Sustained Release Drug Formulation

Introduction • The basic goals of therapy is to achieve a steady-state blood or tissue level that is therapeutically effective and nontoxic for an extended period of time. • This objective can be accomplished by maximizing drug availability. • This can be done by increasing the drug absorption.

Objectives of drug delivery • The two aspects most important to drug delivery. • Spatial Placement:relates to targeting a drug to a specific organ or tissue. • Temporal Placement:- refers to the controlling the rate of the drug delivery to the target tissues.

1

Convention Drug therapy

Convention Drug therapy • Convention drug therapy is of short duration of action. • This is due to the inability of conventional dosage forms to control temporal delivery.. • If an attempt is made to maintain drug blood levels in the therapeutic range for longer period of time • For e.g. By increasing the dose, then toxic level may be produced at early times.

2

Problems with conventional drug therapy • If the dosing intervals is not appropriate for the biological half life of the drug, large “peaks” and “valleys” in drug blood level may results. • The drug blood level may not be within the therapeutics range at sufficiently early time. • Patient noncompliance with multiple dosing regimen.

Sustained Release • The conventional dosage forms • Dosage form ÆAbsorption poolÆ Target poolÆ • The rate of absorption is rate limiting step

• Sustained Release

• Dosage form Æ Target poolÆ • The release of the drug from the dosage from is rate limiting step.

3

Application

Classification • No immediate –release delivery systems may classified as follows:• Delayed release • Sustained release • Controlled • Prolonged

• Site specific release • Receptor release

4

• Delayed release:- system uses repetitive intermitted dosing of a drug from one or more immediate release units incorporated in a single dosage form.

• Sustained Release:- includes any drug delivery system that achieves slow release of drug over and extended period of time.

5

• Site specific:- targeting the drug effectively to a certain biological location.

Potential advantages of sustained release • Avoid patient compliance problem • Employ less total drug

• Minimizing or eliminate local side effects. • Minimizing or eliminate systemic side effects. • Minimize drug accumulation.

• Improve the efficiency of the treatment • Cure or control condition more promptly • Reduce the fluctuation in drug level. • Improves bioavailability

• Economy

6

Controlled Release: Art or Science?

dMt dt CONTROLLED t

RELEASE FORMULATION dMt dt

t

DIFFUSION-CONTROLLED

CHEMICALLY-ACTIVATED

Matrix Systems Membrane Reservoirs

Biodegradable Polymers Pendant Chain Chemistry

CONTROLLED RELEASE PULSATILE SOLVENT-ACTIVATED Swellable Gels Osmotic Systemsrs

pH- or Temperature- Sensitive Electric or Ultrasonic Multi-Compartmental

7

Swellable Hydrogel Systems

ξ

Solvent Absorption

ξ Drug

Drug released by diffusion; Rate controlled by gel mesh space, ξ, and polymer relaxation

Diffusion in Porous Systems

8

Adjusting the Drug Flux Through Polymers •

Change of the Polymer Structure (Crosslinking, Crystallinity) • Change Of Thickness (Multilaminate Systems) • Change Of Barriers (Porosity) • Change Of Solubility (Plasticizers)

Adjusting the Drug Flux Through Polymers •

Change of the Polymer Structure (Crosslinking, Crystallinity) • Change Of Thickness (Multilaminate Systems) • Change Of Barriers (Porosity) • Change Of Solubility (Plasticizers)

9

3. Solvent-activated controlled

the active agent is dissolved or dispersed within a polymeric matrix and is not able to diffuse through that matrix. advantage ˙ complex control disadvantage ˙ generally more bulky devices and require implantation

Osmotically Controlled Systems ƒ

Consider Polymer with Drug Incorporated Throughout

ƒ

Presence of Highly Soluble Drug Leads to very High Osmotic Pressure

ƒ

As a Result, the Release System Starts Rupturing

10

The Oros® System

Elementary Osmotic Pump Cross Section

“Push-Pull” Osmotic Tablet

11

Osmotic Pump Systems ƒ Advantages ƒ Release Rates are Independent of Agent Properties ƒ Can Deliver Macromolecules and Ionic Species ƒ Relatively High Fluxes ƒ Release Rates are not Dependent on Environmental Conditions

Osmotic Pump Systems Disadvantages ƒ Subject to dose dumping if membrane breaks ƒ [e.g. someone chews it]

ƒ Slightly more expensive to formulate than coating tablets ƒ Possible hole plugging

12

Targeted Drug Delivery •

Chemotherapy targets all proliferating cells Æ toxic to normally dividing cells: • • •

•

Purpose: • • •

•

Bone marrow Skin GI mucosa Increase drug specificity to pathological tissue Increase drug therapeutic efficacy Decrease systemic toxicity

Methods: •

•

Passive targeting Æ Enhanced Permeability & Retention effect Active targeting

Cancer • In 2000, 1.4 million cases of cancer • 560,000 deaths, > 1,500 people a day • 1/4 of deaths in US are from cancer • Cancer cost: • $37 billion direct medical costs • $11 billion low productivity

13

• Passive Targeting

• Minimizes non-specific interactions which may lead to renal excretion or uptake by the reticuloendothelial system • Utilizes carrier physiochemical characteristics such as size and hydrophobicity

•

Enhanced Permeability and Retention Effect (EPR) • Leaky capillaries allow extravasation of drug carriers • Deficient lymphatic system surrounding tumors leads to entrapment of large molecules within the tumor • Result: passive accumulation of molecules

Leaky tumor vasculture allows drug/carrier to enter

Lower permeability of vasculature in normal tissue prevents drug carrier from escaping to areas where it is not needed

= drug carrier

Poor lymphatic drainage traps molecules in the tumor

14