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Published by Ahmed M. Al-Zahrani
Sustained release formulations
Sustained release formulations

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A SEMINAR ON

SUSTAINED RELEASE DRUG DELIVERY SYSTEM
presented by MANE PRASHANT P. M.Pharm (1st year) Dept.of Pharmaceutical Technology H.K.E‟S COP,GLB.

Under The Guidance Of S.B.SHIRSAND M.Pharm.(P.hd)

Sustain Release Drug Delivery System

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.

INTRODUCTION 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 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 .

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

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

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

.INTRODUCTION 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.

The difference between controlled release and sustained release, Controlled drug delivery- which delivers the drug at a pre determined rate for a specified period of time Controlled release is perfectly zero order release that is the drug release over time irrespective of concentration. Sustain release dosage form- is defined as the type of dosage form in which a portion i.e. (initial dose) of the drug is released immediately, in order to achieve desired therapeutic response more promptly, and the remaining(maintanance dose) is then released slowly there by 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.

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.

Plasma concentration v/s time curve

. release rate & dose consideration A) Release rate consideration :In conventional dosage form Kr>Ka in this the release of drug from dosage form is not rate limiting step.e.Concept of sustained release formulation The Concept of sustained release formulation can be divided in to two considerations i.

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

B) Dose consideration :To achieve the therapeutic level & sustain for a given period of time for the dosage form generally consist of 2 part a) Initial (primary) dose there for the total dose „W‟ can be. W= Di + K0 r. W = Di + Dm In a system. Td Td = time desired for sustained release from one dose. b) maintenance dose . the therapeutic dose release follows zero order process for specified time period then.

However a constant drug can be obtained by suitable combination of Di & Dm that release the drug by first order process. W = Di + K0 r Td – K0 r Tp Tp = time of peak drug level. then W = Di + ( Ke Cd /Kr ) Vd .If maintenance dose begins to release the drug during dosing t=O then.

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.

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.

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 1st 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.

P E A K V A L L Y .

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. .

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

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. .

. Reduction in health care cost through improved therapy.Merits. 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. Improved patient convenience and compliance due to less frequent drug administration. shorter treatment period. Reduction in fluctuation in steady-state level and therefore better control of disease condition.

administer monitor patients.Less frequency of dosing and reduction in personnel time to dispense. since the high blood level peaks that may be observed after administration of a dose of high availability drug can be reduced. . Better control of drug absorption can be obtained.

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

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

e.g.Diazepam and Phenytoin Drug with slow rate of absorption and elimination i. as they remain longer time in the body. 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.e. .CHARACTERITICS OF DRUG FOR FORMULATION AS SUSTAINED RELEASE DOSAGE FORM:- •Drug should exhibit neither very fast rate of absorption nor excretions Drug with higher rate of absorption and excretion are usually inherently long acting and their formulation in SRDF is not necessary..

. 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.g.•Drug should be uniformly absorbed throughout GI tract. They should require relatively small doses. e.Riboflovin is not absorbed in 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.

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

these may be divided in two types. Biological properties . 1.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 . Physicochemical properties 2.

Dosage forms. 5.R. 4.(excreation) 5.Biological Factors 1. Partition coefficient and molecular size. 4.Factors to be considered In S. Physiological Factors: 1. Pka . Metabolism. 3. Dosage size. 2. Protein binding. 6. Absorption. Margin of safety 3. 1. 2. Distribution. Aqueous Solubility. Biological half life. Drug stability.

The maximum half-life for absorption should be approximately 3-4 hr otherwise. 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.Biological Factors Absorption. extent and uniformity in absorption of drug are important factor when considering its formulation in to controlled release system. 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. The rate. Absorption of drug need dissolution in fluid before it reaches to systemic circulation.

drug like Kanamycine and gentamycine shows absorption are different sites. extent and uniformity of absorption of a drug are important factors considered while formulation of sustained release formulation. If the rate of absorption is below 0.The rate.23/hr then it is difficult to prepare sustained release formulation.17/hr and above the 0. It we assume that transit time of drug must in the absorptive areas of the GI tract is about 8-12 hrs. . an another important criteria is the through absorption of drug in GIT tract. Riboflavin like drug absorbed effectively by carrier transport and at upper part of GIT that make it preparation in SRDF difficult. As the rate limiting step in drug delivery from a sustained-release system is its release from a dosage form. rather than absorption.

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

For design of sustained/ controlled release products. one must have information of disposition of drug.Distribution: The distribution of drugs into tissues can be important factor in the overall drug elimination kinetics. . consequently apparent volume of distribution assumes different values depending on time course of drug disposition. 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.

.colled T/P ratio.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. 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/C0 Where: C0= initial drug concentration immediately after an IV bolus injection In case of two compartment model.

. 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.Vss = (1+K12/K21)/V1 Where: V1= volume of central compartment K12= rate constant for distribution of drug from central to peripheral K21= rate constant for distribution of drug from peripheral to central Vss= estimation of extent of distribution in the body Vss results concentration in the blood or plasma at steady state to the total mount of the drug present in the body during respective dosing or constant rate of infusion.

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

either in lumen of intestine.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. this also will make preparation of sustained release product difficult. can show decreased bio-availability from slower-releasing dosage forms. 1. Drug that are significantly metabolized before absorption. If there is a variable blood level of drug through a first-pass effect.Metabolism: There are two areas of concern relative to metabolism that significantly restrict sustained release formulation. . 2.

.Most intestinal wall enzymes systems are saturable. allowing more complete conversion of the drug to its metabolite. Process device a specific period. As drug is released at a slower rate to these regions less total drug is presented to the enzymatic.

Biological half life. The usual goal of sustained release product is to maintain therapeutic blood level over an extended period. 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. . to this drug must enter the circulation at approximately the same rate at which it is eliminated.

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

phenotoin.e) Margin of safety: In general the larger the volume of therapeutic index safer the drug. = 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..g.e. Phenobarbital. Drug with very small values of therapeutic index usually are poor candidates for SRDF due to pharmacological limitation of control over release rate .induced digtoxin. .

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

5 .  If an oral product has a dose size greater that 500mg it is a poor candidate for sustained release system. In general a single dose of 0.1.1.Dosage size. .0 gm is considered for a conventional dosage form this also holds for sustained release dosage forms. in most cases generates a substantial volume product that unacceptably large. Since addition of sustaining dose and possibly the sustaining mechanism will.

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

with values on the order of 10-8 being most common for drugs with molecular weight greater than 500.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. values of diffusion coefficient for intermediate molecular weight drugs. 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. through flexible polymer range from 10-8 to 10-9 cm2 / sec.

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 .

Since drugs must be in solution before they can be absorbed. 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. there fore it is best absorbed in the intestine. .g.: Tetracycline dissolves to greater extent in the stomach than in the intestine.3.Aqueous Solubility. because of limited GI transit time of undissolved drug particles and limited solubility at the absorption site. compounds with very low aqueous solubility usually suffer oral bioavailability Problems. E. Most of drugs are weak acids or bases. for drugs with low water solubility will be difficult to incorporate into sustained release mechanism.

Cs Where dc/dt = dissolution rate Kd= dissolution rate constant A = total surface area of the drug particles Cs= aqueous solubility of the drug .A.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.

So = solubility of unionized form Ka= Acid dissociation constant H+= H ion concentration . For weak acids St= So(1+Ka/H+) = So (1+10pH-pKa ) Where St = total solubility of weak acid.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.

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 . 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.Similarly for Weak Bases St = So (1+H+/Ka) = So (1+10pKa-pH ) if a poorly soluble drug was consider as a suitable candidate for formulation into sustained release system. their absorption will be poor.

The stability of drug in environment to which it is exposed. for drugs that are unstable in stomach. is another physico-chemical factor to be considered in design at sustained/ controlled release systems. systems that prolong delivery ever the entire course of transit in GI tract are beneficial. 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. Degradation will proceed at the reduced rate for drugs in the solid state.4. base hydrolysis and enzymatic degradation. .Drug stability.

.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. 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. When these drugs are administered from a sustained dosage form to achieve better bio availability. However for some drugs which are unstable in small intestine are under go extensive Gut –Wall metabolism have decreased the bio availability .

However drugs that exhibit high degree of binding to plasma proteins also might bind to biopolymers in GI tract which could have influence on sustained drug delivery. especially it is high degree of drug binding occurs. The presence of hydrophobic moiety on drug molecule also increases the binding potential.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. 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.

In general charged compound have a greater tendency to bind a protein then uncharged compound. digoxide. due to electrostatic effect. Eg amitryptline. electrostatic binding. diazepam. cumarin. dicaumarol.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 binding of the drugs to plasma proteins(eg. . The main force of attraction are Wander-vals forces . novobiocin. hydrogen binding.

An important assumption of the there is that unionized form of the drug is absorbed and permeation of ionized drug is negligible.5 and pka range for basic drug whose ionization is ph sensitive around 7.0. Presenting drug in an unchanged form is adventitious for drug permeation but solubility decrease as the drug is in unchanged form.0.11.7.0 are ideal for the optimum positive absorption . since its rate of absorption is 3-4 times lesser than the unionized form of the drug.6.Pka: (dissociation constant) The relationship between Pka of compound and absorptive environment. The pka range for acidic drug whose ionization is PH sensitive and around 3.

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

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

Parenteral forms 3. Oral forms 2. Multilayer tablets d. Repeat action tablets e. Common sustained action dosage forms a. Slow core release tablets c. Spansules b.1. Liquid products f. Transdermal system .

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

.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.

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. . materials & additives to form a tablet in which drug is embedded in a matrix core of the retardant. One of the least complicated approaches to the manufacture of sustained release dosage form involves the direct compression of drug.

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

Thereafter. . the porosity of the release unit & the solubility of the drug. 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. drug particle located at the surface of the release unit will be dissolved and the drug released rapidly. the amount of the drug in the matrix.Initially.

• Untreated drug granulated • Both mixed . Slowly eroding matrix 2. glycerides. stearic acid. Inert plastic matrix 1. cellulosic materials etc.Slowly eroding matrix Consists of using materials or polymers which erode over a period of time such as waxes.Types of matrix systems Two types of matrix systems 1. Principle: • Portion of drug intended to have sustained action is combined with lipid or cellulosic material and then granulated.

polyamide or polymethacrylate. polystyrene. Embedding drug in Inert plastic matrix Principle: Drug granulated with an inert. polyvinyl acetate.2. insoluble matrix such as polyethylene. 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. .

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

Microencapsulation is rapidly expanding technique as a process. .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. it is a means of applying relatively thin coating to small particles of solid or droplets of liquids and dispersion.

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

The complex can be prepared by incubating the drug-resin solution or passing the drug solution through a column containing ion exchange resin. Here the drug is released slowly by diffusing through the resin particle structure. .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.

RSO3-H+ Resins functional groups Anionic Exchange resins – RNH3+ OH- . Types: There are two types of IER Cationic Exchange resins .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.

NH2 is basic drug B-COOH is acidic drug . R-NH3 OH H2O - + HOOC – B RNH3+ -OOC-B + Where A.Structurally made up of a stable acrylic polymer of styrene-divinyl benzene copolymer. R-SO H +H N–A 3 2 + 2. Mechanism of action IER combine with drug to form insoluble ion complexes – NH + R-SO – + 3 3 -A 1.

Drug can be slowly liberated by exchange with ions present in G.I.2 Intestinal fluid. remain in contact with slightly basic pH for 6hrs.These resinates are administered orally 2 hrs in stomach in contact with acidic fluid at pH 1.T. .

+ HOOC-B Un dissociated Thus carboxylic acid will be poorly dissociated in stomach and thus absorbed.In the stomach ®- SO3.A + HCl ®-SO3 - H+ + A-NH3+ Cl- ®-NH3+ -OOC –B + HCl ®-NH3+Cl. .NH3+ .

.A + NaCl ®-NH3+ -OOC – B + NaCl ®.In the Intestine ®.NH3+ .-SO3 - Na+ + A-NH3+ ClBasic pH un dissociated ®-NH3+Cl.+ Na+-OOCB Sodium salt of acid (dissociation of acid salt unabsorbed) Amine salt will be poorly dissociated in intestine and thus absorbed.SO3.

Further a drug. 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. rate of administration may sometime be fruitfully employed to obtain sustained action of a medicament. .Parenteral forms The following parameters are generally manipulated in the design of parenteral forms: A) Route of administration Route of administration of drugs are very many and all of them do not afford same rate of absorption. may remain active over extended period of time giving a sustained action lasting for mouths. placed under the skin in the form of an implant. Hence. A drug given by intravenous injection may attain a certain blood concentration almost instantaneously.

. Adrenaline is sometime administered with local anesthetics to delay absorption of drugs and to prolong duration of their action. C)Vaso-constrication The rate of passage of drugs. constriction of blood vessels may be employed to prolonged action. administered intradermally or intramuscularly. 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.B)Vehicles Vehicles significantly alter the bioavailability profile and may be employed to obtain sustained action. depends to a considerable extent upon their area of contact with blood vessels. Hence.

D) Particle size The particle size governs the dissolution rate and hence the bioavailability of drug. This principle is used in the formulation of the hypodermic tablets which retain their size over long period of time releasing the drug slowly. . In some cases an analog is synthesized which gives it the desired capacity of prolonged action. E)Chemical modification of the drug The structure of the drug molecules can sometime be chemically modified such that their action is intact while ADME characteristics get altered. Consequently this parameter may be exploited to prolong its 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.

“pulsed system”. . while chlorphenactin palmitate is an example of pro-drug since the palmitate has to hydrolyse in the g. where two hydrogen atoms are replaced by methyl groups enabling it to give prolonged effect.i. Such systems are popularly refered to as “triggered system”. 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.t.Lidocaine. to produce chloromycetin which is the therapeutic agent. is an example of analog approach. The principles made use of there designs are briefly discussed below.

Such devices have been used in antibiotic as well. 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. marketed by a german firm has a drug reservoir and a timing device linked to a computer. 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. .Portable pumps Zyklomat pump.

drug reservoir. Gradually their use may extended to other conditions requiring specified drug administration programmes. consist of peristaltic pump. Such unit have been employed for administration of drug in cancerous and neurological disorders.Implantable devices Implantable devices marketed in USA and designed for implantation in the body. . 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.

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

Osmotic pumps Osmotic 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.

. However.Implantable magnetically triggered systems These 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. by an oscillating magnetic field the drug diffuse out in pulses to the system.

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.Biodegradable system In biodegradable system the drug is incapsulated in a polymer whose erosion is pH dependent. .

Naltrexone has been thus linked with a hapten moiety and coated with antibodies.Antibody coated particles In 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. .

Common sustained action dosage form •Spansules: Spansules are hard gelatin capsules filled with coated granules or beads. They are marketed by manufacturer under variety of trade names. The upper layer generally disintegrates rapidly releasing the drug which builds up blood level. •Slow core released tablets: These 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. . Thereafter the drug is slowly leached out from the core.

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.•Multilayer tablets: Multilayer tablets consist of 2-3 separate layers which release drug at different rates. . In three layers tablets. the other is designed to disintegration after sometime and the third may remain intact releasing drug at a slow pace. one layer may be for immediate disintegration.

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

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

• Necessary to ensure batch to batch uniformity in production of a proven dosage form. In vitro evaluation 2.Two types 1. Obtain in vitro / in vivo correlation . Kinetics or rate of drug release from the dosage form can be measured in simulated gastric and intestinal fluids. In vivo evaluation In vitro evaluation : • Acquire guidelines for formulation of dosage form during development stage before clinical trials.

Modified disintegration testing apparatus (apparatus 3) At a specified time intervals measurement of drug is made in simulated gastric fluid / intestinal fluid.In vitro quality control tests include: 1. Rotating basket (apparatus 1) 2.2 hrs in gastric fluid and 6 hrs in intestinal fluid . Paddle (apparatus 2) 3. .

Unit to unit variation.I. . Release of loading dose.e. predictability of release properties.Data is analysed to see  Dose dumping i.. Maintenenance dose is released before the period is completed. 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. Dose that is unavailable is not released in G.T.

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

Advantages: Measure release profile of disintegrating dosage units such as powder materials.Rotating bottle method: Samples are tested in 90 ml bottles containing 60 ml of fluid which are rotated end over end in a 370 C bath at 40 rpm. granular materials. 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. . if permeability is properly defined . suspensions.

Media used: •Simulated gastric fluid or pH 1.Column flow through apparatus Drug is confined to a relatively small chamber in a highly permeable membrane filters. pancreatin and pepsin can be added. .2 •Simulated intestinal fluid pH 7. Dissolution fluid might be re-circulated continuously from the reservoir allowing measurement of cumulative release profile. Duration of testing 6-12hrs.2 •Temperature 37oC •If required bile salts.

0 4.0 2.0 Amount Dissolved Between 15% and 40% Between 25% and 60% Between 35% and 75% Not less than 70 % .0 8.Example- Specifications for Aspirin Extended.release Tablets Time (hr) 1.

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.Test may or may not be blind and cross over design. . over .A single dose administered and effect measured time (24hrs) . diet. size. activity and sex.In vivo evaluation A clinical trial. occupation.

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

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

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

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

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

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

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

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

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

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