Prepared by: Murari Pavan M.Pharm(Pharmaceutics) Gautham college of pharmacy.

Sustained Release Dosage Form

Sustained released dosage forms are designed to achieve a

prolonged therapeutic effect by continuously releasing medication over an extended period of time after administration of a single dose.

In case of injectable dosage forms, this period may vary

from day to months. In case of orally administrator forms, how ever this period is measured in hours and critically depends on residence time of the dosage form in the gastro intestinal tract.

 Mixture of drugs might be utilized to potentate, synergies

or antagonize given drug actions. Alternatively drug mixtures may be formulated in which the rate or extent of drug absorption is modified. Sustained released dosage forms design embodies this approach to control of drug action i.e. through a process of either drug modification or dosage form modification, the absorption process and subsequently drug action can be controlled.

CONVENTIONAL DRUG THERAPY:

To gain an appreciation for the value of controlled

drug therapy it is useful to review some fundamental

aspects of conventional drug delivery.
Consider single dosing of a hypothetical drug that follows

a simple one-compartment pharmacokinetic model for disposition.

Modified-release delivery systems are four types:

1. Delayed release 2. Sustained release 3. Site-specific targeting 4. Receptor targeting
Delayed-release systems are those that use repetitive,

intermittent dosing of a drug from one or more immediate-release units incorporated into a single dosage form. Ex: repeat-action tablets and capsules, and enteric-coated tablets where timed release is achieved by a barrier coating.

 Sustained-release systems include any drug-delivery sys-

tem that achieves slow release of drug over an extended period of time. If the systems can provide some control, whether this be of a temporal or spatial nature, or both, of drug release in the body, or in other words, the system is successful at maintaining constant drug levels in the target tissue or cells, it is considered a controlled-release system.

 Site-specific and receptor targeting refer to targeting of a

drug directly to a certain biological location. In the case of site-specific release, the target is adjacent or in the diseased organ or tissue.
For receptor release, the target is the particular receptor

for a drug within an organ or tissue. Both of these systems satisfy the spatial aspect of drug delivery and are also considered to be controlled drug-delivery systems.

Advantages of sustained release dosage form: Avoid patient compliance problems. Minimize or eliminate local side effects. Minimize or eliminate systemic side effects. Obtain less potentiation or reduction in drug activity with chronic use. Minimize drug accumulation with chronic dosing. Cure or control condition more promptly. Improve control of condition, i.e. reduce fluctuation in drug level. Improve bioavailability of some drugs.

 Make use of special effects, e.g. sustained-release aspirin for morning relief of arthritis by dosing before bedtime.
Constant blood levels achieve desired effect and this effect is maintained for an intended period of time. Better management of disease state is achieved by reduction or elimination of fluctuation in drug blood levels. For drugs having specific window for absorption increased bioavailability can be attained by localizing

the SRDF in that particular region of the GIT. Economy

DISADVANTAGES OF SUSTAINED RELEASE DOSAGE FORMS:

Administration of sustained release medication dose

not permits prompt termination of therapy. Immediate changes in the drug needed during therapy such as might he encountered if significant adverse effects are noted cannot be accommodated. The physician has less flexibility in adjusting dosage regimen. More costly process and equipment are involved in manufacturing many sustained release dosage forms.

 Dose dumping: It is phenomenon where relative large

quantity of drug is released introducing potential toxicity. This is related to manufacturing process. Unpredictable and poor in vitro and in vivo relationship. Need additional patient education.

RELEASE RATE AND DOSE CONSIDERATION:

As mentioned earlier, conventional dosage forms include

solution, suspension, tablets, emulsion, aerosols, foams, ointments, and suppositories. For the purpose of this discussion, these dosage forms can be considered to release their active ingredients into an absorption pool immediately. This is illustrated in the following simple kinetic scheme:

Kr

Ka

Ke

Dosage form--- -Absorption pool----Target area ---- Drug release Absorption Elimination
The absorption pool represents a solution of the drug at the site

of absorption, Kr, Ka, and Ke, are first order rate constants for drug release, absorption, and overall elimination, respectively. Immediate release from conventional dosage form implies that Kr>>>Ka,

 Alternatively, that absorption of drug across a biological

membrane, such as the intestinal epithelium, is the rate limiting step in delivery of the drug to it target area For nonimmediate-release dosage forms, Kr<<<Ka, that is, dosage form is the rate limiting step. This causes the above kinetic Kr Ke Dosage form -------Target area ------- Drug release Elimination

 The ideal goal in designing a controlled-release system is

to deliver drug to the desired site at a rate according to the needs of the body, i.e. a self-regulated system based on feedback control. In the absence of feedback control, constant blood drug level is achieved by continuous intravenous infusion where a drug is provided to the patient at a constant rate just equal to its rate of elimination. This implies that the rate of delivery must be independent of the amount of drug remaining in the dosage form and constant over time. That is, release from the dosage form should follow zero-order kinetics, as shown by Kr = Rate In = rate Out = Ke. Cd. Vd. .. (1)

Where, Kr- is the zero-order rate constant for drug release (amount/time) Kc- is the first-order rate constant for overall drug elimination (timed) Cd is the desired drug level in the body (amount/volume) Vd is volume space in which drug is distributed.

The values of Ke, Cd, and Vd, needed to calculate Kr are

obtained from appropriately designed single dose pharmacokinetic studies. Equation (1) provides the method to calculate the zero order release rate constant necessary to maintain a constant drug blood or tissue level for the simplest case, where drug is eliminated by first order kinetics.

 More complex elimination kinetics and other factor affecting

their disposition are involved. This in turn affects the nature of release kinetics necessary to maintain constant drug blood level. It is important to recognize that while zero-order release may be desirable theoretically, non zero-order release may be equivalent clinically to constant release in many cases. To achieve a therapeutic level promptly and sustain the level for a given period of time, the dosage form generally consists of two parts: an initial priming dose, Di, that releases drug immediately and maintenance or sustaining dose, Dm. the total dose, W, thus required for the system is

W = Di +Dm(2)

 For a system in which the maintenance dose releases drug

by a zero-order process for a specified period of time. The total time is W = Di + Kr Td(3) Where Kr-the zero-order rate constant for drug release Td- the total time desired for sustained release from one dose.

 If the maintenance dose begins release of drug at the time

of dosing (t= 0), it will add to that which is provided by the initial dose, thus increasing the initial drug level. In this case a correction factor is needed to account for the added drug from the maintenance dose W = Di + Kr T d - Kr Tp (4) The correction factor, Kr Tp is the amount of drug provided during the period from t = 0 to the time of the peak drug level, Tp. No correction factor is needed if the dosage form is constructed in such a fashion that the maintenance dose does not begin to release drug until time Tp.

 However, satisfactory approximations of a constant drug

level can be obtained by suitable combinations of the initial dose and a maintenance dose that releases its drug by a first-order process. The total dose for such a system is
W = Di + (Ke Cd/Kr) Vd Dm Ke Tp ..(5)

Where,
Kr-is the first-order rate constant for drug release (time-I), Ke, Cd, and Vd, are as defined previously.

 If the maintenance dose begins releasing drug at t = 0, a

correction factor is required just as it was in the zero-order case. The correct expression in this case is W = Di + (ke Cd/kr) Vd Dm ke Tp .(6) To maintain drug blood levels within the therapeutic range Over the entire time course of therapy, most controlled-release drug-delivery systems are, like conventional dosage forms, administered as multiple rather than single doses. For an ideal controlled-release system that releases drug by zero-order kinetics, the multiple dosing regimens are analogous to that used for a constant intravenous infusion.

Thank you