Design of Sustained Release Dosage Forms

1. SALMAN BIN ABDUL AZIZ UNIVERSITY COLLEGE OF PHARMACY • PHARMACEUTICS- IV • (PHT 414 ) • Dr. ShahidJamil Design of Sustained Release Dosage Forms L9-10

2. 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.)

3. Flow diagram of immediate release (multiple dose tablet and capsules), controlled release (zero order) and sustained release. L9-10

4. 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.

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. Figure 2 shows a general pharmacokinetic model of an ideal sustained release dosage form. L9-10

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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

21. 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