ocdds by raghav modified

02/10/16 RAGHAVENDRA KUMAR GUNDA

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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

(Y 10MPH0621)


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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 systemicallyFor 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 COMPLIANCEPEAKVALLEY PDC VS TIMEFLUCTUATIONS IN DRUG LEVELSOVER MEDICATION

MISSING OF DOSE

CSS IS DIFFICULT

FOR NARROW TI DRUGSUNDER 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 correlationPoor systemic availability(depends upon GI residing time)Increased potential for first pass clearanceHigh 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

PHYSICALHYDRATION, IONTOPHORESIS, SONOPHORESIS

HYDRODYNAMIC,VAPOUR,OSMATIC PRESSURES

MAGNETIC

CHEMICAL

PH ACTIVATED

HYDROLYSIS

IONIZATION

BIOCHEMICALENZYME 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 FOLLOWSVITAMINSMINERALSHORMONESDRUGS DRUGS

DIURETICS & CVS DRUGS

ACETAZOLAMIDE, ISOSORBIDE, PAPVERINE

ANTIMICROBIALTETRACYCLIN

CNSAMPHETAMINE,

CAFFEINE, PHENOBARBITAL,

PROCHLORPERAZINE

GI BELLADONNA ALKALOIDS,

HYOSCINE, TRI DIHEXETHYL

CHLORIDEPYRIDO STIGMINE

RESPIRATORYAMINOPHYLLINE

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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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

DimetappExtentabs

Bromphen. Robins

DonnantalExtentabs

..... Robins

QuinidexExtentabs

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 drug

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-TrimetonRepetabs

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 pressureIt 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,2ndedition,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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