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Show related SlideShares at end. Full Name Comment goes here. Are you sure you want to Yes No. Embeds 0 No embeds. No notes for slide. Prakash Dr Rashmi G. It was first described for use as an IV anesthetic induction in Ingestion of even 50 hyptonic doses does not endanger life-there is no loss of consciousness and patient can be aroused; respiration is not so depressed as to need assistance.
Only on IV injection the BP falls and contractility decreases. Sustain release dosage form- is defined as the type of dosageform in which a portion i. Sustained release implies slow release of the drug over a timeperiod. It may or may not be controlled release. Rationality in designing S. 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.
The above criteria i. So that effort for developing S. F must be directed primarilyaltering the release rate. 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 some case, control of drug therapy can be achieved bytaking advantage of beneficial drug interaction that affect drugdisposition and elimination. 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. 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. 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. These difficulties may be overcome by: This is fixed by the dosage form design. Consequentlydisease states that alter drug disposition, significant patient variationand so forth are not accommodated. 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.
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. 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.
Factors to be considered In S. Biological Factors Physiological Factors: Partition coefficient and 2. Margin of safety 6. The rate, extent and uniformity in absorptionof drug are important factor when considering its formulation in tocontrolled release system. The rate of release ismuch slower than rate of absorption.
The maximum half-life forabsorption should be approximately hr otherwise, the devicewill pass out of potential absorptive region before drug release iscomplete. 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 hrs.
If the rate of absorption is below 0. 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. 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.
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. 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.
There are two areas of concern relative to metabolism thatsignificantly restrict sustained release formulation. 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. 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. 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. 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.
It is imperative that the drug release pattern is precise so that theplasma drug concentration achieved in under therapeutic range. Partition coefficient and molecular size. Tetracycline dissolves to greater extent in the stomach than inthe intestine, there fore it is best absorbed in the intestine. Since weakly acidic drugs will exist in the stomach pH ,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.
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. This is because more drug is delivered insmall intestine and hence subject to degradation. NitroglycerineThe presence of metabolizing enzymes at the site or pathway canbe utilized. 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. 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. 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 times lesser than the unionized form ofthe drug. The pka range for acidic drug whose ionization is PH sensitive andaround 3. Classification of polymersNatural polymers Semi synthetic Synthetic polymerseg. Xanthan gum, polymers eg. Insoluble, inert Polyethylene, polyvinyl chloride, methyl acrylates- methacrylate copolymer, ethyl cellulose.
Insoluble, erodable Carnauba wax Stearyl alcohol, Stearic acid, Polyethylene glycol. Castor wax Polyethylene glycol monostearate Trigycerides3. Common sustained action dosage forms a. Slow core release tablets c. Repeat action tablets e. Thismethod is a single means for obtaining the desired drug availabilityrate is limited to poorly soluble drug. 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. Types of matrix systemsTwo types of matrix systems1. Slowly eroding matrixConsists of using materials or polymers which erode over a periodof time such as waxes, glycerides, stearic acid, cellulosic materialsetc.
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: 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. 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.
Structurally made up of a stable acrylic polymer ofstyrene-divinyl benzene copolymer. Mechanism of actionIER combine with drug to form insoluble ioncomplexes1.