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Sustain Release Drug Delivery System PREPARED BY: SONAM M. GANDHI

contents: 

contents INTRODUCTION RATIONALATY IN DESIGNING S.R.D.F. CONCEPT OF S.R.D.F. 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 CONSIDERD IN S.R.D.F. Formulation of sRDF. PROBLEMS DURING S.R.D.F. EVALUATION OF S.R.F. DOSE DIFFERENCE AS COMPARE TO CONVENTIONAL ONE.

WHAT IS DRUG DELIVERY SYSTEMS?: 

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.

HISTORY: 

HISTORY 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

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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 .”

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W ith many drugs, 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. Needs of SRDS To eliminate the need for multiple dosage regimens To eliminate the undesirable side effects

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Rationality in designing S.R.Dosage form. The basic objective in dosage form design is to optimize the delivery of medication so as to achieve a measure of 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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Plasma concentration v/s time curve

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Concept of sustained release formulation The Concept of sustained release formulation can be emphasized with reference to 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.

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The above criteria i.e. (Kr>Ka) is in case of immediate release, where as in non immediate (Kr<Ka) i.e. release is rate limiting step. Thus effort of developing S.R.F must be directed primarily altering the release rate. the rate should be independent of drug removing in the dosage form over constant time. The release should follow zero order kinetics Kr = rate in = rate out = KeVd.Cd Where Ke = overall elimination (first order kinetics). Vd = total volume of distribution. Cd = desired drug concentration.

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B) Dose consideration : - To achieve the therapeutic level & sustain for a given period of time for the dosage form generally consist of 2 part Initial primary dose b) maintenance dose there for the total dose ‘ W ’ can be. W = Di + Dm In a system, the therapeutic dose release follows zero order process for specified time period then, W= Di + K 0 r. Td Td = time desired for sustained release from one dose.

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If maintenance dose begins to release the drug during dosing t=O then, W = Di + K 0 r Td – K 0 r Tp Tp = time of peak drug level. 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

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Sustained release, sustained action, prolonged action, controlled release, 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, this period may vary from days to month, in case of orally administrated forms, however, this period is measured in hours & critically depends on the residence time of the dosage form in GI tract.

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In some case, control of drug therapy can be achieved by taking advantage of beneficial drug interaction that affect drug disposition and elimination. E.g.:- the action of probenicid, which inhibit the excretion of penicillin, thus prolonging it’s blood level. Mixture of drug might be utilized to attend, synergize, or antagonize given drug action. Sustained release dosage form design embodies this approach to the control of action i.e. through a process of either drug modification, the absorption process, and subsequently drug action can be controlled.

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The difference between controlled release and sustained release, controlled drug delivery- 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. 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 resulting 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.

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Repeat-action versus sustained-action drug therapy A repeat-action tablet may be distinguished from its sustained-release product dose release the drug in slow controlled manner and consequently does not give a plasma concentration time curve which resemble that of a sustained release product. A repeat action tablet usually contains two dose of drug; the 1 st being released immediately following per oral administration in order to provide a repeat onset of therapeutic response. The release of second dose is delayed, usually by means of an enteric coat. Consequently, when the enteric coat surrounding the second dose is breached by the intestinal fluid, the second dose is release immediately.

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figure shows that the plasma concentration time curve obtained following the administration of one repeat- action preparation exhibit the “PEAK & VALLY”. 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.

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Difficulties arise in maintaining the drug concentration in the therapeutic range. Patient incompliance due to increase frequency of dosing, therefore chances of missing the dose of the drugs with short half life Difficulty to attain steady state drug concentration. Fluctuation may lead to under medication or over medication.

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These difficulties may be overcome by: Developing the new better and safer drug with long half life & large therapeutic indices. Effective and safer use of existing drugs through concept and techniques of controlled and targeted drug delivery.

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Merits. Improved patient convenience and compliance due to less frequent drug administration. Reduction in fluctuation in steady-state level and therefore better control of disease condition and reduced intensity of local or systemic side effects. Increased safety margin of high potency drug due to better control of plasma levels.

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Less frequency of dosing and reduction in personnel time to dispense, administer monitor patients. Better control of drug absorption can be obtained, since the high blood level peaks that may be observed after administration of a dose of high availability drug can be reduced. Maximum utilization of drug enabling reduction in total amount of dose administered. Reduction in health care cost through improved therapy, shorter treatment period .

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Disadvantage / Demerits.. Decreased systemic availability in comparisn to immediate release conventional dosage forms; this may be due to incomplete release, increased first-pass metabolism, increased instability, insufficient residence time for complete release, site specific absorption, pH dependent solubility etc., Poor in-vivo, in-vitro correlation. Possibility of dose dumping due to food, physiologic or formulation variable or chewing or grinding of oral formulation by the patient and thus increased risk of toxicity.

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Retrieval of drug is difficult in case of toxicity, poisoning or hypersensitivity reaction. The physician has less flexibility in adjusting dosage regimens. This is fixed by the dosage form design. Sustained release forms are designed for the normal population i.e. on the basis of average drug biologic half-life’s. Consequently disease states that alter drug disposition, significant patient variation and so forth are not accommodated. Economics factors must also be assessed, since more costly processes and equipment are involved in manufacturing many sustained release forms.

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Factors to be considered In S.R.Dosage forms. 1.Biological Factors a) Biological half life. b) Absorption. Distribution. Metabolism.

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Biological half life . The usual goal of sustained release product is to maintain therapeutic blood level over an extended period , 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.

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Drugs with half-life shorter than 2 hours. Such as e.g.: Furosemide , levodopa are poor for sustained release formulation because it requires large rates and large dose compounds with long half-life. compound with long half life More than 8 hours are also generally not used in sustaining forms, because their effect is already sustained. E.g.; Digoxin, Warfarin, Phenytoin etc.

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Absorption. The characteristics of absorption of a drug can be greatly effects its suitability of sustained release product. The rate of release is much slower than rate of absorption. The maximum half-life for absorption should be approximately 3-4 hr otherwise, the device will pass out of potential absorptive region before drug release is complete. Compounds that demonstrate true lower absorption rate constants will probably be poor candidates for sustaining systems .

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The rate, extent and uniformity of absorption of a drug are important factors considered while formulation of sustained release formulation. As the rate limiting step in drug delivery from a sustained-release system is its release from a dosage form, rather than absorption. It we assume that transit time of drug  must in the absorptive areas of the GI tract is about 8-12 hrs.

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The distribution of drugs into tissues can be important factor in the overall drug elimination kinetics. Since the distribution factor not only lowers the concentration of drug but 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. For design of sustained/ controlled release products, one must have information of disposition of drug. Distribution:

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Metabolism: There are two areas of concern relative to metabolism that significantly restrict sustained release formulation. 1.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. 2. If there is a variable blood level of drug through a first-pass effect, this also will make preparation of sustained release product difficult.

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Most of the intestinal wall enzymes systems are saturable. As drug is released at a slower rate to these regions less total drug is goes to the enzymatic Process . at specific period, allowing more complete conversion of the drug to its metabolite. Drug that are significantly metabolized before absorption, either in lumen of intestine, can show decreased bio-availability from slower-releasing dosage forms.

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2. Physiological Factors: a) Dosage size. b) Partition coefficient and molecular size. c) Aqueous Solubility. d)Drug stability. e) Protein binding.

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1.Dosage size. In general a single dose of 0.5 - 1.0 gm is considered for a conventional dosage form this also holds for sustained release dosage forms.

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2. Partition coefficient and molecular size. Partition coefficient is the fraction of drug in an oil phase to that of an adjacent aqueous phase. High partition coefficient compound are predominantly lipid soluble and have very low aqueous solubility and thus these compound persist in the body for long periods. Partition coefficient and molecular size influence not only the penetration of drug across the membrane but also diffusion across the rate limiting membrane

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The ability of drug to diffuse through membranes its so called diffusivity & diffusion coefficient is function of molecular size (or molecular weight). Generally, values of diffusion coefficient for intermediate molecular weight drugs, through flexible polymer range from 10-8 to 10-9 cm2 / sec. with values on the order of 10-8 being most common for drugs with molecular weight greater than 500. Thus high molecular weight drugs and / or polymeric drugs should be expected to display very slow release kinetics in sustained release device using diffusion through polymer membrane.

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3.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 transit time of undissolved drug particles and limited solubility at the absorption site. E.g.: Tetracycline dissolves to greater extent in the stomach than in the intestine, therefore it is best absorbed in the intestine.

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Most of drugs are weak acids or bases, since the unchanged form of a drug preferentially permeates across lipid membranes, drugs aqueous solubility will generally be decreased by conversion to an unchanged form. for drugs with low water solubility will be difficult to incorporate into sustained release mechanism.

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4.Drug stability. The stability of drug in environment to which it is exposed, is another physico-chemical factor to be considered in design of sustained/ controlled release systems, drugs that are unstable in stomach can be placed in slowly soluble 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. Because of Degradation reduced rate of drugs release in the solid state.

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Compounds that are unstable in the small intestine may demonstrate decreased bioavailability when administered form a sustaining dosage from. This is because more drug is delivered in small intestine and hence subject to degradation. for drugs that are unstable in stomach, systems that prolong delivery ever the entire course of transit in GI tract are beneficial.

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5.Protein binding. It is well known that many drugs bind to plasma protein with the influence on duration of action. Drug-protein binding serve as a depot for drug producing a prolonged release profile , especially when it is high degree of drug binding occurs. Extensive binding to plasma proteins will be evidenced by a long half life of elimination for drugs and such drugs generally most require a sustained release dosage form. However drugs which show high degree of binding to plasma proteins also might bind to bio-polymers in GI tract which could have influence on sustained drug delivery.  The presence of hydrophobic moiety on drug molecule also increases the binding potential .

Evaluation of formulation: 

Evaluation of formulation Evaluation of characteristics of powder blend and tablets The various characteristics of powder blend like bulk density, tapped density, angle of repose, particle size and drug content were studied. The formulated tablets were evaluated for hardness, friability, uniformity of weight and drug content.

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Drug content of formulated tablets Five tablets from each formulation were randomly chosen, pulverized(reduce to powder) and weight equivalent to 50mg of Drug was extracted with 100ml phosphate buffer (pH 7.4 ). subsequent filtered solution was further diluted in phosphate buffer (pH 7.4) in such a way that theoretical concentration was same as that of standard concentration. Resultant solutions were analyzed by using a UV spectrophotometer (in triplicate) and the average results taken .

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In vitro dissolution studies The dissolution studies were performed in triplicate for all the batches in a dissolution rate test apparatus. The release studies were performed at 100 rpm in 900 ml of phosphate buffer pH 7.4 at 37 ± 0.2 ο C. Five milliliters sample were withdrawn at predefined intervals, and the volume of the dissolution medium was maintained by adding the same volume of fresh buffer in dissolution medium. The absorbance of the withdrawn samples was measured spectrophotometrically at ………… nm.

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Studying the effect of tablet hardness on release profile: After performing the dissolution test on the best formulations obtained from the polymers investigated, another series of tablets with a hardness value of 3 KP units lower was compressed from the same formulations. The tablets were then tested for their release behavior the same way as above.

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Problem during sustained released formulation For drugs with elimination half life less than two hrs, that are administered in large doses, a sustained release dosage from may not contain large quantity of drug, on the other hand, drugs with elimination half lives of 3 hrs or more are sufficiently sustained in the conventional doses, and sustained release is generally not necessary.

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e.g. Administering drugs like warfarin (anticoagulant), whose pharmacological effect is delayed relative to its blood profile, so no clinical advantage in sustained release formulation.

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There are various hydrophilic polymers which are used to sustain the drug release. Waxes are one of the material which can be use to coat the drug in order to control the release but some polymers are incompatible with drug, and form precipitation. There is problems of dose dumping.

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Evaluation of sustained release formulation: During formulation development, testing methods should be designed to provide answer to the following questions Does the product “ dump ” maintenance dose before the maintenance period is complete? Sustained release product are subjected to either of two modes of failure, insufficient dose is release or too much drug is made available too quickly. What fraction of the dose remains unavailable, i.e. what fraction will not be released in the projected time of transit in the GI tract? What is effect of physiologic variables on drug release? For e.g.: delayed gastric empting, interaction between drug and GI constituent ’ s composition and volume of GI fluid.

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Is the loading dose released immediately? Is release of the maintenance dose delayed? If so, is the delay time within the desired range? What is the stability of the formulation with respect to its drug release profile?

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