Design of Sustained Release Dosage Forms SALMAN BIN ABDUL AZIZ UNIVERSITY COLLEGE OF PHARMACY Design of Sustained Release Dosage Forms PHARMACEUTICS- IV (PHT 414 ) Dr. Shahid Jamil 4/27/2017 L9-10
INTRODUCTION DEFINITIONS:- SRF’s describes the slow release of a drug substance from a dosage form to maintain therapeutic response for extended period (8-12hrs)of time. Time depends on the dosage form. In oral form it is in hours, and in parenteral’s it is in days and months. Ex: Aspirin SR, Dextrim SR. Controlled release dosage form: In this the rate or speed at which the drug is released is controlled. Ex: Adalat CR (Nifidipine), Dynacirc CR (Isradipine.)
Flow diagram of immediate release (multiple dose tablet and capsules), controlled release (zero order) and sustained release. L9-10 4/27/2017
CONCEPT The goal of SRDF’s is to obtain Zero order release from the dosage form. Zero order release is a release which is independent of the amount of drug present in the dosage form. Usually SRDF’s do not follow zero order release but they try to mimic zero order release by releasing the drug in a slow first order fashion. Pharmacological action is seen as long as the drug is in therapeutic range, problems occur when drug concentration is above/below therapeutic range.
With many drugs, the basic goal of therapy is to achieve a steady-state blood or tissue level that is therapeutically effective and nontoxic for an extended period of time. The design of proper dosage regimens is an important element in accomplishing this goal. Dosage regimen: the frequency of administration of drug in a particular dose is called as dosage regimen A basic objective in dosage form design is to optimize the delivery of medication so as to achieve a measure of control of the therapeutic effect in the face of uncertain fluctuations in the in vivo environment in which drug release takes place. L9-10 4/27/2017
This is usually accomplished by maximizing drug availability, i. e This is usually accomplished by maximizing drug availability, i.e., by attempting to attain a maximum rate and extent of drug absorption. control of drug action through formulation also implies controlling bioavailability to reduce drug absorption rates. L9-10 4/27/2017
The Sustained Release Concept Sustained release, sustained action, prolonged action, controlled release, extended action, timed release, depot, and repository dosage forms are terms used to identify drug delivery systems that are designed to achieve a prolonged therapeutic effect by continuously releasing medication over an extended period of time after administration of a single dose. L9-10 4/27/2017
In the case of inject able dosage forms, this period may vary from days to months. In the case of orally administered forms, this period is measured in hours and critically depends on the residence time of the dosage form in the gastrointestinal (GI) tract. The term "controlled release" has become associated with those systems from which therapeutic agents may be automatically delivered at predefined rates over a long period of time. Products of this type have been formulated for oral, inject able, and topical use, and include inserts for placement in body cavities as well. L9-10 4/27/2017
Before proceeding with the design of a sustained release form of an appropriate drug, the formulator Should have an understanding of the pharmacokinetics of the candidate. Should be assured that pharmacologic effect can be correlated with drug blood levels. Should be knowledgeable about the therapeutic dosage range, including the minimum effective and maximum safe doses. L9-10 4/27/2017
Design (Theory) To establish a procedure for designing sustained release dosage forms, it is useful to examine the properties of drug blood-level- time profiles characteristic of multiple dosing therapy of immediate release forms. L9-10 4/27/2017
Figure 1 shows typical profiles observed after administration of equal doses of a drug using different dosage schedules: every 8 hours (curve A), every 3 hours (curve B), and every 2 hours (curve C). FIG 1. Multiple patterns of dosage that characterize non-sustained peroral administration of a drug with a biologic half-life of 3 hr and a half-life for absorption of 20 min. Dosage intervals are: A, 8 hr; B, 3 hr; C, 2 hr; and D, 3 hr (loading dose is twice the maintenance dose). E, Constant rate intravenous infusion. L9-10 4/27/2017
Where: t: is the dosing interval, t1/2: is the biologic half-life. If t = t1/2, Di = 2Dm. Selection of the proper dose and dosage interval is a prerequisite to obtaining a drug level pattern that will remain in the therapeutic range. L9-10 4/27/2017
Elimination of drug level oscillations can be achieved by administration of drug through constant-rate intravenous infusion. Curve E in Figure 1 represents an example whereby the infusion rate was chosen to achieve the same average drug level as a 3- hour dosage interval for the specific case illustrated. The objective in formulating a sustained release dosage form is to be able to provide a similar blood level pattern for up to 12 hours after oral administration of the drug. To design an efficacious sustained release dosage form, one must have a thorough knowledge of the pharmacokinetics of the drug chosen for this formulation. L9-10 4/27/2017
Figure 2 shows a general pharmacokinetic model of an ideal sustained release dosage form. 4/27/2017
Measurements of drug blood level are assumed to correlate with therapeutic effect and drug kinetics are assumed to be adequately approximated by a one-body-compartment model. That is, drug distribution is sufficiently rapid so that a steady state is immediately attained between the central and peripheral compartments, i.e., the blood-tissue transfer rate constants, k12 and k21, are large. L9-10 4/27/2017
Under the foregoing circumstances, the drug kinetics can be characterized by three parameters: The elimination rate constant (ke) or biologic half-life (t1/2 = 0.693/ke) The absorption rate constant (ka). The apparent distribution volume (Vd), which defines the apparent body space in which drug is distributed. L9-10 4/27/2017
For the two-body compartment representation of drug kinetics, Vc is the volume of the central compartment, including both blood and any body water in which drug is rapidly perfused. L9-10 4/27/2017
The specific parameters that must be taken into account in optimizing sustained release dosage form designs, is shown in Figure 2 at the absorption site are: The loading or immediately available portion of the dose (Di). The maintenance or slowly available portion of the dose (Dm). The time (Tm) at which release of maintenance dose begins (i.e., the delay time between release of Di and Dm). The specific rate of release (kr) of the maintenance dose. L9-10 4/27/2017
Figure 3 shows the form of the body drug level time profile that characterizes an ideal peroral sustained release dosage form after a single administration. L9-10 4/27/2017
Tp is the peak time. h is the total time after administration in which the drug is effectively absorbed. Cp is the average drug level to be maintained constantly for a period of time equal to (h - Tp) hours; it is also the peak blood level observed after administration of a loading dose. The portion of the area under the blood level curve contributed by the loading and maintenance doses is indicated on the diagram. L9-10 4/27/2017
To obtain a constant drug level, the rate of drug absorption must be made equal to its rate of elimination. Consequently, drug must be provided by the dosage form at a rate such that the drug concentration becomes constant at the absorption site. L9-10 4/27/2017