Ocdds by raghav modified

02/10/16 RAGHAVENDRA KUMAR
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GUIDED BY:
MR.A.KISHORE BABU SIR M.PHARM
ASSISTANT PROFESSER
DEPT.OF PhARmAcEuTIcS
A.m.REDDY mEmORIAL cOLEGE OF
PhARmAcY
PRESNTED BY :
RAGHAVENDRA KUMAR
GUNDA
(Y10MPH0621)

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DRUG:
It is a chemical agent intended for
cure, prevention, mitigation, treatment or
therapy for a disorder/disease
in human being and animal
DOSAGE FORM:
It is defined as the combination of
active drug component along with
non drug moieties
CONTROLLED RELEASE:
One which delivers the drug at a
pre-determined rate locally or systemically
For specified long period of time
SUSTAINED RELEASE:
The system of prolonged release either
Systemically or locally.
CONVENTIONAL RELEASE:
Immediate/Prompt release dosage forms

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The frequency of administration /dosing interval of any drug depends upon
HALF LIFE, MEAN RESIDENCE TIME(MRT), THERAPEUTIC INDEX
For conventional release the dosing interval much shorter than it’s halflife so following
limitations were observed
POOR PATIENT COMPLIANCE
PEAKVALLEY PDC VS TIME
FLUCTUATIONS IN DRUG LEVELS
OVER MEDICATION
MISSING OF DOSE
CSS IS DIFFICULT
FOR NARROW TI DRUGS
UNDER MEDICATION

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• Reduced potencies because of
partial degradation
• Toxic levels of administration
• Increase costs associated with
excess dosing
• Compliance issue due to
administration pain
Challenges in Oral Drug Delivery
Development of drug delivery system Delivering
a drug at therapeutically effective rate to desirable
site.
Modulation of GI transit time
Transportation of drug to target site.
Minimization of first pass elimination

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Why control drug delivery?
Goal of more sophisticated drug delivery
techniques
1.Deploy to a target site to limit side
effects
2.Shepard drugs through specific areas of
the body without degradation
3.Maintain a therapeutic drug level for
prolonged periods of time
4.Predictable controllable release rates
5.Reduce dosing frequent and increase
patient compliance
Toxicity level
Injection
Controlled release
Therapeutic Level
Time
As the cost and complexity of individual drug molecules has
risen the problems with the classical delivery strategies over
took their benefits.

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Hence there is a need to Develop a better, safer drugs with long half-life with larger
Therapeutic Index
Effective, safer use of existing drugs through Concepts& Techniques of
Controlled Release Drug Delivery System
To minimize the fluctuation in PDC
To attain feasibility for CR of drugs
Correlation in In-vivo In-vitro aspects& Models
To optimize the delivery of medication to achieve
good therapeutic response
The total amount of drug administered is sed
Some times Drug Interactions
also prolongs the release
Ex:probencid the
excretion of PENICILLIN
-

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REDUCTION IN DOSING FREQUNCY
SE FLUCTUATION IN CIRCULATING DRUG LEVEL
PATIENT COMPLIANCE
AVOIDANCE OF NIGH TIME DOSING
MORE UNIFORM EFFECT(PHARMACOLOGICAL)
REDUCTION IN GI IRRITATION AND OTHER RELATED SIDE EFECTS
IMPROVED EFFICACY/SAFETY RATIO
Continuous oral delivery of drugs at predictable & reproducible kinetics
for predetermined period throughout the course of GIT.

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Dose dumping.
Reduced potential for accurate dose adjustment.
Need of additional patient education.
Stability problem.
Poor Invivo-Invitro correlation
Poor systemic availability(depends upon GI residing time)
Increased potential for first pass clearance
High cost as compared individual
Drug reaches to liver via portal vein, higher the oral dose, greater possibility of saturating hepatic
metabolism. Smaller dose/ slow release from formulation less chance to saturate

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RATE CONTROLLED DRUG DELIVERY SYSTEM
RATE PRE PROGRAMMED
POLYMER MEMBRANE
PERMEATION CONTROL
MATRIX DIFFUSION
MICRO RESERVOIR PARTITIONED
ACTIVATION MODULATED
PHYSICAL
HYDRATION, IONTOPHORESIS,
SONOPHORESIS
HYDRODYNAMIC,VAPOUR,
OSMATIC PRESSURES
MAGNETIC
CHEMICAL
PH
ACTIVATED
HYDROLYSIS
IONIZATION
BIOCHEMICAL
ENZYME
ACTIVATED
BIOCHEMICAL
ACTIVATED
FEED BACK
REGULATED
SITE
TARGETTED
BIO EROSION BIO RESPONSIVE
EX: INSULIN

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History of Controlled Drug Delivery
 Wurster technique 1949
 Coacervation (liquid encapsulation) 1953
 Mircroencapsulation 1960’s
• 65% of all current drugs use some form of micro-
encapsulation
 Implants 1970’s
 Transdermal 1980’s
 Site directed systems 1990’s

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SOME SUBSTANCES AVAILABLE FOR CONTROLLED RELEASE ARE AS FOLLOWS
VITAMINS
MINERALS
HORMONES
DRUGS DRUGS
DIURETICS & CVS
DRUGS
ACETAZOLAMIDE,
ISOSORBIDE,
PAPVERINE
ANTIMICROBIAL
TETRACYCLIN
CNS
AMPHETAMINE,
CAFFEINE,
PHENOBARBITAL,
PROCHLORPERAZINE
GI
BELLADONNA
ALKALOIDS,
HYOSCINE, TRI
DIHEXETHYL
CHLORIDE
PYRIDO STIGMINE
RESPIRATORY
AMINOPHYLLINE
CPM, BPM

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COMPOUNDS THAT ARE UNSUITABLE FOR CONTROLLED RELEASE
DEPEND UPON ELEMINATION HALFLIFE AND DOSE i.e t1/2 < 2.0 hours, larger doses of api.
CHARACTERISTIC DRUGS
Not effectively absorbed in Lower
Intestine
IBUPROFEN, FERROUS SALTS
Adsorbed, excreted rapidly biological t
½< 1 hr
PENICILLIN-G,
FUROSEMIDE
Long biological t ½ > 12 hr DIAZEPAM, PHENYTOIN
Larger doses (> 1 gm) SULPHONAMIDES
Cumulative action& un desirable side
effects, drugs with low Therapeutic
Index
PHENOBARBITAL,
DIGOXIN
Precise dosage titrated to individuals ANTI-COAGULANTS, CARDIAC
GLYCOSIDES
No clear advantages for
CONTROLLED RELEASE
GRISEOFULVIN

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 Dissolution controlled release
 Diffusion controlled release
 Diffusion and dissolution controlled release
 Ion exchange resins
 pH independent formulations
 Osmotically controlled release
 Altered density formulations.

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16
Dissolution Definition:
 Solid substances solubilizes in a given
solvent.
 Mass transfer from solid to liquid.
 Rate determining step: Diffusion from solid
to liquid.
 Several theories to explain dissolution –
Diffusion layer theory (imp)
Surface renewal theory
Limited solvation theory.

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Dissolution-Controlled Systems
 Alternating layers of rate-controlling coats
 Group of beads with different coatings
• (Spansule, SmithKline Beecham)
• dC/dt = kd*A(Cs-C) = D/h*A(Cs-C)
• dC/dt=dissolution rate, kd=dissolution rate const
• D=diffusion coefficient, Cs=saturation solubility
• C=concentration of solute in bulk solution

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Types of Dissolution Controlled
Systems
Two types of dissolution-
controlled, pulsed delivery
systems
A: Single bead-type device
with alternating drug and rate
controlling layer
B: Beads containing drug
with differing thickness of
dissolving coats

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Bioerodible and Combination Diffusion and
Dissolution System
 Strictly speaking, therapeutic systems will never be dependent on
dissolution only or diffusion only.
 Bioerodibile devices, however, constitute a group of systems for which
mathematical descriptions of release is complex.
 The complexity of the system arises from the fact that, as the polymer
dissolves, the diffusion path length for the drug may change. this usually
results in a moving-boundary diffusion system.
 Zero-order release can occur only if surface erosion occurs and surface
area does not change with time.
 The inherent advantage of such a system is that the bioerodible property of
the matrix does not result in a ghost matrix.

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Representation of a
Bioerodible Matrix System
Drug is dispersed in the
matrix before release at
time = 0.
At time = t, partial
release by drug
diffusion or matrix
erosion has occurred

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Characteristics of Bioerodible Matrix
Systems
 Advantages
• all the advantages of matrix dissolution system
• removal from implant sites is not necessary
 Disadvantages
• difficult to control kinetics owing to multiple processes
of release
• potential toxicity of degraded polymer

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Bioerodible and Biodegradable Controlled
Release Polymers
These polymers are designed to degrade within the
body
• Polylactides (PLA)
• Polyglycolides (PGA)
• Polylactide-co-glycolides (PLGA)
• Polyanhydrides
• Polyorthoesters

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Degradation of Biodegradable
Polymers
These materials degrade within the body as a result of natural
biological processes, eliminating the need to remove a drug delivery
system after release of the active agent has been completed
 Bulk hydrolysis - the polymer degrades in a fairly uniform manner
throughout the matrix
 Surface Eroding - degradation occurs only at the surface of the
polymer, resulting in a release rate that is proportional to the surface
area of the drug delivery system

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Biodegradable Polymers
Drug delivery from
(a) bulk-eroding and
(b) surface-eroding
biodegradable systems.

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Noyes Whitney Equation
dc/dt = kD.A (Cs – C )
dc/dt = D/h A. (Cs – C)
dc/dt = Dissolution rate.
k= Dissolution rate constant (1st
order).
D = Diffusion coefficient/diffusivity
Cs = Saturation/ maximum drug solubility.
C =Con. Of drug in bulk solution.
Cs-C=concentration gradient.
h =Thickness of diffusion layer.

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Matrix Type
 Also called as Monolith dissolution
controlled system.
 Controlled dissolution by:
1.Altering porosity of tablet.
2.Decreasing its wettebility.
3.Dissolving at slower rate.
 First order drug release.
 Drug release determined by
dissolution rate of polymer.
 Examples: Dimetane extencaps,
Dimetapp extentabs.
Soluble drug
Slowly
dissolving
matrix

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Matrix Dissolution Products
Product Active Ingred. Manufacturer
Dimetapp
Extentabs
Bromphen. Robins
Donnantal
Extentabs
..... Robins
Quinidex
Extentabs
Quinidine Robins
Tenuate Dospan Diethylprop. Merrel

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Encapsulation
 Called as Coating dissolution
controlled system.
 Dissolution rate of coat depends
upon stability & thickness of
coating.
 Masks
colour,odour,taste,minimising GI
irritation.
 One of the microencapsulation
method is used.
 Examples: Ornade spansules,
Chlortrimeton Repetabs
Soluble dru
Slowly
dissolving or
erodible coat

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Encapsulated Dissolution
Products
Product Active Ingred Manufacturer
Ornade Spansules PPA, chlorphen. SKB
Contact PPA, others SKB
Diamox Sequels Acetazolamide Lederle(WA)
Chlor-Trimeton
Repetabs
Chlorphen. Schering

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Diffusion
 Major process for absorption.
 No energy required.
 Drug molecules diffuse from a region of higher concentration to
lower concentration until equilibrium is attainded.
 Directly proportional to the concentration gradient across the
membrane.

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Matrix Diffusion Types
 Rigid Matrix Diffusion
Materials used are insoluble plastics such as PVP & fatty
acids.
 Swellable Matrix Diffusion
1. Also called as Glassy hydrogels.Popular for sustaining
the release of highly water soluble drugs.
2. Materials used are hydrophilic gums.
Examples : Natural- Guar gum,Tragacanth.
Semisynthetic -HPMC,CMC,Xanthum
gum.
Synthetic -Polyacrilamides.
Examples: Glucotrol XL, Procardia XL

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Matrix system
Rate controlling
step:
Diffusion of dissolved
drug in matrix.

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Matrix Diffusional Products
Product Manufacturer
Procan SR Parke Davis
Desoxyn Abbot
Choledyl SA Parke Davis

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Higuchi Equation
Q = DE/T (2A.E Cs)Cs.t)1/2
Where ,
Q=amt of drug release per unit surface area at time t.
D=diffusion coefficient of drug in the release medium.
E=porosity of matrix.
Cs=solubility of drug in release medium.
T=tortuosity of matrix.
A=concentration of drug present in matrix per unit
volume.

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Reservoir System
 Also called as Laminated matrix device.
 Hollow system containing an inner core surrounded
in water insoluble membrane.
 Polymer can be applied by coating or micro
encapsulation.
 Rate controlling mechanism - partitioning into
membrane with subsequent release into surrounding
fluid by diffusion.
 Commonly used polymers - HPC, ethyl cellulose &
polyvinyl acetate.
 Examples: Nico-400, Nitro-Bid

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Reservoir diffusion System
Rate controlling
steps :
Polymeric content in
coating, thickness of
coating, hardness of
microcapsule.

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Reservoir Diffusional Products
Product Manufacturer
Nico-400 Jones
Nitro- Bid Marion
Nitrospan Rorer

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Dissolution & Diffusion Controlled Release system
 Drug encased in a partially soluble
membrane.
 Pores are created due to dissolution
of parts of membrane.
 It permits entry of aqueous medium
into core & drug dissolution.
 Diffusion of dissolved drug out of
system.
 Ex- Ethyl cellulose & PVP mixture
dissolves in water & create pores of
insoluble ethyl cellulose membrane.
Insoluble
membrane
Pore created by
dissolution of soluble
fraction of membrane
Entry of
dissolution
fluid
Drug
diffusion

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Osmosis
- Movement of solvent from lower to higher concentration.
- The passage of solvent into a solution through
semipermeable membrane.
Semipermeable Membrane
Molecules are permitted only to one component (Water).
Osmotic pressure
It is the hydrostatic pressure produced by a solution in a space
divided by a semipermeable membrane due to difference in
concentration of solutes.
Osmotic pressure controlled DDS

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Osmotic Pressure Controlled System
 Provides zero order release
 Drug may be osmotically active, or combined with an
osmotically active salt (e.g., NaCl).
 Semipermeable membrane usually made from cellulose
acetate.
 More suitable for hydrophilic drug.
 Examples: Glucotrol XL, Procardia XL,

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Equation
(Q/t) z = Pw Am/ hm (πs-πe )
(Q/t)= Rate of zero order drug release.
Pw, Am & hm= water permeability, effective surface
area & thickness of semipermeable membrane.
πs= osmotic pressure of saturated solution of
osmotically active drug or salt in system.
πe = osmotic pressure of GI fluid.

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Modifications
- Immediate release system.
- Osmotically active compartment system

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Immediate Release System
 Activation of system is done.
 Dividing a dose into two parts.
 One third immediate release.
 Two third controlled release.
 Encapsulated into semipermeable
membrane.
e.g. : Phenyl propanolamine.

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Osmotically active system
 Two compartments
separated by movable
partition.
 Osmotically active
compartment absorbs
water from GIT.
 Creates osmotic
pressure.
 Partition moves
upward & then drug
releases.
 Ex: Nifedipine.
Movable
partition
Delivery orifice
Osmotically active
compartment
Drug compartment

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Some Popular Brand names used for OCDDS
 Spansule capsule ( SK & F )
 Sequal capsule (Lederle )
 Extentab tablets ( Robins )
 Timespan tablet ( Roche )
 Dospan tablet ( Merrell Dow )
 Chronotab tablet ( Schering )
 Plateau capsule ( Marion )
 Tempule capsule ( Armour )

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Ion exchange resins
 It is based on the formation of drug resin complex formed when a ionic
solution is kept in contact with ionic resins. The drug from these complex
gets exchanged in gastrointestinal tract and released with excess of Na+
and Cl- present in gastrointestinal tract.
 Resin + - Drug - + Cl- goes to resin + Cl- + Drug-
Where x- is cl- conversely
 Resin - - drug+ + Na +goes resin – Na+ + Drug
 These systems generally utilize resin compounds of water insoluble cross –
linked polymer. They contain salt – forming functional group in repeating
positions on the polymer chain. The rate of drug diffusion out of the resin
is sustained by the area of diffusion, diffusional path length and rigidity of
the resin which is function of the amount of cross linking agent used to
prepare resins

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PH -independent formulations
 Drugs administered oraly encountered pH ranging from 7 in
mouth,1 to 4 in stomach, and 5 to 7 in small intestine.since
most of the drugs are eighter weak acids or weak bases,their
release from sustained formulations is PH dependent.
 However buffer can be added to the formulation to help
maintain a constant PH there by rendering pH-independent
release.
 To this end,salts of amino acids,citric acid,phthalic
acid,phosphoric acid or tartrate acid are commonly used
because of their physiological acceptibility.
 e.g. propoxyphene in a buffered sustained release formulation,
which significantly increase reproducibility

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Altered density formulations
 1.High desity approch: the density of the pellets must exceed that of
normal stomach content(1.04g/cm3) and should be atleast 1.4
 In preparing such formulations,drug can be coated on a heavy core or
mixed with heavy inert materials such as barium sulfate,titanium dioxide
,iron oxide.
 2.low density approch : Globular shells which have an apparen
density lower than that of gastric fluid can be used as a carrier of drug
for sustained release purpose.polysterol,poprice,and even popcorn are
all good condidates as carriers.
 The surface of these empty shells is undercoated with sugar or with a
polymeric material such as methacrylic polymer and cellulose acetate
pthalate.the undercoated shell is then coated by a mixture of drug with
polymers such as ethylcellulose and hydroxypropylcellulose.Final
product floats on GIT fluid.

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Conclusion
 By and large, these are based on the principles diffusion,
dissolution, or ion exchange and, only recently, on the principle
of osmosis. Regardless of the mechanism of sustained release,
however, more and more of these systems are becoming
polymer based.
 There are also those which are based on the bioadhesion
principle whose goal is to promote the retention of a delivery
system, hence drug release, at a specific region in the GI tract
 Though CDDS appears appear to be feasible, The Timing for
practical development is difficult to predict; safety, cost, efficacy
are those factors need to be evaluated.

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BIBLIOGRAPHY
Novel drug delivery system , volume 50, Y.W.Chien, pg nos 1-55
Novel drug delivery system by N.K.jain 4th
edition, pg no1-4,54-
61
The theory & practice of industrial pharmacy, Leon Lachman ,
Herbert A.Lieberman, Joseph L.Kanig,3 rd edition. Pg no 430-445
The Eastern pharmacist, november 1993. Sustained release
drugs, V R.Gudsoorkar & D.Rambhau ,page 27-32
Biopharmaceuitics & pharmacokinetics, D M.Brahmankar & Sunil
B. Jaiswal, 1st
edition 1995, pg nos 220-235, 3335-371
Li. V.H., "Influence of drug properties and routes of drug
administration on the design of sustained and controlled release
systems" Chapter 1 in "Controlled drug delivery : fundamentals
and applications" edited by Robinson J.R.,
VincentLee,2nd
edition,Marcel Dekker Inc., Volume 29, 1978: 5-
36pp

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Continue……………
Hui ho-wah, "Design and fabrication of oral controlled release drug
delivery systems“ chapter 9 in "Controlled drug delivery; fundamentals
and applications", edited by Robinson J.R., Vincent Lee, 2nd edition,
Marcel Dekker Inc., Volume 29, 1978: 391-420pp.

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Joseph.R.Robinson pointed out the importance of drug delivery
system “Unless a drug can be delivered to it’s target area at a
rate and concentration that minimize the side effects and
maximize the therapeutic effect of drug will not be maximally
beneficial to patient and in the extreme an otherwise useful
drug may be discarded ”

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