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SUSTAINED RELEASE FORMULATIONS

Prof. Dr. Basavaraj K. Nanjwade M. Pharm., Ph. DDepartment of PharmaceuticsKLE University’s College of Pharmacy, Belgaum- 590010, Karnataka, IndiaCell No: 0091 9742431000E-mail: bknanjwade@yahoo.co.in

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IntroductionIntroduction

ConceptConcept

Advantages and disadvantagesAdvantages and disadvantages

Physicochemical propertiesPhysicochemical properties

Biological propertiesBiological properties

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The period between 1950 to 1970 is considered as period of Sustained drug release.

The main AIM of preparing sustained release formulation’s was intended to modify and improve the drug performance by

Increasing the duration of drug action.

Decreasing the frequency of dosing.

Decreasing the required dose employed.

Providing uniform drug delivery.

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DEFINITIONS:-

SRF’s describes the slow release of a drug substance from a dosage form to maintain therapeutic response for extended period (8-12hrs)of time. Time depends on the dosage form. In oral form it is in hours, and in parenteral’s it is in days and months. Ex: Aspirin SR, Dextrim SR.

Controlled release dosage form: In this the rate or speed at which the drug is released is controlled.

Ex: Adalat CR (Nifidipine), Dynacirc CR (Isradipine.)

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The of SRDF’s is to obtain Zero order release from the dosage form.

Zero order release is a release which is independent of the amount of drug present in the dosage form.

Usually SRDF’s do not follow zero order release but they try to mimic zero order release by releasing the drug in a slow first order fashion.

Pharmacological action is seen as long as the drug is in therapeutic range, problems occur when drug concentration is above/below therapeutic range.

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PARENTRALS

Pellets Solutions

Suspensions

Repeat action

Mixed release granules

Multilayer granules

Porous inert carrier

Osmotic system

Ion exchange resin

Slightly soluble salts complexes

ORAL

suspensions

Capsules

Tablets

Slow release

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Improved patient compliance: Less frequent dosing Allows whole day coverage.

Decreased local and systemic side effects. Decreased GIT irritation. Decreased local inflammation.

Better drug utilisation. Decreased total amount of drug used. Minimum drug accumulation on chronic dosing.

Improved efficiency in treatment. Uniform blood and plasma concentration. Decreased fluctuation in drug level i.e uniform pharmacological

response. Increased bioavailability of some drugs Special effects: SR Aspirin gives symptomatic relief in Arthritis

after waking Economy

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DOSE DUMPING :Increase quantity of drug release causes

dumping of drug which in turn leads to toxicity.

REDUCED POTENTIAL FOR ACCURATE DOSE

ADJUSTMENT: Administrating a fraction of drug is not possible.

NEED FOR ADDITIONAL PATIENT EDUCATION:

“Do not Crush or Chew the dosage unit”.

“ Tablet residue may appear in stools”.

STABILITY PROBLEMS: The complexity of SRF’s will lead to

stability problem.REDUCTION IN SYSTEMIC AVAILABILITY: Example

Theophylline, Procainamide and vitamin combinations.

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Retrieval of the drug is difficult in case of toxicity / poisoning /

hypersensitive reaction.

Higher cost of the formulation.

Half life: Drugs having shorter half life (less than one hour) and

drugs having longer half life (More than twelve hrs) cannot be

formulated as SRDF’s.

If a dosage form contains more than 500mgs., of active

ingredient formulation of SRDF’s is difficult.

If CRDF is required (With New polymers) cost of government

approval is very high.

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DRUG PROPERTIES: Stability, solubility, partition coefficient

and protein binding are to be considered.

ROUTE OF DRUG DELIVERY: Area of the body where drugs

are applied or administered play a vital role.

TARGET SITES: To minimize side effects, its desired to

maximize the fraction of dose applied.

ACUTE OR CHRONIC DOSING: Cure, Control and length of

drug therapy must be considered.

THE DISEASE: Pathological conditions play a significant role.

THE PATIENT: Ambulatory/ bedridden, young or old, etc.,

must be considered.

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AQUEOUS SOLUBILITY & pKa

PARTITION COEFFICIENT

DRUG STABILITY

PROTEIN BINDING

MOLECULAR SIZE & DIFFUSIVITY

DOSE SIZE

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AQUEOUS SOLUBILITY

For a drug to be absorbed, it must first dissolve in the

aqueous phase surrounding the site of administration.

AqS of a drug influences its dissolution rate which in turn

establishes its concentration in solution.

Dissolution rate is related to AqS solubility as shown by

Noyes Whitney equation under sink condition( CGIT»C)

dc/ dt= KD ACS

dc/ dt- dissolution rate

KD - dissolution rate constant

A- Total surface area of drug particles.

CS- Aqueous saturation solubility.

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Drugs with low aqueous solubility have low dissolution rate and

have oral bioavailability problems. E.g.: Tetracycline.

Drugs with high aqueous solubility are undesirable to formulate

SRDF’s. E.g.: Aspirin.

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The aqueous solubility of weak acids & weak bases is governed by the pKa of the compound and pH of the medium.

FOR WEAK ACID

St = So(1+Ka\[H ] =So(1+10pH-pKa)

St – Total solubility of the weak acid So – Solubility of the un-ionized form Ka – Acid dissociation constant H - Hydrogen ion concentration

Weakly acidic drug exist as unionized form in the stomach

absorption is favored by acidic medium

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FOR WEAK BASES:

St = So(1+[H ] \Ka) =So(1+pKa-pH)

St – Total solubility of both conjugate and free base form of weak base.

So– Solubility of the free base.

Weakly basic drug exists as ionized form in the stomach

hence absorption of this type is poor in this medium.

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PARTITION COEFFICIENT

Between the time of drug administration & elimination it diffuse

through several membranes ( Lipid barrier’s)

Oil/Water partition coefficient plays a major role in evaluating

the drug penetration.

K=Co/Cs

Where..

Co= Equilibrium concentration in organic phase.

Cs= Equilibrium concentration in aqueous phase.

Drugs with extremely high partition coefficient are very oil soluble and penetrates in to various membranes very easily.

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Contd……….. The relationship between tissue penetration and partition

coefficient for the drug is known as Hansch Correlation.

Log K

Log

act

ivit

y

The activity of the drug is a function of its ability to cross

membranes and interact with receptors. The more

effectively the drug crosses the membrane the greater is the

activity

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Contd……..

There is an optimum partition coefficient for a drug in which it

permeates membrane effectively and shows greater activity.

Partition coefficient with higher or lower than the optimum are

poorer candidates for the formulation

Unionized water soluble are highly absorbed from the intestine

and lipid soluble drugs are absorbed from the tissue.

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Contd……..

Values of partition coefficient below optimum result in the

decreased lipid solubility and remain localized in the first

aqueous phase it contacts.

Values larger than the optimum , result in poor aqueous

solubility but enhanced lipid solubility and the drug will not

partition out of the lipid membrane once it gets in.

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Solid state undergoes degradation at much slower rate than

in the suspension or solution etc..

Drugs stable in stomach gets released in stomach and which

are unstable gets released in intestine.

Drugs with stability problems in any particular area of G.I.T

are less suitable for the formulation.

Drugs may be protected from enzymatic degradation by

incorporation in to a polymeric matrix.

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Drug binding to plasma proteins (albumins) & resulting retention of the drug in the vascular space.

Drug-protein complex can serve as a reservoir in vascular

space.

Main forces for binding are Vander Waal forces, hydrogen bonding , electrostatic forces.

Charged compounds has greater tendency to bind proteins than uncharged ones.

Extensive binding of plasma proteins results in longer half-life of elimination for the drug

E.x..95% binding in Amitriptyline , diazepam , diazepoxide.

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The ability of the drug to diffuse through a membrane is called diffusivity (Diffusion coefficient). It is the function of its molecular size (molecular weight).

In most polymers it is possible to relate log D

to some function of molecular size as,

Log D = -Svlog V + Kv = -Smlog M+ Km

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Contd...,

V – Molecular volume.M – Molecular weight.Sv, Sm, Kv & Km are constants

The value of D is related to the size and shape of the cavities, as well as the drugs.

The drugs with high molecular weight show very slow kinetics.

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For those drugs requiring large conventional doses, the

volume of sustained dose may be too large to be practical.

The compounds that require large dose are given in

multiple amounts or formulated into liquid systems.

For oral route the volume of product is limited by patients.

For IM,IV or SC routes its tolerated.

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ABSORPTIONDISTRIBUTIONMETABOLISMELIMINATION & HALF LIFESIDE EFFECTS & MARGIN OF SAFETYROLE OF DISEASED STATEROLE OF CIRCADIAN RHYTHM

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The release of a drug from a dosage form is important than

its absorption.

The reason of poor absorption are poor water solubility, low

partition coefficient, acid hydrolysis and metabolism.

For SRDF’s rate of release is much slower than the rate

of absorption.

Transit time of drug is between 9-12hrs.

Maximum absorption half-life should be 3-4hr.

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Continued..

Low density pellets, capsules or tablets are formulated which

float on top of gastric juice and delay their transfer out of

stomach e.g. PABA

GI retention for drugs with poor absorption can be increased

by enhancers.

Bioadhesive materials is made which has high affinity to the

mucin coat.

A drug that is slowly absorbed is poor candidate for SRDF

eg.,Gentamycin, Hexamethonium

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Distribution of drugs in to vascular & extra vascular spaces is an important factor.

Apparent volume of distribution & drug concentration in tissue to that of plasma at steady state are important parameters for distribution. It is called T\P ratio.

Calculation of this distribution is mainly based on one compartment pharmacokinetic models.

It is given by.. V= Dose\CoCo–Initial concentration immediately after i.v bolus injection

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For two compartment models, the total volume of distribution is given by the apparent volume of the distribution at steady state

Vss = (1+K12\K21)V1Where. V1 - Volume of the central compartment K12-Rate constant for distribution of the drug from central compartment to peripheral K21 - Peripheral to the central compartment blood or plasma to the total volume.

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Metabolic conversion of drug to another chemical form.

Factors associated with metabolism are;

Ability of drug to induce or inhibit enzyme synthesis. This

results in fluctuating drug blood level with chronic dosing.

Fluctuating drug blood level due to intestinal metabolism or

through a hepatic first pass effect. Ex.., intestinal metabolism

upon oral dosing are hydralazine , salicylamide , nitroglycerine.

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Rate of elimination of the drug is described quantitatively by its biological half life i.e.. T1/2.

The half life of the drug is related to its apparent volume of distribution and its systemic clearance.

t1/2 = 0.693V/CLs = 0.693 AUC/dose

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Contd...

A drug with shorter half life requires frequent dosing.

Drugs with half life 2hr should not be used ,since such system

requires unexpectedly large release rate and large doses.

E.x.., Ampicillin , Cephalosporin

Drugs with half life greater than 8 hrs should not be used,

formulation of such drugs is unnecessary.

E.x.., Diazepam, Digitoxin , Digoxin

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SRDF is useful in minimizing the side effects of the drug.Slow release potassium – SR of potassium to prevent gastric irritation. Timed release of aspirin – to prevent gastric irritation.

Measure of margin of safety of the drug is THERAPEUTIC INDEX(TI). TI = TD50\ED50

TD50 = median toxic dose ED50 = median effective dose.

For potent drugs TI value is small. Larger the value of TI safer the drug.Drugs with small value of TI are poor candidates for the formulation.A drug is considered to be relatively safe if TI exceeds 10.Some drugs of TI less than 10 are Digitoxin, Digoxin and Phenobarbitone.

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Different methods used are..

BASED ON DRUG MODIFICATION.

BASED ON DOSAGE FORM MODIFICATION.

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BASED ON DRUG MODIFICATION:

COMPLEX FORMATION

DRUG-ADSORBATE PREPARATION .

PRO DRUG SYNTHESIS.

ION EXCHANGE RESINS.

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Complex formation:

The rate of dissolution of solid complex in biological fluids

and rate of dissociation of complex in the solution are considered

and they depend upon pH and composition of gastric and

intestinal fluids.

Drug-adsorbate preparation:

In this product is insoluble. Drug availability is determined

by rate of disabsorption.

Pro drug synthesis:

They are inactive and need enzymatic hydrolysis for

regeneration. Solubility, absorption rate of prodrug must be lower

than parent drug.

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Ion exchange resins:

They are water insoluble, cross linked polymers

containing salt forming groups. The drug is bound to the resin

by using chromatographic column or by prolonged contact.

Drug release from this complex depends on pH &

property of resin. Drug that is attached to the resin is released

by exchanging with the ions present in the GIT.

Resin+ -Drug- +X- Resin+- X- + Drug-

Example: Biphetamine.

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BASED ON DOSAGE FORM MODIFICATION.

Microencapsulation:

It’s a process in which tiny particles are surrounded by

uniform coating (microcapsule) or held in a matrix of polymer

(microsphere.) Spray drying is used which involves rapid

evaporation of the solvent from the drug surface.

Barrier coating:

In this one quarter of the granules are in non sustained

form for sudden drug release, remaining part are coated for

sustained release. Both these granules are filled in hard gelatin

capsule or compressed in a tablet, and the release mechanism is

by diffusion. Coating material used are fats, waxes.

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Matrix embedding: Drug is dispersed in a matrix of retardant material which may be encapsulated or compressed in a tablet.

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Name Marketer Dosage form IndicationCarbotrol

Glucotrol Xl

Adderall XR

Procardia Xl

Ortho Evra

Dura gesic

Shri Us

Pfizer

Shri US

Pfizer

Ortho – Mcneil

Janssen

Oral capsule

Oral TabletOral Tablet

Oral Capsule Oral Capsule

Oral TabletOral Tablet

Trans Dermal PatchTrans Dermal Patch

Trans Dermal PatchTrans Dermal Patch

Epilepsy

Hyperglycaemia

ADHD

Angina / Hypertension

Contraceptive

Chronic pain

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1) Text book of Sustained release dosage form by Y.S.Robinson,

Decker Series.

2) Controlled release dosage form by Y.W.Chien.

3) Ansel’s Pharmaceutical Dosage forms and Drug delivery

Systems.

4) Tutorial Pharmacy by Cooper and Gunns.

5) Remington’s Pharmaceutical Sciences

6) Text book of Pharmaceutics by Bentley and Drivers.

7) www.google.co.in (CRDF design- google book result- cherng-

jukin).

8) Text book of Pharmaceutical Sciences by Aulton.

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Queries

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