contentsINTRODUCTIONRATIONALATY 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 CONCENTRATIONIN 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.FEVALUATION 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.
INTRODUCTIONThe history of controlled release technology is divided into three time periodsFrom 1950 to 1970 was the period of sustain drug releaseFrom 1970 to 1990 was involved in the determination of theneeds of the control drug deliveryPost 1990 modern era of controlled release technology
INTRODUCTIONBefore initiating a discussion of sustained release dosage forms, it isnecessary to provide a short explanation of terminology usedbecause there is considerable confusion in this area. The generalconsensus is that controlled release denotes systems, which canprovide some control, whether this is of a temporal or spatial nature,or both, of drug release in the body. In other words, the systemsattempts to control drug concentration in the target tissue or cells.Thus, prolonged release or sustained release systems, which onlyprolong therapeutic blood or tissue levels of the drug for anextended period of time, cannot be considered as controlled releasesystems by this definition. They are distinguished from rate-controlled drug delivery systems, which are able to specify therelease rate and duration in vivo precisely, on the basis of simple invitro tests. Drug targeting, on the other hand, can be considered as aform of controlled release in that it exercises spatial control of drugrelease within the body.
INTRODUCTIONIn the conventional therapy aliquot quantities of drugs areintroduced into the system at specified intervals of time with theresult that there is considerable fluctuation in drug concentrationlevel as indicated in the figure. HIGH HIGH LOW LOW
INTRODUCTIONHowever, an ideal dosage regimen would be one, in which theconcentration of the drug, nearly coinciding with minimumeffective concentration (M.E.C.), is maintained at a constant levelthroughout the treatment period. Such a situation can be graphicallyrepresented by the following figure CONSTANT LEVEL
INTRODUCTION What is Sustain Release Dosage Form? “Drug Delivery system that are designed to achieve prolongedtherapeutic effect by continuously releasing medication over anextended period of time after administration of single dose.” The basic goal of therapy is to achieve steady state blood level thatis therapeutically effective and non toxic for an extended period oftime.The design of proper dosage regimen is an important element inaccomplishing this goal.
The difference between controlled release and sustained release, Controlled drug delivery- which delivers the drug at a predetermined rate for a specified period of time Controlled release is perfectly zero order release that is thedrug release over time irrespective of concentration. Sustain release dosage form- is defined as the type of dosageform in which a portion i.e. (initial dose) of the drug is releasedimmediately, in order to achieve desired therapeutic response morepromptly, and the remaining(maintanance dose) is then releasedslowly there by achieving a therapeutic level which is prolonged,but not maintained constant. Sustained release implies slow release of the drug over a timeperiod. 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 thedelivery of medication to achieve the control of therapeutic effect inthe face of uncertain fluctuation in the vivo environment in whichdrug release take place. This is usually concerned with maximum drug availability byattempting to attain a maximum rate and extent of drug absorptionhowever, control of drug action through formulation also impliescontrolling bioavailability to reduce drug absorption rates.
Concept of sustained release formulation The Concept of sustained release formulation can be dividedin to two considerations i.e. release rate & dose considerationA) Release rate consideration :- In conventional dosage form Kr>Ka in this the release of drugfrom dosage form is not rate limiting step.
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. So that effort for developing S.R.F must be directed primarilyaltering the release rate. the rate should be independent of drugremoving in the dosage form over constant time. The release rate should follow zero order kinetics Kr = rate in = rate out = KeVd.CdWhere Ke = overall elimination (first order kinetics). Vd = total volume of distribution. Cd = desired drug concentration.
B) Dose consideration :-To achieve the therapeutic level & sustain for a given period of timefor the dosage form generally consist of 2 parta) Initial (primary) dose b) maintenance dosethere for the total dose „W‟ can be. W = Di + Dm In a system, the therapeutic dose release follows zero orderprocess for specified time period then, W= Di + K0 r. TdTd = time desired for sustained release from one dose.
If maintenance dose begins to release the drug duringdosing t=O then, W = Di + K0 r Td – K0 r TpTp = time of peak drug level. However a constant drug can be obtained by suitablecombination of Di & Dm that release the drug by first orderprocess, then W = Di + ( Ke Cd /Kr ) Vd
Sustained release, sustained action, prolonged action,controlled release, extended action, time release dosage formed areterms used to identify drug delivery system that are designed toachieve a prolonged therapeutic effect by continuously releasingmedication over an extended period of time after administration ofsingle dose . In case of injectable dosage form, this period may varyfrom days to month, in case of orally administratedforms, however, this period is measured in hours & criticallydepends on the residence time of the dosage form in GI tract.
In some case, control of drug therapy can be achieved bytaking advantage of beneficial drug interaction that affect drugdisposition and elimination. E.g.:- the action of probenicid, whichinhibit the excretion of penicillin, thus prolonging it‟s blood level. Mixture of drug might be utilized to attend, synergize, orantagonize given drug action. Sustained release dosage form design embodies thisapproach to the control of action i.e. through a process of eitherdrug modification, the absorption process, and subsequently drugaction can be controlled.
Repeat-action versus sustained-action drug therapy A repeat-action tablet may be distinguished from itssustained-release product by the release of the drug in slowcontrolled manner and consequently does not give a plasmaconcentration time curve which resemble that of a sustained releaseproduct. A repeat action tablet usually contains two dose of drug;the 1st being released immediately following oral administration inorder to provide a repeat onset of therapeutic response. The releaseof second dose is delayed, usually by means of an enteric coat. Consequently, when the enteric coat surrounding the seconddose is breached by the intestinal fluid, the second dose is releaseimmediately.
figure shows that the plasma concentration time curveobtained by the administration of one repeat- action preparationexhibit the “PEAK & VALLY”. Profile associated with theintermittent administration of conventional dosage forms. The primary advantage provide by a repeat-action tabletover a conventional one is that two (or occasionally three) dosesare administration without the need to take more than one tablet.
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 halflife.Difficulty to attain steady state drug concentration.Fluctuation may lead to under medication or over medication.
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 andtechniques of controlled and targeted drug delivery.
Merits.Improved patient convenience and compliance due to lessfrequent drug administration.Reduction in fluctuation in steady-state level and therefore bettercontrol of disease condition.Increased safety margin of high potency drug due to bettercontrol of plasma levels.Maximum utilization of drug enabling reduction in total amountof dose administered.Reduction in health care cost through improved therapy, shortertreatment period.
Less frequency of dosing and reduction in personnel time todispense, administer monitor patients.Better control of drug absorption can be obtained, since the highblood level peaks that may be observed after administration of adose of high availability drug can be reduced.
Demerits..Decreased systemic availability in comparisn to immediaterelease conventional dosage forms; this may be due to incompleterelease, increased first-pass metabolism, increasedinstability, insufficient residence time for complete release, sitespecific absorption, pH dependent solubility etc.,Poor in-vivo, in-vitro correlation.Possibility of dose dumping due to food, physiologic orformulation variable or chewing or grinding of oral formulation bythe patient and thus increased risk of toxicity.
Retrieval of drug is difficult in case of toxicity, poisoning orhypersensitivity 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 populationi.e. on the basis of average drug biologic half-life‟s. Consequentlydisease states that alter drug disposition, significant patient variationand so forth are not accommodated.Economics factors must also be assessed, since more costlyprocesses and equipment are involved in manufacturing manysustained release forms.
CHARACTERITICS OF DRUG FOR FORMULATION AS SUSTAINED RELEASE DOSAGE FORM:-•Drug should exhibit neither very fast rate of absorption norexcretionsDrug with higher rate of absorption and excretion are usuallyinherently long acting and their formulation in SRDF is notnecessary, as they remain longer time in the body.e.g.- Diazepam and PhenytoinDrug with slow rate of absorption and elimination i.e. short half lifeless then 2 hr are difficult to formulate as system requires a largerunit dose size and may contribute to patient complains problem andalso difficult to control the release rate of drug.
•Drug should be uniformly absorbed throughout GI tract.Drug that are absorbed poorly and at unpredictable rate are not goodcandidate for SRDF because there release rate and absorption aredepending on the position of drug in the GI tract and rate movementof drug.e.g.- Riboflovin is not absorbed in GI tract.They should require relatively small doses.Some drug like sulfonamide require larger dose for therapeuticactivity so this kind of drug are difficult to form in SRDF as unitdose increases to an extent where it is difficult to swallow bypatient.
•They should have good margin of safety i.e. that their therapeuticindex should be relative range.•The drug should not show any cumulative action, any undesiredside effect as in case of dose dumping it might produce toxicity.Some drug does not have any clear advantage for SRDF likeCqiseuilin.
Drug properties relevant to sustained release formulationThe 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 properties2. Biological properties
Factors to be considered In S.R.Dosage forms.1.Biological Factors Physiological Factors: 1. Absorption. 1. Dosage size. 2. Partition coefficient and 2. Distribution. molecular size. 3. Metabolism. 3. Aqueous Solubility. 4. Biological half 4. Drug stability. life.(excreation) 5. Protein binding. 5. Margin of safety 6. Pka
Biological Factors Absorption.Absorption of drug need dissolution in fluid before it reaches tosystemic circulation. The rate, extent and uniformity in absorptionof drug are important factor when considering its formulation in tocontrolled release system. Absorption= dissolutionThe characteristics of absorption of a drug can be greatly effectsits suitability of sustained release product. The rate of release ismuch slower than rate of absorption. The maximum half-life forabsorption should be approximately 3-4 hr otherwise, the devicewill pass out of potential absorptive region before drug release iscomplete.Compounds that demonstrate true lower absorption rate constantswill probably be poor candidates for sustaining systems.
The rate, extent and uniformity of absorption of a drug areimportant factors considered while formulation of sustainedrelease formulation. As the rate limiting step in drug delivery from asustained-release system is its release from a dosage form, ratherthan absorption. It we assume that transit time of drug must in the absorptiveareas of the GI tract is about 8-12 hrs. If the rate of absorption is below 0.17/hr and above the0.23/hr then it is difficult to prepare sustained release formulation.an another important criteria is the through absorption of drug inGIT tract, drug like Kanamycine and gentamycine shows absorptionare different sites, Riboflavin like drug absorbed effectively bycarrier transport and at upper part of GIT that make it preparationin SRDF difficult.
As the rate limiting step in drug delivery from a sustained-releasesystem is its release from a dosage form, rather than absorption.Rapid rate of absorption of drug, relative to its release is essential ifthe system is to be successful.
Distribution: The distribution of drugs into tissues can be important factor inthe overall drug elimination kinetics. Since it not only lowers the concentration of drug but it also canbe rate limiting in its equilibrium with blood and extra vasculartissue, consequently apparent volume of distribution assumesdifferent values depending on time course of drug disposition. For design of sustained/ controlled release products, one musthave information of disposition of drug.
Two parameters that are used to describe distributioncharacteristics are its apperent volume of distribution and the ratioof drug concentration in tissue that in plasma at the steady state theso- colled T/P ratio. The apparent volume of distribution Vd is nearly a proportionalconstant that release drug concentration in the blood or plasma tothe amount of drug in the body. In case of one compartment model Vd = dose/C0Where:C0= initial drug concentration immediately after an IV bolusinjectionIn case of two compartment model.
Vss = (1+K12/K21)/V1Where:V1= volume of central compartmentK12= rate constant for distribution of drug from central toperipheralK21= rate constant for distribution of drug from peripheral tocentralVss= estimation of extent of distribution in the body Vss results concentration in the blood or plasma at steady stateto the total mount of the drug present in the body during respectivedosing or constant rate of infusion. Equation 2 is limited to thoseinstance where steady state drug concentration in both thecompartment has been reached. At any other time it tends tooverestimate or underestimate.
To avoid ambiguity inherent in the apparent volume ofdistribution as an estimation of the amount of drug in the body. TheT/P ratio is used. The amount of drug in the body can be calculated by T/P ratio asgiven bellow. T/P = K12 (K21-β)Where: β = slow deposition constantT= amount of drug in peripheral
Metabolism:There are two areas of concern relative to metabolism thatsignificantly restrict sustained release formulation.1.If drug upon chronic administration is capable of either inducingor inhibition enzyme synthesis it will be poor candidate forsustained release formulation because of difficulty of maintaininguniform blood levels of drugs.2. If there is a variable blood level of drug through a first-passeffect, this also will make preparation of sustained release productdifficult.Drug that are significantly metabolized before absorption, either inlumen of intestine, can show decreased bio-availability fromslower-releasing dosage forms.
Most intestinal wall enzymes systems are saturable. As drug isreleased at a slower rate to these regions less total drug is presentedto the enzymatic. Process device a specific period, allowing morecomplete conversion of the drug to its metabolite.
Biological half life.The usual goal of sustained release product is to maintaintherapeutic blood level over an extended period, to this drug mustenter the circulation at approximately the same rate at which it iseliminated. The elimination rate is quantitatively described by thehalf-life (t1/2)Therapeutic compounds with short half life are excellentcandidates for sustained release preparation since these can reducedosing frequency.
Drugs with half-life shorter than 2 hours. Such as e.g.:Furosemide, levodopa are poor for sustained release formulationbecause it requires large rates and large dose compounds with longhalf-life. More than 8 hours are also generally not used insustaining forms, since their effect is already sustained.E.g.; Digoxin, Warfarin, Phenytoin etc.
e) Margin of safety: In general the larger the volume of therapeutic index safer thedrug. Drug with very small values of therapeutic index usually arepoor candidates for SRDF due to pharmacological limitation ofcontrol over release rate .e.g.- induced digtoxin, Phenobarbital,phenotoin. = TD50/ED50Larger the TI ratio the safer is drug.It is imperative that the drug release pattern is precise so that theplasma drug concentration achieved in under therapeutic range.
2. Physiological Factors: a) Dosage size. b) Partition coefficient and molecular size. c) Aqueous Solubility. d)Drug stability. e) Protein binding. f) Pka
1.Dosage size.In general a single dose of 0.5 - 1.0 gm is considered for aconventional dosage form this also holds for sustained releasedosage forms. If an oral product has a dose size greater that 500mg it is a poorcandidate for sustained release system, Since addition of sustainingdose and possibly the sustaining mechanism will, in most casesgenerates a substantial volume product that unacceptably large.
2. Partition coefficient and molecular size.When the drug is administered to the GIT ,it must cross a varietyof biological membranes to produce therapeutic effects in anotherarea of the body.It is common to consider that these membranes are lipidic,therefore the Partition coefficient of oil soluble drugs becomesimportant in determining the effectiveness of membranes barrierpenetration.Partition coefficient is the fraction of drug in an oil phase to thatof an adjacent aqueous phase.
High partition coefficient compound are predominantly lipidsoluble and have very low aqueous solubility and thus thesecompound persist in the body for long periods.Partition coefficient and molecular size influence not only thepenetration of drug across the membrane but also diffusion acrossthe rate limiting membraneThe ability of drug to diffuse through membranes its so calleddiffusivity & diffusion coefficient is function of molecular size (ormolecular weight).Generally, values of diffusion coefficient for intermediatemolecular weight drugs, through flexible polymer range from 10-8to 10-9 cm2 / sec. with values on the order of 10-8 being mostcommon for drugs with molecular weight greater than 500.
Thus high molecular weight drugs or polymeric drugs should beexpected to display very slow release kinetics in sustained releasedevice using diffusion through polymer membrane.Phenothiazines are representative of this type of compound
3.Aqueous Solubility.Since drugs must be in solution before they can be absorbed,compounds with very low aqueous solubility usually suffer oralbioavailability Problems, because of limited GI transit time ofundissolved drug particles and limited solubility at the absorptionsite.E.g.: Tetracycline dissolves to greater extent in the stomach than inthe intestine, there fore it is best absorbed in the intestine.Most of drugs are weak acids or bases, since the unchanged formof a drug preferentially permeates across lipid membranes drugsaqueous solubility will generally be decreased by conversion to anunchanged form. for drugs with low water solubility will be difficultto incorporate into sustained release mechanism.
Aqueous solubility and pKaThese are the most important to influence its absorptive behavior and its aqueous solubility ( if it‟s a weak acid or base) and its pKaThe 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.CsWhere dc/dt = dissolution rate Kd= dissolution rate constant A = total surface area of the drug particles Cs= aqueous solubility of the drug
Dissolution rate (dc/dt) is constant only when Surface Area A isthe initial rate is directly proportional to the Aqueous solubility(Cs) hence Drug with low aqueous solubility have low dissolutionrate and its suffer low bioavailability problem.The aqueous solubility of weak acid and bases are controlled bypKa of the compound and pH the medium.For weak acidsSt= So(1+Ka/H+) = So (1+10pH-pKa )Where St = total solubility of weak acid.So = solubility of unionized formKa= Acid dissociation constantH+= H ion concentration
Similarly for Weak BasesSt = So (1+H+/Ka) = So (1+10pKa-pH )if a poorly soluble drug was consider as a suitable candidate forformulation 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 favoredfrom this acidic environment on the other hands weakly basic drugswill be exist primarily in the ionized form (Conjugate Acids) at thesame site, their absorption will be poor.in the upper portion of the small intestine the pH is more alkalinepH 5-7 and the reverse will be expected for weak acids
4.Drug stability.The stability of drug in environment to which it is exposed, isanother physico-chemical factor to be considered in design atsustained/ controlled release systems, drugs that are unstable instomach can be placed in slowly soluble forms or have their releasedelayed until they reach the small intestine.Orally administered drugs can be subject to both acid, basehydrolysis and enzymatic degradation. Degradation will proceed atthe reduced rate for drugs in the solid state, for drugs that areunstable in stomach, systems that prolong delivery ever the entirecourse of transit in GI tract are beneficial.
Compounds that are unstable in the small intestine maydemonstrate decreased bioavailability when administered form asustaining dosage from. This is because more drug is delivered insmall intestine and hence subject to degradation.However for some drugs which are unstable in small intestine areunder go extensive Gut –Wall metabolism have decreased the bioavailability .When these drugs are administered from a sustained dosage formto achieve better bio availability, at different routes of the drugsadministered should be chosenEg. NitroglycerineThe presence of metabolizing enzymes at the site or pathway canbe utilized.
5.Protein binding.It is well known that many drugs bind to plasma protein with theinfluence on duration of action.Drug-protein binding serve as a depot for drug producing aprolonged release profile, especially it is high degree of drugbinding occurs.Extensive binding to plasma proteins will be evidenced by a longhalf life of elimination for drugs and such drugs generally mostrequire a sustained release dosage form. However drugs that exhibithigh degree of binding to plasma proteins also might bind to bio-polymers in GI tract which could have influence on sustained drugdelivery. The presence of hydrophobic moiety on drug moleculealso increases the binding potential.
The binding of the drugs to plasma proteins(eg.Albumin) resultsin retention of the drug into the vascular space the drug proteincomplex can serves as reservoir in the vascular space for sustaineddrug release to extra vascular tissue but only for those drugs thatexhibited a high degree of binding.The main force of attraction are Wander-vals forces , hydrogenbinding, electrostatic binding.In general charged compound have a greater tendency to bind aprotein then uncharged compound, due to electrostatic effect.Eg amitryptline, cumarin, diazepam, digoxide, dicaumarol,novobiocin.
6.Pka: (dissociation constant) The relationship between Pka of compound and absorptiveenvironment, Presenting drug in an unchanged form isadventitious for drug permeation but solubility decrease as thedrug is in unchanged form.An important assumption of the there is that unionized form of thedrug is absorbed and permeation of ionized drug is negligible, sinceits rate of absorption is 3-4 times lesser than the unionized form ofthe drug.The pka range for acidic drug whose ionization is PH sensitive andaround 3.0- 7.5 and pka range for basic drug whose ionization is phsensitive around 7.0- 11.0 are ideal for the optimum positiveabsorption
Classification of polymersNatural polymers Semi synthetic Synthetic polymerseg. Xanthan gum, polymers eg. Polyesters, polyurethanes, eg. Celluloses such as polyamides, Guar gum, HPMC, NaCMC, polyolefins etc polycarbonates, Ethyl Karaya gum cellulose etc. etc
Classification Of Polymers Used In Sustained Release Drug Delivery Systems According To Their Characteristics:Sr.no Polymer characteristics Material1. 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 Trigycerides3. Hydrophilic Methylcellulose, Hydroxyethylcellulose, HPMC, Sodium CMC, Sodium alginate, Galactomannose Carboxypolymethylene.
1. Oral forms2. Parenteral forms3. Common sustained action dosage forms a. Spansules b. Slow core release tablets c. Multilayer tablets d. Repeat action tablets e. Liquid products f. Transdermal system
DESIGN OF ORAL SUSTAINED ACTION PRODUCTS Formulation methods used to obtain the desired drugavailability 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 containingdrug(microencapsulation).• Forming complexes of the drug with material such as ionexchange resins.
1) Increasing the particle size of the drug:- The purpose of increasing particle size is to decrease thesurface to volume ratio slow the rate of drug availability. Thismethod is a single means for obtaining the desired drug availabilityrate is limited to poorly soluble drug.
2) Embedding the drug in matrix:- Matrix may be defined as uniform dispersion of drug insolid which is less soluble than a drug in the dispersion fluid, &which for the continuous external phase of the dispersion effectivelyimpeder the passage of the drug from the matrix to the dispersionfluid. One of the least complicated approaches to themanufacture of sustained release dosage form involves the directcompression of drug, materials & additives to form a tablet inwhich drug is embedded in a matrix core of the retardant.
Polymers:-• Insoluble, inert - polyethylene, polyvinyl chloride, methyl acrilate,ethylcellulose.•Insoluble, erodible – carnauba wax, stearyl alcohol, castor wax.•Hydrophilic – methyl cellulose, hydroxyl ethyl cellulose, sodiumcarboxymethyl cellulose, sodium alginate. In a matrix system the drug is dispersed as solid particle withina porous matrix formed of a water insoluble polymer, such as poly-vinyl chloride.
Initially, drug particle located at the surface of the release unitwill be dissolved and the drug released rapidly. Thereafter, drugpartical at successively increasing distance from the surface of therelease unit will be dissolved and release by diffusion in the pores tothe exterior of the release unit. The main formulation factor by which the release rate frommatrix system can be controlled are; the amount of the drug in thematrix, the porosity of the release unit & the solubility of the drug.
Types of matrix systemsTwo types of matrix systems1. Slowly eroding matrix2. Inert plastic matrix1.Slowly eroding matrixConsists of using materials or polymers which erode over a periodof time such as waxes, glycerides, stearic acid, cellulosic materialsetc.Principle:• Portion of drug intended to have sustained action is combined withlipid or cellulosic material and then granulated.• Untreated drug granulated• Both mixed
2. Embedding drug in Inert plastic matrixPrinciple: 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.
Methods of preparationPreparation of matrix tablets: Solidify Granulate Grind Powder Suspension of drug in wax Granulate Drug Tablets
3) Coating the drug or a dosage form containing the drug (microencapsulation) The method for retarding drug releasefrom the dosage form is to coat itssurface with a material(polymers) thatretards penetration by the dispersionfluid. Drug release depends upon thephysiochemical nature of coatingmaterial. Microencapsulation is rapidlyexpanding technique as a process; it is ameans of applying relatively thin coatingto small particles of solid or droplets ofliquids and dispersion.
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 formulationconcepts for creams, ointments, aerosols, dressing, plasters,suppositories & injectables. Polymers: - polyvinyl alcohol, polyacrylic acid, ethylcellulose, polyethylene, polymethacrlate, poly (ethylene-vinylacetate), cellulose nitrite, silicones, poly (lactide-co-glcolide)
4) Chemically reacting the drug with material such as an ion-exchange resin:- Sustained delivery of ionizing acidic & basic drug can beobtained by complexing them with insoluble non-toxic anionexchanger and cation exchanger resin respectively. Here the drug is released slowly by diffusing through the resinparticle structure. The complex can be prepared by incubating the drug-resinsolution or passing the drug solution through a column containingion exchange resin.
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 moleculesIER are capable of exchanging positively or negatively charged drug molecules to form insoluble poly salt resinates.Types:There are two types of IER Resins functional groupsCationic Exchange resins - RSO3-H+Anionic Exchange resins – RNH3+ OH-
Structurally made up of a stable acrylic polymer ofstyrene-divinyl benzene copolymer.Mechanism of actionIER combine with drug to form insoluble ion complexes1. R-SO3 – H+ + H2N – A R-SO3 – NH3+ - A - +2. R-NH3 OH + HOOC – B RNH3+ -OOC-B + H2O Where A- NH2 is basic drug B-COOH is acidic drug
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.
In the stomach -®- SO3- NH3+ - A + HCl ®-SO3 H+ + A-NH3+ Cl-®-NH3+ -OOC –B + HCl ®-NH3+Cl- + HOOC-B Un dissociatedThus carboxylic acid will be poorly dissociated in stomach and thusabsorbed.
In the Intestine -®- SO3- NH3+ - A + NaCl ®- -SO3 Na+ + A-NH3+ Cl - Basic pH un dissociated ®-NH3+ -OOC – B + NaCl ®-NH3+Cl- + Na+-OOCB Sodium salt of acid (dissociation of acid salt unabsorbed)Amine salt will be poorly dissociated in intestine and thus absorbed.
Parenteral formsThe following parameters are generally manipulated in the design ofparenteral forms: A) Route of administrationRoute of administration of drugs are very many and all of them donot afford same rate of absorption. A drug given by intravenousinjection may attain a certain blood concentration almostinstantaneously, while the same drug administered intramuscularlymay take considerable time to build up that level since it takes timeto diffuse from muscular tissues into the blood stream. Further adrug, placed under the skin in the form of an implant, may remainactive over extended period of time giving a sustained action lastingfor mouths. Hence, rate of administration may sometime befruitfully employed to obtain sustained action of a medicament.
B)Vehicles Vehicles significantly alter the bioavailability profile and may beemployed to obtain sustained action. If a drug is suspended in alipophilic vehicle and injected in tissues like muscles it gives alonger action than when it is given in aqueous media. C)Vaso-constricationThe rate of passage of drugs, administered intradermally orintramuscularly, depends to a considerable extent upon their area ofcontact with blood vessels. Hence, constriction of blood vesselsmay be employed to prolonged action. Adrenaline is sometimeadministered with local anesthetics to delay absorption of drugs andto prolong duration of their action,
D) Particle sizeThe particle size governs the dissolution rate and hence thebioavailability of drug. Consequently this parameter may beexploited to prolong its action. This principle is used in theformulation of the hypodermic tablets which retain their size overlong period of time releasing the drug slowly. E)Chemical modification of the drugThe structure of the drug molecules can sometime be chemicallymodified such that their action is intact while ADME characteristicsget altered. In some cases an analog is synthesized which gives itthe desired capacity of prolonged action. Sometime pro-drugapproach is possible whereby a derivative of the drug is evolvedwhich is slowly regenerated into the original drug in the presence ofbody fluids.
Lidocaine, where two hydrogen atoms are replaced by methylgroups enabling it to give prolonged effect, is an example of analogapproach, while chlorphenactin palmitate is an example of pro-drugsince the palmitate has to hydrolyse in the g.i.t. to producechloromycetin which is the therapeutic agent.Pro-drug which consist of reservoir of drug whose flow into thebody is calculated either by some body indicator like insulin or bycondition of body is calling for specified inputs of drugs. Suchsystems are popularly refered to as “triggered system”, “pulsedsystem”. The principles made use of there designs are brieflydiscussed below.
Portable pumpsZyklomat pump, marketed by a german firm has a drug reservoirand a timing device linked to a computer. It can administerhormones like LHRH every one and a half hours for 20 days. Yetanother example is a four channel porgrameable portable syringepump having four 30 ml. syringes programmed to deliver drug atany predetermined rate. A personal computer transfer theprogramme to a control cartridge which is plugged in the pumpsystem. Such devices have been used in antibiotic as well.
Implantable devicesImplantable devices marketed in USA and designed forimplantation in the body, consist of peristaltic pump, drug reservoir,battery and a control unit. The drug administration programme isentered on a personal computer and is transmitted by a control unitto the pump system through skin. Such unit have been employed foradministration of drug in cancerous and neurological disorders.Gradually their use may extended to other conditions requiringspecified drug administration programmes.
Infusor devicesThese devices are light weight, portable, disposable and elastomericinfusion systems. They generally have a small reservoir of drugsufficient for half day, a day or 5day needs and carry commandmodules operable by patients. For control of pain, patientsthemselves can operate the system every 5-6 min. such systemshave few side effects and allow optimal pain control.
Osmotic pumpsOsmotic pumps are specifically beneficial in veterinary medicineand enable zero order drug delivery. The pumping device are linkedwith programmable catheter to permit patterned drug delivery andhave largely used for LHRH hormone delivery in animals to induceovulation.
Implantable magnetically triggered systemsThese system have a porous matrix with drug embedded in it alongwith a few magnetic pellets. In the normal course very little drug isreleased. However, by an oscillating magnetic field the drug diffuseout in pulses to the system.
Biodegradable systemIn biodegradable system the drug is incapsulated in a polymerwhose erosion is pH dependent. The outer core of the coat is ahydrogel with immobilized enzymes like glucose oxidase whichconvert glucose into gluconic acid everytime its level rises in blooddecreasing pH and thereby causing erosion of polymer and releaseof drug.
Antibody coated particlesIn these dosage form the drug is convalently linked to a hapten andcoated with corresponding antibodies. When the drug is to bereleased more haptens are introduced which displace the antibodycoating enabling release of drug. Naltrexone has been thus linkedwith a hapten moiety and coated with antibodies.
Common sustained action dosage form•Spansules:Spansules are hard gelatin capsules filled with coated granules orbeads. They are marketed by manufacturer under variety of tradenames.•Slow core released tablets:These tablets consist of a core of drug mixed up with substancesfrom which drug can be slowely leached out by GIT fluid. On to thecore is compressed another layer consisting of drug and otherexcipients. The upper layer generally disintegrates rapidly releasingthe drug which builds up blood level. Thereafter the drug is slowlyleached out from the core.
•Multilayer tablets:Multilayer tablets consist of 2-3 separate layers which release drugat different rates. In two layers tablets one of the layers is designedfor immediate disintegration while the other remains firm and intactthroughout its sojourn in the intestines. In three layers tablets, onelayer may be for immediate disintegration, the other is designed todisintegration after sometime and the third may remain intactreleasing drug at a slow pace.
•Repeat action tablets:Repeat action tablets are regarded to be prototypes of sustainedaction products but in fact they are not. In these tablets a seconddose is released only after the first is practically worn off and thereis no continuous release. These tablets usually consist of a core anda coat. The initial dose is in the coat and the following one in thecore.•Liquid products:It is possible to formulate liquid product, having sustained action,by suspending coated granules or particles in a suitable liquid mediawhich has no action on the coats of the granules. These formulationare similar to suspensions.
EvaluationDrug release is evaluated based on drug dissolution fromdosage form at different time intervals.Specified in monograph.Various test apparatus and procedures – USP, Chapter <724>.
Two types1. In vitro evaluation2. In vivo evaluationIn 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
In vitro quality control tests include:1. Rotating basket (apparatus 1)2. Paddle (apparatus 2)3. 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
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 agitationStability of the formulationUltimately does the observed profile fit expectations.
Other apparatus specific for SR evaluations Rotating bottle Stationary basket / rotating filter Sartorius absorption and solubility simulator Column-type flow through assembly
Rotating bottle method:Samples are tested in 90 ml bottles containing 60 ml of fluid whichare rotated end over end in a 370 C bath at 40 rpm.Sartorius deviceIncludes an artificial lipid membrane which separates thedissolution chamber from simulated plasma compartment in whichthe drug concentration are measured or dialysis membrane may beused.Advantages:Measure release profile of disintegrating dosage units such aspowder materials, suspensions, granular materials, if permeability isproperly defined .
Column flow through apparatusDrug is confined to a relatively small chamber in a highlypermeable membrane filters.Dissolution fluid might be re-circulated continuously from thereservoir 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.
Example-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 %
In vivo evaluationA 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.
Evaluation and testing:•During formulation•Precompression granular properties•Post compression test
During formulation development, testing method should bedesigned to provide answer of the following question. Does the product “dump” maintenance dose before themaintenance period is complete? Sustained release product issubjected to either of two modes of failure, insufficient dose isrelease or too much drug is made available too quickly. What fraction of the dose remains unavailable, i.e. whatfraction will not be released in the projected time of transit in the GItract? What is effect of physiologic variables on drug release? Fore.g.: delayed gastric empting, interaction between drug and GIconstituent‟s composition and volume of GI fluid.
is the loading dose released immediately? Is release of themaintenance dose delayed? If so, is the delay time within thedesired range? What is the stability of the formulation with respect to its drugrelease profile? What is the sensitivity of drug release profile to processvariables?
Precompression granular properties:Hausner ratio a similar index has been defined by hausner (1967):Hausner ratio = tapped density/ poured density×100. Value less than 1.25 indicate good flow (=20% Carr), where asgreater than 1.25 indicates poor flow (=33%Carr), between1.25 and1.5, added glident normally improve flow.Angle of repose It is simple practical technique for measuring resistance topartical movement.
It is the maximum angle that can be obtained between thesurface of the powder pile and the horizontal plane.Bulk density It is great importance when one the size of a high doseformulation in which there are large difference in drug andexcipients densities. Bulk density is determined by pouring presived (40-mesh) bulkdrug into a graduated cylinder via a large funnel and measuring thevolume and weight “as is”
Tapped density: Tapped density is determined by placing a graduated cylindercontaining a known mass of drug and taps (1000) for mechanicaltapper until the powder bed volume has reached a minimum. Usingthe weight of drug in the cylinder and this minimum volume, thetapped density may be computed.Carr`s index: a simple test to evaluate the flowability of a powder bycomparing the poured density and tapped density of a powder andthe rate at which it packed down.Carr‟s index (%) = tapped – poured density/tapped density×100
Post compression test:Hardness: the force required to break a tablet in a diametriccompression test (Monsanto hardness tester).Wt variation: mean of 10 tablets.Friability: loss of drug during handling, manufacturing, packaging,and shipping.General appearance: visual identity and overall “elegance,” lot tolot & tablet to tablet uniformity. Size, shape, color, presence or absence of an odor, taste, surfacetexture, physical flows and consistency.
Unique identification marking: the type of informational marking placed on a tablet usuallyinclude the company name or symbol, a product code such as thatfrom the National Drug Coad number, the product name or theproduct potency.Organoleptic properties: colour, odor, taste.
Drug content of formulated tablets Five tablets from each batch were randomly chosen,pulverized and weight equivalent to 50mg of Drug was extractedwith 100ml phosphate buffer (pH 7.4). Aliquot from subsequentfiltered solution was further diluted in phosphate buffer (pH 7.4) insuch a way that theoretical concentration was same as that ofstandard concentration. Resultant solutions were analyzed by usinga UV spectrophotometer and the average results taken.
Disintegration: the first important step toward solution is breakdown of thetablet into smaller particle or granules for rapidly available to thebody. The USP device- 6 glass tube – 3 inch long open at top, 10-mesh screen.temp 370c ± 2 in simulated intestinal fluid. 28-32 cycle per minute.
Dissolution: The dissolution studies were performed in triplicate for all thebatches in a USP dissolution rate test apparatus. The release studies were performed at 50 rpm in 900 ml ofphosphate buffer pH 7.4 at 37 ± 0.2οC. Five milliliters sample werewithdrawn at predefined intervals, and the volume of the dissolutionmedium was maintained by adding the same volume of fresh bufferin dissolution medium. The absorbance of the withdrawn samples was measuredspectrophotometrically at ………… nm.
Problems during formulation of SR dosage form Film Coating ChallengesOne of the main challenges in film coating is developing a processthat is easily controlled and able to generate reproducible andreliable films. It is important to consider the Minimum FilmFormation Temperature (MFT) for a given polymeric coatingproduct. It has been shown that it is only possible to form acontinuous polymer film above the MFT; the dispersed particleswill not fully coalesce below the MFT, and, as a result, no filmformation will occur.Ethyl cellulose and other methacrylate polymers have MFTs that arehigher than room temperature, making film formation much moredifficult.
Prevent Drug DumpingA further challenge in sustained release film coating is to preventdrug dumping. One of the recent trends in oral sustained release ismulti-particulates, a formulation in which the drug dose is dividedover a multiple-unit system made up of many small, discreteparticles. Multi-particulates have several advantages over single-unit systems, including less local irritation due to better distributionand less variability in gastrointestinal transit time due to their smallsize. More importantly, even if failures occur in a few multi-particulate units, drug dumping is not as severe as it is when failuresoccur in a single-unit system.
Release and Compression ForceWhen investigating the degree of drug release from compressedtablets, it is important to consider the relationship between drugrelease and compression force. Drug release from compressedpellets coated with Aquacoat is significantly faster than it is fromun-compressed pellets. The higher the compression force, the fasterthe release rate, which indicates the existence of damaged filmcoatings after compression.
There is no doubt that the importance of sustained release drugdelivery has increased during the last 20 years. This growth isreflected in the proliferation of sustained release drugs that havebeen commercialized largely due to the availability of effectivesustained release coating products. Process improvements and therole of plasticizers and other protective excipients have helpedprovide cost and performance benefits. Many of the challengescaused by sustained release coatings can now be overcome.
MARKETED CONTROLLED RELEASE PRODUCT Composition Product Name ManufacturerTabletCarbamazepine Zen Retard IntasDiazepam Calmrelease – TR NatcoDiclofenac sodium Dic – SR Dee Pharma LimitedDiclofenac sodium Nac – SR SystopicDiclofenac sodium Agile – SR Swift
Diclofenac sodium Dicloram SR UniqueDiclofenac sodium Doflex SR Nicholas PiramalDiclofenac sodium Mobinase – SR CroslandDiclofenac sodium Monovac – SR Boehringer – MannheimDiclofenac sodium Relaxyl - SR Franco – IndianDiclofenac sodium Voveran – SR Ciba – GeigyDiltiazem Dilzem SR Torrent
Diltiazem Hcl Diltime SR AlidacLithium carbonate Lithosun – SR SunpharmaNifedipine Nyogard LA Searle (I) LtdNifedipine Calcigard Torrent RetardNifedipine Depin Retard Cadila Health CareSalbutamol TheoAsthalin CiplaTheophylline SRTerbutaline Sulphate, Theobric – SR RemidexTheophyllineAnhydrous
Theophylline Theo PA WelcomeTheophylline Theo Stan – CR Stancare AnhydrousVerapamil Calpatin SR Boehringer – hydrochloride MannheimVerapamil Calapatin 240 SR Boehringer – hydrochloride Mannheim
CapsulesChlorpheniramine Coldvir – SR Dee Pharmamaleate, Phenylepinephrine LtdhydrochlorideDiazepam Elcoin RanbaxyDiclofenac sodium Diclotal CR Blue CrossDiclofenac sodium Nalco TR NatcoDried Ferrous Sulphate, Feron SR Dee PharmaFolic acid LtdDried Ferrous Sulphate, Fefol EskayefFolic acid Spansules
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