Sustained release drug delivery system

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A drug delivery system that are design to achieve prolonged release of medication over an extended period of time for therapeutic effect in a single dose.

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A SEMINAR ON SUSTAINED RELEASE DRUG DELIVERY SYSTEM presented by MANE PRASHANT P. M.Pharm (1 st year) Dept.of Pharmaceutical Technology H.K.E’S COP,GLB. Under The Guidance Of S.B.SHIRSAND M.Pharm.(P.hd)

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Sustain Release Drug Delivery System

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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. METHOD OF FORMULATION OF S.R.D.F EVALUATION OF S.R.F. PROBLEMS DURING FORMULATION. MARKETED PRODUCT OF SRDF. REFERENCES.

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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. INTRODUCTION

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The history of controlled release technology is divided into three time periods From 1950 to 1970 was the period of sustain drug release From 1970 to 1990 was involved in the determination of the needs of the control drug delivery Post 1990 modern era of controlled release technology HISTORY INTRODUCTION

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Before initiating a discussion of sustained release dosage forms, it is necessary to provide a short explanation of terminology used because there is considerable confusion in this area. The general consensus is that controlled release denotes systems, which can provide some control, whether this is of a temporal or spatial nature , or both, of drug release in the body. In other words, the systems attempts to control drug concentration in the target tissue or cells. Thus, prolonged release or sustained release systems, which only prolong therapeutic blood or tissue levels of the drug for an extended period of time, cannot be considered as controlled release systems by this definition. They are distinguished from rate-controlled drug delivery systems, which are able to specify the release rate and duration in vivo precisely, on the basis of simple in vitro tests. Drug targeting, on the other hand, can be considered as a form of controlled release in that it exercises spatial control of drug release within the body. INTRODUCTION

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

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However, an ideal dosage regimen would be one, in which the concentration of the drug, nearly coinciding with minimum effective concentration (M.E.C.), is maintained at a constant level throughout the treatment period. Such a situation can be graphically represented by the following figure CONSTANT LEVEL INTRODUCTION

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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.” 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. INTRODUCTION

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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 C ontrolled 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 achieving a therapeutic level which is prolonged, but not maintained constant. Sustained release implies slow release of the drug over a time period. It may or may not be controlled release.

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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 to achieve the control of therapeutic effect in the face of uncertain fluctuation in the vivo environment in which drug release take place. This is usually concerned with maximum drug availability by attempting to attain a maximum rate and extent of drug absorption however, control of drug action through formulation also implies controlling bioavailability to reduce drug absorption rates.

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Plasma concentration v/s time curve

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Concept of sustained release formulation The Concept of sustained release formulation can be divided in to two considerations i.e. release rate & dose consideration 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. S o that effort for 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 rate 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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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. A repeat action tablet usually contains two dose of drug; the 1 st being released immediately following 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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PEAK VALLY

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figure shows that the plasma concentration time curve obtained by the administration of one repeat- action preparation exhibit the “PEAK & VALLY”. Profile associated with the intermittent administration of conventional dosage forms. 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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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. Increased safety margin of high potency drug due to better control of plasma levels. Maximum utilization of drug enabling reduction in total amount of dose administered. Reduction in health care cost through improved therapy, shorter treatment period. Merits.

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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.

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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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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, as they remain longer time in the body. e.g.- Diazepam and Phenytoin Drug with slow rate of absorption and elimination i.e. 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.

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Drug should be uniformly absorbed throughout GI tract. Drug that are absorbed poorly and at unpredictable rate are not good candidate for SRDF because there release rate and absorption are depending on the position of drug in the GI tract and rate movement of drug. e.g.- Riboflovin is not absorbed in GI tract. They should require relatively small doses. 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.

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They should have good margin of safety i.e. that their therapeutic index should be relative range. The drug should not show any cumulative action, any undesired side effect as in case of dose dumping it might produce toxicity. Some drug does not have any clear advantage for SRDF like Cqiseuilin .

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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. For the purpose of discussion it is convenient to describe the properties of the drugs as being either physico -chemical or biological ,these may be divided in two types . 1. Physicochemical properties 2. Biological properties

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Factors to be considered In S.R.Dosage forms. 1.Biological Factors Absorption. Distribution. Metabolism. Biological half life.( excreation ) Margin of safety Physiological Factors: Dosage size. Partition coefficient and molecular size. Aqueous Solubility. Drug stability. Protein binding. Pka

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Biological Factors Absorption. Absorption of drug need dissolution in fluid before it reaches to systemic circulation. The rate, extent and uniformity in absorption of drug are important factor when considering its formulation in to controlled release system. Absorption= dissolution 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. 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. an another important criteria is the through absorption of drug in GIT tract, drug like Kanamycine and gentamycine shows absorption are different sites, Riboflavin like drug absorbed effectively by carrier transport and at upper part of GIT that make it preparation in SRDF difficult.

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As the rate limiting step in drug delivery from a sustained-release system is its release from a dosage form, rather than absorption. Rapid rate of absorption of drug, relative to its release is essential if the system is to be successful.

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The distribution of drugs into tissues can be important factor in the overall drug elimination kinetics. 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. For design of sustained/ controlled release products, one must have information of disposition of drug. Distribution:

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Two parameters that are used to describe distribution characteristics are its apperent volume of distribution and the ratio of drug concentration in tissue that in plasma at the steady state the so- colled T/P ratio. 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. In case of one compartment model Vd = dose/C 0 Where: C 0 = initial drug concentration immediately after an IV bolus injection In case of two compartment model.

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V ss = (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 V ss = estimation of extent of distribution in the body V ss 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. Equation 2 is limited to those instance where steady state drug concentration in both the compartment has been reached. At any other time it tends to overestimate or underestimate.

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To avoid ambiguity inherent in the apparent volume of distribution as an estimation of the amount of drug in the body. The T/P ratio is used. The amount of drug in the body can be calculated by T/P ratio as given bellow. T/P = K12 (K21-β) Where: β = slow deposition constant T= amount of drug in peripheral

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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. 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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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. Process device a specific period, allowing more complete conversion of the drug to its metabolite.

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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. More than 8 hours are also generally not used in sustaining forms, since their effect is already sustained. E.g.; Digoxin , Warfarin , Phenytoin etc.

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e) Margin of safety: In general the larger the volume of therapeutic index 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 .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 so that the plasma drug concentration achieved in under therapeutic range.

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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. f) Pka

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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. If an oral product has a dose size greater that 500mg it is a poor candidate for sustained release system, Since addition of sustaining dose and  possibly the sustaining mechanism will, in most cases generates a substantial volume product that unacceptably large.

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2. Partition coefficient and molecular size. When the drug is administered to the GIT ,it must cross a variety of biological membranes to produce therapeutic effects in another area of the body. It is common to consider that these membranes are lipidic , therefore the Partition coefficient of oil soluble drugs becomes important in determining the effectiveness of membranes barrier penetration. Partition coefficient is the fraction of drug in an oil phase to that of an adjacent aqueous phase.

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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 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.

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Thus high molecular weight drugs or polymeric drugs should be expected to display very slow release kinetics in sustained release device using diffusion through polymer membrane. Phenothiazines are representative of this type of compound

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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, there fore it is best absorbed in the intestine. 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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Aqueous solubility and pKa These are the most important to influence its absorptive behavior and its aqueous solubility ( if it’s a weak acid or base) and its pKa The aqueous solubility of the drug influences its dissolution rate which in turn establishes its concentration in solution and hence the driving force for diffusion across the membranes as shown by Noye’s Whitney’s equation which under sink condition that is dc/ dt = Kd.A.Cs Where dc/ dt = dissolution rate Kd = dissolution rate constant A = total surface area of the drug particles Cs= aqueous solubility of the drug

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Dissolution rate (dc/ dt ) is constant only when Surface Area A is the initial rate is directly proportional to the Aqueous solubility (Cs) hence Drug with low aqueous solubility have low dissolution rate and its suffer low bioavailability problem. The aqueous solubility of weak acid and bases are controlled by pKa of the compound and pH the medium. For weak acids St= So(1+Ka/H + ) = So (1+10 pH-pKa ) Where St = total solubility of weak acid. So = solubility of unionized form Ka= Acid dissociation constant H + = H ion concentration

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Similarly for Weak Bases St = So (1+H + /Ka) = So (1+10 pKa-pH ) if a poorly soluble drug was consider as a suitable candidate for formulation into sustained release system. Since weakly acidic drugs will exist in the stomach pH 1-2 , primarily in the unionized form their absorption will be favored from this acidic environment on the other hands weakly basic drugs will be exist primarily in the ionized form (Conjugate Acids) at the same site, their absorption will be poor. in the upper portion of the small intestine the pH is more alkaline pH 5-7 and the reverse will be expected for weak acids

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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 at 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 . Degradation will proceed at the reduced rate for drugs in the solid state, 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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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. However for some drugs which are unstable in small intestine are under go extensive Gut –Wall metabolism have decreased the bio availability . When these drugs are administered from a sustained dosage form to achieve better bio availability, at different routes of the drugs administered should be chosen Eg . Nitroglycerine The presence of metabolizing enzymes at the site or pathway can be utilized.

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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 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 that exhibit 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 .

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The binding of the drugs to plasma proteins( eg.Albumin ) results in retention of the drug into the vascular space the drug protein complex can serves as reservoir in the vascular space for sustained drug release to extra vascular tissue but only for those drugs that exhibited a high degree of binding. The main force of attraction are Wander- vals forces , hydrogen binding, electrostatic binding. In general charged compound have a greater tendency to bind a protein then uncharged compound, due to electrostatic effect. Eg amitryptline , cumarin , diazepam, digoxide , dicaumarol , novobiocin .

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The relationship between Pka of compound and absorptive environment, Presenting drug in an unchanged form is adventitious for drug permeation but solubility decrease as the drug is in unchanged form. An important assumption of the there is that unionized form of the drug is absorbed and permeation of ionized drug is negligible, since its rate of absorption is 3-4 times lesser than the unionized form of the drug. The pka range for acidic drug whose ionization is PH sensitive and around 3.0- 7.5 and pka range for basic drug whose ionization is ph sensitive around 7.0- 11.0 are ideal for the optimum positive absorption 6.Pka: (dissociation constant )

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Natural polymers eg . Xanthan gum, polyurethanes, Guar gum, polycarbonates, Karaya gum etc Semi synthetic polymers eg . Celluloses such as HPMC, NaCMC , Ethyl cellulose etc. Synthetic polymers eg . Polyesters, polyamides, polyolefins etc Classification of polymers

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Sr.no Polymer characteristics Material 1. Insoluble, inert Polyethylene, polyvinyl chloride, methyl acrylates-methacrylate copolymer, ethyl cellulose. 2. Insoluble, erodable Carnauba wax Stearyl alcohol, Stearic acid, Polyethylene glycol. Castor wax Polyethylene glycol monostearate Trigycerides 3. Hydrophilic Methylcellulose, Hydroxyethylcellulose , HPMC, Sodium CMC, Sodium alginate, Galactomannose Carboxypolymethylene . Classification Of Polymers Used In Sustained Release Drug Delivery Systems According To Their Characteristics :

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1. Oral forms 2. Parenteral forms 3. Common sustained action dosage forms Spansules Slow core release tablets Multilayer tablets Repeat action tablets Liquid products Transdermal system

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Formulation methods used to obtain the desired drug availability rate from sustained action dosage form include……. Increasing the particle size of the drug. Embedding the drug in matrix. Coating the drug or dosage form containing drug(microencapsulation). Forming complexes of the drug with material such as ion exchange resins. DESIGN OF ORAL SUSTAINED ACTION PRODUCTS

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1) Increasing the particle size of the drug:- The purpose of increasing particle size is to decrease the surface to volume ratio slow the rate of drug availability. This method is a single means for obtaining the desired drug availability rate is limited to poorly soluble drug.

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2) Embedding the drug in matrix:- Matrix may be defined as uniform dispersion of drug in solid which is less soluble than a drug in the dispersion fluid, & which for the continuous external phase of the dispersion effectively impeder the passage of the drug from the matrix to the dispersion fluid. One of the least complicated approaches to the manufacture of sustained release dosage form involves the direct compression of drug, materials & additives to form a tablet in which drug is embedded in a matrix core of the retardant.

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Polymers:- Insoluble, inert - polyethylene, polyvinyl chloride, methyl acrilate, ethylcellulose. Insoluble, erodible – carnauba wax, stearyl alcohol, castor wax. Hydrophilic – methyl cellulose, hydroxyl ethyl cellulose, sodium carboxymethyl cellulose, sodium alginate. In a matrix system the drug is dispersed as solid particle within a porous matrix formed of a water insoluble polymer, such as poly-vinyl chloride.

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Initially, drug particle located at the surface of the release unit will be dissolved and the drug released rapidly. Thereafter, drug partical at successively increasing distance from the surface of the release unit will be dissolved and release by diffusion in the pores to the exterior of the release unit. The main formulation factor by which the release rate from matrix system can be controlled are; the amount of the drug in the matrix, the porosity of the release unit & the solubility of the drug.

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Types of matrix systems Two types of matrix systems Slowly eroding matrix Inert plastic matrix Slowly eroding matrix Consists of using materials or polymers which erode over a period of time such as waxes, glycerides , stearic acid, cellulosic materials etc. Principle: Portion of drug intended to have sustained action is combined with lipid or cellulosic material and then granulated. Untreated drug granulated Both mixed

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Principle: Drug granulated with an inert, insoluble matrix such as polyethylene, polyvinyl acetate, polystyrene, polyamide or polymethacrylate . Granulation is compressed results in MATRIX Drug is slowly released from the inert plastic matrix by leaching of body fluids Release of drug is by diffusion. 2. Embedding drug in Inert plastic matrix

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Preparation of matrix tablets: Solidify Grind Suspension of drug in wax Powder Granulate Drug Granulate Tablets Methods of preparation

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3) Coating the drug or a dosage form containing the drug (microencapsulation) The method for retarding drug release from the dosage form is to coat its surface with a material(polymers) that retards penetration by the dispersion fluid. Drug release depends upon the physiochemical nature of coating material. Microencapsulation is rapidly expanding technique as a process; it is a means of applying relatively thin coating to small particles of solid or droplets of liquids and dispersion.

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The application of microencapsulation might will include, sustained release or prolonged action medication, taste masked, chewable tablet, powder and suspension, single layer tablets. Containing chemically incompatible ingredient & new formulation concepts for creams, ointments, aerosols, dressing, plasters, suppositories & injectables. Polymers: - polyvinyl alcohol, polyacrylic acid, ethyl cellulose, polyethylene, polymethacrlate, poly (ethylene-vinyl acetate), cellulose nitrite, silicones, poly (lactide-co-glcolide)

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4) Chemically reacting the drug with material such as an ion-exchange resin:- Sustained delivery of ionizing acidic & basic drug can be obtained by complexing them with insoluble non-toxic anion exchanger and cation exchanger resin respectively. Here the drug is released slowly by diffusing through the resin particle structure. The complex can be prepared by incubating the drug-resin solution or passing the drug solution through a column containing ion exchange resin.

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Principle: Is based on preparation of totally insoluble ionic material Resins are insoluble in acidic and alkaline media They contain ionizable groups which can be exchanged for drug molecules IER are capable of exchanging positively or negatively charged drug molecules to form insoluble poly salt resinates . Types: There are two types of IER Cationic Exchange resins - RSO 3 - H + Anionic Exchange resins – RNH 3 + OH - Resins functional groups

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Structurally made up of a stable acrylic polymer of styrene- divinyl benzene copolymer. Mechanism of action IER combine with drug to form insoluble ion complexes 1. R-SO 3 – H + + H 2 N – A R-NH 3 + OH - + HOOC – B RNH 3 + - OOC-B + H 2 O Where A- NH 2 is basic drug B-COOH is acidic drug R-SO 3 – NH 3 + - A 2.

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These resinates are administered orally 2 hrs in stomach in contact with acidic fluid at pH 1.2 Intestinal fluid, remain in contact with slightly basic pH for 6hrs. Drug can be slowly liberated by exchange with ions present in G.I.T.

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® -SO 3 - H + + A-NH 3 + Cl - ® - SO 3 - NH 3 + - A + HCl ® -NH 3 + - OOC –B + HCl ® -NH 3 + Cl - + HOOC-B Un dissociated Thus carboxylic acid will be poorly dissociated in stomach and thus absorbed . In the stomach

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® -NH 3 + - OOC – B + NaCl ® -NH 3 + Cl - + Na + - OOCB Sodium salt of acid (dissociation of acid salt unabsorbed) Amine salt will be poorly dissociated in intestine and thus absorbed. ® - -SO 3 - Na + + A-NH 3 + Cl - ® - SO 3 - NH 3 + - A + NaCl Basic pH un dissociated In the Intestine

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Parenteral forms The following parameters are generally manipulated in the design of parenteral forms: Route of administration Route of administration of drugs are very many and all of them do not afford same rate of absorption. A drug given by intravenous injection may attain a certain blood concentration almost instantaneously, while the same drug administered intramuscularly may take considerable time to build up that level since it takes time to diffuse from muscular tissues into the blood stream. Further a drug, placed under the skin in the form of an implant, may remain active over extended period of time giving a sustained action lasting for mouths. Hence, rate of a dministration may sometime be fruitfully employed to o btain sustained action of a medicament.

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B)Vehicles Vehicles significantly alter the bioavailability profile and may be employed to obtain sustained action. If a drug is suspended in a lipophilic vehicle and injected in tissues like muscles it gives a longer action than when it is given in aqueous media. C) Vaso-constrication T he rate of passage of drugs, administered intradermally or intramuscularly, depends to a considerable extent upon their area of contact with blood vessels. Hence, constriction of blood vessels may be employed to prolonged action. Adrenaline is sometime administered with local anesthetics to delay absorption of drugs and to prolong duration of their action,

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D) Particle size T he particle size governs the dissolution rate and hence the bioavailability of drug. Consequently this parameter may be exploited to prolong its action. This principle is used in the formulation of the hypodermic tablets which retain their size over long period of time releasing the drug slowly. E)Chemical modification of the drug T he structure of the drug molecules can sometime be chemically modified such that their action is intact while ADME characteristics get altered. In some cases an analog is synthesized which gives it the desired capacity of prolonged action. Sometime pro-drug approach is possible whereby a derivative of the drug is evolved which is slowly regenerated into the original drug in the presence of body fluids.

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Lidocaine , where two hydrogen atoms are replaced by methyl groups enabling it to give prolonged effect, is an example of analog approach, while chlorphenactin palmitate is an example of pro-drug since the palmitate has to hydrolyse in the g.i.t . to produce chloromycetin which is the therapeutic agent. Pro-drug which consist of reservoir of drug whose flow into the body is calculated either by some body indicator like insulin or by condition of body is calling for specified inputs of drugs. Such systems are popularly refered to as “ triggered system ” , “ pulsed system ” . The principles made use of there designs are briefly discussed below.

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Portable pumps Z yklomat pump, marketed by a german firm has a drug reservoir and a timing device linked to a computer. It can administer hormones like LHRH every one and a half hours for 20 days. Yet another example is a four channel porgrameable portable syringe pump having four 30 ml. syringes programmed to deliver drug at any predetermined rate. A personal computer transfer the programme to a control cartridge which is plugged in the pump system. Such devices have been used in antibiotic as well.

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Implantable devices Implantable devices marketed in USA and designed for implantation in the body, consist of peristaltic pump, drug reservoir, battery and a control unit. The drug administration programme is entered on a personal computer and is transmitted by a control unit to the pump system through skin. Such unit have been employed for administration of drug in cancerous and neurological disorders. Gradually their use may extended to other conditions requiring specified drug administration programmes .

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Infusor devices T hese devices are light weight, portable, disposable and elastomeric infusion systems. They generally have a small reservoir of drug sufficient for half day, a day or 5day needs and carry command modules operable by patients. For control of pain, patients themselves can operate the system every 5-6 min. such systems have few side effects and allow optimal pain control.

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Osmotic pumps O smotic pumps are specifically beneficial in veterinary medicine and enable zero order drug delivery. The pumping device are linked with programmable catheter to permit patterned drug delivery and have largely used for LHRH hormone delivery in animals to induce ovulation.

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Implantable magnetically triggered systems T hese system have a porous matrix with drug embedded in it along with a few magnetic pellets. In the normal course very little drug is released. However, by an oscillating magnetic field the drug diffuse out in pulses to the system.

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Biodegradable system I n biodegradable system the drug is incapsulated in a polymer whose erosion is pH dependent. The outer core of the coat is a hydrogel with immobilized enzymes like glucose oxidase which convert glucose into gluconic acid everytime its level rises in blood decreasing pH and thereby causing erosion of polymer and release of drug.

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Antibody coated particles I n these dosage form the drug is convalently linked to a hapten and coated with corresponding antibodies. When the drug is to be released more haptens are introduced which displace the antibody coating enabling release of drug. Naltrexone has been thus linked with a hapten moiety and coated with antibodies.

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Common sustained action dosage form Spansules : S pansules are hard gelatin capsules filled with coated granules or beads. They are marketed by manufacturer under variety of trade names. Slow core released tablets: T hese tablets consist of a core of drug mixed up with substances from which drug can be slowely leached out by GIT fluid. On to the core is compressed another layer consisting of drug and other excipients . The upper layer generally disintegrates rapidly releasing the drug which builds up blood level. Thereafter the drug is slowly leached out from the core.

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Multilayer tablets: M ultilayer tablets consist of 2-3 separate layers which release drug at different rates. In two layers tablets one of the layers is designed for immediate disintegration while the other remains firm and intact throughout its sojourn in the intestines. In three layers tablets, one layer may be for immediate disintegration, the other is designed to disintegration after sometime and the third may remain intact releasing drug at a slow pace.

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Repeat action tablets: R epeat action tablets are regarded to be prototypes of sustained action products but in fact they are not. In these tablets a second dose is released only after the first is practically worn off and there is no continuous release. These tablets usually consist of a core and a coat. The initial dose is in the coat and the following one in the core. Liquid products: I t is possible to formulate liquid product, having sustained action, by suspending coated granules or particles in a suitable liquid media which has no action on the coats of the granules. These formulation are similar to suspensions.

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Evaluation Drug release is evaluated based on drug dissolution from dosage form at different time intervals. Specified in monograph. Various test apparatus and procedures – USP, Chapter <724>.

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Two types In vitro evaluation In vivo evaluation In vitro evaluation : Acquire guidelines for formulation of dosage form during development stage before clinical trials. Kinetics or rate of drug release from the dosage form can be measured in simulated gastric and intestinal fluids. Necessary to ensure batch to batch uniformity in production of a proven dosage form. Obtain in vitro / in vivo correlation

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In vitro quality control tests include: Rotating basket (apparatus 1) Paddle (apparatus 2) Modified disintegration testing apparatus (apparatus 3) At a specified time intervals measurement of drug is made in simulated gastric fluid / intestinal fluid. - 2 hrs in gastric fluid and 6 hrs in intestinal fluid

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Data is analysed to see Dose dumping i.e., Maintenenance dose is released before the period is completed. Dose that is unavailable is not released in G.I.T. Release of loading dose. Unit to unit variation, predictability of release properties. Sensitivity of the drug to the process variables Composition of the simulated fluid Rate of agitation Stability of the formulation Ultimately does the observed profile fit expectations.

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Other apparatus specific for SR evaluations Rotating bottle Stationary basket / rotating filter Sartorius absorption and solubility simulator Column-type flow through assembly

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Rotating bottle method: Samples are tested in 90 ml bottles containing 60 ml of fluid which are rotated end over end in a 37 0 C bath at 40 rpm. Sartorius device Includes an artificial lipid membrane which separates the dissolution chamber from simulated plasma compartment in which the drug concentration are measured or dialysis membrane may be used. Advantages: Measure release profile of disintegrating dosage units such as powder materials, suspensions, granular materials, if permeability is properly defined .

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Column flow through apparatus Drug is confined to a relatively small chamber in a highly permeable membrane filters. Dissolution fluid might be re-circulated continuously from the reservoir allowing measurement of cumulative release profile. Duration of testing 6-12hrs. Media used: Simulated gastric fluid or pH 1.2 Simulated intestinal fluid pH 7.2 Temperature 37oC If required bile salts, pancreatin and pepsin can be added.

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Specifications for Aspirin Extended- release Tablets Time (hr) Amount Dissolved 1.0 Between 15% and 40% 2.0 Between 25% and 60% 4.0 Between 35% and 75% 8.0 Not less than 70 % Example-

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In vivo evaluation A clinical trial, testing the availability of the drug being used in the form prepared by noting its effect versus time. Preliminary in vivo testing of formulation carried out in a limited number of carefully selected subjects based on - Similar body built, size, occupation, diet, activity and sex. - A single dose administered and effect measured over time (24hrs) - Test may or may not be blind and cross over design.

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MARKETED CONTROLLED RELEASE PRODUCT Composition Product Name Manufacturer Tablet Carbamazepine Zen Retard Intas Diazepam Calmrelease – TR Natco Diclofenac sodium Dic – SR Dee Pharma Limited Diclofenac sodium Nac – SR Systopic Diclofenac sodium Agile – SR Swift

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Diclofenac sodium Dicloram SR Unique Diclofenac sodium Doflex SR Nicholas Piramal Diclofenac sodium Mobinase – SR Crosland Diclofenac sodium Monovac – SR Boehringer – Mannheim Diclofenac sodium Relaxyl - SR Franco – Indian Diclofenac sodium Voveran – SR Ciba – Geigy Diltiazem Dilzem SR Torrent

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Diltiazem Hcl Diltime SR Alidac Lithium carbonate Lithosun – SR Sunpharma Nifedipine Nyogard LA Searle (I) Ltd Nifedipine Calcigard Retard Torrent Nifedipine Depin Retard Cadila Health Care Salbutamol Theophylline TheoAsthalin SR Cipla Terbutaline Sulphate, Theophylline Anhydrous Theobric – SR Remidex

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Theophylline Theo PA Welcome Theophylline Anhydrous Theo Stan – CR Stancare Verapamil hydrochloride Calpatin SR Boehringer – Mannheim Verapamil hydrochloride Calapatin 240 SR Boehringer – Mannheim

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Capsules Chlorpheniramine maleate, Phenylepinephrine hydrochloride Coldvir – SR Dee Pharma Ltd Diazepam Elcoin Ranbaxy Diclofenac sodium Diclotal CR Blue Cross Diclofenac sodium Nalco TR Natco Dried Ferrous Sulphate, Folic acid Feron SR Dee Pharma Ltd Dried Ferrous Sulphate, Folic acid Fefol Spansules Eskayef

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Dried Ferrous Sulphate, Folic acid, Ascorbic acid Ultiron – TR Stancare Dried Ferrous Sulphate, Folic acid, Vit . B12, Vit . C, Vit . B2 Convinon TR Ranbaxy Ferrous Fummarate , Zinc Sulphate Monohydrate Ziberrin – TR Recon Flurbiprofen Arflur SR FDC Indomethacin Indoflam TR Recon Isosorbide Dinnitrate Cardicap TR Natco Ketoprofen Profenid CR Rhone– Poulenc

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Nifedipine Nicardia J. B. Chemicals & Pharmaceuticals Nifedipine Indocap SR J. B. Chemicals & Pharmaceuticals Nifedipine Cardules Retard Nicohlas Piramal Nitroglycerin Angispan TR Lyka Vitamin C, B2, B1, Nicotinamide, Pantothenic acid, Dried Ferrous Sulphate Pesovit Spansules Eskayef

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Transdermal Estrogen Estraderm TTS Ciba – Geigy Nitroglycerine Nitorderm TTS Ciba – Geigy Nicotine Nicotine Patch Ciba – Geigy

References :

References Leon lachman – The theory and practic of industrial pharmacy. Michael E Alton - Pharmaceutics The science of dosage form design. N.K. Jain – Controlled & novel drug delivery. S.P. Vyas & Khar – Controlled Drug delivery, Brahmankar – Text Book of Biopharmaceutics & Pharmacokinetics. Yie.W.Chein - Controlled & Novel Drug Delivery, CBS publishers. Painter,P & Coleman ,M – “ Fundamental of Polymer science”. IUPAC. Glossary of Basic terms in polymer science”. Pure application -1996. www.goggle.com FORMULATION | Sustained Release Coatings By Nigel Langley, PHD, MBA, and Yidan Lan , Issue Date: June 2009

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