INTRODUCTION TO SUSTAINED-RELEASE DOSAGE FORMS A sustained-release dosage form is designed to maintain constant levels of a drug in the patient's bloodstream

by releasing the drug over an extended period. Maintaining constant blood levels of the drug in the bloodstream increases the therapeutic effectiveness of the drug.

Many SRDF (suspensions, prodrugs and oil depots) have been used traditionally, where as others such as liposomes, polymeric microspheres and gels, implants, and needle-free injections have been introduced and approved in recent years. sustained release dosage forms are designed to release a drug at a predetermined rate by maintaining a constant drug level for a specific period of time with minimum side effects. This can be achieved through a variety of formulations, including liposomes and drugpolymer conjugates (commonly referred to as hydrogels). It is the definition for the controlled release dosage form rather than sustain release. Time release technology, also known as sustained-release (SR), sustained-action (SA), extended-release (ER, XR, or XL), time-release or timed-release, controlledrelease (CR), modified release (MR), or continuous-release (CR or Contin), is a mechanism used in pill tablets or capsules to dissolve slowly and release a drug over time. The advantages of sustained-release tablets or capsules are that they can often be taken less frequently than instant-release formulations of the same drug, and that they keep steadier levels of the drug in the bloodstream. Today, most time-release drugs are formulated so that the active ingredient is embedded in a matrix of insoluble substance(s) (various: some acrylics, even chitin; these substances are often patented) such that the dissolving drug must find its way out through the holes in the matrix. Some drugs are enclosed in polymer-based tablets with a laserdrilled hole on one side and a porous membrane on the other side. Stomach acids push through the porous membrane, thereby pushing the drug out through the laser-drilled hole. In time, the entire drug dose releases into the system while the polymer container remains intact, to be later excreted through normal digestion. In some SR formulations, the drug dissolves into the matrix, and the matrix physically swells to form a gel, allowing the drug to exit through the gel's outer surface. Micro-encapsulation is also regarded as a more complete technology to produce complex dissolution profiles. Through coating an active pharmaceutical ingredient around an inert core, and layering it with insoluble substances to form a microsphere you are able to obtain more consistent and replicable dissolution rates in a convenient format you can mix and match with other instant release pharmaceutical ingredients in to any two piece gelatin capsule. There are certain considerations for the formation of sustained-release formulation:

If the active compound has a long half-life (over 6 hours), it is sustained on its own. If the pharmacological activity of the active compound is not related to its blood levels, time releasing has no purpose. If the absorption of the active compound involves an active transport, the development of a time-release product may be problematic. Finally, if the active compound has a short half-life, it would require a large amount to maintain a prolonged effective dose. In this case, a broad therapeutic window is necessary to avoid toxicity; otherwise, the risk is unwarranted and another mode of administration would be recommended.

Benefits

for short half-life drugs, sustained release can mean less frequent dosing and thus better compliance. reduce variations in plasma/blood levels for more consistent result.

Problems

More complicated formulation, may be more erratic in result. A sustained release product may contain a larger dose, i.e. the dose for two or three (or more) 'normal' dosing intervals. A failure of the controlled release mechanism may result in release of a large toxic dose. more expensive technology

ADVANTAGES One advantage of sustained-release dosage forms is that medication must be administered less often than other dosage forms. Another advantage is that it reduces fluctuations of drug concentration in the blood. (See figures 6-2 and 6-3 for a graphic illustration of this principle.) Thus, the patient is not repeatedly subjected to amounts of the drug which are less than adequate or more than adequate. Nor does the blood chemistry undergo repeated chemical imbalances, which might be detrimental to the patient's health. Sustained-Release Dosage Form Definition: Sustained-release dosage forms (SRDF) are drug delivery systems that are used for drugs that cannot be formulated using the traditional forms or when a sustained- and controlled-release pattern is required to elicit desired pharmacological action of a drug. The goal of a sustained-release dosage form is to maintain therapeutic blood or tissue levels of the drug for an extended period by continuously releasing medication over an extended period of time after administration of a single dose. In order to be a possibility for inclusion in a sustained-release form, a drug should be efficiently absorbed over a major portion of the gastrointestinal tract, have a relatively short biological half-life, and it should not have a narrow therapeutic index. Many SRDF (suspensions, prodrugs and oil depots) have been used traditionally, where as others such as liposomes, polymeric microspheres and gels, implants, and needle-free injections have been introduced and approved in recent years. In long-term treatments,

extended release of the pharmaceutical compound offers such potential benefits as sustained blood levels, attenuation of adverse effects, and opportunity for improved patient compliance. The disadvantages are less flexibility of physician in adjusting dosage regimens and higher price of manufacturing. Extended-release products contain a higher drug load and thus any loss of integrity of the release characteristics of the dosage form has potential problems. Time Release Technology also known as Sustained-release (SR), extended-release (ER, XR, or XL), time-release or timed-release, controlled-release (CR), or continuous-release (CR or Contin) pills are tablets or capsules formulated to dissolve slowly and release a drug over time. The advantages of sustained-release tablets or capsules are that they can often be taken less frequently than instant-release formulations of the same drug, and that they keep steadier levels of the drug in the bloodstream. The first Sustained release tablets were made by Howard Press, in Hoboken, NJ in the early 50's and the first tablets relased under his process patent were called "Nitroglyn" and made under license by Key Corp., in Florida. Today most are formulated so that the active ingredient is embedded in a matrix of insoluble substance (various: some acrylics, even chitin, these are often patented) so that the dissolving drug has to find its way out through the holes in the matrix. In some SR formulations the matrix physically swells up to form a gel, so that the drug has first to dissolve in matrix, then exit through the outer surface. The difference between controlled release and sustained release is that controlled release is a perfectly zero order release; that is, the drug releases over time irrespective of concentration. Sustained release implies slow release of the drug over a time period. It may or may not be controlled release. GUIDELINES FOR THE DESIGN AND EVALUATION OF ORAL PROLONGED RELEASE DOSAGE FORMS Ministry of Health and Welfare, Japan (March 11, 1988) In recent years, in association with progress and innovation in the field of pharmaceutical technology, there has been an increasing effort to develop prolonged release dosage forms for many drugs. Correspondingly, a growing number of new prolonged release dosage forms have been submitted for regulatory approval. Prolonged release dosage forms have many advantages in safety and efficacy over immediate release drug products in that the frequency of dosing can be reduced, drug efficacy can be prolonged and the incidence and/or intensity of adverse effects can be decreased. However, some prolonged release dosage forms have less clear rationale or are developed for active ingredients which are not appropriate for prolonged release dosage forms. In other cases, prolonged release dosage forms are designed without full consideration of the basic properties of the drugs. Moreover, standards for dissolution tests, which are important for evaluating prolonged release dosage forms, have not appropriately been established. As a result, it is often difficult to evaluate whether a prolonged release dosage form is acceptable or not. Incomplete or undesirable prolonged release drugs may

merely cause therapeutic confusion and, in addition may interfere with development and spread of good quality drugs. As part of the effort to ensure and promote drug reliability, it appears necessary to establish appropriate guidelines for the design and evaluation of prolonged release dosage forms. The present guidelines are prepared for oral prolonged release dosage forms, mainly for drugs with new pharmaceutical forms. However, many of the general principles of the guideline are also applicable to other controlled release dosage forms. 1. Factors to be studied in dosage form design 1. I The properties of the active ingredient The following characteristics of drugs are critical in ensuring their efficacy and safety. Therefore they should be sufficiently studied to fulyl characterize the drug. i) Elimination half life: Drugs with long elimination half lives are generally undesirable for prolonged release dosage forms unless designed to prevent toxic effects due to a peaking effect or to reduce the dose. ii) The first pass effect: Bioavailability may be significantly impaired if the release rate is retarded for drugs that suffer from an extensive first pass effect. iii) The absorption site: If the absorption site is limited, absorption is likely to decrease and variable bioavailability will occur for typical prolonged release dosage forms. iv) Adverse reactions: Undesirable adverse reactions may develop by using prolonging drug release. It is desirable to clarify following factors: i) Correlation of clinical response with blood-drug concentrations or tissue concentrations at the site of action. ii) Induction or inhibition of drug metabolizing enzymes by the prolonged blood concentration, casual change of pharmacological response and the possibility of tolerance or addiction for the drug. iii) Interactions with other drugs due to protein binding. 1. I. 1 Pharmacodynamics The major purpose for developing prolonged release formulations of the drug is generally to maintain the blood concentration of the active ingredient at therapeutically effective levels. Therefore, it is desirable that average minimum effective concentration and optimal therapeutic concentrations be clarified for each drug by evaluating blood concentrations of the active ingredient or therapeutic moiety(s) including active metabolite(s) in relation to drug efficacy. The intra- and intersubject variations should be investigated for further confirmation of those levels. It is also desirable to investigate toxic blood drug concentrations. If the effective blood drug concentration is not known, estimates should be made from dose levels, blood concentrations, and clinical data based on the immediate release drug product. If effective blood drug concentration is unclear, the usefulness of the prolonged release dosage form should be demonstrated by well-designed clinical studies. 1. I. 2 Biopharmaceutics Information on the biopharmaceutical properties of the active ingredient for a prolonged release dosage form is essential in rational formulation design. Particular attention should be given to the following six factors: 1) location of major absorption sites or specificity in the site of absorption, 2) absorption rate, 3) the elimination half life of the drug, 4)

whether absorption is non-linear due to the saturated drug absorption, first pass effects, or other reasons, 5) whether elimination is non-linear due to drug metabolism saturation or other factors, and 6) inactivation or metabolism of the drug in the body, including the gastrointestinal tract. The above points should be clarified in humans if possible, or in animals if the evaluation in humans is difficult. It is also desirable that the effect of food, drugs likely to be used concurrently and physiological factors such as renal or hepatic function on the absorption, distribution, metabolism and excretion of the drug be studied and evaluated. In addition, it is useful to study effects of age, sex and smoking on the pharmacokinetics of the drug. 1.1.3 Chemistry and physicochemistry Chemical and physicochemical properties of drugs, especially, pH- solubility characteristics should be clarified. 1.2 Factors due to physiological condition The release of an active ingredient from a prolonged release dosage form, and its absorption are inevitably affected by physiological factors in the gastrointestinal tract. Prolonged release dosage forms are more susceptible to these factors than immediate release dosage forms. Therefore, the possible effects of the physiological factors should be fully considered for the dosage form design. If the drug is intended for use in a specific subpopulation, attentions should be paid to the specific physiology of the subpopulation. 1 .2.1 Transit characteristics of the dosage form through the gastrointestinal tract The transit rate of a dosage form through the gastrointestinal tract is known to depend on the formulation properties such as size, form, specific gravity and adhesiveness of the preparation and physiological properties such as the length, size and motility of the gastrointestinal tract; and on the composition and volume of the gastrointestinal content. It is also affected by food, diseases, posture, and stress. The bioavailability of drugs often depends on the gastrointestinal transit rate of the dosage form. Therefore, the traveling characteristics of the dosage form through the gastrointestinal tract should be fully considered in designing advantageous dosage forms. 1.2.2 Physiology of the gastrointestinal tract The physiological characteristics of the gastrointestinal tract (the volume, composition, pH, surface tension and viscosity of the gastrointestinal content; and gastrointestinal motility) vary greatly from site to site. Prolonged release dosage forms remain in the gastrointestinal tract longer than conventional preparations. Therefore, physiological conditions of the gastrointestinal tract can affect the release of active ingredients of these forms much more than release from conventional forms. Noteworthily, gastric pH varies from acidic to neutral, and these variations can affect release of the active ingredient from the dosage form. These points should be considered when a formulation is being designed and assessed. 1.3 Prototype dosage forms and selection of the final dosage form Desirable criteria of performance for prolonged release dosage forms are: duration of appropriate blood drug concentration for a sufficient time with minimal influence of food and physiological conditions of the gastrointestinal tract; and minimal contribution to intra- and intersubject variation. To select the best possible dosage form, all candidate

forms should be fully tested for release characteristics. Moreover the pharmacokinetic profile should be evaluated in an appropriate species of animal or volunteer.

2. Factors to be studied in the final dosage forms 2.1 Evaluation of the final dosage form 2. I. 1 Release characteristics A. Evaluation of the release characteristics The release of the active ingredient from the preparation in the gastrointestinal tract is affected by many physiological factors including the mechanical force exerted by the digestive tract in relation to its movement, and the volume, composition, pH, surface tension, and viscosity of the gastrointestinal fluid. Therefore, the in vitro release behaviors should be investigated under as many conditions as possible to understand possible effects of gastrointestinal variables on in vivo release. To achieve stable blood concentrations, it is generally desirable to prepare prolonged release dosage forms whose release rates are minimally pH dependent. Therefore, release of the active ingredient should be evaluated at multiple levels of pH, such as 1.2, 4.0 and 6.8, representing typical gastrointestinal pH variation. Considering the variation in gastrointestinal motility; agitation rates should also vary more than 2 levels among 50, 100 and 200 rpm, when the paddle method is used, at an appropriate pH. If it is anticipated that the release rate is influenced by the wettability, ionic strength and composition of the test medium, their effects should also be investigated. It is also desirable to perform release tests using different kind of apparatus. On the other hand, taking into consideration the variation of mechanical stress in the gastrointestinal tract, the drug release from prolonged release dosage forms containing an active ingredient with a narrow therapeutic window should be tested by the methods having a high mechanical stress, such as JP disintegration test method, the rotating flask method using beads and solubility simulator. B. Specifications for dissolution testing The specifications for drug releases should be established for quality control of prolonged release dosage forms. Basically, it is desirable to employ the release tests which can predict the blood level profile of the drug as precisely as possible. It is also desirable to set the specification including sampling time and amount of drug to be released so as to show the release profile as accurately as possible. The tolerable range of the drug release change depending on the effect of the release rate on absorption or a related pharmacodynamic property (therapeutic window, toxicity or adverse reactions). Therefore, based on the relation between release rate and blood concentration or pharmacological effects, the tolerable range should be set within limits which do not allow great changes in blood concentrations or in clinical efficacy. The narrow tolerance limits should be set as much as possible to decrease the variation in drug release which will provide stable clinical effects. If the relation between the release rate and blood concentration is not clear, or if sufficient data are not available to prove the correlation, it is difficult to set rational specification. In such a case it is desirable to set specifications using the second method (paddle method) in the Japanese Pharmacopoeia at sampling time points of 20-40%, 40-

60%, and more than 70% of the labeled amount of the active ingredient is released. If 100 rpm and 900 ml of test fluid was used for the paddle method, the tolerance ranges at 1st, 2nd and 3rd points should be set within 15%, 15% and 10% of the average release, respectively. At the 3rd sample point, only lower limit is acceptable instead of the tolerance range. The acceptance criteria of the drug release follow the criteria of dissolution or release tests of JP XI or USP XXI. C. Stability test Specimens for long term stability tests should be subject to dissolution testing and comply with the standards of the specifications. 2.1.2 Pharmacokinetics A. Comparison of the prolonged release dosage form with an immediate release dosage form As far as possible, the pharmacokinetics of the prolonged release dosage form should be compared with the immediate release product in healthy volunteers. Pharmacokinetic evaluation should be made, based on blood concentration data, except for the case that the concentrations of the active ingredient can be determined at the site of action whose effective concentrations are known. Data on drug concentration in the urine, saliva, or other body fluids will be accepted only when the concentrations of the active ingredient in the blood or at the site of action are correlated with that in these fluids. Unless the drug shows linear pharmacokinetics within the clinical dose range, the investigation should be made at two dose levels, high and low. i) Single dose study: The usefulness of the new prolonged release dosage form given according to the dosage regimen should be evaluated by comparing the blood concentration with that of the immediate release dosage form or alternative forms such as solution or a powder; or with a prolonged release product which has already been approved, when better prolonged release characteristics are claimed. The parameters to be compared are AUC (zero to the final sampling time), AUC (0-), Cmax, the duration of the minimum effective concentration, or optimal effective concentrations of the active ingredient if these concentrations are known or can be estimated. It is desirable to determine the time to reach the minimum effective concentration or the optimal effective concentration, Tmax, absorption rate constant, elimination rate constant, clearance, extent of absorption and MRT and VRT by the moment analysis method. ii) Multiple dose study: Prior to a multiple dose study, a blood concentration profile at steady state for multiple dosing of both standard and test dosage forms should be simulated from the single dose pharmacokinetic trials. In the multiple dose studies, it should be ascertained that Cmax and Cmin at steady state are within the estimated ranges, and the usefulness of the prolonged release dosage form should be evaluated by comparing it with the reference product in 1) Cmax, 2) Cmin, 3) the difference between Cmax and Cmin or the ratio (dosage form index, Cmax/Cmin), and the duration of the minimum effective concentration or that of optimal effective concentration. For drugs with non-linear absorption or elimination, those with a narrow therapeutic window, or those which may cause severe adverse reactions, the blood concentration profile at steady state should be characterized by multiple dose studies. When multiple dose studies in healthy volunteers are not done, the usefulness of the prolonged release dosage form should be shown using the simulated parameters, where it is necessary to confirm that

Cmax and Cmin are within the predicted range, by monitoring blood concentrations in clinical studies. B. Effect of dosing conditions and physiological factors Factors which might affect the pharmacokinetics of a prolonged release dosage form should be studied in which food is particularly an important factor because it is know to affect transit of dosage forms in gastrointestinal tracts, disintegration, and release of the drug. Therefore, the blood concentration profiles of the prolonged release dosage form should be compared between fasting and fed conditions. If a significant effects of food was observed, a special caution should be included in the dosage regimen (i.e. indication of drug administration only after meals), and it should be clarified whether the food effect was related to the drug itself or dosage forms by performing similar food studies using the drug solution or the immediate release product, although the studies are not needed when there is published evidence. In addition, as far as possible, it is desirable to clarify other factors of food (e.g., the volume and composition of meal, and intervals between food and drug administration) affecting the in vivo release and absorption. It is also desirable to investigate diurnal variations of pharmacokinetic parameters. 2.1.3 Clinical efficacy The clinical usefulness of the prolonged release dosage form should be shown comparing it with its already approved immediate release product or its already approved prolonged release product (if a better prolonged release dosage form is claimed). If the relation between the pharmacological effectiveness and blood concentration is unclear, the usefulness should be proved by the well-controlled clinical studies where the effective and toxic concentrations should be investigated by monitoring blood concentrations of the drug. 2.2 Establishment of dosing regimen The appropriate dosing regimen should be established during Phase I and 11 clinical studies in which it is recommended that the blood concentrations are monitored during Phase 11 clinical trials to establish a better dosing regimen. 2.2.1 Factors of particular importance in establishing dosing regimen i) Overdose or dose dumping: Sustained release dosage forms might be more likely to produce significant adverse and toxic effects than immediate release dosage forms in case of overdose or dose dumping because of the higher doses of active ingredients which are absorbed over a prolonged time. Dose dumping, e.g. resulting from crushing by the teeth, may be another problem with prolonged release dosage forms. This is of particular concern for drugs with a narrow therapeutic window, and so studies are desired to establish preventive measures and actions to be taken in such cases. ii) Disease state: The physiological changes in gastrointestinal tract, liver, kidneys, or heart due to diseases often affect absorption, distribution and elimination of drugs and there is a possibility that prolonged release dosage forms are particularly susceptible to the changes. In such cases, the dosing regimen should be studied and established as to reflect the pathological changes. iii) Combination therapy: If any other drug is used concurrently, it may affect the absorption, distribution, and elimination of the drug contained in the prolonged release dosage form. As a result, blood concentrations of the drug may be changed, and this may affect the efficacy. The possible effect of drugs which might be used together in practice

should be studied, and suitable indications and special warnings for the concurrent use of other drugs should be established. 2.2.2 Dosing guidelines Recommendations for dosing conditions, frequency of dosing per day, and dose levels (initial dose, maintenance dose, dose adjustment for insufficient response, and the maximum tolerable dose) should be established, based on the available pharmacokinetic data during Phase 11 clinical studies. The action to be taken if toxic signs or adverse effects develop should also be specified in these guidelines. Detailed dosing guidelines including information about dose adjustment based on blood concentration monitoring or changes in renal clearance of each patient may be useful to maximize the therapeutic efficacy by making the utmost use of the advantages of the prolonged release dosage form. It is desirable to set up corresponding detailed guidelines particularly for prolonged release products containing A) drugs, blood concentrations of which may change strikingly by minimal changes in dose (drugs with non-linear absorption or elimination), B) drugs, the clearance and blood concentrations of which are susceptible to physiological conditions, age and so forth, C) drugs with a narrow therapeutic window, and D) drugs which might cause tolerance and/or severe adverse effects.

PARAMETERS REQUIERED FOR SUSTAINED RELEASE DRUG DELIVERY SYSTEM

Abstract:
Oral drug delivery is the largest and the oldest segment of the total drug delivery market. It is the fastest growing and most preferred route for drug administration. Use of different release retardant for oral sustained release of drugs is a common practice in the pharmaceutical industry. In this study discusses formulation and manufacturing variables affecting the design and performance of the extended-release product by using selected practical examples.Optimal therapy of a disease requires an efficient delivery of active drugs to the tissues, organs that need treatment. Very often doses far in excess to those required in the cells have to be administered in order to achieve the necessary therapeutically effective concentration. This unfortunately may lead to undesirable, toxicological and immunological effects in non-target tissue. A controlled release dosage forms leads to better management of the acute or chronic disease condition.

Full Text:
INTRODUCTION SUSTAINED RELEASE 1 2, 3, 13, 14, 15, 16 Sustained release tablets and capsules are commonly taken only once or twice daily, compared with counterpart conventional forms that may have to take three or four times daily to achieve the same therapeutic effect. Typically, sustained release products provide an immediate release of drug that promptly produces the desired therapeutic effect, followed by gradual release of additional amounts of drug to maintain this effect over a

predetermined period. The sustained plasma drug levels provide by sustained release products often times eliminates the need for night dosing, which benefits not only the patients but the care given as well. The basic rationale of a sustained drug delivery system is to optimize the Biopharmaceutic, Pharmacokinetic and Pharmacodynamic properties of a drug in such a way that its utility is maximized through reduction in side effects and cure or control of condition in the shortest possible time by using smallest quantity of drug, administered by the most suitable route. The novel system of drug delivery offer a means of improving the therapeutic effectiveness of incorporated drugs by providing sustained, controlled delivery and / or targeting the drug to desired site. The goal of any drug delivery system is to provide a therapeutic amount of drug to the proper site in the body to achieve promptly and then maintain the desired drug concentration. There is a continuously growing interest in the pharmaceutical industry for sustained release oral drug delivery systems. There is also a high interest for design a dosage formulation that allows high drug loading, particularly for actives with high water solubility. Oral route has been the most popular and successfully used for sustained delivery of drugs because of convenience and ease of administration, greater flexibility in dosage form design and ease of production and low cost of such a system. The sustained release systems for oral use are mostly solid and based on dissolution, diffusion or a combination of both mechanisms in the control of release of drugs. In this type of dosage forms, a sufficient amount of drug is initially made available to the body to cause a desired pharmacological response. The remaining fraction is released periodically and is required to maintain the maximum initial pharmacological activity for some desirable period of time in excess of time expected from usual single dose. MECHANISM OF DRUG RELEASE On exposure to aqueous fluid, hydrophilic matrices take up water, and polymer starts hydrating to form a gel layer. Drug release is controlled by diffusions barriers / or by surface erosion. An initial burst of soluble drug may occur due to surface leaching when a matrix containing a swellable glassy polymer comes in contact with an aqueous medium, there is an abrupt change from a glassy to a rubbery state which is associated with swelling process with time, water infiltrator deep into the case increasing the thickness by the gel layer. Concomitantly the outer layer becomes fully hydrated and states dissolving or eroding. When water reaches the center of the system and the concentration of drug fells below the solubility value, the release rate of drug begins to reduce. At the same time, an increase in thickness of the barrier layer with time increases the diffusion path length, reducing the rate of drug release. Drug release kinetic associated with these gel layer dynamic, range initially from Fickian to annomalous (Non Fickian) and subsequently from quasi Constant ( near Zero order ) to constant. In general, two major factors control the drug release from swelling controlled matrix system. They include 1. The rate of aqueous medium infiltration into the matrix, followed by a relaxation process (hydration, gelatin or swelling) 2. The rate of matrix erosion

FIGURE 1 As a result of these simultaneous processes, two front are evident, a swelling front, where the polymer get hydrated, and an eroding front. The distance between these two fronts are called diffusion layer thickness. Diffusion layer thickness depends on the selective rate at which the swelling and eroding fronts move in relation to each other. If the polymer gets slowly, solvent can penetrate deep into the glassy matrix the dissolving the drug; there for gel layer thickness and it stability are council in controlling drug release. Swelling of HPMC matrix tablet was higher for higher a molecular weight. They attributed this to the large hydrodynamic volume occupied by higher molecular weight chain when hydrated. As the polymer chain becomes more hydrated and the gel becomes more dilute, the disentanglement concentration may be reached that is, the critical polymer concentration below which the polymer chain disentangle and detached from gelled matrix. Potential advantages and disadvantages of sustained release dosage forms 3, 4 Advantages: i] Patient Compliance: Lack of compliance is generally observed with long term treatment of chronic disease, as success of drug therapy depends upon the ability of patient to comply with the regimen. Patient compliance is affected by a combination of several factors, like awareness of disease process, patient faith in therapy, his understanding of the need to adhere to a strict treatment schedule. Also the complexity of therapeutic regimens, the cost of therapy and magnitude of local and or systemic side effect of the dosage form. The problem of lack of patient compliance can be resolved to some extent by administering controlled release drug delivery system. ii] Reduced 'see- saw' fluctuation: Administration of a drug in a conventional dosage form [except via intravenous infusion at a constant rate] often results in 'see saw' pattern of drug concentration in the systemic circulation and tissue compartments. The magnitudes of these fluctuations depend on drug kinetics such as the rate of absorption, distribution, elimination and dosing intervals. The 'see-saw' or 'peak and valley' pattern is more striking in case of drugs with biological half lives of less than four hours, since prescribed dosing intervals are rarely less than four hours. A well designed controlled release drug delivery system can significantly reduce the frequency of drug dosing and also maintain a more steady drug concentration in blood circulation and target tissue cells. iii] Reduced total dose: Controlled release drug delivery systems have repeatedly been shown to use less amount of total drug to treat a diseased condition. By reducing the total amount of drug, decrease in systemic or local side effects are observed. This would also lead to greater economy. iv] Improved efficiency in treatment: Optimal therapy of a disease requires an efficient delivery of active drugs to the tissues, organs that need treatment. Very often doses far in excess to those required in the cells have to be administered in order to achieve the necessary therapeutically effective concentration. This unfortunately may lead to undesirable, toxicological and immunological effects in non-target tissue. A controlled release dosage forms leads to

better management of the acute or chronic disease condition. v] Economy: (a) In comparison with conventional dosage forms the average cost of treatment over an extended period may be less. (b) Economy also may results from a decrease in nursing time and hospitalization. Also 1. Reduce blood level oscillation characteristic of multiple dosing of conventional dosage forms. 2.Reduce amount of drug administration 3.Maximizing availability with a minimum dose. 4.Control of drug absorption; high peak level peaks that may be observed after administration of high availability drug can be reduced. 5.Safety margin of high potency drugs can be increased. vi} Improved therapy: a) Sustained blood level: The dosage form provides uniform drug availability / blood levels unlike peak and valley pattern obtained by intermittent administration. b) Attenuation of adverse effects: The incidence and intensity of undesirab effects caused by excessively high peak drug concentration resulting from the administration of conventional dosage forms is reduced. c) It is seldom that a dose is missed because of non-compliance by the patient. Disadvantages: i) Dose dumping: Dose dumping is a phenomenon where by relatively large quantities of drug in a controlled release formulation is rapidly released, introducing potential toxic quantities of the drug into the systemic circulation. Dose dumping can lead to fatalities in case of potent drug, which have a narrow therapeutic index e.g. Phenobarbital. ii) Less flexibility in accurate dose adjustment: In conventional dosage forms, dose adjustments are much simpler e.g. tablet can be divided into two fractions. In case of controlled release dosage forms, this appears to be much more complicated. Controlled release property may get lost, if dosage form is fractured. iii) Poor In Vitro In Vivo correlation: In controlled release dosage form, the rate of drug release is deliberately reduced to achieve drug release possibly over a large region of gastrointestinal tract. Here the so called Absorption window becomes important and may give rise to unsatisfactory drug absorption in vivo despite excellent in-vitro release characteristics. iv) Patient variation: The time period required for absorption of drug released from the dosage form may vary among individuals. Co-administration of other drugs, presence or absence of food and residence time in gastrointestinal tract is different among patients. This also gives rise to variation in clinical response among the patient. Factors of consideration in Design of sustained Release Dosage Forms: 5,6,3,7,4,8,9 The therapeutic efficacy of drug under clinical conditions is not simply a function of its intrinsic pharmacological activity but also depends upon the path of the drug molecule from the site of administration to the target site. Different conditions encountered by the

drug molecule while traversing the path of distribution may alter either the effectiveness of the drug or affect the amount of the drug reaching the receptor site. A] Pharmaceutics: This refers to the development/manufacturing of an efficient delivery system in which the drug has maximum physiological stability and optimum bioavailability. B] Biopharmaceutics/ pharmacokinetics: This involves the study of absorption, distribution, metabolism and excretion of the drug, before and after reaching the target site and evaluation of the relationship between delivery system and therapeutic response. C] Pharmacodynamics/ Clinical Pharmacology: It is the study of the mechanism of action and clinical efficacy of a drug administered in dosage form in terms of onset, intensity and duration of pharmacological activity. Table.1 - Characteristics of Drugs Unsuitable for oral Sustained Release Forms Characteristics Drugs Not effectively absorbed in the lower intestine Riboflavin, Ferrous salts Absorbed and excreted rapidly; short biologic half-lives (< 1hr) Penicillin G, furosemide Long biologic half-lives (>12 hr) Diazepam, phenytoin Large doses required (>1g) Sulfonamides Cumulative action and undesirable side effects; drugs with low therapeutic indices. Phenobarbital, digitoxin Precise dosage titrated to individual is required Anticoagulants, cardiac glycosides No clear advantage for sustained release formulation Griseofulvin BIOPHARMACEUTICAL FACTORS Dissociation constant Pka: A drug to be absorbed it first must dissolve in the aqueous phase surrounding the site of administration and then partition in the absorbing membrane. Two of the most important Physicochemical properties of a drug that influence its absorptive behavior are its aqueous solubility and if it is a weak acid or base its Pka. These properties pay an influential role in the performance of controlled release systems. Partition Coefficient: The partition coefficient is another important drug property, which influences the design of oral controlled delivery by two ways; it is an important property that governs the permeation of drug particles through biological membrane. The diffusion of drug molecules across rate controlling membrane or through the matrix systems essentially relies on partition coefficient. Drug stability: The stability of the drugs at the site of its release and exposure bio-milieu is one more drug property that can influence the design of oral controlled drug delivery. Drugs that are unstable in gastric pH can be developed as slow release dosage form and drug release can be delayed till the dosage form reaches the

intestine. Drugs that undergo gut-wall metabolism and show instability in small intestine are not suitable for controlled drug delivery systems. Absorption: The rate, extent and uniformity of absorption of a drug are important factors when considering its formulation into a controlled release system. Since the rate limiting step in drug delivery from a controlled release system is its release from a dosage form, rater than absorption, a rapid rate of absorption of drug relative to its release is essential if the system is to be successful. Distribution: The distribution of a drug into vascular and extra vascular spaces in the body is an important factor in its overall elimination kinetics. Two parameters that are used to describe the distribution characteristics of a drug are its apparent volume of distribution and the ratio of drug concentration in the tissue to that in plasma at the steady state called T/P ratio. The magnitude of the apparent volume of distribution can be used as a guide for additional studies and as a predictor for a drug dosing regimen and hence the need to employ a controlled system. Metabolism: Drugs that are significantly metabolized before absorption either in the lumen or tissue of the intestine can show decreased bioavailability from slower releasing dosage forms. Formulation of these enzymatically susceptible compounds as Prodrug is another viable solution. Side Effects and Safety considerations: The side effects of some drugs are mainly developed due to the fluctuation in the plasma concentrations. The incidences of side effects can be minimized by controlling the concentration within therapeutic range at any given time. Disease State : Even, in some cases are considered before the designing of an oral controlled delivery. This can be explained by the following classical examples. Aspirin is a drug of choice for rheumatic arthritis, and it is nota suitable candidate for sustained release dosage form. Still an aspirin sustained release dosage from could be advantageous to maintain therapeutic concentrations, particularly through out the night, thus alleviating morning stiffness. Criteria to be met by drug proposed to be formulated in sustained release dosage forms. 10,11,2,3,12 a)Desirable half-life: The half life of a drug is an index of its residence time in the body. If the drug has a short half life (less than 2 hours), the dosage form may contain a prohibitively large quantity of the drug. On the other hand, drug with elimination half life of eight hours or more are sufficiently sustained in the body, when administered in conventional dosage from, and controlled release drug delivery system is generally not necessary in such cases. Ideally, the drug should have half-life of three to four hours. b) High therapeutic index:

Drugs with low therapeutic index are unsuitable for incorporation in controlled release formulations. If the system fails in the body, dose dumping may occur, leading to fatalities eg. Digitoxin. c) Small dose: If the dose of a drug in the conventional dosage form is high, its suitability as a candidate for controlled release is seriously undetermined. This is chiefly because the size of a unit dose controlled release formulation would become too big, to administer without difficulty. d) Desirable absorption and solubility characteristics: Absorption of poorly water soluble drug is often dissolution rate limited. Incorporating such compounds into controlled release formulations is therefore unrealistic and may reduce overall absorption efficiency. e) Desirable absorption window: Certain drugs when administered orally are absorbed only from a specific part of gastrointestinal tract. This part is referred to as the absorption window. Drugs exhibiting an absorption window like fluorouracil, thiazide diuretics, if formulated as controlled release dosage form are unsuitable. f) First pass clearance: As discussed earlier in disadvantages of controlled delivery system, delivery of the drug to the body in desired concentrations is seriously hampered in case of drugs undergoing extensive hepatic first pass metabolism, when administered in controlled release forms.