THERAPEUTIC SYSTEMSAND

NOVEL DRUG DELIVERY DEVICES

Prepared by: S. Campbell-Elliott B Pharm., M Pharm Sc

What are these systems/devices?

Manipulated formulation design to alter release characteristics

Drug released is :- controlled

- with predetermined rate - with predetermined duration

- predetermined location of release

RationaleRationale

Reduced fluctuations between maximum and minimum morphine levels

two-way crossover study in healthy men (N=24) comparing sustained-release morphine tablets (SR) with immediate-release morphine. Data represent plasma morphine levels from 48-60 hours. Finn JW, et al. Placebo-blinded study of morphine sulfate sustained-release.

J Clin Oncol. 1993;11:967972.

Sustained desired therapeutic concentrations (less peaks/troughs)

Reduce frequency of admin and compliance

Reduce side effect profile Provides controlled drug

release (≈ zero order) Available in various

dosage formulations (focus will be on oral and TTS)

Types of Modified release oral formulations Prolonged Release : absorption occurs over a long

time; onset may be delayed due to slower release rate

Sustained Release: initial release; then gradual over long period

Extended Release: drug released slowly; used to maintain plasma levels for long periods; reduces frequency of admin

Note: Modified/Controlled-release refers to any modification i.e. also includes delayed-release

Criteria for selection Biological Half-life : t1/2 must be >2hrs but less than 8 hrs Absorption : not suitable for slow absorption rates or site-

specific absorption Metabolism : not suited for drugs with high pre-systemic

and hepatic metabolism Therapeutic range: ideal for drugs with narrow

therapeutic range** Dose size: Not useful for large doses Aqueous solubility: not suited for drugs with very high or

low rates of dissolution Partition coefficient: ideal for drugs with logP ≈ 2.5-3.3 Stability: suited for relatively stable drug throughout the

GIT Disease state: considered more useful in chronic vs acute

states

Advantages/Disadvantages of Extended/Sustained release Oral preps

DISADVANTAGES

↑ cost Based on design

unpredictable bioavail.

Possible ‘dose-dumping’

risk of ↑ drug conc in plasma and toxicities

ADVANTAGES

↓ frequency of admin ↑ patient compliance ↓ plasma drug conc. with improved therapeutic goals ↓ side effect profile

Types of Oral Delivery Devices(extended/sustained-release)

OROS Push-Pull- contains bilayer; core of drug (60-80%)withexcipients and push layer (20-40%) with hydrophilic expanding compartment

- Both layers absorb water from GIT to form drug solution/susp while push compartment swells and drug leaves via orifice

- Rate of release is determined by volume of waterthat enters and force from push compartment

-pH and GI motility has little effect on formulation

e.g. Cardura XL®; Procardia XL®; Concerta®The osmotic push–pull tablet: cross-section of bilayer tablet before and after ingestion. Optional drug ‘overcoat’can be included if required. Curr Med Res Opin 2006; 22(10)

OROS Push-Pull System cont’d Advantages:

Disadvantages:

Care/Advice:

Types of Oral Delivery Devices cont’d

Membrane-Controlled (Reservoir)

- Drug is contained in reservoir surrounded by rate controlling polymer (determines drug release; flux across membrane described by Fick’s Law; system contains more drug than needed to provide driving force

- Partition coefficient of drug will affect drug movement from core

- “Lag time” may result from delay in diffusion of drug from reservoir to membrane surface or a ‘burst effect’ due to saturation of membrane

- Device vacates the GIT intact

- Damage may result in ‘dose dumping’

e.g. Cardizem CR

Membrane-Controlled (Reservoir)

Advantages:

Disadvantages:

Care/Advice:

Types of Oral Delivery Devices cont’d Matrix-controlled Device- Drug combined with soluble or insoluble matrix/carrier; tablet then

compressed- With soluble polymers, rate of drug release depends on water

entry and this is controlled by tablet porosity or addition of hydrophilic additives

- ‘Insoluble’ matrices consist of a plastic (polyethylene) and a hydrophilic (methylcellulose) material mixed with drug; this swells when in contact with GI fluids and drug slowly diffuses from matrix

- Drug release explained by Higuchi* (drug release may be altered by drug and matrix parameters e.g. drug conc. in matrix, drug solubility, porosity, tortuosity and nature of polymer)

*Higuchi T. Rate of release of medicaments….J.Pharm Sci 1961;50:874

Matrix-controlled Devicecont’d- Remains intact throughout the GIT- e.g. Ferrogradumet®, Theo-Dur®, Naprosyn® SR

BIOERODIBLE MATRIX SYSTEM- Drug is dispersed in polymer which erodes when in

contact with GITreleasing the drug- Similar benefits of matrix system but matrix erodes

within the GITe.g. Sinemet ®CR

Matrix-controlled Devicecont’d Advantages:

Disadvantages:

Care/Advice:

Types of Oral Delivery Devices cont’d

Ion-exchange System- Consists of drug bound (via ionic bonds) to water-

insoluble resins which have salt-forming functional groups

- Upon contact with GI fluids containing ions of ‘like’ charge to the drug, an exchange occurs at the drug-resin binding site. Drug ‘switches’ binding with endogenous ions e.g. H+, K+, Na+, releasing drug to diffuse from water-swollen resin

e.g. Duromine ®, Biphetamine®

Ion-exchange Systemcont’d Advantages:

Disadvantages:

Care/Advice:

Types of Oral Delivery Devices cont’d

Spansules- drug-loaded granules, pellets or beads which are then

coated with a slowly dissolving polymer (may be compressed or placed in a gelatin capsule)

- Drug release may be controlled by dissolution rate of coat or ** thickness of the coating used

- Spansules is a capsule consisting of a number of groups of drug-loaded beads having coats of varying thickness; each group of beads within the capsule are then colour-coded

e.g. Dexedrine ®, Ornade®