LIQUID SUSTAINED RELEASE SYSTEMS

K.SRAVAN(256212886047)

M.PHARM Dept.of pharmaceutics

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CONTENTSINTRODUCTIONMERITS ANDDEMERITSAPPROACHES TO LIQUID SUSTAINED RELEASE SYSTEMMETHOD OF PREPARATIONEVALUATIONAPPLICATIONS

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WHAT IS DRUG DELIVERY SYSTEM?

The term “drug delivery systems’’ refer to the technology utilized to present the drug to the desired body site for drug release and absorption.

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Conventional Modified

Drug Delivery

Sustained

Extended

Site-specific

Pulsatile

Enteral

Parenteral

Other

In the conventional therapy aliquot quantities of drugs are introduced into the system at specified intervals of time with the result that there is considerable fluctuation in drug concentration level as indicated in the figure.

HIGH

LOW

HIGH

LOW

INTRODUCTION

What is Sustain Release Dosage Form? “Drug Delivery system that are designed to achieve prolonged therapeutic effect by continuously releasing medication over an extended period of time after administration of single dose.” The basic goal of therapy is to achieve steady state blood level that is therapeutically effective and non toxic for an extended period of time. The design of proper dosage regimen is an important element in accomplishing this goal.

The difference between controlled release and sustained release,

Controlled release is perfectly zero order release that is the drug release over time irrespective of concentration.

Controlled drug delivery- which delivers the drug at a pre determined rate for a specified period of time.

Sustain release dosage form- is defined as the type of dosage form in which a portion i.e. (initial dose) of the drug is released immediately, in order to achieve desired therapeutic response more promptly, and the remaining(maintanance dose) is then released slowly there by achieving a therapeutic level which is prolonged, but not maintained constant.

Sustained release implies slow release of the drug over a time period. It may or may not be controlled release.

Rationality in designing S.R.Dosage form.

The basic objective in dosage form design is to optimize the delivery of medication to achieve the control of therapeutic effect in the face of uncertain fluctuation in the vivo environment in which drug release take place.

This is usually concerned with maximum drug availability by attempting to attain a maximum rate and extent of drug absorption however, control of drug action through formulation also implies controlling bioavailability to reduce drug absorption rates.

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The history of controlled release technology is divided into three time periods

From 1950 to 1970 was the period of sustain drug release

From 1970 to 1990 was involved in the determination of the needs of the control drug delivery

Post 1990 modern era of controlled release technology

HISTORY

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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. Providing uniform drug delivery.

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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 parenterals it is in days and months.

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.

HOW IS THE DRUG RELSEASED

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Improved patient compliance Decreased local and systemic side effects. Better drug utilization. Improved efficiency in treatment. Increased bioavailability of some drugs Special effects: SR Aspirin gives symptomatic relief

in Arthritis in the morning. Economic in preparation

MERITS

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Dose dumping

Reduced potential for accurate dose adjustment:

stability problems:

Retrieval of the drug is difficult in case of toxicity /

poisoning and hypersensitive reaction.

Higher cost of the formulation.

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

DEMERITS

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The dosage forms which are liquid in nature and are

capable of delivering the drug in a sustained manner

are called as liquid sustain release systems.

They generally include suspensions , emulsions, gels

etc.

WHAT ARE LIQUID SUSTAINED RELEASE SYSTEMS

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Mainly used for ease of swallowing in paedeatric and

geriatric use

Ease of formulation

Economic in preparation

Better bioavailability

than solid dosage forms

Flexibility in dose adjustment

WHY LIQUID SUSTAINED RELEASE SYSTEMS?

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SuspensionsLiquid crystalline phasesDrug – resin complexesIn situ gel formationMicroencapsulationMesogenic moleculesEmulsions/ multiple emulsions

APPROACHES TO LIQUID SUSTAINED RELEASE SYSTEMS

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A method of preparing sustained-action liquid dosage forms

for various compounds is by microencapsulating the

biologically active ingredient and subsequently suspending

the microencapsulated form in a vehicle saturated with the

biologically active ingredient.

It is possible to formulate liquid product, having sustained

action, by suspending coated granules or particles in a

suitable liquid media which has no action on the coats of the

granules. These formulation are similar to suspensions.

GENERAL METHOD OF PREPARATION

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Polymers used--- carbopol 934p, ethylcellulose(suspensions), HPMC, eudragit RL30D

Resins used--- AMBERLITE(drug resin complexes), carboxylated styrene crosslinked by di vinyl benzene

Drugs used– theophylline, proponolol, timolol,etc

Other materials such as oil, peptides are also used.

Materials used

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Suspensions are biphasic dosage forms in which the solid phase is suspended in a liquid phase.

To produce a sustained release liquid dosage form the drug is encapsulated with in a suitable polymer and then it is formulated as suspension using tragacanth as suspending agent.

SUSPENSIONS

The techniques like spray drying includes 2 different methods for preparation of suspensions1st methodsolution of drug and polymer are used as feed solution (solvent used ethanol /water 80:20, acetone)2nd methoddispersion of drug in polymer solution was feed solution( solvent used methylene chloride)

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Among sustained-release drug delivery systems, microcapsules have received much attention because of uniform distribution in GI tract which leads to uniform absorption and decreasing risk of local effects on GI tract.

Another advantage of microparticulate systems is their feasibility to be Incorporated into liquid dosage forms such as suspensions.

SUSPENSIONS

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Polymer– hydroxy propyl methyl cellulose phthalate 1.5%PEG6000 - plasticizer Formulation- sustained release suspension of

theophylline microcapsules

suspensions

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Heating of polymer

below its Tg

pressurized at 28mpa for 30sec-

5min

temperature maintained above

tg

Liquid crystalline phases

method of preparation

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liquid crystal system

thermo tropic

lyotropic

nematic

smectic

cholesteric

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Lyotropic crystals in invitro condition provide sustained release.

Provides thermodynamically , kinetically stable matrix

Investigations done using polar lipid-water-peptide Released peptide was found out using

immunoreactivity of peptide in plasma Peptide is absorbed in pseudo zero order Lyotropic LC acts as parenteral depot Peptide protected against degradation

Liquid crystalline phases

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Ion exchange resins are solid and suitably insoluble high

molecular weight polyelectrolytes that can exchange their

mobile ions of equal charge with the surrounding medium. size of the ion-exchange resins -about 20 to about 200 µm

particle sizes. Drug – resinate complexes are prepared by batch and column

method Influence of formulation on rate and equilibrium was

done using ion exchange resin. Diffusion of drug from resin particles controlled by particle

diffusion process.

Drug resin complexes

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Coated with SURELEASE(aqueous ethyl cellulose dispersion)

pH has no effect on drug release. Increase in ionic concentration, increase in rotation

speed will increase the release The drug release follows first order kinetics Strong acidic cationic exchange resin AMBERLITT

IRP69 ( SR, taste masking, drug stabilizing agent) is used.

Drug resin complexes

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The size and state of the particle in the internal phase play an important role in the final status of the microparticles.

The choice of the internal and the external phase of the emulsion, type of emulsifier and method of homogenizing two phases will effectively determine the characteristics of the final microparticles.

EC is a non-biodegradable and biocompatible and gastro-resistant polymer which has been extensively used as drug release retardant which easily forms microcapsules with a one-step encapsulation method

Micro encapsulation

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Preparation of sustained release microcapsules using emulsion- solvent evaporation method using EC.

Preparation has two strategies. The first being preparation of o/w emulsion containing

EC dissolved in dichloromethane+ drug as oily phase. 1.5%SLS in water as aqueous phase. Where oily phase is

added to aqueous phase. 45 min stirring to remove DCM. And then the microcapsules are obtained.

Micro encapsulation

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The second strategy containing drug and EC as oily phase in acetone.

Added to external phase 1.3% tween 80 in 100ml liq.paraffin.

Stirred for 5 hrs Microcapsules are then obtained These are then formulated as suspensions

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In situ gel formation

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Elderly patients with swallowing dysfunction may benefit from the oral administration of liquid dosage forms with in situ gelling properties.

Gels are made by using METHYL CELLULOSE a thermo reversible gelation properties containing polymer and sodium alginate having ion responsive gelation properties

This is mainly done for ease of administration and provides suitable integrity for the drug in stomach to produce sustained release.

Generally used gelling agents are chitosan, pectin(0.1-2%), sodium alginate(0.25-1%), methylcellulose(2%),

In situ gel formation

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Mixtures of 2.0% methylcellulose and 0.5% alginate containing 20% d-sorbitol were of suitable viscosity for ease of swallowing by dysphagic patients and formed gels at temperatures between ambient and body temperature allowing administration in liquid form and in situ gelation in the stomach

A 2.0% methylcellulose/0.5% alginate formulation showed improved sustained release compared to that from 2.0% methylcellulose and 0.5% alginate solutions and from an aqueous solution of paracetamol

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Mesogen is the fundamental unit of a liquid crystal that induces structural order in the crystals.

Typically, a liquid-crystalline molecule consists of a rigid moiety and one or more flexible parts.

The rigid part aligns molecules in one direction, whereas the flexible parts induce fluidity in the liquid crystal.

This rigid part is referred to as mesogen, and it plays a crucial role in the molecule. The optimum balance of these two parts is essential to form liquid-crystalline materials.

Mesogenic molecules

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MULTIPLE EMULSIONS

Multiple emulsion (w/o/w or o/w/o), Prepared by two step procedure

First step (o/w)Primary emulsion

Second step (o/w/o)Secondary emulsification phase

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Oil + Aqueous phase Low HLB surfactant + Oil

Blend and heat up to 70-80º C

Formation of very fine droplets

Heat and blend with low shear

Oil

Multiple emulsion

Blend with low shear

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Viscosity

surface tension

conductivity

Syringability

pH

Globule size

Test for sterility

Microscopic method

Particle size distribution

Entrapment efficiency 39

Evaluation of Multiple Emulsions

Syringability

All the formulation were tested by different size of needle under the

guidance by the experters (Physicians) and the data obtained was put

in tabulated form.

The O/W/O multiple emulsion with a minimum concentration of

surfactants showed excellent syringability. The multiple emulsion

prepared with maximum concentration of surfactants and for given

time period entrapped 83.14 % of Hydroxyprogesterone.

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Globule/droplet size determination

Droplet size was determined by the microscopy, the compound

microscope was used to determine the droplet size of the formulation.

It was found that the droplets decrease in size with increase in the

concentration of surfactants. The average diameters of the dispersed

water droplets in o/w/o emulsions

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Multiple Emulsion

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Entrapment efficiency

The entrapment efficiency is the capacity of the multiple emulsions

that how much quantity of drug is entrapped in the internal phase. It

was calculated in %.

All the formulations were centrifuged at high speed and the

separated phase was evaluated for drug content.

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Sterility Test

All the formulations were subjected for the sterility test by direct

inoculation method (I.P.).

The sterility test was carried out for aerobic and anaerobic

microorganism, fluid thioglycollate media and soybean casein

digest media was used for sterility test. 44

Stability study

The stability study was carried out of optimized formulation Fa.

Formulation was stored in amber colored ampoule at 40o C for three

months. It was evaluated for physical characteristics.

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In -vitro diffusion study

•The drug release profile of all formulations was studied in buffer

media (pH 7.4 and Alcohol 20%) by using K-Cell.

•The cellulose membrane used as a barrier.

•The drug release profile was studied for 24 hrs.

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• The amount of the drug diffused out was relatively small,

indicating that the water layer of the multiple emulsion shows a

stable diffusion barrier, thus the drug was released mainly by

permeation through this membrane.

• The comparative drug diffusion studies were carried out,

comparison with the marketed formulation and shown the

percentage drug release of marketed formulation more than the

multiple emulsions.

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Microscopic method Dissolution studies Entrapment efficiency pH Viscosity surface tension Sedimentation volume Degree of flocculation Ease of dispersibility

EVALUATION

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Liquid crystalline phases are applied for cosmetics In treatment of paradontitis the drug is dispersed in gel

such that it adheres to the gum pockets. LC of DNCG is applied as mast cell stabilizer used as

prophylactic agent in asthma & hay fever Used in treatment of bronchial asthma

APPLICATIONS

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Drug form

Hydroxy progesterone Multiple emulsion

Timolol Liquid eye drops

Theophylline Suspension

Propranolol Hydrochloride Drug resin complex

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Kenneth J. Fredrick. Performance and problems of pharmaceutical suspensions, Journal of Pharm. Sciences. 50,531-35,1961

George M., Grass IV, Robinson J. "Sustained and controlled release drug delivery systems" ,"Modern Pharmaceutics" edited by Banker G.S., Rhodes C.T., 2nd edition, Marcel Dekker, 1990: 639-658pp.

Longer M.A., Robinson J.R. "Sustained release drug delivery system" ,"Remington's pharmaceutical sciences" 18th edition, Mack Publishing Company, 1990: 1675-1684pp.

References

Brahmnkar DM, Jaiswal SB: Biopharmaceutics and Pharmacokinetics – A Treatise. 1sted. Delhi: Vallabh Prakashan; 1995. p. 62, 282.

Liberman HA, Martin A, Gilbert R,. Banker S: Pharmaceutical Dosage Forms: Disperse system: Marcel Dekkar. Volume III; 1994; p. 423-471.

Liberman HA, Martin R, Gilbert R, Banker S: Pharmaceutical Dosage Forms: Disperse system: Marcel Dekkar. Volume II,;1994; p. 47- 97, 261 – 310, 183- 239.

Liberman HA, Martin R, Gilbert R, Banker S: Pharmaceutical Dosage Forms: Disperse system: Marcel Dekkar. Volume III; 1994; p. 423-471.

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