract , mainly large intestine.

Targeted delivery of drugs to the colon is usually to achieve one or more of four objectives. To reduce dosing frequencyTo delay delivery to the colon to achieve high local concentrations

in the treatment of diseases of the distal gut,To delay delivery to a time appropriate to treat acute phases of

disease (chronotherapy),To deliver to a region that is less hostile metabolically, e.g., to

facilitate absorption of acid and enzymatically labile materials, especially peptides.

Oral route is considered to be most convenient for administration of

drug to patient.

Colon is used as site of Targeted drug delivery.

Colon was considered as a BLACK-BOX , as most of the drug are

absorbed from the upper part of the GI tract.

Prime objective-Beneficial in the treatment of colon diseases.

Increase the pharmacological activity.

Reduce dosing & side effects.

Prevent drug from degradation.

As most of the conventional drug delivery systems for treating colon disorders such as inflammatory bowel diseases, infectious diseases and colon cancer are failing as the drugs don't reach the site of action in appropriate concentration.

Thus an effective and safe therapy of these colonic disorders using site specific drug delivery system.

The therapeutic advantages of targeting drug to the diseased organ include,a)Delivery of drug in its intact form as close as possible to the target site.b)The ability to cut down the conventional dose.c) Reduced incidence of adverse side effects.

WHY COLON TARGETED DRUG DELIVERY IS NEEDED?

In recent times the colon-specific delivery systems(CSDDS) are also gaining importance for the systemic delivery of protein and peptide drugs . This is because,

i)as the peptide and protein drugs are destroyed and inactivated in acidic environment of stomach or by pancreatic enzymes (or) by parenteral route which is inconvenient and expensive.

ii) Due to the negligible activity of brush border membrane peptidase activity and less activity of pancreatic enzymes the colon is considered as the most suitable site.

ADVENTAGES

The site specific delivery of drug to lower part of GIT, for

localized treatment of several colonic diseases. (ulcerative

colitis, Chron's disease, carcinomas and infections)

Prevent drug from degradation

Ensure direct treatment at disease site. Suitable absorption site for Protein & Peptide drug. Used to prolong the drug therapy. Improved drug utilization.

Multiple manufacturing steps.

Microflora affects activity of drug via metabolic degradation of the

drug.

Bioavailability of drug may be low due to potentially binding of

drug in a nonspecific way to dietary residues, intestinal secretions,

mucus or faecal matter.

Non availability of an appropriate dissolution testing method to

evaluate the dosage form in-vitro.

Drug should be in solution form before absorption and there for

rate limiting step for poor soluble drugs.

Limitations / Challenges/Difficulties

Substantial variation in gastric retention time may affect drug delivery.

Diseased condition may affect the colonic transit time and drug release profile.

pH level of colon may vary between individuals due to disease, state and temperature of food consumed.

Application

In local colonic pathologiesSystemic delivery of protein and peptidePotential site for the treatment of diseases sensitive to circadian rhythms (asthma, angina and arthritis)For the drugs that are absorbed through colon such as steroids (….efficacy..)For the treatment of disorders like IBS, colitis, crohn’s disease (…where it is necessary to attain high concentration of drugs)

Table 1. Colon targeting diseases, drugs and sites

Target sites Disease conditions Drug and active agents

Topical action Inflammatory Bowel Diseases, Irritable bowel disease and Crohn’s disease. Chronic pancreatitis

Hydrocortisone, Budenoside, Prednisolone, Sulfaselazine, Olsalazine, Mesalazine, Balsalazide

Local action Pancreatactomy and cystic fibrosis, Colorectal cancer

Digestive enzyme supplements 5-Flourouracil

Systemic action To prevent gastric irritation To prevent first pass metabolism of orally ingested drugs Oral delivery of peptides Oral delivery of vaccines

NSAIDS Steroids Insulin

Disorders of Colon

Inflammatory bowels disease

Ulcerative colitis

Crohn’s disease

Colon Cancer

Colon and rectum cancer - 10% in men and 11% women >55,000 Total Colorectal Cancer Deaths

Anatomy of Colon

Anatomy & physiology of colon

The GI tract is divided into stomach, small intestine & large intestine.The colon itself is made up of the caecum, ascending colon, hepatic flexure, transverse colon, splenic flexure, descending colon, sigmoid colon.It is about 1.5 m long.Although it varies in diameter from approx 9 cm in caecum & 2 cm in sigmoid colon.The wall of colon is composed of 4 layers: serosa, muscularis externa, sub mucosa & mucosa.Serosa consists of areolar tissue, muscularis externa composed of an inner circular layer of fibers, sub mucosa is layer of connective tissue, mucosa is divided into epithelium lamina propria & muscularis mucosae

Function of colon Formation of suitable environment for colonic

microorganism.Act as storage reservoirs of waste matter.Removal of content of colon at proper time.Absorption of potassium ion & water from

lumen, concentrating fecal content & secretion & excretion of potassium & bicarbonates.

Gastrointestinal Transit --Gastric emptying of various dosage form is highly

inconsistant & depends primary on whether the subject is fed or fasting & properties of dosage form.

The arrival of dosage form in colon is determined by rate of gastric emptying & intestine transit time. Intestinal transit time Organ Transit time (hrs) Stomach <1 (fasting) >3 (fed) Small intestine 3-4 Large intestine 20-30

Factors to be considered for colonic drug delivery1. pH in the colon: pH of the GI tract is subjected to both inter & intra subject

variation. On entry in to the colon, the pH dropped to 6.4 . The pH in

the mid colon & the left colon is 6.0- 7.6

Location pHOral cavity 6.2-7.4Esophagus 5.0-6.0Stomach Fasted condition 1.5-2.0

Fed condition 3.0-5.0Small intestine Jejunum 5.0-6.5

Ileum 6.0-7.5Large intestine Right colon 6.4

Mid & left colon 6.0-7.6

2. Gastrointestinal transit:Gastric emptying of dosage forms is highly variable & depends primarily on whether the subject is fed or fasted.The arrival of an oral dosage form at the colon is determined by the rate of gastric emptying & the small intestinal transit time.The transit time of dosage form in GIT:

Organ Transit time (hrs)

Stomach <1 (fasting), >3 (fed)

Small intestine 3-4

large intestine 20-30

3. Colonic microflora:Many compounds taken orally are metabolized by gut bacteria.Drug release depends on enzymes that are derived from microflora present in colon.These enzymes are used to degrade coatings/matrices as well as to break bonds between an inert carrier and an active agent resulting in the drug release from the formulation.Important metabolic reactions carried out by intestinal bacteria : hydrolysis, reduction, dehydroxylation, decarboxylation, dehalogenation, deamination, acetylation, esterification.

Drug absorption in the colonDrugs are absorbed passively by either paracellular or transcellular route.Transcellular absorption involves the passage of drugs through cells.(Lipophilic drug)Paracellular absorption involves the transport of drug through tight junction between cells. ( Hydrophilic drug)The colon may not be the best site for drug absorption since the colonic mucosa lacks well defined villi as found in the small intestine.The colon contents become more viscous with progressive absorption of water as one travels further through the colon. This causes a reduced dissolution rate, slow diffusion of drug through the mucosa.

Role of absorption enhancersThe permeability of drugs can be modified by the use of chemical enhancers.These enhancers increase transcellular & paracellular transport through one of the following mechanism: 1. By modifying epithelial permeability via denaturating

membrane proteins.2. By reversibly disrupting the integrity of lipid bilayer of

colon.Category ExampleNSAIDs Indomethacin Calcium ion chelating agent EDTASurfactants Polyoxyethylene lauryl

etherBile salts GlycocholateFatty acids Sodium caprylateMixed micelles Oleic acid glycocholate

Drugs used for local effects in colon against GIT diseases.

Drugs poorly absorbed from upper GIT.

Drugs for colon cancer.

Drugs that degrade in stomach and small intestine.

Drugs that undergo extensive first pass metabolism.

Drugs for targeting.

Criteria of drug selection

Pharmaceutical Approaches for Targeting Drugs to Colon

pH sensitive systemsMicrobially triggered system

◦ Prodrugs ◦ Polysaccharide based systems

Timed release systemsOsmotically controlled drug delivery systemsPressure dependent release systems

An oral colonic delivery system should retard drug release in the stomach and small intestine but allow complete release in the colon.

A variety of strategies has been used and systems have been developed for the purpose of achieving colonic targeting .

Approaches to colon specific drug delivery

1. Coating with pH dependent polymers: The underlying principle of this approach has been employment of polymers that are able to withstand the lower pH values of the stomach, but that disintegrate and release the drug as the pH in the small bowel increases.Selection of enteric polymer dissolving at pH 7 is likely to cause drug release in terminal small bowel.The pH in the transverse colon is 6.6 and 7.0 in the descending colon. Use of pH dependent polymers is based on these differences in pH levels. The polymers described as pH dependent in colon specific drug delivery are insoluble at low pH levels but become increasingly soluble as pH rises.These processes distribute the drug throughout the large intestine and improve the potential of colon targeted delivery systems.

Examples: Cellulose Acetate Phthalate (CAP)CAP is a white free-flowing powder. It is insoluble in water, alcohols, and chlorinated hydrocarbons, but soluble in acetone and its mixtures with alcohols, ethyl acetate–IPA mixture.

Enteric polymers Optimum pH for dissolution

Polyvinyl acetate phthalate (PVAP) 5.0

Cellulose acetate trimelitate (CAT) 5.5

Hydroxypropyl methyl cellulose phthalate (HPMCP)

>5.5

Methacrylic acid copolymer, Type C (Eudragit L100-55)

>6.0

Cellulose acetate phthalate (CAP) (Aquateric)

6.0

Shellac 7.0

Table. pH of commonly used enteric polymers.

Cellulose Acetate Phthalate:

Methacrylic Acid Copolymers:These are anionic copolymers and are very commonly utilized for

enteric coating, including application in colonic delivery.

Eudragit L

Shellac:Shellac is a material of natural origin used for enteric coatings. It

is a purified resinous secretion of the insect Laccifer lacca.

Hydroxypropyl Methylcellulose Phthalate (HPMCP):HPMCP is a white powder or granular material. It is a more

flexible polymer than CAP. Commercially, the available forms are HPMCP-50 and HPMCP-55.

EudracolTM

The microflora of the colon is in the range of 1011 -1012 CFU/ mL, consisting mainly of anaerobic bacteria, e.g. bacteroides, bifidobacteria, eubacteria, clostridia, enterococci, enterobacteria and ruminococcus etc.

Microflora produces a vast number of enzymes like glucoronidase, xylosidase, arabinosidase, galactosidase, nitroreductase, azareducatase, deaminase, and urea dehydroxylase.

Presence of the biodegradable enzymes only in the colon, the use of biodegradable polymers for colon-specific drug delivery.

These polymers shield the drug from the environments of stomach and small intestine, and are able to deliver the drug to the colon.

Microbially Triggered Drug Delivery to Colon

A Prodrug is a pharmacologically inactive derivative of a parent

molecule that require some form of transformation in vivo to release the active drug at the target site.

This approach involves covalent linkage between the drug and its carrier. Biotransformation is carried out by a variety of enzymes, mainly of

bacterial origin, present in the colon. The enzymes that are mainly targeted for colon drug delivery include azoreducatase-galactosidase, β- xylosidase, nitroreductase, glycosidase deaminase, etc.

PRODRUG

For colonic delivery , prodrug is designed to undergo minimal hydrolysis in upper tracts of GIT & undergo enzymatic hydrolysis in colon there by releasing the active drug moiety from drug moiety.

Metabolism of azo compound by intestinal bacteria is one of most extensively studied bacterial metabolic process.

The azo linkage exhibits a wide range of thermal, chemical, photochemical and pharmaceutical properties.

The azo compounds are extensively metabolized by the intestinal bacteria.

Sulphasalazine, which was used for the treatment of rheumatoid arthritis. This compound has an azo bond between 5-ASA and sulphapyridine.

Include naturally occurring polysaccharides obtained from plant (guar gum, inulin), animal (chitosan, chondrotin sulphate), algal (alginates) or microbial (dextran) origin.

The polysaccrides can be broken down by the colonic microflora to simple saccharides. Therefore, they fall into the category of “generally regarded as safe” (GRAS).

AZOREDUCTASES POLYSACCHARIDASES

Of the multitude of bacterial enzymes that are produced in colon, 2 main classes are:-

40

Prodrugs

Drug Carrier Molecule

Enzymatic stimuli in the biological environment of the GIT

breaks the bond

Concept of

prodrugs

Prodrugs

Drug Carrier Molecule

Concept of

prodrugs

Prodrugs

Drug Carrier Molecule

Concept of

prodrugs

Prodrugs

Drug Carrier Molecule

Concept of

prodrugs

41

Bacteria in colon

Hydrolysis of sulphasalazine (A) into 5-aminosalicylic acid (B) andsulfapyridine (C).

(A)

(B)

(C)

Prodrugs: Example,Sulfasalazine is mainly used for the treatment of inflammatory bowl diseases.

Chemically it is 5-amino salicylic acid (5-ASA) coupled with sulphapyridine by azo bonding.

On reaching the colon, the azo bond is reduced by azoreductases to 5-ASA & sulphapyridine.

The active moiety is 5-ASA & sulphapyridine acts as carrier to deliver 5-ASA in colon.

Azo polymeric new drugIn which use of polymers as drug carriers for drug

delivery to colon .Synthetic, naturally, sub-synthetic polymers used

form colon targeted polymeric prodrug with azo linkage between polymer & drug moiety.

The various azo polymers are evaluated for coating materials over drug core. These are susceptible to cleavage by azo reductase enzyme.

Coating of protein & peptide drug capsules crosslinked with azoaromatic group Polymer to protect drug from degradation in stomach & small intestine. In colon azo bonds reduced & drug is released 43

1)Azo bond conjugate:- Azoreductase enzyme produced in colon by colonic

bacteria which degrades azo bond. This principle is utilized in preparation of prodrug

derivative of active drug for targeting in colon.

Sulphasalazine(SASP) is prodrug of 5-ASA. It is conjugated with sulphapyridine through azo bond. Sulphasalazine was introduced for the treatment of rheumatoid arthritis and anti-inflammatory disease.

Carrier moiety conjugated with 5-amino salicylic acid

Prodrug of 5-amino salicylic acid

p-aminohippurate (4-amino benzoyl glycine)

ipsalazine,

p- 4-amino benzoyl-β-alanine

balsalazine

p-aminobenzoate HB-313

nonabsorbable sulphanilamide ethylene polymer

poly-ASA

a dimer representing two molecules of 5-ASA that are linked via an azo bond

olsalazine (OSZ)

45

Polysaccharide based delivery system

Polysaccharides offer an alternative substrate for the

bacterial enzymes present in the colon.

Most of them are hydrophilic in nature.

Natural polysaccharides are either modified or mixed

with water insoluble polymers.

46

Polysaccharides as carriers:The colonic microflora secretes a number of enzymes that are capable of hydrolytic cleavage of glycosidic bonds.

These include β-d-glucosidase, β-dgalactosidase, amylase, pectinase, xylanase, α-d-xylosidase, and dextranases.

Natural polysaccharides like pectin & inulin are not digested in stomach & small intestine but are degraded in colon by resident bacteria.

The bacteria converts polysaccharides to gases such as methane, carbon dioxide, hydrogen & to short chain fatty acids.

These polysaccharides thus have the potential as non-toxic carriers for colon specific drug delivery.

63

Polysaccharides used for Colon Drug Delivery

• Chitosan

• Pectin

• Guar gum

• Chondroitin sulphate

• Dextran

• Cyclodextrins

• Almond gum

• Locust bean gum

• Inulin

• Boswellia gum

• Karaya gum

49

Different bacterial species acting on Polysaccharides in colon

Polysaccharides Bacterial species

Amylose

ChitosanChondroitin sulphateCyclodextrinsDextranGuar gum

BacteriodesBifidobacteriumBacteriodesBacteriodesBacteriodesBacteriodesBacteriodesRuminococccus

Polysaccharides Drug targeted to colon

Guar gumPectinInulinAmylaseCyclodextrin (β)DextranChitosanEudragits

Rofecoxib , TinidazoleNaproxenAzathioprine5-Amino salicylic acidAlbendazole Ibuprofen Satranidozole5-fluorouracil

List of few studies on Polysaccharides

50

MARKETED PREPERATION

MARKETED PRODUCTS

51

Time release dosage forms:Nonbiodegradable polymers are used.They are generally nonspecific with respect to pH-solubility characteristics and the employment of these polymers as carrier matrices for colonic delivery often utilizes a time-dependent mechanism.

This provides an initial lag phase of low or no release during transit through the upper gastrointestinal tract.

The lag time usually starts after gastric emptying because most of the time-controlled formulations are enteric coated.

The enteric polymer coat prevents drug release in the stomach.

Drug release from these systems is not pH dependent.

Various polymers used are: polyacrylates, methylcellulose, HPMC, CMC etc.

Lag phase of~ 5 h is

observed.

This system, first described by Shah & co-workers, uses lag time to achieve colon delivery.

System consist of 3 main parts: An outer enteric coat, inner semipermeable polymer membrane, and a central core having swelling excipients and an active component.

The outer enteric coating prevents drug release until the tablet reaches the small intestine.

In the small intestine, the enteric coating dissolves allowing gastrointestinal fluids to diffuse through the semipermeable membrane into the core.

The core swells until after a period of 4–6 h, when it bursts, and releases the active component in the colon.

Platform Technologies

PULSINCAP

OROS-CT

CODES™

PORT® SYSTEM

TIME CLOCK® SYSTEM

COLAL-PRED™

Pulsincap:

Hydrogel capsule

Pulsincap and Hydrophilic Sandwich Capsules

Erodible plug time-delayed capsule:

OROS-CT

CODES™

PORT® SYSTEM

TIME CLOCK® SYSTEM

Solid dosage form coated with lipid barriers containing carnauba wax and bees wax along with surfactants. Further coated with enteric coating polymer to prevent premature drug release, but the release is independent of pH or digestive state of the gut

Enteric coatingWax coating withsurfactant

Drug core

COLAL-PRED™

Pellets containing the drug (prednisolone metasulphobenzoate) with a coating of ethylcellulose and a specific form of amylose (derived from starch).

After completion of succsesful phase I and II trials ‘Alizyme’ obtained approval for Phase III clinical trial of COLAL-PREDTM in maintenance of remission of ulcerative colitis.

Advantages

Patient compliance and treatment efficacy

Useful in treatment of ulcerative colitis, crohn's disease,

irritable bowel syndrome and carcinomas

Low dose is required ,so less side effect

Used for local and systemic action

Gastric irritation can be avoided

DisadvantagesThere is less fluid in colon than in small intestine and

hence, dissolution is a problem for water soluble drugs.

Binding of drug to dietary residues, intestinal

secretions etc., reduce concentration of free drugs.

Some micro flora may degrade the drug.

Small luminal surface area and relative tightness of

tight Junctions in colon, delay the systemic absorption.

Onset of action is slow.

ApplicationsLOCAL ACTIONS1.    Ulcerative colitis.2.    CHRON'S disease.3.    Irritable bowel syndrome.4.    Metastatic human colon cancer.

SYSTEMIC ACTIONS1. Molecules degraded/poorly absorbed from upper G.I.T

such as peptides and proteins are better absorbed from colon.

2. For achieving chemotherapy for diseases that are sensitive to circadian  rhythm such as Asthma, angina, arthritis.

The OROS-CT (Alza corporation) can be used to target the drug locally to the colon for the treatment of disease or to achieve systemic absorption.

The OROS-CT system can be a single osmotic unit or may incorporate as many as 5-6 push-pull units, each 4 mm in diameter, encapsulated within a hard gelatin capsule.

For treating ulcerative colitis, each push pull unit is designed with a 3-4 h post gastric delay to prevent drug delivery in the small intestine. Drug release begins when the unit reaches the colon.

OROS-CT units can maintain a constant release rate for up to 24 hours in the colon or can deliver drug over a period as short as four hours.

Osmotic Controlled Drug Delivery (ORDS-CT)

Delivery port

Osmet pump

Depend up on the osmotic pressure exerted by osmogens on drug compartment with which though drug get released slowly through the orifice.

OROS-CT (Alza corporation)

Immediately after the OROS-CT is swallowed, the gelatin capsule containing the push-pull units dissolve

Because of its enteric coating, each push-pull unit is prevented from absorbing water in the acidic environment.

As the unit enter the small intestine, the coating dissolve in this higher pH (pH >7), water enters the unit, causing the osmotic push compartment to swell and concomitantly creates a flowable gel in the drug compartment.

Swelling of the osmotic push layer forces drug gel out of the orifice.

MARKETED PRODUCTS

Sr. no.

Marketed name Company name

Disease Drug content

1) Mesacol tablet Sun pharma, India

Ulcerative colitis

Mesalamine

2) SAZO Wallace , India Ulcerative colitis, crohn’s disease

Sulphasalazine

3) BUSCOPAN German remedies

Colonic motility

Hyoscine butyl bromide

4) Entofoam Cipla, India Ulcerative colitis

Hydrocortisone acetate

For evaluation, not any standardized evaluation technique is available for evaluation of CDDS because an ideal in vitro model should posses the in-vivo conditions of GIT such as pH, volume, stirring, bacteria, enzymes, enzyme activity, and other components of food.

These conditions are influenced by the diet, physical stress, and these factors make it difficult to design a standard in-vitro model.

EVALUATION

1. In vitro dissolution study2. In vitro enzymatic degradation test3. Relative colonic tissue exposure4. Relative systemic exposure to drugs5. -Scintigraphy6. Magnetic moment imaging study7. Drug delivery index8. High frequency capsule

1. In vitro methods:

The ability of the coats/ carriers to remain in the physiological environment of the stomach and small intestine is generally assessed by conducting drug release studies in,

• Drug release study in 0.1 N HCl for 2 hours (mean gastric emptying time)

• Drug release study in phosphate buffer for 3 hours (mean small intestine transit time PH 6.8)

These dissolution studies can be carried out by using paddle or basket or flow through dissolution apparatus.

IN-VITRO DISSOLUTION TESTDissolution of CDDS is usually complex, dissolution Describe

in USP Disso. Carried out by conventional basket method.Dissolution tests for CDDS in different media simulating pH

condition & times likely to be encountered at various location in GI tract.

Following media were used- pH 1.2 to simulate gastric fluid. pH 6.8 to simulate jejunal region of small intestine. pH 7.2 to simulate ileum segment.Enteric coated CDDS studied in gradient disso. Study in 3 buffer

systems. 2 hr at pH 1.2, then 1 hr at pH 6.8& finally at pH 7.475

BioDis-III (Apparatus III)• Ideal for the dissolution profiling of extended release

dosage forms.

• It is designed to meet or exceed current USP specification.

• It used a reciprocating motion to dip the inner tube into media.

• At the designated time, the entire row of inner tubes raises and moves to the next row of media.

Bio-Dis III• Capable of running unattended upto 6 days and can store upto 25

programms.

• 7 sample tubes which automatically traverse upto 6 rows of corresponding outer tubes filled with different media.

• With accessories, the appropriate media volume can vary from 100, 300 ml (USP) or 1000 ml.

BioDis III

In vitro enzymatic degradation test

Method 1:

Drug release in buffer medium containing enzymes(e.g.pectinase, dextranase) or rat or guinea pig or rabbit decal contents

Amount of drug release in particular time directly proportional to the rate of degradation of polymer carrier.

Method 2:

Incubating carrier drug system in fermenter

Suitable medium containing colonic bacteria (streptococcus faecium or B.ovatus)

Amount of drug released at different time intervels determined.

B R Nahata College of Pharmacy Mandsaur (M.P.)

2 In vivo methods:

Animal models

Rats, mice, pigs and dogs animal models were reported for colon targeted drug delivery systems.

For simulating the human physiological environment of the colon, appropriate animal model selection is depends on its approach and design of system.

For example, guinea pigs have glycosidase and glucuronidase activities in the colon and digestive anatomy and physiology is similar to that of human, so they are appropriate in evaluating prodrugs containing glucoside and glucuronate conjugated for colonic delivery.

Techniques which are used for monitoring the in vivo behavior ofcolon targeted drug delivery are String technique, Endoscopy, Radiotelemetry, Roentegenography, Gamma scintigraphy.

String technique : In these studies, a tablet was attached to a piece of string and the subject swallowed the tablet, leaving the free end of the string hanging from his mouth.

At various time points, the tablet was withdrawn from the stomach by pulling out the string and physically examining the tablet for the signs of disintegration.

Endoscope technique:It is an optical technique in which a fiber scope (gastro scope) is used to directly monitor the behavior of the dosage form after ingestion.This method requires administration of a mild sedative to facilitate the swallowing of the endoscopic tube. The sedative alter the gastric emptying and GI motility.

Radiotelemetry :This technique involves the administration of a capsule that consist of a small pH probe interfaced with a miniature radio transmitter which is capable of sending a signal indicating the pH of the environment to an external antenna attached to body of the subject.

So it is necessary to physically attach the dosage form to the capsule which may effect the behaviour of the dosage form being studied.

Reoentgenography :The inclusion of a radio-opaque material into a solid dosage form enables it to be visualized by the use of X-rays.

By incorporating Barium sulphate into a pharmaceutical dosage form, it is possible to follow the movement, location, and the integrity of the dosage form after oral administration by placing the subject under a fluoroscope and taking a series of X-rays at a various time points.

Gamma scintigraphyThe most useful technique, to evaluate the in vivo behavior of dosage forms in animals and humans is external scintigraphy or gamma scintigraphy

It requires the presence of a gamma emitting radio active isotope in the dosage form that can be detected in vivo by an external gamma camera.The dosage form can be radio labeled using conventional labeling or neutron activation methods.