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SUSTAINED RELEASE DRUG DELIVERY SYSTEM
Sustain Release Drug Delivery System
Introduction Rationality in designing S.R.D. Concept of S.R.D. Difference between c .r. and s. r. Repeat-action vs. sustained-action drug therapy. Difficulties arise in maintaining the drug concentration in therapeutic range . Overcome of these difficulties. Merits. De-merits. Factors to be considered in S.R.D. Method of formulation of S.R.D Evaluation of S.R.D.. Problems during formulation. Marketed product of S.R.D.. References.
WHAT IS DRUG DELIVERY SYSTEMS?
The term “drug delivery systems’’ refer to the technology utilized to present the drug to the desired body site for drug release and absorption.
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 .
can be considered as a form of controlled release in that it exercises spatial control of drug release within the body. prolonged release or sustained release systems. on the basis of simple in vitro tests. In other words. The general consensus is that controlled release denotes systems. . which can provide some control. or both. of drug release in the body. it is necessary to provide a short explanation of terminology used because there is considerable confusion in this area. whether this is of a temporal or spatial nature. on the other hand. They are distinguished from ratecontrolled drug delivery systems. the systems attempts to control drug concentration in the target tissue or cells.Before initiating a discussion of sustained release dosage forms. Drug targeting. cannot be considered as controlled release systems by this definition. which are able to specify the release rate and duration in vivo precisely. Thus. which only prolong therapeutic blood or tissue levels of the drug for an extended period of time.
HIGH HIGH LOW LOW .INTRODUCTION 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.
nearly coinciding with minimum effective concentration (M. is maintained at a constant level throughout the treatment period.INTRODUCTION However.E. an ideal dosage regimen would be one.C.). in which the concentration of the drug. Such a situation can be graphically represented by the following figure CONSTANT LEVEL .
” 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. .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 design of proper dosage regimen is an important element in accomplishing this goal.
in order to achieve desired therapeutic response more promptly.e. Sustain release dosage form. .which delivers the drug at a pre determined rate for a specified period of time Controlled release is perfectly zero order release that is the drug release over time irrespective of concentration.The difference between controlled release and sustained release. Controlled drug delivery. (initial dose) of the drug is released immediately. It may or may not be controlled release. Sustained release implies slow release of the drug over a time period. but not maintained constant. and the remaining(maintanance dose) is then released slowly there by achieving a therapeutic level which is prolonged.is defined as the type of dosage form in which a portion i.
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.Dosage form.Rationality in designing S.R. control of drug action through formulation also implies controlling bioavailability to reduce drug absorption rates. This is usually concerned with maximum drug availability by attempting to attain a maximum rate and extent of drug absorption however. .
Plasma concentration v/s time curve .
. release rate & dose consideration A) Release rate consideration :In conventional dosage form Kr>Ka in this the release of drug from dosage form is not rate limiting step.Concept of sustained release formulation The Concept of sustained release formulation can be divided in to two considerations i.e.
e.Cd Where Ke = overall elimination (first order kinetics). release is rate limiting step. . Cd = desired drug concentration.F must be directed primarily altering the release rate. where as in non immediate (Kr<Ka) i.e. (Kr>Ka) is in case of immediate release.The above criteria i. The release rate should follow zero order kinetics Kr = rate in = rate out = KeVd. the rate should be independent of drug removing in the dosage form over constant time. Vd = total volume of distribution.R. So that effort for developing S.
the therapeutic dose release follows zero order process for specified time period then. W= Di + K0 r. b) maintenance dose . Td Td = time desired for sustained release from one dose. W = Di + Dm In a system.B) Dose consideration :To achieve the therapeutic level & sustain for a given period of time for the dosage form generally consist of 2 part a) Initial (primary) dose therefore the total dose ‘W’ can be.
W = Di + K0 r Td – K0 r Tp Tp = time of peak drug level.If maintenance dose begins to release the drug during dosing t=O then. However a constant drug can be obtained by suitable combination of Di & Dm that release the drug by first order process. then W = Di + ( Ke Cd /Kr ) Vd .
however. sustained action. . extended action. time release dosage formed are terms used to identify drug delivery system that are designed to achieve a prolonged therapeutic effect by continuously releasing medication over an extended period of time after administration of single dose . In case of injectable dosage form. controlled release.Sustained release. in case of orally administrated forms. this period may vary from days to month. prolonged action. this period is measured in hours & critically depends on the residence time of the dosage form in GI tract.
synergize.In some case. through a process of either drug modification. E. which inhibit the excretion of penicillin. thus prolonging it’s blood level.g.:. Mixture of drug might be utilized to attend. . and subsequently drug action can be controlled. control of drug therapy can be achieved by taking advantage of beneficial drug interaction that affect drug disposition and elimination. or antagonize given drug action.e. Sustained release dosage form design embodies this approach to the control of action i.the action of probenicid. the absorption process.
when the enteric coat surrounding the second dose is breached by the intestinal fluid. The release of second dose is delayed. usually by means of an enteric coat. the 1st being released immediately following oral administration in order to provide a repeat onset of therapeutic response. A repeat action tablet usually contains two dose of drug. Consequently. the second dose is release immediately.Repeat-action versus sustained-action drug therapy A repeat-action tablet may be distinguished from its sustained-release product by the release of the drug in slow controlled manner and consequently does not give a plasma concentration time curve which resemble that of a sustained release product. .
P E A K V A L L Y .
. The primary advantage provide by a repeat-action tablet over a conventional one is that two (or occasionally three) doses are administration without the need to take more than one tablet.figure shows that the plasma concentration time curve obtained by the administration of one repeat. Profile associated with the intermittent administration of conventional dosage forms.action preparation exhibit the “PEAK & VALLY”.
therefore chances of missing the dose of the drugs with short half life. Patient incompliance due to increase frequency of dosing.Difficulties arise in maintaining the drug concentration in the therapeutic range. Difficulty to attain steady state drug concentration. Fluctuation may lead to under medication or over medication. .
. Effective and safer use of existing drugs through concept and techniques of controlled and targeted drug delivery.These difficulties may be overcome by: Developing the new better and safer drug with long half life & large therapeutic indices.
Merits : Improved patient convenience and compliance due to less frequent drug administration. . Reduction in health care cost through improved therapy. Maximum utilization of drug enabling reduction in total amount of dose administered. Reduction in fluctuation in steady-state level and therefore better control of disease condition. shorter treatment period. Increased safety margin of high potency drug due to better control of plasma levels.
.Less frequency of dosing and reduction in personnel time to dispense. Better control of drug absorption can be obtained. administer monitor patients. since the high blood level peaks that may be observed after administration of a dose of high availability drug can be reduced.
Possibility of dose dumping due to food. Poor in-vivo. pH dependent solubility etc.. increased first-pass metabolism. insufficient residence time for complete release. physiologic or formulation variable or chewing or grinding of oral formulation by the patient and thus increased risk of toxicity. Decreased systemic availability in comparisn to immediate release conventional dosage forms.. in-vitro correlation. site specific absorption. this may be due to incomplete release. increased instability. .Demerits.
on the basis of average drug biologic half-life’s.Retrieval of drug is difficult in case of toxicity. Economics factors must also be assessed. The physician has less flexibility in adjusting dosage regimens. poisoning or hypersensitivity reaction. This is fixed by the dosage form design. Consequently disease states that alter drug disposition. since more costly processes and equipment are involved in manufacturing many sustained release forms. significant patient variation and so forth are not accommodated.e. . Sustained release forms are designed for the normal population i.
.Diazepam and Phenytoin Drug with slow rate of absorption and elimination i. e.e.CHARACTERITICS OF DRUG FOR FORMULATION AS SUSTAINED RELEASE DOSAGE FORM:•Drug should exhibit neither very fast rate of absorption nor excretions Drug with higher rate of absorption and excretion are usually inherently long acting and their formulation in SRDF is not necessary. short half life less then 2 hr are difficult to formulate as system requires a larger unit dose size and may contribute to patient complains problem and also difficult to control the release rate of drug. . as they remain longer time in the body.g.
. Some drug like sulfonamide require larger dose for therapeutic activity so this kind of drug are difficult to form in SRDF as unit dose increases to an extent where it is difficult to swallow by patient.Riboflovin They should require relatively small doses.. e. Drug that are absorbed poorly and at unpredictable rate are not good candidate for SRDF because their release rate and absorption are depending on the position of drug in the GI tract and rate movement of drug.•Drug should be uniformly absorbed throughout GI tract.g.
that their therapeutic index should be relative range.•They should have good margin of safety i.e. . •The drug should not show any cumulative action. any undesired side effect as in case of dose dumping it might produce toxicity.
Physicochemical properties 2.Drug properties relevant to sustained release formulation The design of sustained release delivery system is subjected to several variables and each of variables are inter-related. 1. Biological properties . properties of the drugs may be divided in two types.
Biological Factors 1. 5. Absorption. Partition coefficient and molecular size. Physiological Factors: 1. Biological half life. 2. Drug stability. Dosage size. 6.(excreation) 5. Distribution. Aqueous Solubility.Factors to be considered In S.Dosage forms. Pka . 2. 4. Margin of safety 3.R. 3. Protein binding. Metabolism. 4.
. The rate of release is much slower than rate of absorption.Biological Factors Absorption. extent and uniformity in absorption of drug are important factor when considering its formulation in to controlled release system. Compounds that demonstrate true lower absorption rate constants will probably be poor candidates for sustaining systems. The maximum half-life for absorption should be approximately 3-4 hr otherwise. Absorption= dissolution The characteristics of absorption of a drug can greatly affects its suitability of sustained release product. Absorption of drug need dissolution in fluid before it reaches to systemic circulation. the device will pass out of potential absorptive region before drug release is complete. The rate.
As the rate limiting step in drug delivery from a sustained-release system is its release from a dosage form. another important criteria is the absorption of drug in GIT tract. rather than absorption. extent and uniformity of absorption of a drug are important factors considered while formulation of sustained release formulation. . Riboflavin like drugs are absorbed effectively by carrier transport at upper part of GIT which makes its preparation in SRDF difficult. drugs like Kanamycine and gentamycine shows absorption at different sites.The rate.
. relative to its release is essential if the system is to be successful. rather than absorption. Rapid rate of absorption of drug.As the rate limiting step in drug delivery from a sustained-release system is its release from a dosage form.
For design of sustained/ controlled release products. one must have information of disposition of drug. Since it not only lowers the concentration of drug but it also can be rate limiting in its equilibrium with blood and extra vascular tissue. consequently apparent volume of distribution assumes different values depending on time course of drug disposition.Distribution: The distribution of drugs into tissues can be important factor in the overall drug elimination kinetics. .
In case of one compartment model Vd = dose/C0 Where: C0= initial drug concentration immediately after an IV bolus injection In case of two compartment model. .colled T/P ratio.Two parameters that are used to describe distribution characteristics are its apparent volume of distribution and the ratio of drug concentration in tissue that is in plasma at the steady state the so. The apparent volume of distribution Vd is nearly a proportional constant that release drug concentration in the blood or plasma to the amount of drug in the body.
Vss = (1+K12/K21)/V1 Where: V1= volume of central compartment K12= rate constant for distribution of drug from central to peripheral K21= rate constant for distribution of drug from peripheral to central Vss= estimation of extent of distribution in the body Vss results concentration in the blood or plasma at steady state to the total mount of the drug present in the body during respective dosing or constant rate of infusion. At any other time it tends to overestimate or underestimate. . Equation 2 is limited to those instance where steady state drug concentration in both the compartment has been reached.
To avoid ambiguity inherent in the apparent volume of distribution as an estimation of the amount of drug in the body. T/P = K12 (K21-β) Where: β = slow deposition constant T= amount of drug in peripheral . The T/P ratio is used. The amount of drug in the body can be calculated by T/P ratio as given bellow.
this also will make preparation of sustained release product difficult. Drug that are significantly metabolized before absorption. either in lumen of intestine. can show decreased bio-availability from slower-releasing dosage forms. .Metabolism: There are two areas of concern relative to metabolism that significantly restrict sustained release formulation. 1. 2.If drug upon chronic administration is capable of either inducing or inhibition enzyme synthesis it will be poor candidate for sustained release formulation because of difficulty of maintaining uniform blood levels of drugs. If there is a variable blood level of drug through a first-pass effect.
Process device a specific period.Most intestinal wall enzymes systems are saturable. As drug is released at a slower rate to these regions less total drug is presented to the enzymatic. allowing more complete conversion of the drug to its metabolite. .
Biological half life. . to this drug must enter the circulation at approximately the same rate at which it is eliminated. The elimination rate is quantitatively described by the half-life (t1/2) Therapeutic compounds with short half life are excellent candidates for sustained release preparation since these can reduce dosing frequency. The usual goal of sustained release product is to maintain therapeutic blood level over an extended period.
More than 8 hours are also generally not used in sustaining forms. E. levodopa are poor for sustained release formulation because it requires large rates and large dose compounds with long half-life. Warfarin.g.Drugs with half-life shorter than 2 hours. since their effect is already sustained. Digoxin. Such as e.: Furosemide. .g.. Phenytoin etc.
e) Margin of safety: In general the larger the volume of therapeutic index the safer the drug.. Drug with very small values of therapeutic index usually are poor candidates for SRDF due to pharmacological limitation of control over release rate .g. = TD50/ED50 Larger the TI ratio the safer is drug. Phenobarbital.induced digitoxin.e. phenotoin. . It is imperative that the drug release pattern is precise so that the plasma drug concentration achieved in under therapeutic range.
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