Oral Sustained ControlledDrug Delivery System Introduction In the conventional therapy aliquot quantities of drugs areintroduced into the system at specified intervals of time.
with the result that there is considerable fluctuation indrug concentration level as indicated in the figure However an ideal dosage regimen would be one in whichthe concentration of the drug nearly coinciding withminimum effective concentration M E C is maintained at.
a constant level throughout the treatment period Such asituation can be graphically represented by the followingConstant Level Sustained Release Dosage Drug Delivery system that are designed to achieve.
prolonged therapeutic effect by continuously releasingmedication over an extended period of time afteradministration of single dose The basic goal of therapy is to achieve steady stateblood level that is therapeutically effective and non toxic.
for an extended period of time The design of proper dosage regimen is an importantelement in accomplishing this goal Advantages 1 Improved patient compliance.
2 Improved efficiency of treatment3 Better drug utilization4 Bio availability of certain drugs can be increased5 Increased safety margin of high potency drugs anddecreased local and systemic side effects.
6 Reduces nursing and hospitalization time Disadvantages 1 Increased variability among dosage units 2 Some of the drugs are not having any advantages if theyare formulated in sustained release form .
3 The physicians having less flexibility in adjusting thedosage regimes Lack of dosage flexibility 4 Longer time to achieve therapeutic blood concentrations 5 Increased variation in bioavailability 6 Enhanced first pass effect .
7 Dose dumping 8 Sustained concentration in overdose cases 9 Greater expense 10 Need for additional patient education Eg Do not chewor crush the dosage form swallow fully 6.
The Difference Between CR SR Controlled drug delivery Delivers the drug at a pre determined rate for a specifiedperiod of time It is perfectly zero order release that is the drug release.
over time irrespective of concentration Sustain release delivery The type of dosage form in which a portion i e initialdose of the drug is released immediately in order toachieve desired therapeutic response more promptly and.
the remaining maintanance dose is then released slowlythere by achieving a therapeutic level which is prolonged but not maintained constant Sustained release implies slow release of the drug over atime period It may or may not be controlled release .
Sustained Release Controlled ReleaseDosage Dosage1 Constitutes dosage form that 1 Constitutes dosage form thatprovides medication over maintains constant drug levelsextended period of time in blood or tissue.
2 SRDF generally do not attain 2 Maintains constant drug levelszero order release kinetics in the blood target tissueusually by releasing the drugin a zero order pattern 3 Usually do not contain 3 Controlled dosage forms.
mechanisms to promote contain methods to promotelocalization of the drug at localization of the drug atactive site active site Rationality Behind S R Dosage Form .
The basic objective in dosage form design is to optimize thedelivery of medication to achieve the control of therapeuticeffect in the face of uncertain fluctuation in the vivoenvironment in which drug release take place This is usually concerned with maximum drug availability.
by attempting to attain a maximum rate and extent of drugabsorption however control of drug action throughformulation also implies controlling bioavailability to reducedrug absorption rates To improve patient compliance by reducing dosing.
frequency To improve efficiency of treatment by maintaining safetymargin of high potency drugs and decreased local andsystemic side effects To reduce nursing and hospitalization time 9.
Plasma Concentration v s Time Curve Drug Properties Relevant to SRFormulation The design of sustained release delivery system issubjected to several variables and each of variables are.
inter related For the purpose of discussion it is convenient to describethe properties of the drugs as being either physico chemical or biological these may be divided in two types 1 Physicochemical properties.
2 Biological properties Factors to be considered in S R dosage forms Biological Factors Physiological1 Absorption.
2 Distribution 1 Dosage size3 Metabolism 2 Partition coefficient andmolecular size4 Biological halflife excretion 3 Aqueous Solubility.
5 Margin of safety 4 Drug stability5 Protein binding Biological Factors CONTD Biological Factors Absorption .
Absorption of drug need dissolution in fluid before itreaches to systemic circulation The rate extent and uniformity in absorption of drug areimportant factor when considering its formulation in tocontrolled release system .
Absorption and Dissolution The characteristics of absorption of a drug can be greatlyeffects its suitability of sustained release product Biological Factors CONTD The maximum half life for absorption should be.
approximately 3 4 hr otherwise the device will pass out ofpotential absorptive region before drug release is complete Compounds that demonstrate true lower absorption rateconstants will probably be poor candidates for sustaining The rate extent and uniformity of absorption of a drug are.
important factors considered while formulation of sustainedrelease formulation As the rate limiting step in drug delivery from a sustained release system is its release from a dosage form ratherthan absorption .
Biological Factors CONTD The transit time of drug must be in the absorptive areasof the GI tract is about 8 12 hrs If the rate of absorption is below 0 17 hr and above the0 23 hr then it is difficult to prepare sustained release.
formulation As the rate limiting step in drug delivery from a sustained release system is its release from a dosage form ratherthan absorption Rapid rate of absorption of drug relative to its release.
is essential if the system is to be successful Biological Factors CONTD Distribution The distribution of drugs into tissues can be importantfactor in the overall drug elimination kinetics .
Since it not only lowers the concentration of drug but italso can be rate limiting in its equilibrium with blood andextra vascular tissue consequently apparent volume ofdistribution assumes different values depending on timecourse of drug disposition .
For design of sustained controlled release products onemust have information of disposition of drug The apparent volume of distribution Vd is nearly aproportional constant that release drug concentration in theblood or plasma to the amount of drug in the body .
Biological Factors CONTD Metabolism There are two areas of concern relative to metabolism thatsignificantly restrict sustained release formulation 1 If drug upon chronic administration is capable of.
either inducing or inhibition enzyme synthesis it willbe poor candidate for sustained release formulationbecause of difficulty of maintaining uniform bloodlevels of drugs 2 If there is a variable blood level of drug through a.
first pass effect this also will make preparation ofsustained release product difficult Drug that are significantly metabolized beforeabsorption either in lumen of intestine can showdecreased bio availability from slower releasing dosage.
Biological Factors CONTD Biological Half Life The usual goal of sustained release product is to maintaintherapeutic blood level over an extended period to this drugmust enter the circulation at approximately the same rate at.
which it is eliminated The elimination rate is quantitativelydescribed by the half life t1 2 Therapeutic compounds with short half life are excellentcandidates for sustained release preparation since these canreduce dosing frequency .
Drugs with half life shorter than 2 hours Such as e g Furosemide levodopa are poor for sustained releaseformulation because it requires large rates and large dosecompounds with long half life More than 8 hours are also generally not used in sustaining.
forms since their effect is already sustained E g Digoxin Warfarin Phenytoin etc Biological Factors CONTD Margin of Safety In general the larger the volume of therapeutic index.
safer the drug Drug with very small values of therapeutic indexusually are poor candidates for SRDF due topharmacological limitation of control over releaserate e g induced digtoxin Phenobarbital phenotoin .
TD50 ED50 Larger the TI ratio the safer is drug It is imperative that the drug release pattern is precise sothat the plasma drug concentration achieved in undertherapeutic range 19.
Physiological Factors 1 Dosage size 2 Partition coefficient and molecular size 3 Aqueous Solubility 4 Drug stability .
5 Protein binding Physiological Factors Dosage Size In general a single dose of 0 5 1 0 gm is considered fora conventional dosage form this also holds for sustained.
release dosage forms If an oral product has a dose size greater that 500mg itis a poor candidate for sustained release system sinceaddition of sustaining dose and possibly the sustainingmechanism will in most cases generates a substantial.
volume product that unacceptably large Physiological Factors Partition Coefficient Molecular Size When the drug is administered to the GIT it must cross.
a variety of biological membranes to producetherapeutic effects in another area of the body It is common to consider that these membranes arelipidic therefore the Partition coefficient of oil solubledrugs becomes important in determining the effectiveness.
of membranes barrier penetration Partition coefficient is the fraction of drug in an oilphase to that of an adjacent aqueous phase High partition coefficient compound are predominantlylipid soluble and have very low aqueous solubility and.
Physiological Factors Partition coefficient and molecular size influence notonly the penetration of drug across the membrane butalso diffusion across the rate limiting membrane The ability of drug to diffuse through membranes its so.
called diffusivity diffusion coefficient is function ofmolecular size or molecular weight Thus high molecular weight drugs or polymeric drugsshould be expected to display very slow release kineticsin sustained release device using diffusion through.
polymer membrane Physiological Factors Aqueous Solubility Since drugs must be in solution before they can be absorbed compounds with very low aqueous solubility usually suffer.
oral bioavailability problems because of limited GI transittime of undissolved drug particles and limited solubility at theabsorption site E g Tetracycline dissolves to greater extent in the stomachthan in the intestine therefore it is best absorbed in the.
intestine Most of drugs are weak acids or bases since theunchanged form of a drug preferentially permeates acrosslipid membranes drugs aqueous solubility will generally bedecreased by conversion to an unchanged form.
For drugs with low water solubility will be difficult toincorporate into sustained release mechanism 24 Physiological Factors Aqueous solubility and pKa These are the most important to influence its absorptive.
behavior and its aqueous solubility if it s a weak acid orbase and its pKa The aqueous solubility of the drug influences its dissolution Physiological Factors Drug Stability .
The stability of drug in environment to which it is exposed is another physico chemical factor to be considered indesign at sustained controlled release systems drugsthat are unstable in stomach can be placed in slowlysoluble forms or have their release delayed until they.
reach the small intestine Orally administered drugs can be subject to both acid base hydrolysis and enzymatic degradation Degradation will proceed at the reduced rate for drugs inthe solid state .
For drugs that are unstable in stomach systems thatprolong delivery ever the entire course of transit in GI tractare beneficial 26 Physiological Factors Compounds that are unstable in the small intestine may.
demonstrate decreased bioavailability whenadministered form a sustaining dosage from This is because more drug is delivered in smallintestine and hence subject to degradation However for some drugs which are unstable in small.
intestine are undergo extensive gut wall metabolismThe transit time of drug must be in the absorptive areas of the GI tract is about 8-12 hrs. If the . rate of absorption is below 0.17/hr and above the 0.23/hr . then it is . difficult to prepare sustained release formulation. As the . rate limiting step . in drug delivery from a sustained-release system is its

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