ORAL DRUG ORAL DRUG DELIVERY DELIVERY SYSTEMSYSTEM

Presented By-Musale Baliram Sugriv M. Pharmacy Ist year (Pharmaceutics)

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Oral controlled release systemOral controlled release systemOral route has been most popular &

successfully used route for controlled delivery of drugs because of following reasons-

Convenience & ease of administration.Greater flexibility in dosage form

design.Ease of production & low cost of such

a system.2

• An oral CDDS can be designed as-• CONTINUOS RELEASE SYSTEM–

release drug continuously over an extended period of time.

• PULSATILE RELEASE SYSTEM– are characterized by a time period of no release followed by a rapid & complete or extended drug release.

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CONTROLLED RELEASE ORAL FORMULATIONA.CONTINUOUS RELEASE SYSTEMS B. PULSED RELEASE SYSTEM

1.CONTINUOUS TRANSIT SYSTEM 1.TIME SPECIFIC SYSTEM MATRIX OSMOTIC PRESSURE RESERVOIR RUPTURABLE COATING

ORAL OSMOTIC SWELLABLE COATING

ION-EXCHANGE RESINS DIFFUSIVE COATING PULSINCAP 2. GASTRORETENTIVE SYSTEM 2.COLON SPECIFIC SYSTEM

LOW DENSITY SYSTEM TIME HIGH DENSITY SYSTEM PH MODIFIED SHAPE SYSTEM TIME/PH DEPENDENT MUCOADHESIVE SYSTEM ENZYME OSMOTIC PRESSURE

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Matrix type oral CDDS Matrix type oral CDDS Are possibly the most common of monolithic

devices for controlling the release of drugs for following reson-

1. Easy of fabricate compared to reservoir 2. No danger of accidental dose dumping

compared to monolithic reservoir.

In such device active agent present as dispersion within polymer matrix. & formed by compression of polymer/ drug matrix or by melting

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Conventional matrix tablet designConventional matrix tablet design

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Reservoir type oral CDDSReservoir type oral CDDSAre those where the drug crystal, particle,

granule, pellet ,minitablet or tablet is present as core encapsulated with a rate controlling wall, film/membrane having a well defined thickness.

Drug release occurs predominantly by diffusion.Advantage of such system – zero order delivery is possible Release rate modulated by polymer type,

polymer membrane thickness, & membrane porosity.

Disadvantage- higher cost of formulation.7

Reservoir pellet design for oral drug Reservoir pellet design for oral drug deliverydelivery

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Oral osmotic (OROS) CDDSOral osmotic (OROS) CDDSBased on diffusion & erosion, osmotic

system are more complex in design but provide better zero-order drug delivery.

They work on principle of osmotic pressure to release the drug at a constant zero-order rate.

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In design OROS system compries of 4 basic component

1.A rigid shape retaining semipermiable membrane(SPM) that surrounds drug/ osmogent core

2.A drug layer3. Osmogent –that embites water & generates

osmotic pressure that drives dispersed drug through delivery orifice.

Commonly used osmogent are sodium chloride, dextrose, mannitol. Swellable osmopolymer include PEO, HPMC.

4.Delivery orifice which is generally laser-drilled into semipermeable membrane.

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GASTRORETENTIVE GASTRORETENTIVE DRUG DELIVERY DRUG DELIVERY

SYSTEMSYSTEM

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• INTRODUCTION• APPROPRIATE CANDIDATE DRUGS

FOR GRDDS• ADVANTAGES• LIMITATIONS• APPROACHES• EVALUATION TEST

CONTENTS

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INTRODUCTION•Oral drug delivery is widely used in

pharmaceutical field to treat the diseases.•Some drugs are absorbed at specific site

only ,these require release at that specific site.

•Gastro retentive drug delivery(GRDDS) is one of the site specific drug delivery for the delivery of the drugs at stomach.

• It is obtained by retaining dosage form into stomach and drug is being released at controlled manner at specific site

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APPROPRIATE CANDIDATE DRUGS FOR GRDDS

•Drugs acting locally in the stomach. E.g. Antacids and drugs for H. Pylori viz.,

Misoprostol.•Drugs that are primarily absorbed in the

stomach. E.g. Amoxicillin•Drugs that is poorly soluble at alkaline pH. E.g. Furosamide, Diazepam, Verapamil,

etc.•Drugs with a narrow absorption window. E.g. Cyclosporine, , Levodopa,

Methotrexate

Drugs which are absorbed rapidly from the GI tract.

E.g. Metronidazole, tetracycline.Drugs that degrade in the colon. E.g. Ranitidine, Metformin.Drugs that disturb normal colonic microbes E.g. antibiotics against Helicobacter pylori.

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ADVANTAGES• Enhanced bioavailability• Sustained drug delivery reduced frequency

of Dosing• Targeted therapy for local ailments in the

upper GIT• Reduced fluctuations of drug concentration• Improved selectivity in receptor activation• Reduced counter-activity of the body• Extended effective concentration• Minimized adverse activity at colon

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LIMITATIONS• The drug substances that are unstable in the

acidic environment of the stomach are not suitable candidates to be incorporated in the systems.

• These systems require a high level of fluid in the stomach for drug delivery to float and work efficiently.

• Not suitable for drugs that have solubility or stability problem in GIT.

• Drugs which are irritant to gastric mucosa are also not suitable.

• These systems do not offer significant advantages over the conventional dosage forms for drugs, which are absorbed throughout GIT.

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APPROACHES FOR PROLONGING THE GASTRIC RESIDENCE TIME

FS

HDS

A SSS

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• High-density systems. (HDS)

• Floating systems. (FS)• Swelling and expanding

systems. (SS)• Mucoadhesive &

Bioadhesive systems. (AS)

FS

HDS

A SSS

Classification of GRDDSClassification of GRDDS

1.LOW DENSITY SYSTEM/ FLOATING DOSAGE FORM

a) Effervescent system /Gas generating system

b) Non-effervescent systems Sweling/expanding system Inherently low density system2.HIGH DENSITY SYSTEM3. MODIFIED SHAPE SYSTEM4. MUCOADHESIVE SYSTEM

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1. LOW DENSITY SYSTEM/ FLOATING 1. LOW DENSITY SYSTEM/ FLOATING DOSAGE FORMDOSAGE FORM

Prepared by incorporating a high level(20-75%w/w) gel-forming hydrocolloids. E.g.:- Hydoxyethylcellulose, hydroxypropylcellulose, HPMC & Sod. CMC into the formulation and then compressing these granules into a tablets or capsules.

It maintains the bulk density less than 1

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Have a bulk density less than gastric fluid & so remain buoyant in stomach called as HYDRODYNAMICALY BALANCED SYSTEM

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a. Effervescent / Gas generating system

It increases size of drug delivery system as well as decrease its density & provides floating properties

This system formulated as matrices / resinate.Following are types of gas generating GRDDS Conventional matrix tablets Layered matrix tablets Core coated tablet Ion-exchange resin complexs

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• GAS GENERATING SYSTEM Carbonates or bicarbonates, which react with

gastric acid or any other acid (e.g., citric or tartaric) present in the formulation to produce CO2 , are usually incorporated in the dosage form, thus reducing the density of the system and making it float on the media.

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b. NON-EFFERVESCENT SYSTEMb. NON-EFFERVESCENT SYSTEMSWELLING / EXPANDING SYSTEMSSWELLING / EXPANDING SYSTEMS

These systems use a gel forming / swellable hydrocolloid such as polysaccharides like guargum, cellulosics- HPMC, synthetic polymers- PEO, carbomer.

It consist of embedding drug powder/ pellets in gel forming hydrocolloids.

After oral administration dosage form swell on contact with gastric fluid

The formed swollen gel-like structure acts as reservoir & allows sustained release of drug through gelatinous mass.

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INHERENTLY LOW DENSITY INHERENTLY LOW DENSITY SYSTEMSSYSTEMS

Two types—a.Entrapment of air (hollow

microspheres/microballoons) Emulsion solvent diffusion

method Modified solvent evaporation

method Dehydration of swollen hydrogel Hollow chamber systemb. Incorporation of low density

materials.25

Polymers used commonly: Polycarbonates, Cellulose acetate, Calcium alginate, Eudragit S, agar and methoxylated pectin etc

HOLLOW MICROSPHERES

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Emulsion- solvent diffusion methodEmulsion- solvent diffusion method

A solution of polymer & drug in ethanol/ methylene chloride is poured in aq. Solution of PVA .ethanol partitions into external aq. Phase & polymer participates around methylene chloride droplets. Then subsequent evaporation of entrapped methylene chloride leads to formation of internal microcavity within microparticles

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MODIFIED SOLVENT MODIFIED SOLVENT EVAPORATION METHODEVAPORATION METHOD

Drug powder is dispersed into solution of cellulose acetate butyrate & eudragit RL 100 in acetone.

The dispersion pressurised under CO2 gas , which dissolves & forms bubbles following the release of pressure.

Generated CO2 bubbles are entrapped within dispersed drug-polymer droplets & leads to formation of internal cavities within hardened microsphers.

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DEHYDRATION OF SWOLLEN DEHYDRATION OF SWOLLEN HYDROGELHYDROGEL

System consist of hydrated drug loaded calcium alginate core, which is coated with PVA membrane .Drying of hydrogel result in formation of air compartment owing to shrinkage of hydrated core

HOLLOW CHAMBER SYSTEM These system prepared by coating drug on hollow core such as poprice , empty gelatin capsules / polystyrene beads followed by coating the drugs with rate- controlling membrane

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• Prepared by dropping sodium alginate solution into aqueous solution of calcium chloride, causing the precipitation of calcium alginate

• Freeze dry in liquid nitrogen at -40oc for 24h.

• Beads-spherical and 2.5 mm

Swellable agents have pore size ranging between 10nm to 10µm.Superporous hydrogels will swell more than the swelling ratio 100,This is achieved by co-formulation of a hydrophilic particulate material, and Ac-Di-Sol (crosscarmellose).

ALGINATE BEADS SUPERPOROUS HYDROGELS

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LOW DENSITY MATERIALSLOW DENSITY MATERIALSFats & low density polymers used to

prepare floating drug matrices.e.g. Polypropylene foam powder ,matrix-forming polymers ,drug & an optional filler.

Polypropylene foam powder based drug microparticals prepared by soaking microporous foam particals in organic solution of drug & polymer.

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2. HIGH DENSITY 2. HIGH DENSITY SYSTEMSYSTEM

Density of system is larger than gastric juice (>1.4 g/ml) , the device settles down to bottom of stomach , remaining located below the pylorus.

Iron oxide , titanium dioxide & barium sulphate used to increase density of drug pellets.

The drug is coated on heavy core & then covered by diffusion controlled membrane.

The approach is not very successful.32

3. MODIFIED SHAPE SYSTEM / UNFOLDING 3. MODIFIED SHAPE SYSTEM / UNFOLDING SYSTEMSYSTEM

These system consist of atleast one erodible polymer , one non-eroidible polymer & drug that is dispersed within polymer matrix.

Drugs incorporated in several geometric shapes such as tetrahedron, ring, disc, spiral, pellet/ sphere which can be packed into gelatine capsule & unfold after dissolution of capsule shell.

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4. BIOADHESIVE SYSTEMS / MUCOADHESIVE 4. BIOADHESIVE SYSTEMS / MUCOADHESIVE SYSTEMSYSTEM

Bioadhesive polymer e.g. carbomer, chitosen used to coat dosage form so that it adheres to gastric mucosa.

Adv.is –in stomach is intimate contact with mucosa leading to short pathways for locally acting drugs such as antibiotics against

H. pylori.

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Marketed productMarketed product

BRAND NAME ACTIVE INGREDIENT

Cifran OD Ciprofloxacin Madoper L-

DOPA,benserazide Valrelease Diazepam Topalkan Aluminium

mg.antacid Almagate flat coat

Aluminium mg. antacid

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EVALUATION TESTS:EVALUATION TESTS:Evaluation of tabletsEvaluation of tablets Buoyancy lag time Buoyancy lag time In vitro dissolution behaviour In vitro dissolution behaviour Swelling index Swelling index Hardness & friability Hardness & friability Weight variation Weight variationEvaluation of microspheres & beads Evaluation of microspheres & beads Particle size analysis Particle size analysis Surface characterization Surface characterizationIn vivo evaluation (Gamma In vivo evaluation (Gamma scientigraphy)scientigraphy)

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Buoyancy lag time & duration of Buoyancy lag time & duration of buoyancybuoyancy

The buoyancy lag time & duration of buoyancy determined in USP dissolution apparatus II in acid enviornment.

The lag time interval between introduction of tablet into dissolution medium & its buoyancy to top of dissolution medium was taken as buoyancy lag time / floating lag time & duration of buoyancy was observed vissually.

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In vitro dissolution behaviourIn vitro dissolution behaviourRelease of medicament studied by USP II

type dissolution apparatus (paddle type) dissolution performed at predetermined speed & temperature 37±0.5ºc in appropriate dissolution medium.

5mL sample withdrawn at predetermined interval .

Absorption of withdrawn sample measured spectrophotometrically with with suitable dilution & corresponding concentration determined from calibration curve.

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Swelling index Swelling index

Tablet weigh individually (W0) & placed in dissolution medium’

Temperature maintain at 37±0.5ºcAt regular interval sample removed &

swollen weight (Wt) of each determined at predefined time interval

% swelling index = Wt- Wo / Wo x 100 Wt– weight of tablet at time tW0– initial weight of tablet.

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Hardness & friabiltyHardness & friabiltyHardness– force applied to break tabletResistance of tablet to chipping, abrasion,

breakage under condition of storage, transformation, handling before usage depends on its hardness.

Measured by using Monsanto hardness tester.Friabilty– Roche friabilatorTake tablet in plastic chamber , revolving at 25

rpm & dropping tablet at height of 6 inch in each revaluation.

%Friabilty = intial wt of tab.—final wt of tab./initial wt

of tabX100

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Weight variationWeight variation USP provides wt. variation test by

weighing 20 tablet individually , calculating average wt & comparing the individual tablet wt. To average.

Tablet meet USP test if no more than 2 tablet outside the % limit.

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Evaluation for microspheres & beadsEvaluation for microspheres & beads

Particle size analysis Surface characterisation Particle size analysis- determined using

optical microscopySurface characterisation- determined

using (SEM) scanning electron microscopy

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In vivo evaluation (Gamma In vivo evaluation (Gamma scientography)scientography)

This method helps to locate dosage form in GI tract by which we can predict & correlate gastric emptying time & passage of dosage form in GIT.

Gamma rays are emitted by nucleotide are focused on camera , which helps to monitor the location of dosage form in GI tract.

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COLON TARGETED DRUG DELIVERY

SYSTEM

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INTRODUCTIONINTRODUCTIONThe most useful drug delivery system to

treat colonic disorder & colon cancer are failing due to inappropriate concentration of drug that do not get to the site of action.

Colon targeted drug delivery system are suitable site for absorption of peptides & proteins.

The CDDS highly desirable for local treatment of variety of bowl diseases such as ulcerative colitis, crohn’s disease,colonic cancer.

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Promising site for drug delivery

Local disorders

Systemic absorption

oDrugs unstable in upper GIT

oDrugs poorly absorbed from GIT

oDrugs that necessitate targeting at site

Colon as a site for drug delivery

Advantages of Colon Targeted Advantages of Colon Targeted drug delivery systemdrug delivery system

Drug directly reaches the target site.

It reduces dose of drug to be administrated.

It minimizes side effect It enhances drug utilization.

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Anatomy & Physiology of colonAnatomy & Physiology of colonGI tract is divided into –

StomachSmall intestineLarge intestine

The large intestine extend from ileocaecal junction to anus which is divided into 3 main parts-colon, rectum, anal canal.

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Colon itself consist of – Caecum (Asending colon) Hepatic flexure (Transvers colon)-

longest Splenic flexure (Descending colon) Sigmoidal colonThe wall of colon composed of 4 layers Serosa Muscularis externa Sub-mucosa Mucosa

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Function of colon 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.

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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 51

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Ulcerative colitis

Inflammatory bowels disease (IBD)

Crohn’s disease

Colonic polyps

Colorectal cancer

Others as amebiasis, diarrhoea etc

Disorders of Colon

Criteria Pharma - cological class

Nonpeptide drug

Peptide drug

Drug used for local effect in colon against disease

Anti-inflammatory drugs

OxyprenololMetoprololNifedine

Amylin Antisense oligonucleotide

Drugs poorly absorbed from upper GIT

Antihypertensive Antianginal drugs

IbuprofenIsosorbidesTheophylline

CyclosporineDesmopressine

Drugs for colon cancer

Antineoplastic drugs

Psedoephedrine

EpoetinGlucagon

Drugs that degrade in stomach & small intestine

Peptides & proteins

5-florouracilDoxorubicin

GonadorelineInsulin

Drugs undergo extensive first pass metabolism

NitroglycerineCorticostroids

Bleomycinenicotine

ProtirelinSermorelin

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Approach for colon targeted Approach for colon targeted drug delivery systemdrug delivery system

Following approaches used for CDDS . 1. By using pH sensitive polymer. 2. Time controlled release drug delivery

system for colon. 3. Microbially controlled system for colon. a) Prodrug b) Azo-polymeric prodrug. c) Polysaccharide based delivery

system. 4. Osmotically controlled drug delivery

system

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Oral administration / Colon targeted dosage form

Remain intact in stomach Remain intact in small lntestine Drug release in colon

High intracolonic drug conc. Dose reduction Improved efficacy APPROACHES OF CDDS

Oral administration/ conventional dosage form

Absorption of drug either in stomach / small intestine

Low intracolonic drug conc. Large dose requried Poor efficacy Low therapeutic index Side effect

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GI TRACT SEGMENT PH

STOMACH 1-3SMALL INTESTINE 5-7.5LARGE INTESTINE 6.8-7.8

RECTUM 7.8-8

1. By using pH sensitive polymer1. By using pH sensitive polymerThe polymer which are pH depended in colon

targeted drug delivery are not suitable at low pH level but become progressively more soluble as pH increase.

Although these pH dependent polymers can protect a drug moiety in stomach from acidic environment.

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Mechanism of action of a pH dependent system for targeted drug

delivery to the colonpH sensitive polymer + drug core

DRUG CORE

Colonic pH

Release of drug in Colon

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Sr. No.

Polymer Threshold pH

1 Eudragit® L 100 6.0

2 Eudragit® S 100 7.0

3 Eudragit® L –30D 5.6

4 Eudragit® FS 30D 6.8

5 Eudragit® FS 30D 5.5

6 Polyvinyl acetate phthalate 5.0

7 Hydroxy propyl methyl cellulose phthalate

4.5-4.8

8 Cellulose acetate trimelliate 4.8

9 Cellulose acetate phthalate 5.0

Polymer of methacrylic acid are

mostly used

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2.Time controlled release drug delivery 2.Time controlled release drug delivery system for colonsystem for colonTime controlled release system (TCRS) such

as sustained release dosage form are also very promising drug delivery system.

However due to potentially large variation of gastric emptying time of dosage form in humans, in these approaches, colon arrival time of dosage forms can not be accurately predicted, resulting in poor colonical availability.

The dosage form may also be applicable as colon dosage forms by prolonging the lag time of about 5-6 hr. 59

» Releases the drug after a predetermined lag time

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

» Drug release from these systems is not pH dependent 60

Lag Phase of 5 hrs.

obeserved

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Disadvantage of these system are-

1. Gastric emptying time varies markedly between subjects / in manner dependent on type & amount of food intake .

2. Gastrointestinal movement , specially peristalsis or contraction in stomach result in gastrointestinal transit of drug.

3. Accelerated transit through different regions of colon has been observed in patients with IBD , carcinoid syndrome & ulcerative colites

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3. Microbially triggered drug 3. Microbially triggered drug delivery to colondelivery to colon

The microflora of colon consist mainly of anaerobic bacteria e.g. bacteroides , bifidobacteria, enterococci, entrobacteria..etc This vast microflora fulfil it’s energy needs by fermenting various types of substrates that have been left undigested in small intestine, e.g. di & tri saccharides , polysaccharides ..etc.for this fermention, microflra produces a vast number of enzyme like glucoronidase, galactosidase, arabinosidase, nitroreductase etc.

Because of presence of biodegradable enzymes only in colon , use of biodegradable polymer for CDDS seems to be more specific approach. 63

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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

a. Prodrug approach for drug a. Prodrug approach for drug delivery to colondelivery to colon

Prodrug is a pharmacologically inactive derivative of parent drug molecule that requires spontaneous /enzymatic transformation in vivo to release active drug.

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.

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Bacteria in colon

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

(A)

(B)

(C)

b. Azo polymeric new drugb. 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

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c. Polysaccharide based c. Polysaccharide based delivery systemdelivery 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.68

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Polysaccharides used for Colon Drug Delivery

• Chitosan

• Pectin

• Guar gum

• Chondroitin sulphate

• Dextran

• Cyclodextrins

• Almond gum

• Locust bean gum

• Inulin

• Boswellia gum

• Karaya gum

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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

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4. Osmotically Controlled Drug Delivery Systems

Delivery portOsmet pump

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

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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 73

EVALUATION TESTEVALUATION TESTIn-vitro dissolution testIn-vivo test string technique Endoscopy technique Gamma scintigraphy Radiotelemetry Roentgenography

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IN-VITRO DISSOLUTION TESTIN-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 7.4

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IN-VIVO METHODIN-VIVO METHOD

String method- A tablet is attached to piece of string & subject swallows tablet, leaving free end of string hanging from his mouth at various times. withdrawing tablet from stomach by pulling out the string & physically examining the tablet for the sign for disintegration.

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Endoscopy technique- It is optical tech. in which fibre gastroscope is used to directly moniter behavior of dosage form after ingestionGamma scintigraphy-Most useful to evaluate in-vivo behavior of dosage form in animal & humans.it requirs presence of gamma emmiting radioactive isotopes

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PULSATILE DRUG PULSATILE DRUG DELIVERY DELIVERY SYSTEMSYSTEM

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PULSATILE DRUG DELIVERY SYSTEM

Is defined as the rapid and transient release of a certain amount of drug molecules within a short time-period immediately after a predetermined off-release period.

In various diseases in which we can recomend the pulsatile drug delivery system such as duodenal ulcer, cardiovascular diseases, arthritis, asthma, diabetes, neurological disorder, cancer, hypertension and hypercholesterolemia .

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Pulsatile drug delivery systems (PDDS) are gaining importance as they deliver a drug at time and site specific manner resulting in improved therapeutic efficacy as well as compliance.

Intelligent drug delivery system capable of adjusting drug release rates in response to a physiological need.

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Necessity of PDDSNecessity of PDDS1.Chronopharmacotherapy of disease which shows

circadian rhythms in their pathophysiology- -asthmatic attack during early morning - heart attack in middle of night - morning stiffness in arthritis 2. Avoiding first pass metabolism ex. Protein & peptide3. For which tolerance is rapidly exists ex. Salbutamol

sulphate4. For targeting specific site in intestine ex. Colon

(sulphasalazine) 5. For programmed administration of hormone & drug6.For drug having short half-life ex. ß-blocker

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Disease Chronological behavior Drugs usedPeptic ulcer Acid secretion is high in

the afternoon and at night.H2blockers

Attention deficit syndrome

Increase in DOPA level in afternoon

Methylphenidate

Cardiovascular diseases

BP is at its lowest during the sleep cycle and rises steeply during the early morning

Nitroglycerin, calcium channel,blocker, ACE inhibitors

Asthma Precipitation of attacks during night or at early morning.

Β2 agonist, Antihistamines

Arthritis Level of pain increases at night

NSAIDs, Glucocorticoids

Diabetes mellitus Increase in the blood sugar level after meal

Sulfonylurea, Insulin

Hypercholesterolemia

Cholesterol synthesis is generally higher during night than day time.

HMG CoA reductase, Inhibitors

Diseases that require pulsatile drug delivery

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Pulsatile DDS classified as- 1. Osmotic pressure release system a.capsule/ tablet composed of large nu.of pellets b. PORT (programmable oral release technology) 2. Reservoir system with rupturable coatings a. Time controlled explosion system (TCES) b. Pulsatile release tablet/compression/press-coated

tablet 3. Reservoir system with swellable/soluble/erodible

coating a. Press-coated/ multilayered tablet b. Hydrophilic sandwich capsule c. Time clock system d. Chronotropic system 4. Capsular system with polymeric plugs (Pulsincap)

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OSMOTIC PRESSURE RELEASE OSMOTIC PRESSURE RELEASE SYSTEMSYSTEM

a.Capsule/ tablet composed of a large number of pellet-

Each pellet has a core that contains therapeutic drug & water soluble osmotic agent. A water-permeable but insoluble polymer film encloses each core.

On exposure to water , it’s penetration into pellets, osmotic agents dissolves ,which causes pellets to swell & drug release.

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Capsule based systems: Single-unit systems are mostly developed in capsule form. The lag time is controlled by a plug, which gets pushed away  by swelling or erosion, and the drug is released as a “Pulse”  from the insoluble capsule body.

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-The plug material consist of insoluble but permeable & swellable polymers. ex. Polymethacrylate.-Erodible polymer- HPMC, PVA, PEO.-Congealed melted polymer- saturated polyglycolated glycerides, glyceryl mono-oleate-Enzymaticaly controlled erodible polymer-pectin, agar

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b. PORT (Programmable oral b. PORT (Programmable oral release technology)release technology)

System composed of gelatin capsule coated with SPM (ex. Cellulosic acetate) that contain immediate release drug ,an insoluble plug (ex. Lipids) & osmotic agent with second release of drug for timed release.

Upon contact with aqueous media, immediate release drug is delivered, water enter into capsule through SPM , which increase osmotic pressure & result in ejection of plug after lag time , following which second dose is delivered.

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2. Reservoir pulsatile with 2. Reservoir pulsatile with rupturable coatingsrupturable coatings

These system consist of 3 layers-1.Drug containing core .2.Pressure generating layer- effervescent excipients ( mixture of citric acid/ tartaric acid & sodium bicarbonate),

swelling agents or osmagents .3. Semipermeable polymer coating.Upon contact with GI fluids, water penetrates through

polymer coating & generate pressure due to effervescence, hydration of swelling polymer or osmosis, then ruptures polymer coating leading to rapid drug release.

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Examples of rupturable Examples of rupturable systemssystems

a. Time controlled explosion system (TCES)

B. Pulsatile release tablet (PRT)/ compression/press-coated tablet.

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a. Time controlled explosion system (TCES)

It has 4 layered spherical pellet structure, consist of inert core surrounded by a layered of drug , a swelling agent & water insoluble polymer membrane made up of ethylcellulose.

It is characterised by rapid drug release with programmed lag time .

When water penetrates through polymer membrane ,swelling agent expands, leading to destruction of membrane with subsequent drug release.

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Time controlled explosion Time controlled explosion system system

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B. Pulsatile release tablet (PRT)/ compression / press-coated tablet

It has core tablet containing a large amount of disintigrant together with active ingredient which is press-coated with outer shell of ethylcellulose that controls water penetration.

When PRT administrated orally, water penetrates through outer shell depending on thickness & composition of coating, disintegrant swells & collapses the outer shell due to high swelling pressure to release the contents as a pulse.

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Press-coated pulsatile drug delivery systems:

1.Press-coated pulsatile drug delivery systems can be used to protect hygroscopic, light-sensitive, oxygen labile or acid-labile drugs.2. relatively simple and cheap.3.These systems can involve direct compression of both the core and the coat. 4. Materials Such as hydrophobic, hydrophilic can be used in press-coated pulsatile drug delivery system.5. involve compression which is easy on laboratory scale.6. Press-coated pulsatile drug delivery formulations can be used to separate incompatible drugs from each other or to achieve sustained release.

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3. Reservoir system with 3. Reservoir system with swellable/soluble/erodible swellable/soluble/erodible

coatingcoating

In this system barrier swells, erodes / dissolves after a specific lag period & drug is subsequently released rapidly.

Lag time depends on thickness of coating layer.Examples – a. Press-coated / multilayered tablets b. Hydrophilic sandwich (HS) capsule c. Time clock system d. Chronotropic system

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a. Press-coated / multilayered tablets

Press-coated system based on swelling, disintegration or erosion mechanism for pulsatile drug delivery.

A release pattern with two pulses obtained from a three layered tablet conatining two drug containing layers separated by a drug free gellable polymeric barrier layer.

- initial rapid release drug layer - drug-free gellable polymeric barrier layer - second pulse generating drug layer - impermeable ethylcellulose layer

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Multilayered tabletMultilayered tablet

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b. Hydrophilic sandwich (HS) capsule

Based on a capsule- within a capsule, in which the inter-capsular space is filled with a layer of hydrophilic polymer (HPMC) .

This effectively creates a hydrophilic sandwich between the two gelatin capsules.

When outer capsules dissolves, sandwich of HPMC forms a gel barrier layer & cause drug release.

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c. Time clock system

Is made up of a solid dosage form, coated with a hydrophobic surfactant layer to which a hydrosoluble polymer is added to improve adhesion to the core.

The outer layer redisperses in aqueous environment in a time proportional to the thickness of film.

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d. Chronotropic system

Consist of drug containing core coated with high viscosity HPMC which is responsible for a lag phase in onset of release.The lag time is controlled by the thickness

and the viscosity grades of HPMC. The system is suitable for both tablets and capsules

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4. Capsular pulsatile system with 4. Capsular pulsatile system with polymeric plugspolymeric plugs

Example of this system is pulsincap—consist of capsule with water soluble cap, an insoluble body filled with drug & sealed with a hydrogel plug .

The length of plug decides lag time.On administration, soluble cap dissolves thereby

allowing the hydrogel plug to swell & expandAfter a predetermined lag time, it is swollen to an

extent that it is ejected from capsule body thereby releasing the drug.

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PULSINCAPPULSINCAP

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The plug material consist of insoluble but permeable & swellable polymers.

ex. Polymethacrylate.Erodible polymer- HPMC, PVA, PEO.Congealed melted polymer- saturated

polyglycolated glycerides, glyceryl mono-oleate

Enzymaticaly controlled erodible polymer-pectin, agar

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Marketed technology of Marketed technology of PDDSPDDS

Technology

Mechanism

Brand name & dosage form

API Disease

pulsincapTM

Rupturable system

Pulsincap TM

Dofetilide Hypertension

OROS Osmotic mechanism

Covera- HS, XL tablet

Verapamil HCL

Hypertension

ADVANTAGES OF PULSATILE DRUG DELIVERY SYSTEM:1. Extended daytime or nighttime activity2. Reduced side effects3. Reduced dosage frequency4. Reduction in dose size5. Improved patient compliance6. Drug adapts to suit circadian rhythms of body functions or diseases.7. Drug targeting to specific site 8. Protection of mucosa from irritating drugs.9. Drug loss is prevented by extensive first pass metabolism .10. Patient comfort and compliance: Oral drug delivery is the most common and convenient for patients, and a reduction in dosing frequency enhances compliance. 105

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EVALUATION OF PDDSEVALUATION OF PDDS Weight variation Thickness Hardness Friability Wetting time Drug content In-vitro dissolution method

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RS