madvancedrugdeliverysystem-180112024821.ppt

ADDS

1. Advanced Drug Delivery
Systems

2. The term “drug delivery systems” refers to the technology
utilized to present the drug to the desired body site for
drug release and absorption. The first drug delivery
system developed was the syringe, invented in 1855,
used to deliver medicine by injection. The modern
transdermal patch is an example of advanced drug
delivery system.
The goal of any drug delivery system is to provide a
therapeutic amount of drug to the proper site in the body
to promptly achieve and then maintain the desired drug
concentration.
This idealized objective points to the two aspects most
important to the drug delivery, namely:
*Spatial placement: relates to targeting of a drug to a
specific organ or tissue.
*Temporal delivery of a drug: refers to controlling the
rate of drug delivery to the target tissue.

3. Dosage Forms
There are numerous dosage form into which a drug substance
can be incorporated for the convenient and efficacious treatment
of a disease. Dosage forms can be designed for administration by
all possible delivery routes to maximize therapeutic response.
Dosage Forms Available For Different Administration Routs:
Oral- Solutions, syrups, elixirs, suspensions, emulsions,
gels, powders, granules, capsules, tablets.
Topical- Ointments, creams, pastes, lotions, gels, solutions,
topical aerosols.
Parenteral- Injections (solutions, suspensions, emulsions forms),
implants, irrigation and dialysis solutions.
Rectal- Suppositories, ointments, creams, solutions, powders.
Lungs- Aerosols (solutions, suspensions, emulsions, powder
forms), inhalation, sprays, gases.
Nasal- Solutions, inhalations.
Eye- Solutions, ointments.
Ear- Solutions, suspensions, ointments.

4. Conventional Dosage Form or Immediate –Release
Dosage Form
Conventional / Immediate –release dosage form is a dosage form
which is formulated / designed to give rapid and complete release
of the drug contained therein immediately after administration.
Kinetic scheme for the extra vascular administration the
conventional dosage form of a drug that follows one –
compartment open model for disposition:
Dosage
Form
Absorption Pool Body Compartment
Urine
Drug
Release
K
r
Absorption
( INPUT )
Elimination
( OUTPUT )
K
a
K
e
Kr, Ka and Ke : first order rate constants for drug release, absorption and overall elimination
respectively.

5. Immediate release from a convenient dosage form implies that
Kr >>> Ka. This means that absorption of a drug across a
biological membrane (e.g. GI epithelium) is the rate–timing
step in delivery of the drug to the body compartment.
For non–immediate–release dosage forms Kr <<< Ka.
i.e. release of drug from the dosage form is the rate limiting
step. Therefore the above scheme reduces to the following:
Dosage
Form
Body Compartment
Urine
Drug
Release
K
r
Elimination
K
e
Essentially,theabsorptivephaseofthekineticscheme
becomesinsignificantcomparedtothedrugrelease.Thusthe
efforttodevelopanon–immediate–releasedosageformmust
beprimarilydirectedatalteringthereleaseratebyaffectingthe
valueofKr.

6. Typical drug blood level vs. time curve / profile for
extra vascular administration of a single dose of the
conventional dosage form of a drug following one –
compartment open model for disposition:
MTC /
MSC
IV rout
Absorption
phase
Ineffective
range
MEC
Therapeutic
range
Rate of drug input
= Rate of drug output
Toxic range
Time

7. Typical drug blood level –time profile for multiple dosage
(non–immediate–release) regimen (equal doses of the
drug at fixed intervals) of a conventional dosage form:
A) For time intervals allowing complete elimination of the
previous dose: A series of isolatedsingle dose profiles
are obtained
MSC
MEC
Dose
Time
Dose Dose

8. B) For the dosing time intervals shorter than the time required
for complete elimination of the previous dose:
MSC
MEC
Time
D DD D D D D D
At the start of the multiple dosage regimen, the blood levels of drug tends
to increase in successive doses. But the rate of drug elimination will
increase as the average blood level of drug rises (first order kinetics) and a
situation is eventually reached when the overall rate of elimination of drug
becomes equal to the overall rate of supply. This situation is called “Steady
State”.
For a drug administered at equal time intervals, the time required
for the average blood levels to reach the 95% of the steady state value is
4.3 times the biological half–life (t½) of the drug. The corresponding figure
for 99% is 6.6 times.

9. Advantages of Conventional Dosage Form:
1. Per unit cost of conventional dosage form is less
than non-immediate release dosage form.
2. More flexibility for the physician for adjusting
dosage form in conventional dosage form.
3. Conventional dosage form can accommodate the
patient variation.
4. No problems with drug having too small half life.
5. Potent drugs can’t be formulated as sustained
release dosage form.

10. Limitations of Conventional Drug Therapy:
1.Unable to maintain therapeutic blood level for a prolonged
period of time.
2. Fluctuation of blood level over successive dosing intervals
(giving peak and valley pattern).
3. Risk of over medication or under-medication because of
drug blood level fluctuation.
4. Require frequent dosingPatient inconvenience + Poor
patient complianceTherapeutic failure / Inefficiency.
5. No therapeutic action during overnight no dose period
Risk of symptom break through in chronic disease.
6. Total amount of drug required is higher over the entire
course of therapy. (compared to SRDF)
7. Local/systemic side effect + overall health care cost is high.

11. Non-Immediate Release Dosage Form
Non-immediate release dosage form is those which do not
release whole amount of drugs contained, immediately after
administration.
Why Non-Immediate Release Dosage Form?
a) Delayed release of an immediate release unit. Ex: Enteric
coated tablet or capsule.
b) Repetitive intermittent release of two or more immediate
release unit incorporated into a single dosage form. Ex:
Repeat action tablet or capsule.
***Although a repeat action dosage form exhibits the same
“peak and valley” pattern as associated with conventional
dosage forms, but it improves patient compliance by reducing
dosing frequency.

12. Types of Non-Immediate Release
Dosage Form :
1. Delayed release dosage form
2. Sustained release dosage form
a) Control release
b) Prolonged release
3. Site specific release dosage form
4. Receptor release dosage form

13. Site–Specific Release and Receptor–
Release Dosage Forms
Site–specific and receptor release dosage
forms offer targeted delivery of a drug directly
to a certain biological location.
In case of site–specific release dosage
forms, the target is the specific receptor for
the drug within an organ or tissue.

14. Sustained Release Dosage
Forms
Sustained release dosage
forms are those dosage forms
which are designed to release drug
continuously at sufficiently slow or
controlled rate over an extended
period of time to provide prolonged
therapeutic effect.
In case of oral dosage forms, this
period is usually measured in
hours. But in case of injectable
dosage forms, the period may
range from days to months or even
years.

15. Sustained release dosage forms can further be
categorized as:
a)ControlledreleaseDosageforms:Thecontrolled
releasesystemistodeliveraconstantsupplyofthe
activeingredient,usuallyatazero-orderrate,by
continuouslyreleasing,foracertainperiodoftime,
anamountofthedrugequivalenttotheeliminatedby
thebody.AnidealControlleddrugdeliverysystemis
theone,whichdeliversthedrugsatapredetermined
rate,locallyorsystematically,foraspecificperiodof
time.
b)Prolongedreleasedosageforms:whichcannot
maintainaconstantbloodlevel,butthebloodlevel
declinesatsuchasufficientlyslowratethatit
remainswithinthetherapeuticrangeforasatisfactory
prolongedperiodoftime.

16. c)Repeatactionpreparation:Adoseofthedrug
initiallyisreleasedimmediatelyafteradministration,
whichisusuallyequivalenttoasingledoseofthe
conventionaldrugformulation.Afteracertainperiod
oftime,asecondsingledoseisreleased.Insome
preparation,athirdsingledoseisreleasedaftera
certaintimehaselapsed,followingtheseconddose.
Advantage:
Itprovidestheconvenienceofsupplyingadditional
Doseordoseswithouttheneedofreadministration.
Disadvantage:
That the blood levels still exhibit the “Peak and
valley” characteristic of conventional intermittent
drug therapy.

17. Extended-Release formulation:
Extended-Release formulations are usually designed to reduce
dose frequency and maintain relatively constant or flat plasma
drug concentration. This helps avoid the side effects associated
with high concentration.
Delayed release preparations:
Thedrugisreleasedatalatertimeafteradministration.The
delayedactionisachievedbytheincorporationofaspecialcoat,
suchasentericcoating,orothertimebarrierssuchasthe
formaldehydetreatmentofsoftandhardgelatincapsules.The
purposesofsuchpreparationsaretopreventsideeffectsrelatedto
thedrugpresenceinthestomach,protectthedrugfrom
degradationinthehighlyacidicpHofthegastricfluid.

18. Site specific targeting:
These systems refer to targeting of a drug directly to a certain
biological location. In this case the target is adjacent to or in the
diseased organ or tissue.
Receptor targeting:
Thesesystemsrefertotargetingofadrugdirectlytoacertain
biologicallocation.Inthiscasethetargetistheparticularreceptorfor
adrugwithinorganortissue.Sitespecifictargetingandreceptor
targetingsystemssatisfythespatialaspectofdrugdeliveryandare
alsoconsideredtobecontrolleddrugdeliverysystems.

19. Time (hrs)
MSC
MEC
A
B
Fig: The blood level–time profile of (A) Controlled–
release (B) Prolonged–release dosage form

20. Advantages of Controlled Release Drug Delivery System.
1) Therapeutic advantage: Reduction in drug plasma level fluctuation,
maintenance of a steady plasma level of the drug over a prolonged time period,
ideally simulating an intravenous infusion of a drug.
2) Reduction in adverse side effects and improvement in tolerability: Drug
plasma levels are maintained within a narrow window with no sharp peaks and
with AUC of plasma concentration Vs time curve comparable with total AUC
from multiple dosing with immediate release dosage form.
3) Patient comfort and compliance: Oral drug delivery is the most common and
convenient for patient and a reduction in dosing frequency enhances compliance.
4) Reduction in Health care cost: The total cost of therapy of the controlled
release product could be comparable or lower than the immediate release product
with reduction in side effects. The overall expense in disease management also
would be reduced. This greatly reduces the possibility of side effects, as the scale
of side effects increases as we approach the maximum safe concentration.
5) Avoid night time dosing: It also good for patients to avoid the at night time.

21. DISADVANTAGES [9]
1) Dose dumping:Dose dumping is a phenomenon whereby relatively large quantity of
drug in a controlled release formulation is rapidly released, introducing potentially toxic
quantity of the drug into systemic circulation. Dose dumping can lead to fatalities in case
of potent drugs, which have a narrow therapeutic index.
2) Less flexibility in accurate dose adjustment: In conventional dosage forms, dose
adjustments are much simpler e.g. tablet can be divided into two fractions. In case of
controlled release dosage forms, this appears to be much more complicated. Controlled
release property may get lost, if dosage form is fractured.
3) Poor In-vitro In-vivo correlation: In controlled release dosage form, the rate of drug
release is deliberately reduced to achieve drug release possibly over a large region of
gastrointestinal tract. Here the so-called ‘absorption window’ becomes important and may
give rise to unsatisfactory drug absorption in-vivo despite excellent in-vitro release
characteristics.
4) Increased potential for first pass clearance: Hepatic clearance is a saturable process.
After oral dosing, the drug reaches the liver via portal vein. The concentration of drug
reaching the liver dictates the amount metabolized. Higher the drug concentration, greater
is the amount required for saturating an enzyme surface in the liver.

22. Conversely,smallertheconcentrationfoundwiththecontrolledreleaseanda
sustainedreleasedosageform,lesseristhepossibilityofsaturatingtheenzyme
surface.Thepossibilityofreduceddrugavailabilityduetothefirstpass
metabolismisthereforegreaterwithcontrolledreleaseandsustainedreleased
formulationthanwithconventionaldosageform.
5) Patient variation: The time period required for absorption of drug released
from the dosage form may vary among individuals. Co-administration of other
drugs, presence or absence of food and residence time in gastrointestinal tract is
different among patients. This also gives rise to variation in clinical response
among the patients.
6) Administration of controlled release medication does not permit prompt
termination of therapy. Immediate changes in drug levels during therapy, such as
might be encountered if significant adverse effects are noted, can not be
accommodated.
7) There is danger of an ineffective action or even absence of it if the therapeutic
substance is poorly absorbed from GIT.

23. 8) Therapeutic agents for which single dose exceeds 1 gm, the technical
process requirements may make the product very difficult or sometimes
impossible to prepare.
9) Therapeutic agents which absorbed by active transport are notgood
candidates for controlled release dosage form e. g. Riboflavin.
10) Economic factors must also be taken into account, since more costly
processes and equipments are involved in manufacturing of many controlled
release dosage forms.

24. While selecting a drug candidate for sustained release system we must
be careful. Drugs having fallowing characteristics are not suitable for
sustained release systems:
1. Those which are not effectively absorbed in the lower intestine
2. Those having short biological half-lives (<1hr) e.g. Furosemide
3. Those having long biological half-lives (>12hrs) e.g. diazepam
4. Those for whom large dose is required e.g. sulphonamides
5. Those with low therapeutic indices e.g. Phenobarbital
6. Those for which no clear advantage of sustained release system e.g.
griseofulvin.
7. Those with extensive first pass metabolism.
8. Those candidates with low solubility and/or active absorption

25. Criteria of a Drug Required for Designing as Sustained
Released Dosage Form:
•They exhibits neither very slow nor very fast
rates (t½<2hrs) of absorption and excretion.
[Drugs having biological half lives of between 4
& 6 hours make good candidates in sustained –
release formulations.]
•They are uniformly absorbedfrom the GIT.
•They are administered in relatively low dose.
•They are used in the treatment of chronicrather
than acute conditions.
•They possess a good margin of safety.
[Accidental dose dumping from potent drugs
may be strongly hazardous.]

26. Drug properties influencing the dosage form: The design of a
controlled release system depends on various factors such as the
route of delivery, the type of drug delivery system, the disease being
treated, the length of therapy, and the properties of the drug. Most
important factor is properties of the drug that are as follows.
A) Physicochemical properties:
1) Aqueous solubility and pKa: Absorption of poorly soluble drugs
is often dissolution rate-limited. Such drugs do not require any
further control over their dissolution rate and thus may not seem to
be good candidates for oral controlled release formulations.
Controlled release formulations of such drugs may be aimed at
making their dissolution more uniform rather than reducing it.

27. 2) Partition coefficient: Drugs that are very lipid soluble or very
water-soluble i.e., extremes in partition coefficient, will
demonstrate either low flux into the tissues or rapid flux followed
by accumulation in tissues. Both cases are undesirable for
sustained release system.
3) Stability of the drug: Since most oral controlled release
systems are designed to release their contents over much of the
length of GI tract, drugs that are unstable in the environment of the
intestine might be difficult to formulate into prolonged release
system.
4) Size of the dose: For drugs with an elimination half-life of less
than 2 hours as well as those administered in large dosages, a
controlled release dosage form may need to carry a prohibitively
large quantity of drug.

28. 5)Molecularsizeanddiffusivity:Inadditiontodiffusionthrough
avarietyofbiologicalmembranes,drugsinmanysustainedrelease
systemsmustdiffusethrougharatecontrollingmembraneor
matrix.Theabilityofdrugtopassthroughmembranes,itssocalled
diffusivity,isafunctionofitsmolecularsize(ormolecularweight).
Animportantinfluenceuponthevalueofdiffusivity,D,inpolymers
isthemolecularsizeofthediffusingspecies.ThevalueofDthusis
relatedtothesizeandshapeofthecavitiesaswellassizeandshape
ofthedrugs.Generally,thevaluesofdiffusioncoefficientfor
intermediatemolecularweightdrugsi.e.,150-400,throughflexible
polymersrangefrom10-6to10-9cm2/sec,withvaluesontheorder
of10-8beingmostcommon.Fordrugswithmolecularweight
greaterthan500,thediffusioncoefficientsinmanypolymers
frequentlyaresosmallthattheyaredifficulttoquantify,i.e.,less
than10-12cm2/sec.Thushighmolecularweightofdrugshouldbe
expectedtodisplayveryslowreleasekineticsinsustainedrelease
deviceswherediffusionthroughpolymericmembrane
ormatrixisthereleasemechanism.

29. B)Biologicalproperties:
1) Absorption: Slowly absorbed drugs or the drugs absorbed with
a variable absorption rate are poorcandidates for a controlled
release system. Water-soluble but poorly absorbed potent
drugs and those absorbed by carrier mediated transport
processes or absorbed through window are poor candidates for
controlled release system.
2)Metabolism:Drugmetabolismcanresultineitherinactivation
ofanactivedrugorconversionofaninactivedrugtoanactive
metabolite.Theprocessofmetabolismcantakeplaceinvarietyof
tissuesbuttheorganmainlyresponsibleformetabolismisliveras
itcontainsvarietyofenzymesystemsandthusgreatestmetabolic
alterationofadrugtakesplaceafteritsabsorptionintothe
systemiccirculation.Thusthemetabolicpatternofadrugmay
influencethechoiceoftherouteofadministration

30. Therearetwofactorsassociatedwithmetabolismthatsignificantly
limitcontrolledreleaseproductdesign.First,ifadrugiscapableof
eitherinducingorinhibitingenzymesynthesisitwillbedifficultto
maintainuniformbloodlevelsofdruguponchronicadministration.
Second,ifthedrugundergoesintestinal(orothertissue)metabolism
orhepaticfirstpassmetabolism,thisalsowillresultinfluctuating
drugbloodlevels.Examplesofdrugsthatundergointestinal
metabolismuponoraladministrationarehydralazine,
salicylamide,nitroglycerin,isoproterenol,chlorpromazine,and
levodopa.Examplesofdrugsthatundergohepaticfirstpass
metabolismare;propoxyphene,nortriptyline,phenacetin,
propranololandlidocaine.Successfulcontrolledreleaseproducts
fordrugsthatareextensivelymetabolizedcanbegeneratedaslong
asthelocation,rateandextentandmetabolismareknownandthe
rateconstant(s)arenottoolarge.Itcanbeassumedthatacontrolled
releaseproductcanbedevelopedaslongasthemetabolismremains
predictable.

31. 3)EliminationorBiologicalhalf-life:Therateofeliminationof
drugisdescribedquantitativelybyitsbiologicalhalf-life.The
biologicalhalf-lifeandhencethedurationofactionofadrugplays
amajorroleinconsideringadrugforcontrolledreleasesystems.
Drugswithshorthalf-lifeandhighdoseimposeaconstraint
becauseofthedosesizeneededandthosewithlonghalf-livesare
inherentlycontrolled.
4)SafetyconsiderationsandSideeffects:Forcertaindrugsthe
incidenceofsideeffectsisbelievedtobeafunctionofplasma
concentration.Acontrolledreleasesystemcan,attimes,minimize
sideeffectsforaparticulardrugbycontrollingitsplasma
concentrationandusinglesstotaldrugoverthetimecourseof
therapy.Themostwidelyusedmeasureofthemarginofsafetyofa
drugisitstherapeuticindex(TI),whichisdefinedas
TI=TD50/ED50

32. Where,TD50ismediantoxicdose&ED50ismedianeffective
dose.
In general, larger the value of TI, safer is the drug. Drugs with very
small values of TI usually are poor candidates for formulation into
CR products primarily because of technological limitations of
precise control over release rates. A drug is considered to be
relatively safe if its TI value exceeds 10.
5)Proteinbinding:Thecharacteristicsofproteinbindingbya
drugcanplayasignificantroleinitstherapeuticeffect,regardless
ofthetypeofdosageform.Extensivebindingtoplasmaproteins
willbeevidencedbyalonghalf-lifeofeliminationforthedrug,
andsuchdrugsgenerallydonotrequireasustainedreleasedosage
form.

33. 6)Diseasestate:Diseasestateisanimportantfactorinconsidering
adrugforcontrolledreleasesystem.Insomeinstancesbetter
managementofthediseasecanbeachievedbyformulatingthedrug
ascontrolledreleasesystem.Forexample,incaseofrheumatoid
arthritis,sustainedreleaseformofaspirinwouldprovidedesired
drugbloodlevels,particularlythroughoutthenight,thusrelieving
morningstiffness.Otherexamplesincludenitroglycerininthe
managementofanginapectorisandbelladonnaalkaloidsand
syntheticanti-cholinergicsinthetreatmentofpepticulcers.
7)Circadianrhythm:Manybiologicalparameterslikeliver
enzymeactivity,bloodpressure,intraocularpressureandsome
diseasestateslikeasthma,acutemyocardialinsufficiency,and
epilepticseizureshavebeenshowntobeinfluencedbycircadian
rhythm.Hencetheresponsetocertaindrugslikedigitalis
glycosides,diuretics,amphetamines, barbiturates,
carbamazepine,ethylalcohol,andchlordiazepoxidedisplaytime
dependentnature.

34. Formulation Methods for Oral SRDF
Commonmethodsusedinthedesignoforally
administeredSDRFincludethreegeneralprinciples:
A.Barrierprinciple
1.Reservoir systems or devices
2.Osmotic Pumps or Systems
B. Embedded matrix principle
1. Matrix Systems or Devices
C. Physico-chemical Modification
1. Ion–Exchange Resin Complexes
2. Other Drug Complexes
3. Drug Adsorbates
4. Prodrugs

35. 1. Reservoir Systems or Devices (Barrier Principle)
These systems or devices consists of a core of drug
material is surrounded by a coat of retardant
barrier (polymeric membrane). The layer of
retardant material separates the drug and the
elution medium.
Drug
Reservoir
C
B
AD
A

36. Mechanism of drug release from a reservoir device:
The release of drug from the reservoir can occur by four
mechanisms:
•i.Diffusion of drug present in the reservoir as a solution or
suspension through the barrier. Here the barrier is
impermeable to the elution medium. For the case of
solution , the release is first order. For suspensions,
release is zero order if membrane diffusion is slower than
dissolution. This principle has been successfully applied
in the development of ophthalmic , intra–vaginal and
transdermalcontrolled release devices.
•ii.Penetration / permeation of elution medium through the
barrier occurs followed by dissolution of the drug in the
reservoir. Later diffusion of the dissolved drug through the
barrier results in availability of drug for absorption.
•iii.Timed erosion of the barrier after sufficient moisture /
elution medium has permeated the membrane.
•IV.Rupture of the barrier after sufficient moisture has
permeated the membrane.

37. Common methods employed to develop
reservoir systems/devices Include:
A. Coating
B. Microencapsulation
A. Coating: A number of reservoir devices
can be prepared by applying the
technology of coating which includes:
a. Mixed release coated granules/ pellets
b. Uniform release coated granules/ pellets
c. Microdialysis cells
d. Drug coat of retardant material over
placebo pellets

38. a. Mixed release coated granules
Drug pellets/ granules are divided into 3 to 4
groups. One group is left uncoated to provide
the initial loading dose and the other groups of
pellets/ granules are coated to different
thicknesses. The various groups are mixed
together and placed in capsules or compressed
into tablets.
Mechanism of drug release: Moisture
penetration through the barrier→ swelling of the
core → rupture of the barrier.

39. The retardant materials used for coating
includes:
-Combination of waxes, fatty acids, alcohols and
esters.
-Enteric materials such as cellulose acetate
phthalate and formalized gelatin.
-Mixture of solid hydroxylated lipids such as
hydrogenated castor oil or glyceryl trihydroxy-
stearate mixed with modified celluloses.
Examples of drugs designed as SRDF by this
method include Erythromycin, Pancreatin etc.

40. b.Uniformreleasecoatedgranules/pellets
Inthismethod,druggranules/pelletsare
uniformlycoatedbyaretardantmaterialthat
slowlyreleasedrugoversufficientlyprolonged
periodoftime.
Retardantmaterialsemployedforthispurpose
includehydrolyzedstyrenemaleicacid
copolymer,partiallyhydrogenatedcottonseedoil
etc.
ExamplesofdrugsdesignedasSRDFbythis
techniqueincludeCrystalsofascorbicacid,
Methylprednisoloneetc.

41. c.Microdialysiscells
Drug pellets are coated with a mixture of ethyl
cellulose (a water insoluble and pH insensitive
polymer) and sodium chloride particles or some other
water soluble materials (e.g. polyethylene glycol).
Release mechanism: Ethyl cellulose when in contact
with GI fluid, the water soluble material will dissolve
and salt will leach out forming pores which acts as a
dialyticmembrane. The elution media then permeates
through dialyticmembrane causing dissolution of the
drug and the drug solution then diffuses through the
essentially intact membrane.
ExamplesofdrugsdesignedasSRDFbythis
techniqueareNitroglycerin,Propoxyphene,Aspirinetc.

42. d. Drug coat of retardant material over placebo
pellets
The drug is suspended in the coating of retardant
material applied onto placebo pellets. The
prepared pellets are placed in capsules. The drug
is released by erosion or rupture of the barrier.
Retardant materials employed include
polyethylene glycol, modified ethyl cellulose,
shellac or cellulose acetate phthalate.
Example of drugs designed as SRDF by this
technique is theophylline.

43. B. Microencapsulation:
Microencapsulation means encapsulation of drug
material in microscopic size particles of a ‘wall
forming’ material.
Microencapsulation is a process by which solids,
liquids or even gases may be encapsulated into
microparticles whose size ranges from several tenths
of 1µ to 5000µ in size through the formation of thin
coating of wall material around the substance being
encapsulated.
Retardant coating materials used are gelatin,
polyvinyl alcohol, ethyl-cellulose, polyvinyl chloride.
The most common method of microencapsulation is
coacervation. Other techniques like, spray drying.

44. Coacervation: In this technique, the prospective
wall–forming material e.g. gelatin, is dissolved in
water. The drug material to be microencapsulated is
added to the solution and the two–phase mixture is
thoroughly stirred until the drug material is broken up
to the desired particle size.
Then a solution of a second material (usually acacia)
is added which concentrates gelatin into tiny liquid
droplets called “coacervates” that encircle drug
particles.
The particles are coated to different thicknesses,
mixed together and compressed into tablets or
placed in capsules.
The drug is released by dissolution of coating
materials.

45. Applicationsofmicroencapsulation:
•Formaskingtest,(acetaminophentab)
•Toreducegastricirritation(KCl)
•Toseparatetheincompatibleingredients
(Aspirintab)
•Topreventvolatilization(menthol)
•Toprotectdrugsfrommoistureandoxidation
(vitApalmitate)
Disadvantages:
•Incompleteordiscontinuouscoating
•Inadequatestability
•Economiclimitations
Examples:Micro–K(KCl)

46. 2. Osmotic Systems / Pumps (Barrier Principle)
This is an example of membrane-controlled release
technology. These systems employ osmotic pressure as the
driving force to cause the release of drug. A constant release of
drug can be achieved if a constant osmotic pressure is
maintained and a few other features of the system are
controlled.
A number of osmotic pumps / systems have been designed by
pharmaceutical manufacturers including:
1. Oral Osmotic Systems
2. Push –Pull Osmotic System
3. Multi Directional Osmotic Drug Absorption System

47. Mechanism of Drug Release: GI fluid enter the
tablet core across the semi-permeable membrane →
dissolve drug→ creates an osmotic gradient across
the membrane →pumps the drug out through the
delivery orifices.
The rate of drug solution release is approximately
one to two drops per hour.

48. 1.MatrixDevices(EmbeddedPrinciple)
•Inthiscase,thedrugisdispersed(embedded)in
amatrixofretardantmaterial,whichmaybe
encapsulatedinparticulateformorcompressed
intotablets.Thedrugmaybeinsoluble(Network
model)orsoluble(Dispersionmodel)inthe
retardantmaterial.
Amongtheinnumerablemethodusedincontrolled
releasedrugfrompharmaceuticaldosageform,
thematrixsystemisthemostfrequentlyapplied;
it’sreleasesystemfordelayandcontrolofthe
releaseofthedrugthatisdissolvedordispersed
inaresistantsupportstodisintegration.

49. Fig. Network model (Drug is
insoluble in the retardant material)
Fig. Dispersion model (Drug is
soluble in the retardant material)

50. To define matrix, it is necessary to know the characters
that differentiate it from other controlled release
dosage forms. Hence the following must be
considered:
•The chemical nature of support (generally, the
support are formed by polymeric net)
•The physical state of drug (dispersed under
molecular or particulate form or both)
•The matrix shape and alteration in volume as a
function of time.
•The route of administration (oral administration
remains the most widely used but other route are
adaptable)
•The release kinetic model.

51. Types of matrix material/devices:
On the basis of the solubility of the materials matrix
devices can be classified into two:
1.Matrixmaybesoluble:Hydrophilicpolymers
2.Matrixmaybeinsoluble:
a.Insolublepolymermatrix(plasticmatrix)
b.Lipidmatrix
c.Insolublebutpotentiallyerodablematrix

52. 1.SolubleMatrix:(HydrophillicMatrix)
Drugcanbedispersedinsolublematrixanddrug
releasedependsonslowdissolutionofthematrixby
elutionmedia.Thisdeliverysystemisalsocalled
swellablesolublematrix.
Ingeneraltheycompriseacompressedmixtureof
drugsandwaterswellablehydrophilicpolymer.The
systemsarecapableofswelling,followedbygel
formation,erosionanddissolutioninaqueousmedia.
Hydratedmatrixlayeroncontactofwaterfurther
controlsthediffusionofwater.Whenouterlayeris
fullyhydrated,iterodesanddrugcontainedis
released.Thus,drugdiffusionandtableterosion
controlstherateofdrugrelease.

53. Hydrophilic materials: e.g. Hydroxy propyl
methyl cellulose, sodium CMC,
methylcellulose, Hydroxy ethyl cellulose.
Natural gums: Galactomannose (guargum),
chitosan, gum acacia, locust bean gum,
sodium alginate, karaya gum, pectins, xanthan
gum.
ExamplesofDrugs:
Sodiumdiclofenac
OramorphSRtablets(Morphinsulfate)

54. 2. Insoluble matrix
a.Plasticor“Skeleton”matrix:Theseareinsoluble
inertpolymerssuchaspolyethylene,polyvinyl
chloride,methylacrylate-methacylatecopolymer
andethylcellulose.Themixtureofdrugandground
polymermaybedirectlycompressedintotablets.
•Releasemechanism:Drugisslowlyreleasedfrom
theinertmatrixbydiffusionfollowingliquid
penetration.Ifchannelingagentisused,diffusion
occursthroughchannels.Releaseratecanbe
modifiedbychangesintheporosity(pore-forming
salts)andcompressionforceofthematrix.
Thisoccurswhenthematrixisinsolubleinwater,and
thedrugisinsolubleinthematrixbutsolubleinwater.

55. •b. Lipid matrix: These are also water insoluble
matrix. Here drug delivered by diffusion or by
surface erosion.
Releasemechanism:Inthismodel,itis
assumedthatdrugisreleasedbyprimarily
diffusionofdrugthroughthematrixand
secondarilypartitionbetweenmatrixandwater.
Thisoccurswhenthematrixisinsolublein
water,butthedrugissolubleinthematrixand
hasahighsolubilityinwater/elutionmedia.

56. c.Insolubleerodablematrix:Thismatrixiswater
insolublebutpotentiallyerodable.Thematrix
includeswaxes,lipidsandrelatedmaterials.
Examplesincludecarnaubawax,castorwax
(hydrogenatedcastoroil)andtriglycerides.
•Thedrugandadditivesaregenerallydepressedin
moltedwax,whichisthencongealed,granulated
andplacedintocapsulesandcompressedinto
tablets.Theloadingdoseisprovidedasuntreated
granulesorasanoutercore.
Releasemechanism:Inthismodel,itisassumed
thatsoliddrugdissolvesfromthesurfacelayerof
thedevicefirst;whenthislayercompletes
deliveringdrug,thenextlayerbeginstobe
depletedbydissolutionanddiffusionthroughthe
matrixtotheexternalsolution.

57. Factors influencing the drug release from
matrix
•Choice of matrix material.
•Amount of drug incorporated in the matrix.
•Viscosity of the hydrophilic material in aqueous
system at a fixed concentration.
•Drug: matrix ratio.
•Tablet hardness, porosity, and density variation.
•Tablet shape and size.
•Solubility of drug in aqueous phase.
•Surfactants and other additives.

58. Advantages of matrix devices
1. With proper control of the manufacturing process, reproducible
release profiles are possible. The variability associated with
them is slightly less than coated release form.
2. Structure allows an immediate release of small amount of
active principle, there is no risk of dose dumping.
3. Their capacity to incorporate active principle is large, which
suits them to delivery of large doses.
4. The manufacturing processes are notably simple. Tablet
formulation can be done via direct compression or by wet
granulation techniques.
5. Large variety of non-expensives gelling agents is approved for
oral use by the competent official organization.
6. The safety margin of high-potency drugs can be increased.
7. The drug release from hydrophilic matrices show a typical time
dependent profile i.e. decreased drug release with time
because of increased diffusion path length.

59. 4. Ion –Exchange Resin Complexes
Ion –exchange resins are water insoluble polymers
containing salt forming groups on the polymer chain.
Resins used are special grades of styrene / divinyl
benzene copolymers that contain substituted acidic
groups (carboxylic and sulfonic for cation
exchanges) or basic groups (quaternary ammonium
for anion exchanges).
Drug is bound to the resin by repeated exposure of
the resin to the drug in a chromatographic column or
by prolonged contact of the resin with the drug
solution.

60. For example, drug-resin salts may be prepared by percolation of
the sodium salt of the resin with a concentrated solution of a drug
hydrochloride salt. The following equation represents the drug
release in-vivo:
Resin –SO
3Na + Drug HCl → NaCl + Resin-SO
3. Drug H
Similarly drug-resinates are prepared by reaction of sodium salts
of acidic drugs with resin chloride.
Resin –NH
4Cl + Drug Na → NaCl + Resin-NH
4.Drug
The resin.drug complex is then washed with ion-free water and
dried. The resulting product can be encapsulated, tabletted or
suspended in ion-free vehicles.
Release in-vivo:
Resin –NH
4.Drug + NaCl (body fluid) → Drug Na + Resin-NH
4Cl

61. 5. Other Drug Complexes
Certain drug substances that are only slowly soluble in the body
fluids are inherently long acting (Griseofulvin).
Thus drugs that are, high water soluble may be bound to
suitable complexing agents to form complexes which are poorly
water soluble and consequently give sustained action.
The steps or mechanism involved in controlling the
release of drug from drug complexes in GI fluid can be
illustrated as follows:
Examples include:
Tannic acid complexes of basic drugs like amphetamine and
antihistamines.
Other complexing agents to prepare complexes of basic drugs
include polygalacturonic acid, algenic acid and arabogalactose
sulfate.
Dissolution Dissociation
DC . solid DC . solution D

62. 6. Drug Adsorbate
Drug adsorbates represent a special case of complex
formation in which the product is essentially insoluble.
Drug availability is determined only by the rate of dissociation
(desorption) and access of the adsorbent surface to water as
well as the effective surface area of the adsorbate.
The mechanism involved in controlling the release of drug from
adsorbates can be illustrated as follows:
The adsorbate, can be formulated as liquid suspensions,
tablets or capsules.
Desorption
AD. Solid D

63. 7. Prodrugs
Prodrugs are therapeutically inactive drug derivatives
that regenerate the parent drug in-vivoby enzymatic or non-
enzymatic hydrolysis.
The steps or mechanisms involved in controlling release of
drug from a prodrug can be depicted by the following scheme:
Desorption Absorption
PD. Solid PD. Solution PD. Plasma
Metabolism
D
Elimination

64. Conventional Drug Therapy
1. Rapid and complete release of
drug immediately after
administration.
2. Absorption is the rate-limiting
step (kr >>> ka).
3. Blood level fluctuates (Peak and
Valley).
4. There is risk of overmedication
or under medication at periods
of time.
5. Frequent dosing.
6. Patient non compliance.
Therapeutic inefficiency / failure.
7. Inconvenience of patient.
Sustained-Release Drug Therapy
1. Slow/controlled release of drug over
an extended period of time.
2. Drug release from the dosage form is
the rate-limiting step (ka >>> kr).
3. Constant blood level is maintained
over a prolonged period (Reduced
fluctuation).
4. Reliable therapy as the risk is
minimized.
5. Reduced frequency of dosing.
6. Improved patient compliance.
7. Enhanced patient convenience with
day-time and night-time medication.
Comparison between conventional and sustained-release drugs

65. 8. No therapeutic action during
overnight no dose period.
9. Risk of symptom breakthrough.
10. Incidence and severity of
untoward effects related to high
-peak plasma concentration .
11. More total dose over the entire
course of therapy.
12. More side effects.
13. Health care cost .
14. Permits prompt testing of
therapy.
15. Incidence of severity of GI side
effects due to dose dumping of
irritant drugs .
16. More flexibility for physician in
adjusting dosage required.
8. Maintains therapeutic action during
overnight no dose period.
9. Improved treatment of many chronic
diseases (minimizing symptom
breakthrough).
10. Incidence and severity of untoward
effects related to high –peak plasma
concentration .
11. Less total dose over the entire
course of therapy.
12. Minimize/eliminate incidence of
local/systemic side effects.
13. Health care cost .
14. Does not prompt.
15. Incidence of severity of GI side
effects due to dose dumping of irritant
drugs .
16. Less flexibility.

66. 17. Can accommodate abnormal
cases of disease safety offering
drug disposition etc.
18. Chance of at any site of GIT
(local irritation ).
19. No problems for drugs with too
short half lives.
20. Per unit cost is less. 
21.
17. Can not accommodate.
18. Chance of at any site of GIT (local
irritation).
19. Not suitable for drugs with too short
half lives, drugs needing specific
requirements for absorption from GIT.
20. Per unit cost is more. 
21.
Time Time